搜索结果：Epilepsy

Epilepsy affects more than 70 million individuals worldwide, contributing to early mortality, disability, and cognitive impairment. Antidepressants have been explored for epilepsy treatment, although their effects and underlying mechanisms remain unclear. Ferroptosis has been implicated in numerous neurological disorders, including epilepsy, but the regulatory mechanisms behind neuronal damage caused by epilepsy remain unclear. This study aimed to investigate the effect of fluoxetine (FLX) on epilepsy and the underlying mechanisms. We established a mouse model of epilepsy induced by kainic acid (KA) to evaluate the effects of the antidepressant FLX on seizure activity in mice, as well as its impact on neural damage and cognitive function. We also clarified the effects of FLX on epilepsy-related neuronal ferroptosis in both the epilepsy mouse model and the glutamate-induced cell death model. The key E3 ligases, key signaling pathways and receptors by which FLX regulates the ubiquitination of GPX4, a crucial ferroptosis regulator, were further investigated. Additionally, we characterized the lysine residue sites and polyubiquitination patterns that participate in the ubiquitination of GPX4. This study demonstrates that FLX provides neuroprotective and cognitive benefits in murine epilepsy models by inhibiting neuronal ferroptosis. FLX stabilizes glutathione peroxidase 4 (GPX4), a ferroptosis regulator, by preventing its ubiquitination and proteasomal degradation. The antiferroptotic effect of FLX is mediated by the Sigma-1 receptor (Sigma1R), as its inhibition reverses the protective effects of FLX on epilepsy and GPX4 stability. In neurons, the FLX/Sigma1R axis suppresses the JNK/p38 MAPK-mediated upregulation of MDM2, an E3 ubiquitin ligase, thereby disrupting MDM2-induced K48-linked polyubiquitination of GPX4 at Lys162 and Lys167. This enhances GPX4 stability and increases antioxidant defenses. These findings reveal a novel molecular pathway (Sigma1R-JNK/p38 MAPK-MDM2-GPX4 axis) through which FLX inhibits ferroptosis, highlighting its therapeutic potential for epilepsy and other ferroptosis-related neurological disorders.

To investigate the associations of intellectual disability (ID) and psychiatric comorbidities with healthcare utilization and mortality among adolescents with epilepsy. A nationwide, population-based observational study using the data from Swedish national patient registries was conducted. Individuals born during 1997-2001 with epilepsy were included and data on healthcare utilization, prescriptions, comorbidities, socioeconomic status and mortality were obtained during a 5-year period (16-20 years of age). We examined associations of psychiatric disorders and ID with healthcare utilization and mortality using unadjusted and covariate-adjusted models. A time-lagged sensitivity analysis was conducted to address potential reverse causation. Of the 2116 participants included in the study, 33% had specialist care contact for ID and 43% had contact for psychiatric disorders. Psychiatric disorders were, after adjustment for covariates, associated with higher odds of both epilepsy-related and all-cause emergency care and inpatient care. Having ID was associated with lower odds of epilepsy-related and all-cause emergency care, but higher mortality. Furthermore, several psychiatric disorders were linked to higher odds of all-cause or epilepsy-related inpatient care or all-cause emergency care. Psychiatric comorbidities and ID are common in young people with epilepsy and were associated with higher healthcare utilization and mortality in the unadjusted analysis. When adjusting for covariates, psychiatric comorbidity was linked to increased care consumption, while having ID was linked to lower emergency care use but higher mortality. These findings indicate that comorbidities are clinically relevant in young persons with epilepsy and support the need for tailored, multidisciplinary follow-up during this important life period. Many adolescents with epilepsy also have mental health or learning difficulties, which may affect their need for healthcare. In this Swedish nationwide study, psychiatric conditions were linked to more emergency visits and unplanned hospital admissions, while intellectual disability was associated with fewer emergency visits but a higher risk of death. These findings highlight the need for tailored, coordinated support for young people with epilepsy during the transition to adult care.

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.

Epilepsy affects approximately 50 million people worldwide and, although primarily attributed to neuronal dysfunction, increasing evidence highlights a critical role of glial cells, particularly astrocytes, in the pathophysiological mechanisms. Mesial temporal lobe epilepsy (MTLE), the most common form of drug-resistant epilepsy, is frequently associated with hippocampal sclerosis (HS) and pronounced astrogliosis. Given the limited efficacy of current anti-seizure medication (ASM) and the side effects of surgical hippocampus removal, there is a need for more specific and effective therapies that potentially address non-neuronal mechanisms. Astrocytes, with their inherent heterogeneity, are key candidates for such approaches due to their role in regulating and maintaining neuronal activity. To investigate subtype-specific astrocyte alterations in MTLE, we performed immunofluorescence analyses of human dentate gyrus (DG) tissue from MTLE patients (HS1, HS2, and noHS according to the International League Against Epilepsy (ILAE) consensus classification of HS in temporal lobe epilepsy) and postmortem controls. We analyzed the expression and spatial distribution of selected functionally relevant astrocytic proteins, including glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), excitatory amino acid transporter 2 (EAAT2), and aquaporin-4 (AQP4). In control tissue, astrocyte subtypes, characterized by combinatorial expression of GFAP, GS, EAAT2, and AQP4, displayed distinct, layer-specific protein expression profiles across the DG compartments. While the subtype identities were largely preserved in MTLE, localization and expression levels of GFAP, EAAT2, and AQP4 were dramatically altered, suggesting functional deficits in glutamate transport and water homeostasis. Since GS expression was unaffected by MTLE, it served as a proxy to quantify the number of astrocytes. In contrast to existing reports, we found that astrocyte numbers did not differ between control and MTLE patients. Our findings demonstrate that astrocyte reactivity in MTLE is not uniform but occurs in a subtype- and region-specific manner. This highlights astrocyte heterogeneity as an important feature of MTLE pathology and underscores the need to consider astrocyte diversity in understanding disease mechanisms and developing precision medicine-based therapeutic strategies. Epilepsy is usually studied as a disease of nerve cells, but support cells, called astrocytes, are also involved. We studied brain tissue from patients with a common form of drug-resistant epilepsy and found that different groups of astrocytes showed distinct changes in proteins that help control brain activity and water movement in the brain. Although the overall number of astrocytes did not change compared with postmortem control patients, the cells displayed strong signs of disease-related reactivity. Our findings highlight astrocytes as potential targets for future epilepsy treatments.

Epilepsy care is often guided by incomplete snapshots: patient-reported seizures, intermittent drug levels and medication histories that may not reflect current exposure. Between these snapshots, clinicians have little objective information about how the brain is responding to antiseizure medication. In this study, we tested whether intracranial EEG synchrony, a measure of coordinated neural activity across intracranial electrodes, tracks antiseizure medication load in patients with drug-resistant epilepsy. We retrospectively studied 80 consecutive patients with drug-resistant epilepsy who underwent presurgical intracranial EEG monitoring at the Hospital of the University of Pennsylvania. Antiseizure medication load was estimated continuously from medication administration records using a validated pharmacokinetic model. Synchrony was computed from intracranial EEG using the Kuramoto order parameter. We first compared synchrony within the same patient during high and low medication exposure. We then tested the continuous association between synchrony and medication load across the epilepsy monitoring unit admission, adjusting for time since admission, seizure timing, wakefulness, time of day and interictal spike rate. Analyses accounted for repeated measurements within patients and tested robustness to temporal structure in the recordings. We also assessed whether synchrony dynamics were preserved when fewer electrodes were sampled. Forty-five patients had sufficient high- and low-exposure data after peri-ictal exclusion. Synchrony was higher during low medication exposure in 32 of 45 patients, corresponding to a median 7.4% increase and a median paired difference of 0.0082 on the 0-1 synchrony scale (sign test P = 0.007; Wilcoxon P < 0.001). In the continuous analysis of 67 patients and 23,402 repeated 10-minute observations, higher synchrony was associated with lower medication load (&#x3b2; = -0.153, 95% confidence interval -0.293 to -0.012, P = 0.033); interictal spike rate was not independently associated with medication load. The inverse association remained evident in circular-shift, temporally binned and likelihood-based sensitivity analyses. Relative synchrony dynamics were preserved under electrode subsampling, with a median correlation of 0.85 with full-array synchrony at 40% sampling. These findings support synchrony as a candidate continuous physiological readout of antiseizure medication load in patients with drug-resistant epilepsy. By linking medication exposure to a measurable brain-network state, synchrony may help move epilepsy monitoring beyond seizure counting alone and toward continuous assessment of how the brain is responding to treatment.

Epilepsy is a global neurological disorder that contributes to a significant disease burden in children and adolescents. About 11 million children worldwide suffer from epilepsy. Most children with epilepsy respond to anti-epileptic drugs and have controlled symptoms. However, drug-resistant epilepsy (DRE) happens in some children which presents a lot of challenges to their quality of life and development. Alternative treatment for DRE is ketogenic diet therapy (KDT) which is also given alongside the regiment. This study aims to compare the prescribed anti-epileptic drug cost of patients receiving KDT compared to the initial pre-diet cost. This study was a descriptive analytical retrospective using outpatient medical records in Dr.Cipto Mangunkusumo General Hospital (RSCM Kiara) from 2021 to 2022. Subjects were patients with drug-resistant epilepsy and underwent a ketogenic diet up to 6 months and aged between 5-18 years old. These patients were then evaluated for their anti epileptic drug costs before starting and after they did a ketogenic diet for up to 6 months with cost evaluation at 3 months interval. The cost of prescribed outpatient antiepileptic drugs were adjusted according to prices set by the Indonesian Ministry of Health. Parents of participants were also surveyed about their satisfaction with KDT using Google Form questionnaire with consent prior to survey. In this study, a comparison between the overall cost of incorporating KDT for 6 months and pre-diet treatment plan was found to have a statistically significant cost reduction for the incorporation of KDT which demonstrated 21.8% overall reduction in outpatient anti epileptic drug costs among 16 patients which was found to be Rp 3,757,812 or 235 US$ (p = < 0.001). This study demonstrated that incorporating KDT for 6 months provides significant financial savings in treatment cost for children with drug-resistant epilepsy.

Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy and represents a major unmet clinical need. While traditional hypotheses of pharmacoresistance have focused on alterations in drug targets, efflux transporter overexpression, and intrinsic disease severity, the gut microbiome has recently emerged as a potentially modifiable factor that may function as a systems-level modifier of these established mechanisms rather than a standalone pathway. The gut microbiome harbors a vast repertoire of drug-metabolizing enzymes capable of directly biotransforming orally administered antiseizure medications (ASMs)-including valproic acid, lamotrigine, carbamazepine, and oxcarbazepine-thereby altering their pharmacokinetics, bioavailability, and therapeutic efficacy. Additionally, microbial metabolites modulate host cytochrome P450 enzymes, nuclear receptors, and efflux transporters such as P-glycoprotein, while bacterial &#x3b2;-glucuronidases influence the enterohepatic recirculation of glucuronidated ASMs. Conversely, chronic ASM exposure reshapes the gut microbial ecosystem, creating a self-perpetuating cycle of dysbiosis and pharmacoresistance. This narrative review synthesizes current evidence on microbiome-ASM interactions in DRE, proposes a concrete experimental pipeline for characterizing ASM-specific microbial biotransformation, and outlines a framework for integrating physiologically based pharmacokinetic modeling with microbiome data. We discuss clinical implications for epileptologists-including the role of therapeutic drug monitoring in detecting microbiome-mediated pharmacokinetic variability, the concept of microbiome-neutral ASM selection, and earlier deployment of the ketogenic diet as a microbiome-targeted intervention. We highlight the translational potential of pharmacomicrobiomics-the study of how microbiome variation influences drug disposition and response-and identify critical knowledge gaps that warrant future investigation. PLAIN LANGUAGE SUMMARY: About one in three people with epilepsy continue to have seizures despite treatment. This review summarizes growing evidence that the gut microbiome-the community of bacteria living in the intestines-can influence how seizure medications work by altering their absorption, metabolism, and clearance. The medications themselves can reshape the microbiome in return, creating a cycle that may sustain treatment failure. Understanding this gut-drug relationship may open new paths to personalized epilepsy care through diet, probiotics, and microbiome-guided prescribing.

Children with generalized or multifocal drug-resistant epilepsy (DRE) without a clearly localizable and safely resectable seizure focus present a significant clinical challenge, as traditional resective interventions are often not viable. Emerging evidence supports the use of neuromodulation-particularly deep brain stimulation (DBS) and responsive neurostimulation (RNS)-for generalized and multifocal epilepsy in adults. However, safety and efficacy data for thalamic neuromodulation in pediatric populations remain limited. This single-institution case series describes, to our knowledge, the largest pediatric cohort treated with thalamic DBS or RNS for generalized or multifocal DRE, providing descriptive data on safety and seizure burden. The authors performed a retrospective chart review of pediatric patients with DRE who underwent thalamic neuromodulation using RNS or DBS at Seattle Children's Hospital between January 2020 and July 2025 with at least 6 months of follow-up. Clinical, surgical, and seizure outcome data were collected, including seizure frequency and complications. Seizure outcomes were stratified into categorical frequency bins, and a trend analysis was performed to evaluate postoperative shifts in seizure burden. Twenty-six patients (mean age 14.5, range 6-20 years) underwent thalamic neuromodulation with DBS (n = 12) or RNS (n = 14). The centromedian nucleus was the target in 24 cases; 1 patient each underwent targeting of the anterior nucleus and pulvinar nucleus. At the last follow-up (median 30.2 months), 65.4% of patients met the responder criteria (&#x2265; 50% seizure reduction), with a higher response in the DBS group (83.3%) compared with the RNS group (50.0%). The median seizure reduction was 75.7% for DBS and 37.5% for RNS. A significant downward shift in seizure frequency was observed postoperatively across the entire cohort (p = 0.031), including among patients with the highest baseline seizure burden. No intraoperative complications occurred. Two patients (7.7%) required device explantation, 1 due to infection and 1 due to behavioral side effects, and 1 patient discontinued therapy without explantation. No instances of sudden unexpected death in epilepsy or hardware malfunction were observed. Thalamic neuromodulation using DBS and RNS was safe and well tolerated in pediatric patients with DRE, including multifocal and generalized seizure onsets. Meaningful seizure reduction was observed across a range of epilepsy phenotypes, with a trend toward greater benefit in the DBS group. These findings support thalamic neuromodulation as a promising treatment option in children with nonlesional DRE and highlight the need for prospective multicenter studies with extended follow-up.

Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant ( prickle-spiny-legs , or pk sple ) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant ( prickle-prickle , or pk pk ) does not, thereby providing a direct genetic connection between epilepsy and ASD through prickle . Comparing headed versus headless pk sple mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pk sple and pk pk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.

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.

Hippocampal sclerosis in temporal lobe epilepsy is linked to cognitive impairment. This study investigates its exacerbating role in visual working memory deficits in right temporal lobe epilepsy and the involvement of contralateral hippocampal subregions. We enrolled 103 patients with right temporal lobe epilepsy (57 with right hippocampal sclerosis and 46 without hippocampal sclerosis) and 36 healthy controls who underwent high-resolution MRI and neuropsychological assessment. Patients with hippocampal sclerosis showed more severe visual working memory impairment, widespread grey matter atrophy and significant volume loss in bilateral cornu ammonis 3 and right dentate gyrus. Contralateral cornu ammonis 3 atrophy correlated with poorer visual working memory performance. Hippocampal sclerosis in right temporal lobe epilepsy is linked to severe visual working memory deficits and extensive bilateral hippocampal atrophy. These findings establish hippocampal sclerosis as a key biomarker and underscore the role of bilateral hippocampal network disruption, with contralateral cornu ammonis 3 integrity influencing cognitive outcomes.

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&#x202f;<&#x202f;.001), and repeat surgery was more common (p&#x202f;<&#x202f;.001). Focal (OR 1.72, p&#x202f;=&#x202f;.005) and cerebral insult related (OR 2.74, p&#x202f;<&#x202f;.001) MRI abnormalities were more frequently treated in the late era. Hemispherectomies, lobectomies and corpus callosotomies were performed less often (all p&#x202f;&#x2264;&#x202f;.001), while focal and multilobar resections remained stable (p&#x202f;>&#x202f;.05). Use of invasive monitoring and electrical stimulation mapping declined over time (p&#x202f;<&#x202f;.001). Seizure freedom rates were stable, however, &#x2265;&#x202f;90% seizure reduction was more common in the late era (OR 1.60, p&#x202f;=&#x202f;.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.

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&#xa0;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.

Temporal lobe epilepsy (TLE) is the most common form of medically refractory epilepsy in adults. While patients with concordant noninvasive findings and hippocampal sclerosis (HS) might proceed directly to surgery, those with discordant data, suspected bilateral involvement, or atypical presentation often require stereoelectroencephalography (SEEG). The diagnostic and therapeutic implications of bilateral temporal sampling remain uncertain. The aim of this study was to evaluate the yield and clinical impact of bilateral SEEG in TLE. The authors retrospectively reviewed data collected from patients with medically refractory epilepsy who underwent bilateral SEEG at a single institution from March 2017 and June 2025. Inclusion criteria were a pre-SEEG hypothesis of temporal onset, nonlesional or mesial TLE, with or without HS, and bilateral hippocampal/amygdala sampling. Patients were grouped as concordant, discordant, or bilateral based on pre-SEEG noninvasive data. The diagnostic yield, number of SEEG studies required to alter 1 patient's initial hypothesis, and seizure outcomes were analyzed. Of 197 patients who underwent SEEG, 54 met inclusion criteria. Pre-SEEG hypotheses were concordant in 20 patients, discordant in 8 patients, and bilateral in 26 patients. SEEG revealed contralateral or bilateral seizure onset in 35% of concordant cases and confirmed unilateral onset in 46% of presumed bilateral cases. Overall, 21% of presumed unilateral TLE showed bilateral involvement. The number needed to treat was 2.9 for the concordant group and 2.2 for the bilateral group. Following SEEG, 38 patients underwent resection, laser ablation, or neuromodulation. At the last follow-up, 49% of patients achieved Engel class I or II outcomes, with best results for those with resection/ablation (79% Engel class I or II). Bilateral SEEG provides clinically meaningful information in both unilateral and bilateral TLE, uncovering contralateral involvement in presumed unilateral cases and confirming unilateral foci in nearly half of presumed bilateral cases. Although SEEG is not necessary for all patients with TLE-HS and concordant studies, when it is indicated, bilateral sampling might be important to avoid misclassification and guide resective/ablative versus neuromodulatory treatment planning.

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.

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.

Microvascular remodeling and blood-brain barrier dysfunction (BBBD) are increasingly recognized as contributors to epilepsy. However, commonly used vascular imaging markers are often state-dependent and lack spatial specificity. We aimed to (1) validate plasma volume fraction (v&#x209a;) derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a sensitive marker of microvascular changes; (2) characterize the v&#x209a; alterations in patients with drug-resistant epilepsy (DRE); and (3) assess the spatial relationship between v&#x209a; abnormalities and BBBD. We analyzed DCE-MRI images from 49 people with epilepsy (PWE) and 68 healthy controls across two sites. v&#x209a; and BBB permeability were quantified using BBBdetect software. Voxel-wise v&#x209a; was estimated using the extended Tofts model, and BBBD was quantified using slope-based permeability mapping. Both measures were summarized using modified z-scores, with suprathreshold abnormality defined as modified z-score&#xa0;>&#xa0;2. We performed region-wise and lobe-wise analyses restricted to gray matter and trained supervised classifiers to distinguish PWE from controls using regional z-v&#x209a; and z-BBBD features. Compared with controls, PWE showed increased voxel-wise and region-wise v&#x209a; abnormality burden, with a non-uniform spatial pattern that includes prominent fronto-temporal elevations and frequent involvement of limbic regions. BBBD was common and spatially diffuse. Restricting analysis to regions with co-occurring suprathreshold v&#x209a; and BBBD reduced spatial diffuseness relative to BBBD alone. Multivariate classification achieved encouraging test performance using vascular and barrier features (balanced accuracy&#xa0;=&#xa0;0.81), with feature importance suggesting complementary contributions from v&#x209a; and BBBD. v&#x209a; is a sensitive DCE-MRI-derived marker of microvascular abnormalities in DRE. Integrating v&#x209a; with BBBD enhances the spatial specificity of abnormality patterns and shows encouraging concordance with the clinically suspected epileptogenic territories, warranting prospective validation against clinical reference standards.

Paediatric drug-resistant epilepsy (DRE) is associated with IQ deficits only partially explained by clinical seizure variables (for example, age of onset, seizure burden, seizure location). Given that intelligence depends on efficient large-scale brain networks, structural connectomics provides a complementary mechanistic framework for explaining residual IQ variance. We tested whether brain-network architecture explains additional IQ variance using global and network-averaged graph-theoretic metrics derived from streamline-count weighted diffusion MRI connectomes. Seventy-one children with DRE (50 focal epilepsy; 21 multifocal epilepsy) and 15 control participants underwent diffusion and T1-weighted MRI. For each participant, a 253&#xa0;&#xd7;&#xa0;253 structural connectome was constructed, edge weights were defined as the number of streamlines, and graph metrics were computed using the Brain Connectivity Toolbox. Nodal metrics were averaged within Yeo's seven functional networks plus a Subcortical network. Associations with IQ were examined using correlations and general linear models (single-network and eight-predictor models). Finally, mediation analyses tested whether network metrics explained IQ differences between controls and children with DRE. Global metrics were not associated with IQ (all p&#xa0;>&#xa0;0.05). Regionally, higher Salience-network betweenness centrality showed a nominal negative association with IQ in the multifocal subgroup (p&#xa0;=&#xa0;0.040*, adjusted R2&#xa0;=&#xa0;0.142). In the eight-network GLM, higher nodal efficiency within the Default Mode Network (DMN) was positively associated with IQ (B = 122.406, p = .013), whereas higher nodal efficiency within the Subcortical Network was negatively associated with IQ (B = -51.942, p = .012). These regional associations did not survive Bonferroni correction. Exploratory mediation analyses suggested that opposing DMN and Subcortical Network effects partially accounted for the observed group difference in IQ. These findings are hypothesis-generating, as the regional associations with IQ were nominal and did not survive family-wise correction. Nevertheless, the mediation effects survived correction, highlighting opposing regional, rather than global, network alterations as candidate correlates of IQ variability in paediatric DRE.