Epilepsia[JOURNAL]
Sun
200 papers
Corpora amylacea and glymphatic system in temporal lobe epilepsy patients: Clinicopathological correlation.
Biancheri D, Rossini L, Cagnoli C … +12 more , De Santis D, Parente A, Ferrario R, Doniselli FM, Rizzi M, Marucci G, Didato G, Dominese A, de Curtis M, Di Giacomo R, Garbelli R, Deleo F
Epilepsia · 2026 May · PMID 42132920 · Publisher ↗
OBJECTIVE: Corpora amylacea (CA), now called wasteosomes, are basophilic inclusions associated with aging, neurodegeneration, and impaired glymphatic waste clearance. Their presence is well described in temporal lobe epi...
OBJECTIVE: Corpora amylacea (CA), now called wasteosomes, are basophilic inclusions associated with aging, neurodegeneration, and impaired glymphatic waste clearance. Their presence is well described in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and related to hippocampal neuronal loss and longer epilepsy duration. Here, we assessed CA deposition in TLE patients submitted to epilepsy surgery with any histological diagnosis and explored its relationship with clinical and neuropsychological variables. Histological signs of the glymphatic system were evaluated. METHODS: Qualitative and quantitative evaluation of CA was performed on neocortical and hippocampal surgical specimens and correlated with age at onset, duration of epilepsy, type of seizure at surgery, antecedents, psychiatric symptoms, and seizure outcome. Podoplanin (PDPN) expression was assessed in a subgroup of patients with high and low CA presence as a histological marker of lymphatic elements. Comparison with nonepileptic tissues was also performed. RESULTS: Fifty consecutive patients were included with the following histological diagnosis: 18 patients with HS only, 10 patients with HS and associated focal cortical dysplasia (type IIIa), seven patients with encephalocele, five cryptogenic patients with no abnormalities on resected brain specimens (no lesion), and 10 patients with other histological findings. Patients with HS were vulnerable to CA accumulation compared to other etiologies. There was a significant association between CA density and duration of epilepsy, independent of age at surgery or other clinical parameters, and the presence of CA was associated with a worse preoperative cognitive profile. Preliminary histological observations from a few cases suggested enlarged perivascular spaces and altered PDPN vascular expression in patients with higher deposition of CA. SIGNIFICANCE: These findings provide evidence that CA accumulation correlates with epilepsy duration and suggest a contribution of altered brain clearance mediated by the glymphatic system to cortical dysfunction and cognitive deficits. Future research on glymphatic alterations and their therapeutic modulation may improve management of TLE and other epileptic or neurodegenerative conditions.
Hemispheric surgery for hemimegalencephaly and hemispheric cortical dysplasia in infants below 12 months of age-A single-center experience.
Pielas M, Kotulska K, Roszkowski M … +3 more , Syczewska M, Jurkiewicz E, Kowalczyk P
Epilepsia · 2026 May · PMID 42132620 · Publisher ↗
OBJECTIVE: Infants with early drug-resistant epilepsy caused by hemimegalencephaly (HME) and hemispheric cortical dysplasia (HCD) pose substantial surgical and critical care challenges and have poor seizure outcome progn...
OBJECTIVE: Infants with early drug-resistant epilepsy caused by hemimegalencephaly (HME) and hemispheric cortical dysplasia (HCD) pose substantial surgical and critical care challenges and have poor seizure outcome prognosis. This study evaluated the safety, complications, and seizure outcomes of hemispheric surgeries in infants younger than 12 months with HME and HCD. METHODS: A retrospective analysis included patients younger than 12 months who underwent functional hemispherectomy or hemispherotomy, between 2005 and 2024, at a national epilepsy surgery referral center. Data included demographics, medical history, age at seizure onset and surgery, duration of surgery, intubation and intensive care unit stay duration, blood product requirements, and perioperative and long-term complications. Seizure outcomes were assessed by Engel classification. RESULTS: Fifteen infants (7 male, 8 female) with HME (13) or HCD (2) were analyzed. Median seizure onset was 3 days (interquartile range [IQR] 1.5-8.5), with all experiencing multiple daily seizures. Patients underwent surgery at a median age of 6.4 months (IQR 4.7-9.1) and with a median body weight of 7200 g (IQR 6900-8560; minimum 6400 g; percentiles 2-91). All infants received intraoperative blood transfusions (median 44.8 mL/kg, IQR 23.8-71.5); total blood requirement was 57.3 mL/kg (range 17.5-239.1). One-third (5/15) required more than one circulating volume. No mortalities occurred. Major complications included intracerebral bleeding (2/15, 13.3%) and intraoperative cardiac arrest (1/15, 6.7%). Frequent adverse events included prolonged postoperative intensive care stay of more than 5 days (6/15, 40%) and shunt placement for postoperative hydrocephalus (4/15, 26.7%). Engel class I outcome at 12-month follow-up was achieved in 8 of 15 (53.3%) overall and in 6 of 13 (46%) of HME cases. SIGNIFICANCE: Hemispheric surgery within the first year of life in patients with HME and HCD is feasible but demanding, with substantial perioperative risk. Seizure-freedom rates in HME are favorable, but lower than in other etiologies. Multidisciplinary management remains crucial for optimal outcomes.
Picture naming: Stereoelectroencephalography and connectivity insights.
Mezjan I, Rech F, Aron O … +2 more , Maillard L, Colnat-Coulbois S
Epilepsia · 2026 May · PMID 42118122 · Publisher ↗
OBJECTIVE: This study investigates the neural substrates of picture naming (PN) using stereoelectroencephalographic (SEEG) stimulations and evaluates the contribution of white matter (WM) fascicles related to the basal t...
OBJECTIVE: This study investigates the neural substrates of picture naming (PN) using stereoelectroencephalographic (SEEG) stimulations and evaluates the contribution of white matter (WM) fascicles related to the basal temporal language area (BTLA) to the broader functional PN network. METHODS: In patients undergoing SEEG for drug-resistant epilepsy, stimulation sites were classified as either eloquent (inducing anomia) or noneloquent (NE). Spatial distribution was assessed along the ventral temporal cortex (VTC). Structural connectivity was analyzed using voxelwise disconnectome mapping, connectivity profiles were compared between eloquent and NE sites, and Uniform Manifold Approximation and Projection (UMAP) was applied to characterize the organization of disconnectomes associated with eloquent sites. RESULTS: Eloquent sites were predominantly located along the VTC, following an anteroposterior gradient, with the highest probability in the posterior fusiform gyrus. These sites showed the strongest overlap with the inferior longitudinal fasciculus (ILF), and eloquent-site disconnectomes primarily involved the ILF and inferior fronto-occipital fasciculus. Voxelwise comparisons revealed distinct network profiles between eloquent and NE sites, characterized by higher inferred connectivity in anomia-derived disconnectomes. UMAP demonstrated an anteroposterior organization of disconnection patterns, reflecting structural heterogeneity across the BTLA. SIGNIFICANCE: PN appears to depend on a ventral temporo-occipital network organized along an anteroposterior gradient within the VTC, where naming performance may rely more on the integrity of ventral WM pathways than on cortical location alone. The BTLA emerges as a structurally heterogeneous region shaped by the progressive overlap of WM pathways from anterior to posterior temporal regions. These results support integrating SEEG mapping and individualized ventral WM assessment into surgical planning.
Depolarization block paradoxically drives surges of neurotransmitter release during seizure activity.
Duan W, Xu Z, Deng S … +14 more , Ke W, Zhang X, Yuan S, Wang K, Li L, Wang S, Liu Y, Li W, Shui W, Tian Y, Lu HD, Guo H, He Q, Shu Y
Epilepsia · 2026 May · PMID 42113533 · Publisher ↗
OBJECTIVE: This study was undertaken to investigate the mechanisms underlying the paradoxical phenomena of excessive neurotransmitter release and suppressed sodium-spike generation due to depolarization block (DB) during...
OBJECTIVE: This study was undertaken to investigate the mechanisms underlying the paradoxical phenomena of excessive neurotransmitter release and suppressed sodium-spike generation due to depolarization block (DB) during seizure activity. METHODS: We employed acute neocortical slices from mice to investigate DB in pyramidal cells (PCs) during epileptiform activity (EA). Local high-K puff was applied to induce DB and monitor glutamate and dopamine release. Additionally, we examined dopamine release in the neocortex during kindling-evoked seizures following acute lesions of dopaminergic axons in the medial forebrain bundle in vivo. RESULTS: Membrane potential levels of DB in PCs during EA remained constant even with strong hyperpolarization, suggesting dependence on an ionic reversal potential. Local high-K puff induced DB in both PC soma and axons, accompanied by glutamate release. Surprisingly, dopamine release in neocortical slices (lacking dopaminergic cell bodies) was also induced by high-K puff or during EA. In animals with bilateral medial forebrain bundle lesions, dopamine release in neocortex was largely preserved during kindling-evoked seizures. SIGNIFICANCE: Our findings demonstrate that, during epileptiform activity, DB is predominantly determined by excessive accumulation of extracellular K, and that axonal rather than somatic DB causes aberrant synaptic transmission. Local extracellular K rises and subsequent axonal DB may trigger neurotransmitter surges during epileptic seizures, providing a novel mechanistic insight into seizure-related neurotransmitter dynamics and a possible explanation for severe epilepsy-associated neuropsychiatric comorbidities.
Effect of epileptogenesis on hypercapnic cardioventilatory response in kainic acid rats.
Apaire A, Collard E, Niyibizi A … +5 more , Kumar NN, Germany Morrison E, Chavez Cerda J, Dereli AS, El Tahry R
Epilepsia · 2026 May · PMID 42113341 · Publisher ↗
OBJECTIVE: Cardioventilatory failure is the leading mechanism proposed to underlie sudden unexpected death in epilepsy (SUDEP), which occurs predominantly at night in patients with generalized tonic-clonic seizures. Inte...
OBJECTIVE: Cardioventilatory failure is the leading mechanism proposed to underlie sudden unexpected death in epilepsy (SUDEP), which occurs predominantly at night in patients with generalized tonic-clonic seizures. Interictal hypercapnic cardioventilatory responses are suggested to be involved, as they are ablated in chronically epileptic kainic acid (KA) rats, a temporal lobe epilepsy model with focal to bilateral tonic-clonic seizures. However, how this impairment emerges during epileptogenesis and whether it is influenced by day/night period remain unclear. Here, we aimed to investigate the progress of hypercapnic cardioventilatory responses through the epileptogenesis of KA rats and whether it is affected by day or night. METHODS: Ventilatory or breathing frequency (f) and heart rate (HR) were measured before, during, and after a 1-h exposure to acute hypercapnia (10% CO) using photoplethysmography in KA and healthy rats. Measurements were performed monthly for 6 months, with additional nocturnal hypercapnia recordings at month 6 to assess day/night modulation. To control for repeated CO exposure, an independent cohort of age-matched KA and healthy rats underwent a single hypercapnia exposure at month 6. RESULTS: In healthy rats, cardioventilatory responses to hypercapnia remained stable over time, with increased f and reduced HR. Conversely, KA rats displayed an abrupt blunting of the f response at month 4, followed by blunting of the HR response at month 6. Correlation analyses revealed a loss of correlation between f and HR following KA injection, which reemerged when the cardioventilatory response to CO was fully ablated. No association was observed between seizure severity and cardioventilatory impairment. KA rats displayed similar deficits regardless of CO exposure frequency, and no day-night differences were detected in either group. SIGNIFICANCE: These findings indicate that cardioventilatory responses are decreased during epileptogenesis in the KA model, suggesting their potential utility for evaluating SUDEP risk.
Pharmacogenomics in epilepsy care across Asia.
Raheja A, Tan Z, Narasimhalu K
Epilepsia · 2026 May · PMID 42104902 · Publisher ↗
The selection of anti-seizure medications (ASMs) in epilepsy remains largely empirical, leading to varied efficacy and a significant burden of adverse drug reactions (ADRs). A pharmacogenomic-based strategy can be used t...
The selection of anti-seizure medications (ASMs) in epilepsy remains largely empirical, leading to varied efficacy and a significant burden of adverse drug reactions (ADRs). A pharmacogenomic-based strategy can be used to personalize ASM selection, as it incorporates genetic information into clinical decision-making. While more than 50 gene-drug associations have been reported in epilepsy, few pairs have strong, replicated evidence with clinical applicability. In Asia, key variants include HLA-B15:02 and HLA-A31:01, which are associated with severe cutaneous adverse reactions (SCARs), and CYP2C9 and CYP2C19 variants, which affect drug metabolism. These pairs have influenced regional regulatory policies, with HLA-B15:02 screening widely implemented prior to carbamazepine use. However, routine practice is still heterogenous due to variability in allele frequencies, healthcare infrastructure, and policy frameworks across countries. We propose evidence-based criteria for clinical implementation of pharmacogenomic markers, emphasizing replicated associations, clinical significance, actionable alternatives, and cost-effectiveness. Currently, HLA-B15:02 possesses the strongest evidence for mandatory screening, while others remain advisory due to limited outcome data. Real-world challenges include incomplete risk prediction from single-allele testing, overlapping drug hypersensitivity profiles, and workflow limitations, particularly in urgent care settings. In lower resource regions, test availability and access are additional hurdles to implementation. Future research should include multiethnic datasets, improved health-economic evaluations, and integration of genomic data into clinical decision-support systems. Advancing polygenic and multi-omics approaches could improve prediction of treatment response and toxicity.
The prevalence and determinants of epilepsy in Ghana: A population-based study in two districts using a three-stage approach.
Darkwa EK, Asiamah S, Awini E … +13 more , Sottie C, Godi A, Williams JE, Atuguba F, Adjei A, Akpalu A, Cross JH, Sander JW, Sen A, Newton CR, Danso-Appiah A, Adjei P, EPInA Investigators
Epilepsia · 2026 May · PMID 42104871 · Publisher ↗
OBJECTIVE: Epilepsy imposes a disproportionate burden in Africa, yet there are no reliable epidemiological data from Ghana. This community-based cross-sectional survey addressed this gap in southeastern Ghana, incorporat...
OBJECTIVE: Epilepsy imposes a disproportionate burden in Africa, yet there are no reliable epidemiological data from Ghana. This community-based cross-sectional survey addressed this gap in southeastern Ghana, incorporating an analytical comparison of confirmed cases and age- and sex-matched controls. METHODS: We conducted a population-based cross-sectional study using a validated tool and a three-stage screening approach to estimate the prevalence of active epilepsy in the two Ghanaian districts of Shai-Osudoku and Ningo-Prampram. The three-stage approach consisted of population screening, detailed individual assessment, and clinical confirmation by specialists. To identify factors associated with epilepsy, we conducted a cross-sectional analysis comparing confirmed cases with age- and sex-matched controls randomly selected from the same population. Trained fieldworkers administered standardized questionnaires to capture sociodemographic data and historical risk exposures. RESULTS: The attrition-adjusted prevalence of active epilepsy was 8.84 per 1000 people (95% confidence interval [CI]: 8.00-9.68), higher in Shai-Osudoku (12.30 per 1000) than in Ningo-Prampram, and greatest in remote rural areas. Prevalence was higher among males (10.53 per 1000) and peaked at ages 20-29 years (11.44 per 1000). The poorest quintile had a prevalence three times that of the wealthiest. In children (≤16 years), fever-related convulsions (adjusted odds ratio [aOR] = 94.75; 95% CI: 17.40-515.96; p < .001) and history of cerebral/severe malaria (1.03; 95% CI: 1.01-1.06; p = .003) were strongly associated with epilepsy; younger males had higher odds (2.78; 95% CI: 1.12-6.88). In adults, household members with epilepsy (6.21; 95% CI: 2.56-15.11), family history (3.55; 95% CI: 1.13-11.19), head injury (24.45; 95% CI: 3.07-194.60), and household ownership of cats (1.76; 95% CI: 1.10-2.81) or pigs (2.26; 95% CI: 1.10-4.66) were significant risk factors. SIGNIFICANCE: Our findings highlight a high burden of epilepsy in southeastern Ghana, with variations observed across geographic, demographic, and socioeconomic groups. Modifiable risks such as head injury and cerebral or severe malaria highlight urgent needs for targeted prevention, improved health care access, and poverty alleviation strategies.
Listening across frequencies: Capturing seizures of all patients to advance antiseizure medication development.
Auvin S, French J
Epilepsia · 2026 May · PMID 42104870 · Publisher ↗
Seizure frequency has been the primary endpoint in epilepsy trials, with enrollment usually requiring ≥4 seizures per month. This threshold is more and more misaligned with clinical reality, as the availability of more t...
Seizure frequency has been the primary endpoint in epilepsy trials, with enrollment usually requiring ≥4 seizures per month. This threshold is more and more misaligned with clinical reality, as the availability of more treatment options has reduced baseline seizure burden, with a risk of excluding a proportion of patients from trials. Although cognitive and developmental outcomes are gaining prominence, seizure control remains essential due to its impact on morbidity and mortality. We have tools to study all types of seizure frequency: Time-to-event designs, including time-to-pre-randomization seizure count or time to the Nth seizure, offer a validated alternative by enabling inclusion across a wider range of seizure frequencies while maintaining methodological rigor. Future trial designs should study cognitive outcomes, while studies focusing on anti-seizure efficacy remain critical.
WONOEP XVII appraisal: The role of the extracellular matrix in epilepsy.
Lugara E, van Vliet EA, Romagnolo A … +5 more , Staley K, Lillis KP, Dulla C, Henshall DC, Kobow K
Epilepsia · 2026 May · PMID 42096301 · Publisher ↗
The extracellular matrix (ECM) is composed of proteoglycans and glycoproteins that regulate the external environment surrounding neurons, glia, and the vascular system. The ECM is vital for maintaining the structure and...
The extracellular matrix (ECM) is composed of proteoglycans and glycoproteins that regulate the external environment surrounding neurons, glia, and the vascular system. The ECM is vital for maintaining the structure and function of the brain and also acts as a reservoir for various signaling molecules and neurotransmitters, modulating synaptic transmission and plasticity. Recent research highlights the important role of ECM proteins in both brain development and various neurological diseases, including epilepsy. Alterations in ECM composition and subsequent remodeling may disrupt physiological network excitability and synaptic connectivity, triggering neuroinflammation with active participation from glial cells, including astrocytes and microglia, and blood-brain barrier function. This influences neuronal function and contributes to the formation of epileptic foci and the development of drug-resistant epilepsy. Understanding the intricate interplay between the ECM and epilepsy may enable the identification of novel biomarkers and development of therapeutic strategies targeting this dynamic microenvironment. In this review, we provide a summary of the discussions held at the XVII Workshop on Neurobiology of Epilepsy (WONOEP), organized in 2023 by the International League Against Epilepsy, on the role of the extracellular space in epilepsy. Specifically, we summarize recent advances in understanding the ECM, its alterations in epilepsy, advanced imaging and omics tools for ECM analysis, and the implications for the development of ECM-based therapeutics and biomarkers for acquired and genetic forms of epilepsy. To complement the material presented at WONOEP, we performed targeted, nonsystematic literature searches in PubMed using topic-specific terms (e.g., "perineuronal nets", "extracellular matrix", "traumatic brain injury", "post-traumatic epilepsy", "chloride") and citation tracking to ensure that key experimental and translational studies relevant to these themes were included.
Management of ring chromosome 20 syndrome: Narrative review and consensus recommendations.
Khamis A, Ricci E, Canevini MP … +6 more , Lagae L, Tokumoto K, Inoue Y, Buckinx T, Watson A, Myers KA
Epilepsia · 2026 May · PMID 42096279 · Publisher ↗
Ring chromosome 20 (ring 20) is a rare genetic condition usually presenting as developmental and epileptic encephalopathy. The disease is caused by fusion of the long and short arms of chromosome 20. Patients are symptom...
Ring chromosome 20 (ring 20) is a rare genetic condition usually presenting as developmental and epileptic encephalopathy. The disease is caused by fusion of the long and short arms of chromosome 20. Patients are symptomatic even if there is no loss of genetic material. Epilepsy in ring 20 is usually drug-resistant, with seizures often significantly debilitating and severely impacting quality of life. We assembled a taskforce of clinician-scientists with expertise in ring 20, as well as caregivers of individuals with ring 20. We then reviewed published literature on ring 20 with a focus on management with the aim of developing recommendations for the treatment of this disorder. Our review found that there are very few high-quality data available to guide treatment in ring 20. The majority of publications are individual case reports or small case series. Based on these limited data, as well as personal experience, we recommend the following. (1) The care team should be multidisciplinary and include at least an epileptologist and allied health specialists (e.g., speech therapist, occupational therapist, physiotherapist, psychologist); (2) patients and families should be referred for genetic counseling; (3) if patients are diagnosed with epilepsy, they and their families should be counseled that seizures are likely to be drug-resistant and life-long; (4) as there is a high incidence of non-convulsive status epilepticus (NCSE), there should be a low threshold for video-EEG monitoring if patients have a change in behavior or level of consciousness; (5) initial epilepsy treatment should be with an oral anti-seizure medication; (6) home rescue medication should be considered given the risk for prolonged seizures and NCSE; (7) for patients with drug-resistant epilepsy, ketogenic diet, vagus nerve stimulation, or deep brain stimulation could all be considered; and (8) caregiver burnout and stress should be screened for and supports provided.
Folic acid supplementation and prevention of adverse offspring outcomes among women with epilepsy: An observational study.
Fu Y, Shi F, Sha L … +54 more , Ma Y, Lin W, Li X, Yan H, Wang P, Fang J, Huang Q, Chen F, Li Y, Kong Q, Huang H, Hu X, Liu C, Wang J, Xiao X, Zhang Q, Mei R, Han Y, Wu Y, He S, Zhang H, Wang K, Zhu Y, Lin W, Peng Z, Zhu X, Wu X, Yu M, Zou M, Zou X, Wu T, He X, Guo H, Zhong M, Zhang Q, Su Y, Liu Y, Feng Q, Wang H, Chen W, Sun Y, Sun M, Zhou J, Zhao H, Guo C, Gao J, Guo Y, Huang J, Sun H, Luo X, Yang R, Qin H, Tomson T, Chen L
Epilepsia · 2026 May · PMID 42096275 · Publisher ↗
OBJECTIVE: Folic acid (FA) is essential for fetal development, while the benefits and optimal dose in pregnant women with epilepsy (PWWE) remain unclear. This study explores effects of FA supplementation, dose, and initi...
OBJECTIVE: Folic acid (FA) is essential for fetal development, while the benefits and optimal dose in pregnant women with epilepsy (PWWE) remain unclear. This study explores effects of FA supplementation, dose, and initiation time on offspring outcomes in PWWE. METHODS: This multi-center cohort recruited PWWE from 58 hospitals in China. Anti-seizure medication (ASM) and FA exposures were categorized by first-trimester use. The primary outcome was a composite of preterm birth, low birth weight (LBW), major congenital anomalies (MCAs), fetal death, and neurodevelopmental delay. Logistic regression models assessed the associations between FA exposure, dose, initiation time, and adverse outcomes, adjusting for demographics and epilepsy characteristics, with stratification by maternal ASM use. Dose-response relationships were analyzed using restricted cubic splines. RESULTS: Among 1013 women with 1209 pregnancies, 952 received FA. In ASM-exposed pregnancies, FA supplementation was associated with lower risks of composite adverse offspring outcomes (adjusted odds ratio [aOR] .59, 95% confidence interval [CI] .387-.911) and fetal death (aOR .127, 95% CI .054-.296), whereas no significant differences were observed between preconception and first-trimester initiation. Compared to no supplement, supplementation with .4 mg/day protected against fetal death (aOR .185, 95% CI .078-.428); doses exceeding .4 mg/day further reduced risk of composite adverse outcomes (aOR .343, 95% CI .162-.675), and doses above 1 mg additionally showed trends toward decreased preterm birth in ASM-exposed pregnancies (aOR .338, 95% CI .104-.943). Compared with .4 mg supplementation, doses above 1 mg/day were associated with a lower risk of LBW (aOR .208, 95% CI .05-.58). SIGNIFICANCE: FA supplementation was associated with lower risks of composite adverse offspring outcomes in ASM-exposed pregnancies, specifically at doses exceeding .4 mg. No such associations were observed in pregnancies not exposed to ASMs. However, the optimal upper limit of high-dose FA supplementation requires further investigation.
Increased interval between seizure clusters across time in pediatric patients treated with the immediate-use seizure medication diazepam nasal spray.
Wheless JW, Segal E, Peters JM … +6 more , Wolf SM, Bougher G, Davis C, Ngo LY, Carrazana E, Rabinowicz AL
Epilepsia · 2026 May · PMID 42096179 · Publisher ↗
OBJECTIVE: Seizure clusters, intermittent increases in seizure activity that differ from a patient's usual seizure pattern, may occur despite treatment with a daily anti-seizure medication. Benzodiazepine-containing imme...
OBJECTIVE: Seizure clusters, intermittent increases in seizure activity that differ from a patient's usual seizure pattern, may occur despite treatment with a daily anti-seizure medication. Benzodiazepine-containing immediate-use seizure medications (ISMs; also called rescue therapies) are the cornerstone of treatment for seizure clusters. Diazepam nasal spray is approved by the U.S. Food and Drug Administration to treat seizure clusters in patients with epilepsy ≥2 years of age. A prior long-term safety study of diazepam nasal spray showed an increased inter-seizure cluster interval (SEIzure interVAL [SEIVAL]) in days across a year in patients 6 to 65 years of age. The current analysis focused on changes in SEIVAL over time in a separate study in children with epilepsy 2 to 5 years of age. METHODS: Patients with epilepsy 2 to 5 years of age were enrolled in an open-label, Phase 1/2a trial of diazepam nasal spray that included a single-dose pharmacokinetics period, 180-day safety period, and optional extension period. Doses of 5, 10, or 15 mg were administered based on weight (0.5 mg/kg). A post hoc analysis evaluated SEIVAL for consecutive 90-day periods overall and in a consistent cohort of patients with persistent use and SEIVALs in each period. RESULTS: Among enrolled patients (n = 36), 22 (61.1%) had ≥1 SEIVAL, with a total of 315 SEIVALs recorded. Mean SEIVAL (±SD) doubled from 25.2 (±21.3) days in Period 1 (n = 20) to 51.9 (±72.4) days in Period 3 (n = 8). In the consistent cohort (n = 7), mean SEIVAL increased from 22.1 (±12.7) days in Period 1 to 27.7 (±25.4) days in Period 3. SIGNIFICANCE: These results corroborate those of the earlier post hoc analysis of data from patients 6 to 65 years of age who received diazepam nasal spray for seizure clusters. These findings suggest a beneficial long-term treatment effect of diazepam nasal spray beyond acute use as an ISM.
Stereo-electroencephalography-guided cross-electrode radiofrequency thermocoagulation in focal epilepsy: A review of current methodologies and outcomes.
Campbell B, Neal A, Cockle E … +8 more , Rayner G, Alpitsis R, Blomfield E, O'Brien TJ, Gutman M, Laing J, Hunn M, McIlroy A
Epilepsia · 2026 May · PMID 42095980 · Publisher ↗
Advances in stereo-electroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RFTC) have led to the development of cross-electrode RFTC, which has been shown to result in significantly larger lesions and...
Advances in stereo-electroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RFTC) have led to the development of cross-electrode RFTC, which has been shown to result in significantly larger lesions and higher seizure-freedom rates compared to standard RFTC methods. Given the novelty of cross-electrode RFTC, herein we review the reported surgical techniques and treatment-related outcomes to date to identify current research gaps and future directions. Ten articles were identified for review including 187 participants who underwent cross-electrode RFTC. Hypothalamic hamartoma (HH) and hippocampal sclerosis (HS) accounted for 52% and 26% of all cases, respectively. The proportion of cases with seizure freedom at last follow-up was 71%, including 84% of the HH cases, 54% of all temporal lobe cases, and 56% of the HS cases. Long-term efficacy in one HS study dropped from 72% at 12 months to 43% at 5 years post-treatment. Most (94%) reported complications resolved. One study reported favorable neuropsychological outcomes in HS cross-electrode RFTC compared to standard resective epilepsy surgery; however, it did not use memory tasks known to be reliable proximal markers of mesial temporal dysfunction/disease. In conclusion, extending RFTC boundaries through cross-electrode methods may improve RFTC efficacy and produce seizure-freedom rates comparable to established epilepsy surgical interventions in the treatment of HH and HS at 12 months, with a low risk of postoperative complications. There is limited research exploring efficacy in non-lesional epilepsy despite these cases often undergoing SEEG for diagnostic purposes and being well placed for cross-electrode RFTC. In addition, there is a lack of research exploring the neurocognitive and psychiatric risks of cross-electrode RFTC.
The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) Portal: An open source resource for neuropsychological research in epilepsy.
Busch RM, Brünger T, Arrotta K … +9 more , Ferguson L, Janecek JK, Swanson SJ, Reyes A, Hurd B, St John M, McDonald CR, Hermann BP, Lal D
Epilepsia · 2026 May · PMID 42095829 · Publisher ↗
OBJECTIVE: The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) is a consensus-based, empirically-driven approach to standardize cognitive phenotyping in epilepsy research that has quickly garner...
OBJECTIVE: The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) is a consensus-based, empirically-driven approach to standardize cognitive phenotyping in epilepsy research that has quickly garnered interest within the epilepsy community. However, manually generating IC-CoDE phenotypes in group data is laborious and time-consuming, particularly in datasets containing heterogenous cognitive measures or batteries, limiting the widespread adoption of IC-CoDE phenotypes to further multicenter epilepsy research. METHODS: To remove this barrier, we developed the IC-CoDE Portal (https://ic-code-portal.ccf.org/), an interactive and user-friendly, web-based platform to support the scientific community in performing IC-CoDE individual level classification through web interface or bulk classification through uploading of data files. The Portal also allows the user to generate and visualize cohort summary statistics of cognitive phenotypes in their dataset, with the option of filtering the data interactively by specified demographic or clinical variables of interest. We further made the resulting IC-CoDE phenotypes downloadable as a spreadsheet to foster offline analysis of cognitive data by members of the epilepsy research community. SIGNIFICANCE: Ascertainment of cognitive profiles is key to understanding the natural heterogeneity in the clinical presentation of the epilepsies and their comorbidities. The IC-CoDE taxonomy can be applied to any comprehensive neuropsychological battery, regardless of the specific test measures and normative data used or the language and culture in which the assessment took place, making it an ideal tool to accelerate international multi-center studies on cognition in epilepsy. We hope that by eliminating some of the barriers associated with cognitive phenotyping, the IC-CoDE Portal will springboard large-scale collaborative efforts to further our understanding of the neuropsychology of the epilepsies.
Quantitative electroencephalographic measures during postmalarial epileptogenesis.
Joshi RB, Mwanza S, Zaveri HP … +12 more , Kasolo J, Masempela A, Musakanya T, Mwale T, Nambeye V, Nyriongo R, Tembo RA, Cortina C, Zhang B, Birbeck GL, Rotenberg A, Patel AA
Epilepsia · 2026 May · PMID 42095801 · Publisher ↗
OBJECTIVE: Severe malaria with neurologic involvement contributes significantly to the global burden of acquired pediatric epilepsy. We studied quantitative electroencephalographic (EEG) measures in postmalarial epilepto...
OBJECTIVE: Severe malaria with neurologic involvement contributes significantly to the global burden of acquired pediatric epilepsy. We studied quantitative electroencephalographic (EEG) measures in postmalarial epileptogenesis. METHODS: A total of 186 patients, aged 6 months to 11 years, with confirmed central nervous system malaria were enrolled in a prospective observational study conducted in Chipata, Zambia. EEG data were collected during acute illness for 179 patients. Patients were followed for 12 months postdischarge with EEG and clinical reviews to assess postmalarial epilepsy (PME) outcomes. A total of 155 patients were seen for 1-month, 144 for 6-month, and 142 for 12-month follow-up. Twenty-six patients were diagnosed with PME. We examined EEG measures (relative power, magnitude-squared coherence [MSC], and approximate entropy [ApEn]) to identify differences between patients who developed PME and those who did not. RESULTS: Relative gamma power at admission was significantly greater in the PME group, whereas at 1-month and 6-month follow-up it was greater in the nonepilepsy group. Alpha and beta power increased in both groups over time, suggesting a prolonged process of neurologic recovery, with greater power in both bands observed in the nonepilepsy group at 12-month follow-up. ApEn was greater in the nonepilepsy group at admission and 1-month and 6-month follow-up. At admission and 1-month follow-up, we observed a significant decrease in beta and gamma MSC in the epilepsy group as compared to the nonepilepsy group. These differences were absent at 6-month follow-up but became more prominent again at 12-month follow-up. SIGNIFICANCE: These and related EEG measures may provide value for risk stratification of patients with severe malaria.
Integrating multivariate resting-state fMRI features to localize epileptic networks in common childhood epilepsy.
Zhang Q, Zhang Z, Li Y … +6 more , He Y, Yang F, Kim J, Tracy JI, Lu G, Zhang Z
Epilepsia · 2026 May · PMID 42090243 · Publisher ↗
OBJECTIVE: Accurate localization of epileptic activity remains challenging when interictal discharges are absent or sparse. Although resting-state functional MRI (rs-fMRI) is noninvasive, individual rs-fMRI metrics provi...
OBJECTIVE: Accurate localization of epileptic activity remains challenging when interictal discharges are absent or sparse. Although resting-state functional MRI (rs-fMRI) is noninvasive, individual rs-fMRI metrics provide inconsistent and incomplete localization. We aimed to determine whether multivariate integration of rs-fMRI features could robustly identify syndrome-specific epileptic activity in childhood epilepsy. METHODS: Using simultaneous EEG-fMRI, we studied children with self-limited epilepsy with centrotemporal spikes (SeLECTS, n = 60) and childhood absence epilepsy (CAE, n = 30) alongside typically developing controls (n = 108). Forty-two rs-fMRI metrics spanning amplitude, connectivity, temporal dynamics, and directional measures were computed for each session. Individual abnormality maps were also generated relative to controls. Partial least squares (PLS) regression was then applied to identify a latent component (PLS1) that maximally covaried with syndrome-specific epileptic activation patterns derived from EEG-fMRI. Spatial correspondence, localization accuracy, non-discharge session sensitivity, and classification performance were evaluated. RESULTS: PLS1 showed strong spatial correspondence with EEG-fMRI-defined epileptic activation patterns in both SeLECTS (rolandic cortex) and CAE (thalamocortical network) (both spin-test r = .68, p < .001). PLS1 showed superior localization performance compared with most single-metric rs-fMRI measures and reached EEG-fMRI-level localization accuracy. Notably, PLS1 detected graded, syndrome-specific abnormalities during non-discharge sessions and distinguished discharge, no-discharge, and control states, an effect that has not been observed with individual rs-fMRI metrics. In classification analyses, PLS1 differentiated CAE from SeLECTS with high accuracy (AUC = .79), performing comparably to the EEG-fMRI-based classification. SIGNIFICANCE: Multivariate integration of rs-fMRI features using a template-guided PLS framework enables sensitive and syndrome-specific detection of epileptic activity, even in the absence of overt discharges. This approach provides a clinically translatable strategy for noninvasive epilepsy network mapping.
Disrupted inhibitory interneuron development in SCN1A Dravet syndrome revealed by patient-derived subpallial organoids.
Mattei C, Mao M, Byars S … +7 more , Syazwan EM, Oliva M, Karle TJ, Richards K, Scheffer IE, Petrou S, Maljevic S
Epilepsia · 2026 May · PMID 42085324 · Publisher ↗
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by loss-of-function variants in SCN1A, with seizures typically emerging during the first year of life. Although DS pathophysio...
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by loss-of-function variants in SCN1A, with seizures typically emerging during the first year of life. Although DS pathophysiology has largely been attributed to inhibitory network dysfunction underlying seizures, early developmental alterations in inhibitory interneurons remain poorly understood. METHODS: We generated inhibitory interneuron-enriched subpallial organoids from patient-derived induced pluripotent stem cells carrying an SCN1A loss-of-function variant and the corresponding isogenic control. Using complementary molecular and functional approaches, including quantitative polymerase chain reaction, bulk RNA sequencing, whole-cell patch-clamp electrophysiology, and two-photon calcium imaging, we investigated early inhibitory interneuron development and functional maturation in a human cellular context. RESULTS: Transcriptomic profiling revealed early dysregulation of ventral forebrain interneuron developmental programs, including altered expression of medial ganglionic eminence-associated transcriptional regulators, preceding inhibitory network dysfunction. Patient-derived organoids exhibited marked reductions in intrinsic neuronal excitability and synaptic activity. Acute application of fenfluramine, a clinically approved antiseizure medication for DS, partially restored neuronal activity, demonstrating the translational relevance of this model. SIGNIFICANCE: These findings demonstrate that SCN1A loss of function disrupts early inhibitory interneuron development and functional maturation, defining a developmental vulnerability that likely precedes the emergence of epilepsy in DS. This work establishes patient-derived inhibitory organoids as a human-relevant platform for dissecting disease mechanisms and evaluating therapeutic responses in SCN1A-related epileptic encephalopathies.
Can we predict surgical outcomes: A systematic review and critical appraisal of clinical prediction models in epilepsy surgery.
Federico AA, Kashyap M, Lin CQY … +3 more , Klein KM, Arimoro OI, Wiebe S
Epilepsia · 2026 May · PMID 42084861 · Publisher ↗
OBJECTIVE: Prediction models are increasingly being sought in epilepsy surgery to predict postoperative outcomes and support clinical decision-making. Studies summarizing the evidence in this area can provide insight int...
OBJECTIVE: Prediction models are increasingly being sought in epilepsy surgery to predict postoperative outcomes and support clinical decision-making. Studies summarizing the evidence in this area can provide insight into the type of surgical prediction models, their methodology, and their performance and inform areas for future research. Our aim was to address these knowledge gaps through a comprehensive systematic review of prediction models in epilepsy surgery. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using four databases. Papers were included if they were primary research studies, human-based, studied adult or pediatric populations, studied people with epilepsy undergoing surgical management, and developed or validated a multivariable tool to predict epilepsy surgery outcomes. Data extraction was reviewed in triplicate, and the quality of evidence in each paper was assessed using the Prediction Model Risk of Bias Assessment Tool. RESULTS: The literature search yielded a total of 11 614 papers, with 42 papers and 113 prediction models included in the final analysis. The median area under the curve and accuracy for all models were .75 (interquartile range = .68-.83) and .76 (interquartile range = .69-.83), respectively. Overall, 54.0% of models underwent internal validation, and 20.4% underwent external validation. Models of cognitive-language outcomes seemed to perform better than those for other outcomes. Overall risk of bias was high in 81% of models, with weakest performance in outcomes and analyses, but trended toward improvement over time. Concerns for applicability were low in 89% of the models. SIGNIFICANCE: Prediction models in epilepsy surgery are rapidly proliferating, but most lack external validation, and many still exhibit a high risk of bias. Therefore, caution is needed when interpreting and applying these predictive tools. Evidence of improvement in methodological quality holds promise for enhancing patient care, if coupled with improved model performance.
Developmental and cell type-specific contributions of thalamic serotonin 2A receptors to absence seizures.
Morais TP, Salamanca G, Vaz SH … +4 more , Sebastião AM, Bombardi C, Crunelli V, Di Giovanni G
Epilepsia · 2026 May · PMID 42084443 · Publisher ↗
OBJECTIVE: Serotonin 2A receptors (5-HTRs) play a complex role in focal and generalized seizures due to their diverse cellular and regional distribution. Although systemic activation of 5-HTRs suppresses absence seizures...
OBJECTIVE: Serotonin 2A receptors (5-HTRs) play a complex role in focal and generalized seizures due to their diverse cellular and regional distribution. Although systemic activation of 5-HTRs suppresses absence seizures (ASs) in Genetic Absence Epilepsy Rats From Strasbourg (GAERS) rats, the contribution of thalamic receptors and their cell-type specificity remains unclear. Here, we performed a developmental immunohistochemical analysis in the nucleus reticularis thalami (NRT) and the ventrobasal thalamic nucleus (VB) of GAERS rats to assess developmental alterations in 5-HTR expression and used genetic manipulation to determine whether the antiabsence effect of systemic 5-HTR activation depends on thalamocortical (TC) neurons or astrocytes. METHODS: Double-immunofluorescence labeling of 5-HTRs with either γ-aminobutyric acid (GABA) or glial fibrillary acidic protein in adult GAERS rats was used to investigate the neuronal and astrocytic distribution of these receptors in the NRT and VB. In addition, [H]GABA uptake and its modulation by 5-HTR activation were assessed in thalamic slices. Electroencephalographic and video recordings in freely moving GAERS were used to evaluate the effects of VB microinjection of TCB-2, a 5-HTR agonist, on ASs. Finally, the cellular mechanisms underlying these effects were investigated using selective shRNA-mediated knockdown of 5-HTRs in either TC neurons or astrocytes in the VB. RESULTS: In the VB, at postnatal day (P) 25, 5-HTRs were mainly expressed in TC neurons and in the majority of the few GABAergic interneurons, whereas by P90 they were exclusively localized to TC neurons. In the NRT, neuronal expression increased from ~60% to nearly 100% over development. Astrocytic 5-HTR expression increased developmentally in the NRT but remained unchanged in the VB. GABA uptake was decreased in GAERS compared to Wistar rats and was not modified by 5-HTR activation. In vivo, intra-VB injection of TCB-2 reduced ASs; this effect was abolished by shRNA knockdown of 5-HTRs in TC neurons, but not in astrocytes. SIGNIFICANCE: The developmental reorganization of thalamic 5-HTR signaling coincides with the expression of ASs, suggesting a contributory role. Our findings indicate that neuronal, but not astrocytic, thalamic 5-HTRs drive seizure modulation, identifying a potential therapeutic target.
Unique deficits in place coding across subfields of the hippocampus in a mouse model of temporal lobe epilepsy.
Boublil BL, Donahue MM, Dang CB … +2 more , Tarcsay G, Ewell LA
Epilepsia · 2026 May · PMID 42080316 · Publisher ↗
OBJECTIVE: Memory problems are comorbid with temporal lobe epilepsy (TLE). Animal models of TLE reveal impairments in spatial firing fields of hippocampal place cells, providing a potential neural substrate for memory pr...
OBJECTIVE: Memory problems are comorbid with temporal lobe epilepsy (TLE). Animal models of TLE reveal impairments in spatial firing fields of hippocampal place cells, providing a potential neural substrate for memory problems. Each subfield of the hippocampus carries out unique aspects of spatial memory, yet little is known about how individual subfields are perturbed. Here, we investigated the spatial coding properties of the three major subfields of the hippocampus. METHODS: Single unit recordings were made from CA1, CA3, and the dentate gyrus (DG) of mice (n = 10, 6 male [M]/4 female [F]) induced with epilepsy using the suprahippocampal kainate model and in control mice injected with saline (n = 6, 3 M/3F). Place cell activity was measured while mice foraged in highly familiar environments to assess basic place cell properties and in novel environments to assess remapping. RESULTS: A lower percentage of cells were classified as place cells in CA1 of epileptic mice, whereas percentages were similar in CA3 and DG compared to control. Place fields of CA1 were less coherent, place fields of CA3 were less stable, and place fields in DG had smaller differences between in-field and out-of-field firing. All regions constructed new distinct maps within the first session of exposure to a novel environment; however, new maps in CA3 trended toward instability. SIGNIFICANCE: These results point to specific deficits within subfields of the hippocampus, which may indicate that there are different cellular and network mechanisms at play. Such heterogeneity would be predicted to contribute differently to memory deficits.
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