OBJECTIVE:Focal cortical dysplasia type II (FCDII) is a cortical malformation representing a common cause of surgically treatable drug-resistant epilepsy. We studied whether FCDII disrupts normal structural interhemispheric asymmetry beyond the lesion location and quantified these asymmetries derived from structural magnetic resonance imaging (MRI) between individuals with FCDII and healthy controls (HC) as well as within FCDII subtypes using surface-based morphometry (SBM). METHODS:Using an open MRI dataset from University Hospital Bonn, we processed T1-weighted images from HC and individuals with FCDII aged over 15 years at the time of scan. We designed a three-stage workflow consisting of SBM using FreeSurfer, visual inspection of atlas-based cortical parcellations, and lesion projection. We extracted five cortical measures of intensity, thickness, volume, curvature, and surface area from 34 regions of interest (ROIs) and computed unsigned interhemispheric asymmetry indices beyond the lesion location. RESULTS:The majority of FCDII lesions annotated in the original dataset were located in the frontal lobe (64.0%). Compared to the HC, individuals with MRI-diagnosed FCDII showed significantly reduced unsigned interhemispheric intensity asymmetry across parietal, temporal, and occipital cortices (q < 0.001). We observed an increase in the unsigned interhemispheric volume asymmetry in the lateral orbitofrontal cortex and in the unsigned interhemispheric surface-area asymmetry in the inferior temporal cortex for FCDII compared to HC (q < 0.001). Subtype analyses revealed greater unsigned interhemispheric intensity asymmetry in caudal anterior cingulate and superior temporal cortices in FCDIIb compared with FCDIIa (q < 0.001). Conversely, precentral unsigned surface-area and volume asymmetries were smaller in FCDIIb relative to FCDIIa (q < 0.001). We observed no significant differences for unsigned interhemispheric cortical thickness and curvature asymmetries after multiple-comparison corrections. SIGNIFICANCE:SBM-derived interhemispheric asymmetry captures cortical alterations in FCDII beyond the focal lesions. Observed differences in group-level unsigned interhemispheric intensity, volume, and surface-area asymmetry indicated cortical alterations that are consistent with distributed cortical involvement between FCDIIa and FCDIIb. These findings may enhance presurgical evaluation by highlighting cortical areas outside the primary lesion that could contribute to seizure generation and achieving seizure-freedom after the operation. PLAIN LANGUAGE SUMMARY:Focal cortical dysplasia type II (FCDII) is a malformation of cortical development associated with drug-resistant epilepsies. FCDII may disrupt normal cortical interhemispheric asymmetries which are understudied in focal, extratemporal epilepsies. We discovered that individuals with FCDII display altered structural cortical interhemispheric asymmetries in intensity, volume, and surface area compared to healthy volunteers, with each FCDII subtype exhibiting a distinct pattern of disrupting the natural asymmetries. Since extra-lesional abnormalities may contribute to incomplete seizure control after surgery, these interhemispheric asymmetry findings could provide complementary information for presurgical evaluations.
OBJECTIVE:Focal to bilateral tonic-clonic seizures (FBTC) are associated with significant morbidity and an elevated risk of sudden unexpected death in epilepsy (SUDEP). The cerebellum has been implicated in modulating the frequency and severity of tonic-clonic seizures. The present study aimed to identify alterations in cerebellar functional connectivity (FC) associated with susceptibility to FBTC in individuals diagnosed with temporal lobe epilepsy (TLE). METHODS:This prospective study involved the recruitment of 30 patients with unilateral TLE, who were classified into two groups: active FBTC (≥1 FBTC in the past year) and inactive FBTC (ongoing focal seizures but no FBTC within the past year, and in some cases no lifetime history), each consisting of 15 patients. Additionally, 20 demographically matched control subjects were included. Resting-state functional MRI (rs-fMRI) and high-resolution T1-weighted imaging were utilised. FC analysis was performed using the CONN toolbox, with a focus on cerebellar and subcortical regions. Group comparisons were executed using Kruskal-Wallis tests, followed by post hoc pairwise analyses. RESULTS:The findings indicated that FC between the posterior vermis and lateral cerebellar lobules (Crus I/II) bilaterally were significantly lower in the active FBTC group compared to healthy controls. In comparison to the inactive group, the active FBTC group exhibited significantly lower FC with the contralateral Crus I and Crus II. In comparison to controls, the TLE groups exhibited lower FC between the posterior vermis and the mediodorsal and pulvinar thalamic nuclei as well as between the flocculonodular lobe and mesial temporal structures (hippocampus, parahippocampus, and amygdala). SIGNIFICANCE:The results demonstrate impaired intracerebellar FC, particularly between the posterior vermis and lateral cerebellar lobules, in individuals with active FBTC, thereby supporting the hypothesis that the cerebellum has a regulatory role in modulating susceptibility to tonic-clonic seizures. PLAIN LANGUAGE SUMMARY:Focal to bilateral tonic-clonic seizures are severe seizures that start in one brain region and spread to both sides of the brain. In this study, people with temporal lobe epilepsy who had recent tonic-clonic seizures showed reduced communication between the posterior vermis and lateral cerebellar regions. Alterations in other cerebellar connections with the thalamus and temporal lobe were related to temporal lobe epilepsy itself. These findings suggest that cerebellar networks may influence vulnerability to tonic-clonic seizure spread and may be relevant to future sudden unexpected death in epilepsy risk research.
OBJECTIVE:To determine the extent to which electroclinical information available at initial evaluation allows classification of idiopathic generalized epilepsy (IGE) syndromes, and to assess the contributions of seizure semiology and age at seizure onset to early syndromic diagnosis. METHODS:We prospectively analyzed a cohort of patients with new-onset seizures who underwent a structured clinical evaluation, including detailed history-taking, 3-h video-EEG, and epilepsy-protocol MRI. Seizure semiology was assessed at three levels: index seizure, initial seizure type, and seizure types identified at initial evaluation. Syndromic classification followed International League Against Epilepsy criteria. Final electroclinical diagnosis, established after longitudinal follow-up, served as reference. Within patients ultimately diagnosed with one of the four IGE syndromes, baseline data were used to determine whether the final syndrome could be assigned at initial evaluation. RESULTS:Of 2699 patients evaluated, 498 (18.4%) met criteria for genetic generalized epilepsy, of whom 401 (80.5%) were classified as having one of the IGE syndromes. Based on initial evaluation, the correct syndrome could be assigned in 366 patients (91.3%), whereas 7 (1.7%) would have been misclassified and 28 (7.0%) were not assignable. Non-assignability was confined to absence epilepsies, reflecting overlap between childhood (CAE) and juvenile absence epilepsy (JAE), whereas misclassification occurred only in juvenile myoclonic epilepsy (JME) presenting with isolated generalized tonic-clonic (GTC) seizures. Classification based on the index seizure alone showed limited accuracy (63.6%), whereas incorporation of seizure types identified through structured history improved classification to 95.0%. Myoclonic seizures were highly specific for JME, whereas absence and GTC seizures required integration with additional features. Age at seizure onset strongly differentiated CAE from JAE (AUC 0.935). SIGNIFICANCE:Electroclinical classification of IGE syndromes is frequently achievable at initial evaluation when based on seizure semiology and age at onset. When classification is not possible, limitations follow predictable electroclinical patterns, supporting a structured, history-driven diagnostic approach. PLAIN LANGUAGE SUMMARY:This study examined how accurately doctors can identify specific types of generalized epilepsy when patients are first evaluated. Among 401 patients with generalized epilepsy, the correct epilepsy syndrome could be identified in more than 90% at the first visit. Looking beyond the first seizure and asking about all seizure types together with age at seizure onset greatly improved diagnosis. While some overlap exists between specific types (like childhood versus juvenile absence epilepsy), a thorough clinical evaluation from the start provides reliable diagnostic direction for patients and supports early and accurate diagnosis.
OBJECTIVE:Cognitive difficulties in juvenile myoclonic epilepsy (JME) are part of the clinical phenotype alongside epileptic seizures; however, the underlying neurophysiological mechanisms remain unclear. Auditory steady-state responses (ASSRs) to repetitive 40- and 80-Hz stimuli are widely used measures of gamma-band oscillations (GBOs) relevant to cognition, but have not yet been investigated in JME. To address this gap, we examined 40- and 80-Hz ASSRs using magnetoencephalography and their relationship with cognitive function in JME. METHODS:In this cross-sectional case-control study, we recorded ASSRs in 16 patients with JME and 16 age- and sex-matched healthy controls (HC). Evoked power and phase-locking factor (PLF) were quantified from magnetic resonance imaging-based source estimates in the bilateral primary auditory cortices and compared between groups using linear mixed-effects models (LMMs). Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Within the JME group, associations between RBANS indices and ASSR measures were examined using age- and sex-adjusted linear regression. Where applicable, p values were adjusted using the Benjamini-Hochberg false discovery rate (FDR) procedure. RESULTS:LMMs showed lower evoked power and PLF in JME than in HC (both group effects p < 0.001). Among the five RBANS indices, only the Attention Index was lower in JME (FDR-adjusted p = 0.02). Within the JME group, the Attention Index was positively associated with both measures (evoked power: B = 16.65, 95% confidence interval [CI], 5.81 to 27.49; PLF: B = 38.82, 95% CI, 13.82 to 63.83; both FDR-adjusted p = 0.03), whereas other indices showed no significant associations. SIGNIFICANCE:Gamma-band ASSRs were reduced in JME and were consistently associated with attentional performance across evoked power and PLF. These exploratory findings suggest that gamma-band ASSRs may help investigate network-level mechanisms, potentially involving thalamocortical dysfunction that link gamma synchronization to attentional performance in JME. PLAIN LANGUAGE SUMMARY:Juvenile myoclonic epilepsy (JME) is associated with cognitive difficulties beyond seizures, but the underlying brain physiology is not fully understood. Using magnetoencephalography, we found that patients with JME showed weaker gamma-band auditory steady-state responses (ASSRs) than healthy participants. Within the JME group, stronger and more synchronized responses were associated with better attention scores, suggesting that gamma-band brain activity may be linked to attentional performance in JME. Together, these findings indicate that ASSRs may provide a useful window into brain mechanisms related to cognitive difficulties, particularly those involving attention, in JME.
OBJECTIVE:To determine how the corpus callosum handles interhemispheric seizure propagation and to assess its potential as a strategic recording locus for state-dependent biomarkers. METHODS:Epileptiform activity was induced in vitro and in vivo using 4-aminopyridine. Propagation dynamics were examined using cross-correlation analysis. Signal features were quantified using root mean square amplitudes, Shannon entropy, and spectral coherence. A previously unreported callosal evoked response, the corpus callosum evoked echo, was characterized pharmacologically (hypocalcemia, hypoxia) and anatomically (callosal disconnection) to determine synaptic dependence and cortical origin. The echo amplitude was evaluated as a predictive biomarker using logistic regression. RESULTS:Epileptiform discharges propagated through the corpus callosum with delays consistent with polysynaptic cellular transmission (24.81 ± 4.09 ms in vitro), and directionality was resolved in vivo. Although the propagation attenuated the seizure signal power, the spectral content of seizures was largely preserved within the corpus callosum. Following epileptogenic induction (pre-seizure), the corpus callosum signal's root mean square increased significantly, supporting its value as a physiological marker of propagated seizure activity. The corpus callosum-evoked echoes were temporally distinct from compound action potentials, were eliminated by synaptic blockade and callosal disconnection, and were selectively vulnerable to metabolic compromise, supporting their dependence on a cortico-callosal feedback loop. The echo amplitude increased during the pre-ictal period, achieving an area under the curve of 0.77 for seizure prediction in vitro. SIGNIFICANCE:These findings identify the corpus callosum as a physiologically active component of epileptic networks rather than a passive transmission pathway. By revealing a previously unrecognized cortico-callosal response and demonstrating its predictive potential, this work supports a network-level framework for epilepsy in which white matter structures contribute directly to seizure generation and may provide targets for physiological monitoring and intervention. PLAIN LANGUAGE SUMMARY:White matter tracts, such as the corpus callosum, have long been dismissed as passive "wires" that merely route seizure activity. This study challenges that paradigm by demonstrating that white matter signals reflect complex epileptic network behavior. By tapping directly into the corpus callosum, we achieved bilateral epilepsy monitoring and a new approach to pinpointing seizure origins within the brain. Furthermore, we uncovered a novel network response called the corpus callosum evoked echo (ccEE), which shows promise as a biomarker for seizure onset. These findings establish white matter as a critical therapeutic target for early seizure forecasting and next-generation, closed-loop neuromodulation.
OBJECTIVE:Genetic testing plays an increasing role in the diagnostic pathway for rare and complex epilepsies. However, significant heterogeneity persists in access, implementation, and interpretation across Europe. This study aimed to assess genetic testing practices, accessibility, and challenges across expert epilepsy centers within the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE) and to identify key challenges and areas for harmonization. METHODS:A cross-sectional survey was developed by the ERN EpiCARE Clinical Genetics Working Group and distributed to 50 EpiCARE member centers across 27 European countries. The questionnaire collected quantitative and qualitative information on available genetic testing modalities, turnaround times, use of rapid testing, multidisciplinary team (MDT) organization, genetic counseling practices, and perceived challenges. Survey findings were complemented by a structured discussion held during the ERN EpiCARE General Assembly. RESULTS:Responses were received from 46 centers (51 responses). Most centers reported access to genetic testing, predominantly through in-house facilities. Whole-exome sequencing was available in 85% of centers, and gene panels were available in 78%. Whole-genome sequencing was available in 59% of centers, frequently restricted to research or performed externally. Turnaround times for standard genetic testing were most commonly between 1 and 6 months. Genetic testing strategies varied by epilepsy subtype, with gene panels most frequently used as first-tier testing, and exome sequencing preferentially applied in developmental and epileptic encephalopathies. Considerable heterogeneity was observed in MDT organization, access to genetic counseling, reimbursement, data-sharing and registry infrastructures. SIGNIFICANCE:Although genetic testing is widely available across ERN EpiCARE centers, substantial disparities persist in its organization, accessibility, and implementation. Addressing these gaps through strengthened multidisciplinary collaboration, harmonized diagnostic strategies, and enhanced European-level coordination will be essential to ensure equitable access to high-quality genetic care for individuals with epilepsy. PLAIN LANGUAGE SUMMARY:Genetic testing is increasingly integrated in the diagnostic pathway for rare and complex epilepsies and treatment decisions. An ERN EpiCARE survey assessed how genetic testing is implemented across specialist epilepsy centers in Europe and identified persistent organizational, financial, and clinical barriers. Although most centers had access to advanced genomic testing, important differences were identified in access, reimbursement, turnaround times, and multidisciplinary expertise. European collaboration and harmonized practices are needed to support equitable access to high-quality genetic care for people living with epilepsy.
OBJECTIVE:To characterize healthcare providers' awareness and education regarding SUDEP and their approaches to SUDEP counseling. METHODS:A voluntary, observational 14-question survey was administered at the 2024 American Epilepsy Society Annual Meeting to healthcare providers who treat patients with epilepsy. The survey was designed to assess SUDEP awareness, clinical training, counseling patterns, and application of SUDEP guidelines. RESULTS:A total of 114 responses were analyzed. Most respondents were epileptologists or neurologists and completed residency or fellowship between 2010 and 2024. A substantial portion of respondents (41%) reported that SUDEP training was not provided during their residency or fellowship. Nearly all respondents were aware of SUDEP risk in epilepsy patients, and 61% reported losing a patient to SUDEP. Despite endorsement by two professional medical associations, 26% of respondents were unaware of the 2017 AAN/AES SUDEP Practice Guidelines. Although almost all respondents reported counseling patients and families about SUDEP risk, only 52% counseled all patients in accordance with the 2017 guidelines, typically at or after the second visit, if at all. Respondents most frequently selected uncontrolled seizures as the top risk factor for SUDEP, followed by >3 generalized tonic-clonic seizures (GTCS), reflecting a discrepancy with guideline recommendations identifying GTCS as the primary risk factor. However, respondents prioritized 'targeting GTCS' similarly to 'seizure freedom' as a mitigation strategy. Most respondents rated SUDEP counseling practices negatively (needs improvement or unsatisfactory), were divided on preferred education/training delivery, and reported not using available counseling resources (PAME, EF, CURE, etc.). SIGNIFICANCE:The survey responses demonstrate modifiable gaps between SUDEP counseling recommendations and clinical practice. Improving residency/fellowship training, awareness of the 2017 AAN/AES SUDEP Practice Guidelines, and use of available counseling resources may help align care with established recommendations. PLAIN LANGUAGE SUMMARY:SUDEP, or sudden unexpected death in epilepsy, is when a person with epilepsy dies suddenly and without another clear cause. This survey of epilepsy care providers asked about SUDEP awareness and how providers discuss SUDEP risk with patients and caregivers. Formal SUDEP education is inconsistent during training, and 26% were unaware of guidelines that help providers discuss SUDEP risk. Counseling is recommended for all patients and caregivers, but just over half of providers do so. Many also did not realize that generalized tonic-clonic seizures are the main risk factor. Increased SUDEP education and improved guideline awareness may improve SUDEP counseling.
OBJECTIVE:Vagus nerve stimulation (VNS) is a commonly used treatment for drug-resistant epilepsy. However, response to VNS is variable, while understanding of this response variability is limited. The vagus afferent network (VagAN), the neural circuits thought to be involved in response to vagal afferents, has been implicated in response prediction in modalities such as diffusion-weighted imaging, functional imaging, and neurophysiology. Structural abnormality in the VagAN from T1w MRI has not yet been studied. METHODS:We assessed if VagAN abnormalities, derived from pre-implantation T1w MRI, were associated with VNS response in 92 individuals with epilepsy two years post-implantation (42 responders, 50 non-responders). We used the first principal component (PC1) from a robust principal component analysis for a variety of region sets trained using 100 healthy controls. We investigated two primary hypotheses. (i) If VagAN regions' PC1 differentiates response groups, (ii) if other region sets did not differentiate response groups. RESULTS:Non-responders had significantly higher VagAN PC1 abnormality scores than both responders ( r = 0.30 , p = 0.008 ) and controls ( r = 0.37 , p < 0.005 ). By contrast, non-VagAN PC1 showed no discriminatory value ( r = - 0.03 , p > 0.05 ). VagAN outperformed all other region sets. SIGNIFICANCE:Structural abnormality of VagAN was associated with non-response to VNS. This suggests that volume abnormalities in key VNS regions correlate negatively with reduction of seizures. Abnormalities in other regions, such as the non-VagAN region set, were not associated with VNS response. This metric, when combined with other modalities, may be a useful measure to improve the selection of individuals with drug-resistant epilepsy for VNS therapy. PLAIN LANGUAGE SUMMARY:Vagus nerve stimulation (VNS) is a common treatment for drug-resistant epilepsy; however, it is not always effective. We tested whether volumes of brain regions related to VNS efficacy and found that abnormality within a set of regions known to be affected by VNS related to non-response. No other set of regions showed this effect implying that this set of regions is uniquely placed to determine if someone may respond to VNS. This work supports the idea that VNS efficacy is limited by an individual's brain abnormality and should be considered in further studies.
OBJECTIVE:To evaluate the effectiveness and tolerability of cenobamate in patients with a significant reduction in concomitant antiseizure medication (ASM) in European cenobamate Early Access Programs (EAPs). METHOD:Anonymized patient data from real-world studies/registries associated with European cenobamate EAPs were pooled. Patients were included if they had significantly reduced their concomitant drug load (i.e., converted to cenobamate monotherapy or reduced from multiple to one concomitant ASM) between baseline and the last visit. Effectiveness, tolerability, and dosage of cenobamate were evaluated. Responses according to therapeutic regimen at last visit were studied. RESULTS:Of 694 patients within cenobamate EAPs, 75 (10.7%) met the inclusion criteria (mean age 39.5 years [range 19-65]). At baseline, the median number of prior ASMs was 10 (interquartile range [IQR] 6-13); 46 patients (61.3%) were taking two, 23 (30.7%) were taking three, and six (8%) were taking four concomitant ASMs at baseline. At the last visit, seven patients (9.3%) were converted to monotherapy and 68 (90.7%) were receiving one concomitant ASM. The median cenobamate dosage at last visit was 300 mg (IQR 200-350). Median cenobamate follow-up was 22 months; 73 patients (97%) had at least 1 year of follow-up and one discontinued cenobamate at 1 year. Twenty-five patients (33.3%) were seizure-free at last visit; 51 (68%) had a ≥50% reduction in seizure frequency. The seizure-freedom rate was numerically, but not significantly, higher in patients converted to monotherapy (57.1%) versus those receiving one concomitant ASM (30.9%; p = 0.16). Cenobamate plus clobazam was the most effective combination. Adverse events (AEs) were reported in 55/75 patients (73.3%); the most common were somnolence (30.7%), dizziness/vertigo (28%), and fatigue (26.7%). No AEs led to treatment discontinuation. SIGNIFICANCE:Cenobamate demonstrated good effectiveness and tolerability in a population of patients within European EAPs who achieved a significant reduction of concomitant ASM. PLAIN LANGUAGE SUMMARY:People with highly drug-resistant epilepsy often need to take several antiseizure medications at the same time. Combined data from European Early Access Programs show that about 10% of people treated with cenobamate were able to stop all other antiseizure medications or reduce treatment to cenobamate plus one other medication. Despite this simplification of treatment, one-third of these patients became seizure-free and more than two-thirds experienced at least a 50% reduction in seizure frequency. Within this group, no patients stopped cenobamate because of side effects.
EEG-based connectivity analysis has emerged as a promising approach for investigating brain network dynamics in clinical epilepsy research. However, the diversity of analytical approaches, preprocessing pipelines, and reporting practices poses challenges to reproducibility and clinical translation. Existing guidelines such as STROBE and GREENBEAN provide valuable frameworks for clinical research and EEG-based biomarker reporting, but they were not designed to address the methodological complexities unique to EEG-based connectivity studies. To address this gap, we propose the Electroencephalography-based Connectivity Studies Evaluation Checklist for Clinical Epilepsy Research (EEG CONNECT), a proposed 24-item reporting checklist tailored to EEG-based connectivity analysis. This checklist covers key elements of study design, data acquisition, analysis methods, and interpretation, and is applicable to both scalp and intracranial EEG. To evaluate current reporting practices and explore the feasibility of the proposed checklist, we conducted a systematic review of 45 peer-reviewed clinical studies published between 2022 and 2024 that used one of four connectivity analysis methods: coherence, transfer entropy, Granger causality, and neural responses to single-pulse electrical stimulation. Articles were assessed based on whether each checklist item was sufficiently, partially, or not reported. The overall mean reporting adherence was 70.3% (standard deviation ±12.9%). Items related to connectivity estimation approach, biological plausibility, and methodological limitations were most frequently underreported. Checklist adherence was correlated with the publishing journal's impact factor (Spearman's rho = 0.358, p = 0.018) and with article citation rate (rho = 0.363, p = 0.014). These findings underscore the need for standardized reporting in EEG connectivity research. EEG CONNECT is a proposed practical framework to support systematic methodological reporting, although its use is not intended to be mandatory. Adoption of this checklist may facilitate comparisons across studies and support the translation of EEG-based connectivity findings into improved understanding and treatment of epilepsy and other brain disorders. PLAIN LANGUAGE SUMMARY: EEG connectivity analysis can help researchers understand how different brain regions interact in epilepsy, but reporting practices vary across studies. We developed EEG CONNECT, a proposed 24-item checklist to support clearer and more consistent reporting of EEG connectivity research. We applied the checklist to 45 recent clinical studies and found that several important methodological details were often underreported, particularly how connectivity was estimated, its biological plausibility, and methodological limitations. EEG CONNECT provides a practical framework that may improve transparency, facilitate comparisons across studies, and support the clinical translation of EEG connectivity research.
Epilepsy comprises a highly heterogeneous group of neurological disorders unified by a persistent predisposition to recurrent seizures, yet driven by remarkably diverse genetic, molecular, and network-level mechanisms. Advances in genomic technologies have revealed that epilepsy arises from a multilayered genetic architecture encompassing rare high-penetrance monogenic variants, common polygenic risk factors, brain-restricted somatic mosaicism, and extensive gene-environment interactions. These genetic substrates converge on core biological pathways regulating neuronal excitability, synaptic transmission, metabolic homeostasis, neuroinflammation, and circuit development. In this review, we synthesize contemporary insights into the genetic and molecular pathophysiology of seizures and epilepsy, with emphasis on mechanisms that destabilize excitation-inhibition balance, promote epileptogenesis, and drive pharmacoresistance. We highlight how ion channel dysfunction, synaptic vesicle cycling defects, mTOR pathway hyperactivation, glial and metabolic failure, and inflammatory cascades interact to lower seizure threshold and remodel neural networks. Beyond classical monogenic and polygenic models, we discuss the emerging role of somatic mutations, polygenic modifiers of rare variants, and dynamic brain-state-dependent seizure susceptibility. We further integrate genetic mechanisms with clinical heterogeneity, including age of onset, seizure type, penetrance, pleiotropy, and treatment response, and review translational implications for precision medicine, pharmacogenomics, and emerging molecular therapies such as antisense oligonucleotides, gene regulation strategies, and cell-based interventions. Understanding the genetic architecture of epilepsy is increasingly informing diagnostic pathways, prognostic stratification, and the development of precision-based therapeutic approaches. PLAIN LANGUAGE SUMMARY: Epilepsy genetics extends beyond single-gene disorders and involves multiple interacting layers of genomic variation. In this review, we integrate evidence across rare variants, polygenic risk, somatic mosaicism, and genetic modifiers to provide a broader framework for understanding seizure susceptibility and clinical diversity. By highlighting convergent biological pathways and their effects on neuronal networks, this work supports more refined approaches to epilepsy classification and future precision medicine strategies.
OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in otherwise healthy patients with epilepsy; about 70% occurs during sleep, and nearly 90% of patients are found prone (face-down). Following a nocturnal seizure, terminal apnea occurs between 2.5 and 10.8 min postictally (median ~ 5 min), defining a narrow but actionable window for intervention. Although body-position sensors are well established in sleep medicine and have been applied in epilepsy, no current product combines prone-position detection with autonomous repositioning into a recovery (sideways) position. METHODS:Korus is a smart mattress made of an array of inflatable cells. Korus consists of a sensor system to rapidly detect body change with high accuracy and a grid of expandable cells that reposition a patient from the prone to the recovery position. RESULTS:Ten normative control subjects were recruited, nine of whom were systematically tested. Each Korus cell generated a lift of 454 kg/cell at 5 cm/s. The sensor array detected body position changes within 5 s. Manually controlling the cells to reposition the subject from prone to recovery was successful in 100% of attempts in an average of 21.75 (±5.85) seconds. Body position detection was 96.8% accurate in detecting the prone position and 92.4% accurate overall in detecting the correct body position (supine, prone, left, right). False body position detection rate was 2.3 events/h. There were no incorrect position detections when subjects switched into the prone position. SIGNIFICANCE:This study demonstrates the feasibility of developing a smart mattress to detect the prone position and rapidly reposition subjects into a recovery position. Future development includes a control system to automate repositioning based on sensor data. The Korus device, when paired with a seizure detection device, may help lower the risk of night-time SUDEP, though the magnitude of any benefit remains to be established. PLAIN LANGUAGE SUMMARY:Sudden unexpected death in epilepsy (SUDEP) most frequently occurs at night, and the prone position is a major risk factor. A device to autonomously reposition a patient to the recovery position may markedly reduce the rates of SUDEP. Here we describe the Korus, a smart mattress with the ability to reposition patients out of the prone position in their sleep.
OBJECTIVE:Dravet syndrome (DS) is a rare early-onset developmental and epileptic encephalopathy with persistent delays between seizure onset and diagnosis. The DS'coverED study aimed to characterize current diagnostic timelines by examining each step and its duration, identifying residual barriers, and actionable solutions to optimize the diagnostic process within real-world clinical pathways. METHODS:A steering committee-eight pediatric neurologists and one representative from the DS European Federation-developed a survey addressed to European pediatric neurologists experienced in DS management. Responders reported information on their medical practice and data on patients' diagnostic pathways from seizure onset to initiation of DS-specific antiseizure medications (ASMs). RESULTS:Fifty-three physicians participated in the study. Analysis of 45 patient diagnostic pathways revealed marked heterogeneity in the DS diagnostic pathway. The median age at formal diagnosis was 15 months, with a median interval of 11 months between seizure onset and diagnosis. While half of the patients received a diagnosis within 1 year of seizure onset, 25% were diagnosed after 23 months of age. Diagnostic delays were primarily associated with late referral to expert centers and prolonged access or turnaround times for genetic testing. Although 45% of responders requested genetic testing promptly after initial consultation, more than half waited for confirmatory results before formally communicating the diagnosis. Initiation of DS-specific ASMs was inconsistent-occurring a median of 3 months after diagnosis but exceeding 9 months in 27% of cases-likely influenced by clinician caution, drug availability, and parental concerns regarding the treatment regimen. SIGNIFICANCE:DS'coverED seeks to fill a critical knowledge gap in the DS diagnostic pathway. The study provides healthcare professionals with benchmarks for refining their diagnostic practices and guiding clinical improvements-ongoing clinician education, better healthcare system coordination, and active caregiver engagement. PLAIN LANGUAGE SUMMARY:The diagnosis of Dravet syndrome, a rare and severe form of childhood epilepsy, is still often delayed after the first seizure. The DS'coverED European survey explored each step of the diagnostic journey and identified residual barriers and opportunities to optimize the time to diagnosis and access to Dravet syndrome-specific antiseizure medications. It provides physicians with actionable solutions that can help improve the diagnostic process of the condition.
OBJECTIVE:Vigabatrin is an effective treatment for infantile epileptic spasms syndrome (IESS), but relapse remains a clinical challenge. The ideal dose and duration of treatment after response are unknown. We set out to identify treatment-related predictors of IESS relapse after initial vigabatrin response. METHODS:We conducted a retrospective cohort study of infants with IESS who achieved electroclinical response within 30 days of vigabatrin initiation (alone or with hormonal therapy) and remained in remission for ≥ 30 days. Time to epileptic spasms relapse was analyzed using the Kaplan-Meier procedure and Cox proportional hazards regression. A linear regression-based propensity score (derived from etiology and latency to vigabatrin initiation) was included in Cox models to adjust for treatment duration confounding. Candidate predictors included age at IESS onset, presence of other seizure types at onset, developmental status, prior relapse, vigabatrin dose, and use of dual therapy (concomitant adrenocorticotropic hormone [ACTH] or prednisolone). RESULTS:Of 164 responders, 63 (38%) relapsed at a median of 7.5 months (IQR: 2.4-18.0) after response. Twenty-one (33.3%) relapses occurred following vigabatrin discontinuation. In propensity score-adjusted multivariable regression, increased relapse risk was associated with prior IESS relapse (HR 2.35; 95% CI 1.24-4.45; P = 0.009), other seizure types at IESS onset (HR 2.31; 95% CI 1.31-4.07; P = 0.004), and abnormal development at IESS diagnosis (HR 1.75; 95% CI 1.04-2.95; P = 0.035). Moderate dosing (100-149 mg/kg/day) was protective versus lower doses (HR 0.47; 95% CI 0.25-0.89; P = 0.020). In an underpowered analysis of vigabatrin exposure as a time-varying covariate, ongoing therapy was not significantly associated with latency to relapse (HR 0.77; 95% CI 0.39-1.49; P = 0.436). SIGNIFICANCE:Relapse after vigabatrin response is common and influenced by identifiable clinical factors. Continued vigabatrin treatment (> 100 mg/kg/day) may reduce relapse risk. Prospective validation is warranted to guide individualized relapse prevention strategies. PLAIN LANGUAGE SUMMARY:Infantile Epileptic Spasms Syndrome is a serious seizure disorder of infancy that can recur even after successful treatment with vigabatrin. In this study of 164 infants, we found that relapse was most common among children with prior relapses, other seizure types, or developmental delays. Infants treated with moderate vigabatrin doses (100-149 mg/kg/day) had the lowest relapse rates. These findings may help clinicians identify which infants face the highest risk and tailor treatment accordingly.
OBJECTIVE:To assess the economic burden, cost components, and individual-level determinants of outpatient epilepsy care in adults in Georgia. METHODS:This longitudinal study of epilepsy-related costs in adults with active epilepsy attending a tertiary epilepsy centre in Tbilisi collected clinical and sociodemographic data over 6 months. Direct and indirect costs were analyzed using descriptive statistics and multivariate regression. RESULTS:Median total epilepsy-related costs in 351 adults (median age 31 years; 44.4% male) for six months were USD 402.22 (IQR: 293.33-578.15), with a mean cost of USD 572.54 ± 789.29, indicating a highly skewed distribution. Direct medical costs, mainly antiseizure medications, accounted for 83.5% of the mean total. Costs were similar across urban and rural residents. In multivariable analysis, males incurred lower total costs than females (CR = 0.86; 95% CI: 0.74-0.99), employment in non-professional roles (CR = 1.47; 95% CI: 1.19-1.81), health insurance coverage (overall p = 0.010), epilepsy type (overall p = 0.014), monotherapy compared with polytherapy (CR = 0.75; 95% CI: 0.64-0.88), and greater seizure frequency (per additional seizure: CR = 1.08; 95% CI: 1.05-1.11). Age showed a weak inverse association with costs, whereas epilepsy duration and disability/social benefit status were not significant predictors. Most participants incurred costs below 40% of their six-month income, although a subset faced a disproportionately high financial burden. SIGNIFICANCE:Epilepsy in Georgia imposes a significant economic burden on adults, driven mainly by medication costs, specialized services, and poor seizure control. This highlights the need for affordable therapies, optimized management, strengthened health system support, and expanded social protection. Future research needs to assess the long-term economic impact of drug-resistant epilepsy. PLAIN LANGUAGE SUMMARY:People with epilepsy often need lifelong treatment, but little is known about the financial burden of epilepsy in Georgia. We studied the cost of epilepsy care for 351 adults over six months. Most spending was on antiseizure medications and medical tests. People who had more seizures or needed more than one antiseizure medication had higher treatment costs. For most people, the cost of epilepsy care was not extremely high, but some experienced much greater expenses than others. Our findings show where the biggest costs come from and may help improve epilepsy care and make treatment more affordable in Georgia.
OBJECTIVE:Self-limited epilepsy with centrotemporal spikes (SeLECTS), although characterized by well-controlled seizures, is frequently associated with persistent cognitive deficits in affected children. This study aimed to investigate whether hub dysfunction of the salience network (SN) is associated with cognitive impairment in SeLECTS, using optically pumped magnetometer- magnetoencephalography (OPM-MEG) within the framework of the triple network model (TNM), which encompasses the salience, default mode, and central executive networks (CENs). METHODS:This cross-sectional case-control study enrolled 30 children with SeLECTS and 15 matched healthy controls (HC). Data acquisition comprised resting-state OPM-MEG, structural MRI, and the Das-Naglieri Cognitive Assessment System (CAS). Within the framework of the TNM, graph theory was employed to analyze hub function in the SN across multiple frequency bands. RESULTS:The SeLECTS group exhibited widespread reductions in functional connectivity across the theta, alpha, and beta bands, with the beta band demonstrating the most pronounced decrease. Graph-theoretical analysis revealed that betweenness centrality of the SN was significantly lower in the SeLECTS group and was independently associated with cognitive scores (B = 248.98, 95% CI 57.95-440.02; β = 0.28, p < 0.05). Exploratory mediation analysis suggested that beta-band SN hub function was statistically consistent with an indirect pathway linking disease status and cognitive performance. SIGNIFICANCE:This OPM-MEG study suggests that beta-band hub dysfunction of the SN is associated with cognitive impairment in children with SeLECTS. These findings provide hypothesis-generating evidence that altered SN hub topology may contribute to cognitive vulnerability in SeLECTS and may serve as a potential MEG-based biomarker of cognitive risk. PLAIN LANGUAGE SUMMARY:Children with a common childhood epilepsy called self-limited epilepsy with centrotemporal spikes may have learning and attention difficulties even when seizures are well controlled. We used a child-friendly magnetic brain-recording method to study how key brain networks communicate at rest. These children showed weaker network communication, especially in the beta frequency band, and a less central role of the salience network was linked to poorer cognitive performance. These findings may help identify children at greater risk of cognitive difficulties.
OBJECTIVE:Bilateral hippocampal compromise in temporal lobe epilepsy (TLE) substantially increases the risk of significant adverse memory outcomes following unilateral anterior temporal lobectomy and may contraindicate surgery. The Spatial Learning Task (SLT) of Lhermitte and Signoret (1972) is a simple object-location arbitrary associative learning task proposed as a marker of bitemporal dysfunction. Here, we test whether the SLT might serve as a useful marker in TLE by examining, in individuals with TLE and hippocampal sclerosis (HS), whether performance on the SLT depends on the laterality of the HS (left, right, bilateral). We hypothesize that performance will be worst in the setting of bilateral HS. METHODS:Retrospective analysis of 63 surgically naïve TLE-HS patients (16 bilateral HS, 28 left HS, 19 right HS) who underwent neuropsychological evaluation at a tertiary epilepsy center. RESULTS:Bilateral HS cases showed significantly poorer SLT learning and learning efficiency compared to right HS cases (p ≤ .005, BF10 ≥ 25). Left HS cases performed comparably to bilateral HS cases on early trials but typically achieved ceiling performance with repetition, reflecting inefficiency rather than capacity loss. An SLT learning score <13 yielded high specificity (96% [95% CI: 0.85-0.99]) but modest sensitivity (44% [95% CI 0.20-0.70]) for identifying bilateral HS cases. SIGNIFICANCE:In the setting of TLE-HS, poor performance on the SLT increases the probability of bilateral hippocampal pathology, supporting its utility as a rule-in indicator. Although intact scores do not reliably exclude bilateral pathology, a low score on this task should prompt further investigations as to possible bitemporal compromise, and suggest risk of adverse memory outcomes following surgery. Prospective, post-operative studies will be required to quantify this risk. PLAIN LANGUAGE STATEMENT:The results of the study show that the ability to learn arbitrary object-location pairings is compromised in the setting of temporal lobe epilepsy with bilateral hippocampal sclerosis (HS). In contrast, patients with unilateral HS generally retained sufficient capacity to learn the task, though those with left HS were slower to acquire the pairings across repeated trials. A low score on this task was a strong indicator of bilateral hippocampal pathology, whereas an intact score did not reliably exclude it. Our results suggest that performance on this simple learning task provides a useful marker of bilateral hippocampal compromise in epilepsy and may be particularly valuable in patients for whom standard memory tests are less suitable. We provide a cutoff score to facilitate clinical interpretation.
