Epilepsia[JOURNAL]
Sun
200 papers
Interictal cardiac repolarization abnormalities improve after surgical seizure resolution in pediatric drug-resistant epilepsy.
Bozdag E, Makaram N, Sabino G … +4 more , Bolton J, Grant EP, Rotenberg A, Tamilia E
Epilepsia · 2026 Jun · PMID 41848583 · Publisher ↗
OBJECTIVE: The current work aims to study interictal T-wave alternans (TWA), a biomarker of cardiac repolarization instability that is elevated in epilepsy, in children with drug-resistant epilepsy (DRE) and to test whet...
OBJECTIVE: The current work aims to study interictal T-wave alternans (TWA), a biomarker of cardiac repolarization instability that is elevated in epilepsy, in children with drug-resistant epilepsy (DRE) and to test whether it normalizes following postoperative seizure resolution. METHODS: In this cohort study, we studied children with DRE who underwent successful epilepsy surgery (Engel class IA). Interictal TWA was computed before and after surgery using electrocardiographic data collected during electroencephalographic video monitoring. These values were compared to each other (Wilcoxon signed-rank test) and to healthy controls (Wilcoxon rank-sum test). Heart rate (HR) and HR variability (HRV) were also assessed and compared. Correlations with clinical variables, including time since surgery and number of antiseizure medications, were analyzed. RESULTS: Preoperative TWA was elevated in children with DRE compared to healthy controls (25.5 μV vs. 13.7 μV, p = .009). Following surgery in DRE, TWA decreased (17.9 μV, p = .002) and was no longer different from control levels (p = .81). Preoperative HRV was reduced compared to controls (p = .02) and did not change postoperatively (p = .70). The TWA percent change did not correlate with the time elapsed since surgery (p = .26). SIGNIFICANCE: Interictal TWA is elevated in children with DRE and normalizes following successful surgical treatment, suggesting that epilepsy-associated cardiac repolarization instability is reversible. TWA may serve as a dynamic biomarker of epilepsy-related cardiac stress and recovery, with potential utility in monitoring treatment response and stratifying cardiac risk. We provide the first evidence that cardiac electrical instability in pediatric DRE, as measured by TWA, improves after seizure resolution through surgery. These findings highlight the relevance of noninvasive cardiac biomarkers in epilepsy management and support further research into TWA as a marker of systemic recovery after surgical seizure treatment.
Non-synaptic GABA release as a trigger for synchronous epileptiform network patterns.
Scalmani P, Uva L, Regondi MC … +3 more , Miele C, Grazioso V, de Curtis M
Epilepsia · 2026 Jun · PMID 41843411 · Publisher ↗
OBJECTIVE: The mechanisms leading to the onset of a focal seizure are still not understood. Experimental data in animal models and patients suggest that both interneurons and principal cells contribute to focal seizure g...
OBJECTIVE: The mechanisms leading to the onset of a focal seizure are still not understood. Experimental data in animal models and patients suggest that both interneurons and principal cells contribute to focal seizure generation. We investigate here whether neurons are driven by non-synaptic γ-aminobutyric acid (GABA) release during seizures generated in models of focal ictogenesis. METHODS: We used the well-established 4-aminopyridine (4AP) seizure model to analyze epileptiform discharges in naïve mouse entorhinal cortex slices and in guinea pig brains maintained in vitro. Pharmacological dissection of epileptiform events was performed during simultaneous field potential and patch-clamp recordings. RESULTS: 4AP (100 μM) elicited periodic and large chloride currents in both principal neurons and GABAergic interneurons that steadily matched simultaneously recorded interictal population spikes. These population spike-associated chloride currents (PSACC) (i) survived glutamate receptor blockade, (ii) were abolished by GABA antagonists and by blocking the synaptic neurotransmitters release, (iii) were reduced by excitatory amino acid transporter antagonist, and (iv) were enhanced by GABA transporter 1 antagonist. Application of the antagonist of bestrophin-1 (BEST-1) channels inhibited both PSACCs and the associated spikes and prevented the occurrence of seizure-like events in entorhinal cortex mouse slices and in the isolated guinea pig brain. SIGNIFICANCE: We propose that GABA released via bestrophin-1 channels induces large and synchronous chloride currents in principal cells and interneurons, and establishes the conditions for the generation of seizure-like events. We propose that neuronal epileptiform discharges are generated by fast transmembrane ion changes imposed by non-vesicular GABA release, possibly sustained by astrocytes.
Ablation of cerebellar Purkinje cells enhances seizure susceptibility and promotes kindling.
Li K, Wu X, He J … +4 more , Zhang Y, Xiong ZQ, Wang X, Ding J
Epilepsia · 2026 Jun · PMID 41842889 · Publisher ↗
OBJECTIVE: Epilepsy is a common neurological disorder characterized by recurrent seizures, often resulting from an imbalance between neuronal excitation and inhibition. Loss of cerebellar Purkinje cells (PCs) has been ob...
OBJECTIVE: Epilepsy is a common neurological disorder characterized by recurrent seizures, often resulting from an imbalance between neuronal excitation and inhibition. Loss of cerebellar Purkinje cells (PCs) has been observed in some patients with chronic epilepsy; however, whether PC loss can initiate seizures or exacerbate seizure severity remains unclear. METHODS: We established a mouse model of selective PC ablation in adulthood using the diphtheria toxin (DT)/DT receptor (DTR) system. Seizure susceptibility (epileptiform discharges, Racine score, and network activation) was assessed thoroughly in two distinct seizure models: the pentylenetetrazol (P-uced acute seizure model and the hippocampal kindling model. Furthermore, in vivo electrophysiology recordings in the deep cerebellar nuclei (DCN) were utilized to explore the single-unit firing characteristics following PC ablation. RESULTS: One month after intraperitoneal (i.p.) DT injection, PC ablation was successfully induced in adult Pcp2-DTR mice. No spontaneous seizures were observed in mice with PC ablation during 48-h wireless electroencephalography/electromyography (EEG/EMG) monitoring. However, PC ablation significantly increased seizure susceptibility in the PTZ-induced acute seizure model and accelerated the kindling process in the hippocampal kindling model. Although baseline DCN firing remained unchanged, these mice displayed a distinct post-ictal DCN electrophysiological signature: significantly enhanced delta/theta power compared to controls, and a decrease in neuronal firing frequency relative to their own baseline, with firing regularity preserved. SIGNIFICANCE: Together, these findings suggest that PC ablation contributes to heightened seizure susceptibility and seizure severity, highlighting a modulatory role of cerebellar circuits in epilepsy.
Thalamic connectivity mirrors spatial maps of network dysfunction in nonlesional focal epilepsy.
Fan JM, Tadayon E, Kudo K … +5 more , Ranasinghe KG, Findlay AM, Knowlton RC, Rao VR, Nagarajan SS
Epilepsia · 2026 Jun · PMID 41842763 · Full text
OBJECTIVE: Focal epilepsy is increasingly conceptualized as a network disorder, yet the extent to which network dysfunction reflects a shared phenotype remains unknown. Spatially conserved patterns of network dysfunction...
OBJECTIVE: Focal epilepsy is increasingly conceptualized as a network disorder, yet the extent to which network dysfunction reflects a shared phenotype remains unknown. Spatially conserved patterns of network dysfunction may implicate a centralized mechanism underlying widespread impairment. Here, we investigate whether network connectivity disruptions are spatially similar across temporal lobe and extra-temporal lobe epilepsy cohorts and whether shared dysfunction aligns with thalamic connectivity profiles. METHODS: We retrospectively analyzed resting-state magnetoencephalographic imaging from 71 individuals with nonlesional, drug-resistant focal epilepsy (n = 45 temporal, n = 26 extratemporal), collected between 2014 and 2023, and healthy controls (n = 18). Source reconstructed time series were bandpass filtered, and long-range functional connectivity was quantified using imaginary coherence. Network disturbance maps were computed as T-score maps, comparing functional connectivity in epilepsy cohorts to controls, across topographical parcels and frequency bands. Spatial similarity of temporal and extratemporal network dysfunction maps were assessed using Pearson correlations. To infer thalamic involvement, shared network dysfunction maps were correlated with normative functional magnetic resonance imaging-derived thalamocortical connectivity profiles. RESULTS: Extra-temporal lobe epilepsy demonstrated reduced global network connectivity relative to controls in the delta (p = .012), alpha (p = .034), and gamma (p < .001) frequency bands. Across all frequencies, the spatial patterns of network disturbances between temporal and extratemporal cohorts were significantly correlated (r = .287-.717, all p < .001), indicating a shared network dysfunction. Shared spatial maps of network dysfunction correlated with normative thalamocortical connectivity profiles, with significant correlations in the anterior, pulvinar, and dorsomedial thalamus. SIGNIFICANCE: Nonlesional focal epilepsy exhibits a common, frequency-dependent pattern of cortical network dysfunction that is spatially aligned with thalamic connectivity, supporting a thalamic hub contribution to widespread network impairment.
Long-lasting remodeling of astrocytes in an Scna1 mouse model of Dravet syndrome.
Genin A, Janvier A, Moujellil-Legagneur T … +8 more , Blaquière M, Chaussy A, Privé R, Duprat F, Mantegazza M, Audinat E, Marchi N, Cresto N
Epilepsia · 2026 Jun · PMID 41841337 · Full text
OBJECTIVE: Dravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by mutations in the SCN1A gene, leading to loss of function of the voltage-gated sodium channel Naᵥ1.1. The latter cause...
OBJECTIVE: Dravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by mutations in the SCN1A gene, leading to loss of function of the voltage-gated sodium channel Naᵥ1.1. The latter causes early onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. METHODS: Using a heterozygous Scn1a knockout (Scn1a/) mouse model that recapitulates the DS-human phenotype, we examined astrocyte remodeling at landmark disease stages, as defined by video-electroencephalography and behavioral readouts. RESULTS: From initial disease aggravation (postnatal day [PN] 20-35) to long-term stabilization (up to PN90), Scn1a/ mice showed increased hippocampal and cortical glial fibrillary acidic protein (GFAP) transcript and protein levels compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a/ mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices, was increased but not sustained long-term. Importantly, these disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a/ mice long-term, along with increased connexin (Cx30 and Cx43) protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a/ mice. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented posttetanic synaptic potentiation. SIGNIFICANCE: In DS, astrocytes undergo long-term remodeling independent of tissue damage. We discuss the association between astrocyte network changes and seizures, as well as synaptic and cognitive deficits.
Patterns of seizure frequency reduction in clinical trial participants with lower baseline seizure frequency.
Kerr WT, Reddy AS, Kok N … +3 more , McFarlane KN, Biju L, French JA
Epilepsia · 2026 Jun · PMID 41830605 · Full text
OBJECTIVE: Inclusion and exclusion criteria of clinical trials for seizures aim to select representative participants with a high enough seizure frequency to evaluate the efficacy of treatment in a relatively short doubl...
OBJECTIVE: Inclusion and exclusion criteria of clinical trials for seizures aim to select representative participants with a high enough seizure frequency to evaluate the efficacy of treatment in a relatively short double-blind period. To inform the selection of seizure frequency-based inclusion criteria, we evaluated the association between baseline seizure frequency and reduction of seizure frequency in the double-blind period. METHODS: Using data from 11 double-blind placebo-controlled trials of antiseizure medications for either focal or generalized onset epilepsy, we evaluated the association of baseline seizure frequency with 50% responder rate and percent reduction of seizure frequency in maintenance. We identified four patterns based on the presence or absence of significant association (p < .05) in placebo, active treatment, both, and neither. We also evaluated whether the time to prerandomization monthly seizure count (T-PSC) design impacted these associations. RESULTS: In 55% of trials (6/11), there was no significant association of maintenance seizure frequency change with baseline seizure frequency. In 19% of trials (2/11), there were parallel elevations in placebo and active treatment responses for lower baseline seizure frequency. In one trial (1/11), that shift was observed in placebo only, whereas there was a ceiling effect of high response in levetiracetam. In the remaining 19% of trials (2/11), there were more seizure frequency reductions in lower baseline seizure frequencies in active treatment but not placebo. These associations were not modified when the T-PSC design was used. SIGNIFICANCE: The association of the magnitude of change in seizure frequency with baseline seizure frequency was inconsistent across trials. In eight of 11 trials, these patterns did not reduce the magnitude of difference between active treatment and placebo and thereby may not reduce statistical power. In only one trial did elevated placebo response reduce the difference between active treatment and placebo. In two trials, active treatment appeared more efficacious in lower seizure frequencies.
KCNJ4 variants disrupt inward-rectifier potassium channel function and cause refractory epilepsy.
Pan H, Liu D, Xu W … +18 more , Li Y, Hu J, Henry O, Fuchs A, Jamra RA, Liu Z, He M, Chen Y, Wu S, Dong X, Chen Y, Wang P, Gu W, Jing H, Tang Y, Wang YJ, Mao X, Xiao N
Epilepsia · 2026 Jun · PMID 41830586 · Full text
OBJECTIVE: Epilepsy is a common neurological disorder with a strong genetic basis, most frequently arising from ion channel dysfunction. Although multiple inwardly rectifying potassium (Kir) channels have been implicated...
OBJECTIVE: Epilepsy is a common neurological disorder with a strong genetic basis, most frequently arising from ion channel dysfunction. Although multiple inwardly rectifying potassium (Kir) channels have been implicated in epileptogenesis, the contribution of KCNJ4, which encodes the Kir2.3 channel, has not previously been established in human epilepsy. The present study aimed to identify pathogenic KCNJ4 variants and to elucidate their functional consequences in the context of epilepsy. METHODS: Trio whole exome sequencing was performed in four unrelated individuals with refractory epilepsy and neurodevelopmental abnormalities. Identified KCNJ4 variants were evaluated for rarity and inheritance patterns. Functional consequences were assessed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes coexpressing wild-type or mutant Kir2.3 together with Kir2.1. Protein expression levels were examined by Western blot analysis to exclude effects attributable to altered channel expression or trafficking. RESULTS: We identified four rare heterozygous missense variants in KCNJ4 (Gly136Ser, Val206Met, Met293Lys, and Glu384Lys), all of which were absent from public population databases. Clinically, affected individuals exhibited a broad phenotypic spectrum ranging from isolated epilepsy to severe developmental and epileptic encephalopathy. Electrophysiological analyses revealed variant-specific functional alterations; the Gly136Ser and Glu384Lys variants significantly increased inwardly rectifying potassium currents, consistent with gain-of-function effects, whereas the Val206Met and Met293Lys variants markedly reduced current amplitudes, indicating loss of function. These functional changes were independent of channel protein expression levels. SIGNIFICANCE: Our findings establish KCNJ4 as a novel epilepsy-associated gene and demonstrate that both gain- and loss-of-function mechanisms of Kir2.3 can contribute to epileptogenesis. This study expands the genetic landscape of epilepsy and highlights the critical role of inward-rectifier potassium channel regulation in neuronal excitability, with potential implications for mechanism-based therapeutic strategies.
Arterial spin labeling performs comparably to 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography for presurgical evaluation in pediatric lesional epilepsy.
Gennari AG, Cserpan D, Kottke R … +5 more , Krayenbühl N, Messerli M, Hüllner MW, O'Gorman Tuura R, Ramantani G
Epilepsia · 2026 Jun · PMID 41830515 · Full text
OBJECTIVE: This study was undertaken to test whether arterial spin labeling (ASL) performs comparably to 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the mainstay functional imaging technique, in...
OBJECTIVE: This study was undertaken to test whether arterial spin labeling (ASL) performs comparably to 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the mainstay functional imaging technique, in pediatric lesional epilepsy, while avoiding radiotracer exposure and additional sedation. METHODS: We retrospectively included children with epilepsy due to focal cortical dysplasia, low-grade epilepsy-associated tumors, or hippocampal sclerosis who underwent standardized magnetic resonance imaging (MRI; including single-delay ASL) and FDG-PET during presurgical evaluation. Lesions, perilesional perfusion, and metabolic abnormalities were segmented and coregistered. Spatial overlap was quantified using DICE scores to compare functional modalities with each other (perfusion-to-metabolism: DICE), with the lesion (metabolism-to-lesion: DICE; perfusion-to-lesion: DICE), and, in seizure-free children, with the resection cavity (lesion-, metabolism-, perfusion-to-resection cavity: DICE). We also assessed the temporal stability of perilesional ASL abnormalities and the presence of remote ipsilateral/contralateral abnormalities. Equivalence testing used the Wilcoxon signed-rank equivalence test with FDG-PET as reference; Cohen κ quantified agreement for remote abnormalities. RESULTS: Fifteen children were included; median ages at FDG-PET and ASL were 7.7 and 7.5 years; 53% required sedation. Median perilesional volumes were 11 339 mm (FDG-PET) and 10 791 mm (ASL); both were larger under sedation (p < .001). Perilesional volumes were equivalent (p = .037). Median DICE and DICE were .3 and .4; equivalence was confirmed (p < .001). Median DICE was .7, indicating strong ASL-FDG-PET concordance. In seizure-free children following surgery, DICE and DICE were both .6 and equivalent (p = .01). ASL findings were stable over time (DICE = .27-.75; n = 4 with repeat ASL). Remote ipsilateral abnormalities were common (ASL 73%, FDG-PET 67%; κ = .53), with poor contralateral agreement (κ = .12). SIGNIFICANCE: ASL yielded perilesional findings equivalent to FDG-PET and showed comparable overlap with the resection cavity in seizure-free children. As a radiation-free technique embedded into routine MRI, ASL reduces logistics and avoids an additional sedation session. These findings support ASL as a practical alternative to FDG-PET for presurgical workup, especially when FDG-PET access is limited.
Interictal and seizure-onset scalp electroencephalographic patterns in malformations of cortical development.
Shakhatreh L, Quiles LEP, Chen Z … +8 more , Gonen OM, Mohidat S, Millist L, Hollis C, Sundram A, Perucca P, O'Brien TJ, Kwan P
Epilepsia · 2026 Jun · PMID 41830499 · Full text
OBJECTIVE: Malformations of cortical development (MCDs) are a frequent cause of drug-resistant epilepsy and a common indication for resective epilepsy surgery. As magnetic resonance imaging (MRI) lacks sensitivity for su...
OBJECTIVE: Malformations of cortical development (MCDs) are a frequent cause of drug-resistant epilepsy and a common indication for resective epilepsy surgery. As magnetic resonance imaging (MRI) lacks sensitivity for subtle MCDs, supplemental diagnostic tools are needed. This study aimed to characterize scalp electroencephalographic (EEG) patterns in MCDs and investigate their association with surgical outcomes. METHODS: This was a retrospective case-control study including patients who underwent inpatient video-EEG monitoring at two Australian hospitals. Cases were individuals with MCDs confirmed on MRI or histopathology; controls included patients with other focal epilepsies. Two epileptologists independently reviewed interictal and seizure-onset EEG patterns using a standardized classification framework. Patterns were compared between cases and controls and assessed with respect to postoperative seizure outcomes, adjusting for antiseizure medication reduction. RESULTS: We included 38 cases with MCDs (52.6% females, median age = 34 years) and 114 controls (45.6% females, median age = 41 years). Among interictal patterns, repetitive epileptiform discharges type 1 and type 2 were more prevalent in patients with MCDs than controls (p = .002 and .005, respectively). Focal fast epileptiform discharges were also more frequent in MCD patients, after excluding nonlesional focal epilepsy controls (p = .038). Among seizure-onset patterns, paroxysmal fast activity was more prevalent in MCDs (p < .001). Among 38 patients who underwent surgery, 70.0% of MCDs and 75.0% of controls had favorable outcomes. No EEG pattern predicted postoperative seizure outcomes. SIGNIFICANCE: Distinct scalp EEG patterns may support differentiation of MCDs from other focal epilepsies. Larger prospective studies are needed to clarify their role in detecting MRI-negative MCD or guiding targeted imaging.
Poststroke epilepsy is associated with vascular cognitive disorder in young stroke patients: The ODYSSEY study.
Reitsma FJ, Verburgt E, Schellekens MMI … +24 more , Hilkens NA, Verhoeven JI, van Alebeek ME, Brouwers PJAM, Arntz RM, van Dijk GW, Gons RAR, van Uden IWM, den Heijer T, van Tuijl JH, de Laat KF, van Norden A, Vermeer SE, van Zagten MSG, Wermer MJH, Nederkoorn PJ, van Rooij FG, van den Wijngaard IR, de Kort PLM, Kessels RPC, Tuladhar AM, van Oostenbrugge RJ, de Leeuw FE, Rouhl RPW
Epilepsia · 2026 Jun · PMID 41830426 · Full text
OBJECTIVE: Cognitive disorder is common after stroke at a young age, especially in patients with poststroke epilepsy (PSE). Whether the causative mechanism is direct (due to epilepsy-related network alterations) or indir...
OBJECTIVE: Cognitive disorder is common after stroke at a young age, especially in patients with poststroke epilepsy (PSE). Whether the causative mechanism is direct (due to epilepsy-related network alterations) or indirect (due to effect-modifiers such as stroke severity) is not fully understood. We assessed the role of PSE in cognitive disorder in young stroke patients by investigating the association between vascular cognitive disorder (VCD) and PSE in young stroke patients, and by investigating the association between cognitive impairment per cognitive domain and PSE. METHODS: In this multicenter prospective cohort study, we investigated the occurrence of PSE in patients aged 18-49 years presenting with a first-ever transient ischemic attack, ischemic stroke, or primary intracerebral hemorrhage between 2013 and 2021 and assessed the cognitive function 1 year after the event. We calculated composite z-scores for seven cognitive domains. VCD was categorized as a composite z-score in any domain between -2.0 SD and -1.5 SD (mild) and <-2.0 SD (major). We performed multivariable regression analyses to examine the association between PSE and VCD and between PSE and cognitive impairment per domain. RESULTS: Eight (median age = 38.6 years, median NIHSS score = 2, 30% male) of 20 patients with PSE (40.0%) had major VCD, compared to 93 (median age = 44.2 years, median NIHSS = 2, 50% male) of 426 patients (20.1%) without PSE (adjusted odds ratio [OR] = 3.96, 95% confidence interval [CI] = 1.24-12.65). Additionally, PSE was independently associated with cognitive impairment in the domain attention and working memory (adjusted OR = 5.09, 95% CI = 1.15-22.59). SIGNIFICANCE: We found independent associations between PSE and major VCD, and between PSE and cognitive impairment in the attention and working memory domain. This could support the "second-hit hypothesis," in which epilepsy following a primary injury relates directly to increased cognitive impairment with a subcortical neuropsychological profile.
Long-term safety of early discontinuation of antiseizure medication after resolution of acute provoked neonatal seizures.
Glass HC, Numis AL, Soul JS … +14 more , Wusthoff CJ, Lemmon ME, Chu CJ, Massey SL, Thomas C, Anwar T, Berl MM, Larson JG, Sturza J, Annis D, Rogers EE, Franck LS, McCulloch CE, Shellhaas RA
Epilepsia · 2026 Jun · PMID 41826797 · Full text
OBJECTIVE: To assess long-term safety of antiseizure medication (ASM) discontinuation after resolution of acute provoked neonatal seizures and prior to hospital discharge. METHODS: Prospective, observational, comparative...
OBJECTIVE: To assess long-term safety of antiseizure medication (ASM) discontinuation after resolution of acute provoked neonatal seizures and prior to hospital discharge. METHODS: Prospective, observational, comparative effectiveness cohort study of neonates with acute provoked seizures born from July 2015 to March 2018, and followed until September 2024, at nine U.S. Neonatal Seizure Registry centers with Level IV neonatal intensive care units and Level IV pediatric epilepsy programs. Duration of ASM treatment was quantified as (1) discontinuation before discharge from the neonatal seizure admission or (2) maintenance at the time of hospital discharge. Outcomes were adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined among enrolled participants by a logistic regression model including seizure etiology, gestational age, therapeutic hypothermia, worst electroencephalography (EEG) background, days of EEG seizures, and discharge neurological exam (all p ≤ .1 in a joint model, except etiology, which was included for face validity). The primary outcome was non-inferiority of cognition (Wechsler Preschool and Primary Scale of Intelligence assessed at age 5-6 years). Secondary outcomes were non-inferiority of functional development (Vineland Adaptive Behavior Scale, 3rd Edition, assessed at 3-8 years) and post-neonatal epilepsy (assessed at 1-8 years). RESULTS: Among 284 children with at least one follow-up, outcomes were similar in the discontinued vs maintained ASM groups for full-scale IQ at age 5 years (adjusted difference +10 points), functional development at ages 3-8 years (adjusted difference 0 points), and post-neonatal epilepsy at ages 1-8 years (adjusted hazard ratio .93, 95% confidence interval [CI] .48-1.80). SIGNIFICANCE: Prolonged administration of ASM for several months after resolution of acute provoked neonatal seizures may expose infants to unnecessary medications. These results provide additional evidence for safety of discontinuing ASM for most neonates soon after the resolution of acute provoked seizures-a practice that is recommended in the International League Against Epilepsy (ILAE) guideline for neonatal seizure management.
Focal seizures during simulated driving: A pilot study.
Nilsson E, Zelenika Zeba M, Strandberg J … +2 more , Lundgren P, Zelano J
Epilepsia · 2026 May · PMID 41826792 · Full text
Cars are increasingly equipped with technology that can be used to analyze driver behavior and alertness, often referred to as driver monitoring systems (DMS). Although initially mainly used to track drivers' attention,...
Cars are increasingly equipped with technology that can be used to analyze driver behavior and alertness, often referred to as driver monitoring systems (DMS). Although initially mainly used to track drivers' attention, DMS are now expanding in the hope of detecting additional forms of driver impairment that may jeopardize driving, such as drowsiness and those caused by sudden medical emergencies. To explore the potential for the latter, we conducted a pilot study to investigate whether technology in modern vehicles, such as eye tracking and driving behavior sensing, can detect abnormalities during seizures. We included 10 patients with focal epilepsy, all of whom had high seizure frequencies and a history of focal impaired awareness seizures. In three subjects, we recorded three definite and one possible electrographic seizure. All seizures were focal, with no motor features. We evaluated driving performance, saccade frequency, eye blink rate, and gaze direction. No clear impact of seizures on driving performance was observed, and eye-related measures showed inconsistent changes. Future studies should explore additional indicators and assess the potential to detect more severe seizures that may have a greater impact on driving performance.
Perturbation-induced responses improved seizure forecasting in epileptic rats.
Chang WC, Lin J, Cheung W … +4 more , Lai A, Cook MJ, Grayden DB, Stacey WC
Epilepsia · 2026 Jun · PMID 41823376 · Full text
OBJECTIVE: The unpredictability of seizures is one of the most challenging aspects of uncontrolled epilepsy for patients. Prior work forecasting seizure risk has measured changes in passive intracranial electroencephalog...
OBJECTIVE: The unpredictability of seizures is one of the most challenging aspects of uncontrolled epilepsy for patients. Prior work forecasting seizure risk has measured changes in passive intracranial electroencephalographic (EEG) signals, but currently, there are no such clinical devices available. Based upon dynamical theory, we hypothesized that the response of the brain to perturbing stimulation provides a robust measurement of seizure risk that outperforms the results from passive EEG. METHODS: To test the hypothesis, we performed more than 8 weeks of periodic electrical stimulation and continuous EEG recordings in epileptic rats induced by intrahippocampal injection of tetanus toxin, in which seizures started spontaneously. RESULTS: Using the perturbation-evoked responses as a predictive biomarker of seizure risk, we built a preictal detection system that had excellent accuracy (area under the receiver operating characteristic curve > .95) at distinguishing the preictal from the interictal states. In comparison, a similar preictal detection system that used only passive features from the same experimental animals was unable to identify the preictal state better than chance. SIGNIFICANCE: Our results advocate for perturbation to be used for seizure prediction purposes, which could improve the efficacy of seizure forecasting when applied clinically.
Decoding epilepsy's molecular blueprint: Machine learning unravels transcriptomic subtypes and regulatory networks.
Weng Y, Ma Y, Hou W … +9 more , Li H, Zhou Y, Zhao R, Li H, Chen L, Ma Y, Jin L, Wang Y, An Y
Epilepsia · 2026 Jun · PMID 41823335 · Full text
OBJECTIVE: Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy. The molecular heterogeneity underlying DRE remains poorly defined, largely due to limited access to resected brain tissu...
OBJECTIVE: Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy. The molecular heterogeneity underlying DRE remains poorly defined, largely due to limited access to resected brain tissue and substantial genetic diversity. Current classifications rely primarily on clinical symptoms and histopathological features rather than molecular mechanisms, constraining mechanistic insight and the development of targeted therapies. This study aimed to develop a transcriptome-based, machine learning-guided framework for molecular classification of DRE. METHODS: We performed comprehensive RNA sequencing on 153 surgically resected samples from 95 patients with DRE. Two transcriptomic subtypes were identified through unsupervised clustering. We also leveraged a weighted correlation network-based framework and systematic transcriptional signature comparison and developed a classification model using machine learning algorithms. RESULTS: Unsupervised clustering revealed two molecular subtypes that diverged from traditional pathological classifications, indicating an alternative transcriptomic basis for epilepsy pathogenesis. A classification model was constructed based on four key differentially regulated pathways: (1) neuroactive ligand-receptor interaction, (2) cAMP signaling, (3) γ-aminobutyric acid (GABA)ergic synapse, and (4) calcium signaling. Among the tested algorithms, the random forest model demonstrated superior performance, achieving 96% classification accuracy with an area under the curve (AUC) of .95. SIGNIFICANCE: These molecular subtypes and their pathways could serve as key molecular hallmarks of epilepsy, offering valuable insights for developing targeted therapies. Moreover, our findings introduce a novel framework for classifying epilepsy based on its molecular nature, potentially connecting the clinical symptoms with the underlying causes more effectively.
Neuroanatomical localization of faciobrachial dystonic seizures in LGI1-antibody encephalitis.
Ahn SH, Karaminiya M, Goh Y … +11 more , Ha WS, Shin Y, Jang Y, Banks S, Jung KY, Chu K, Lee SK, Kim KM, Hong SB, Irani S, Lee ST
Epilepsia · 2026 May · PMID 41823021 · Publisher ↗
Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine-rich glioma inactivated 1 (LGI1)-antibody encephalitis...
Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine-rich glioma inactivated 1 (LGI1)-antibody encephalitis. This study aims to describe the electrophysiologic mechanism underlying these pathognomonic symptoms. LGI1-antibody encephalitis patients with active symptoms were enrolled from two separate centers in South Korea and the United States. Patients were evaluated with simultaneous magnetoencephalography (306 channels) and electroencephalography. Regional alterations in neuronal excitability represented by interictal epileptiform discharges were present in the faciobrachial area of the motor cortex, insula, and somatosensory cortex, somatotopically aligned with each of the ictal semiologies observed in patients. FBDS and other LGI1-antibody encephalitis-specific spells localized to cortical regions neuroanatomically corresponding to ictal semiologies: the faciobrachial homunculus (FBDS), insular cortex (paroxysmal dizziness spells), and somatosensory cortex (thermal sensory attacks). Our findings support the ictal hypothesis underlying these unique phenomena.
Unstable slow oscillations couple with epileptogenic fast-rhythm bistability in sleep-related epilepsy: A stereoelectroencephalographic study.
Burlando G, Belforte C, Siebenhühner F … +12 more , Tullio LD, Chiarella L, Myrov V, Zubler F, Roascio M, Cardinale F, Palva S, Palva JM, Tassi L, Nobili L, Arnulfo G, Wang SH
Epilepsia · 2026 Jun · PMID 41804706 · Full text
OBJECTIVE: Although slow waves in δ (.5-4 Hz) characterize non-rapid eye movement (NREM) sleep, in patients with sleep-related epilepsy, seizures most frequently emerge during NREM stage 2, known to be promoted by δ-band...
OBJECTIVE: Although slow waves in δ (.5-4 Hz) characterize non-rapid eye movement (NREM) sleep, in patients with sleep-related epilepsy, seizures most frequently emerge during NREM stage 2, known to be promoted by δ-band instability. Meanwhile, the epileptogenic zone (EZ) shows localized bistability in β-γ-band (15-200 Hz) neuronal oscillations, indicating a catastrophic shift toward seizure. We aim to clarify the mechanistic link between δ-band synchrony and β-γ-band bistability in epilepsy. METHODS: We studied a cohort of 14 patients with sleep hypermotor epilepsy (22.3 ± 10.8 years old, seven males). Seven- to 9-h stereoelectroencephalographic sleep recordings were segmented into 10-min uninterrupted, interictal N2 and N3 epochs, and phase synchrony, phase-amplitude coupling (PAC), and bistability were assessed. Canonical correlation was examined to answer whether PAC links δ phase to β-γ bistability. RESULTS: Compared to non-EZ, the EZ exhibited larger 15-200-Hz bistability along with stronger 2-8-Hz and 15-100-Hz synchrony throughout N2 and N3. Compared to N3, N2 showed stronger PAC between 2-30-Hz phases in the non-EZ and 5-150-Hz amplitudes in the EZ. Canonical correlations between δ phase modulated PAC, and both bistability and synchrony were identified during N2 (r = .86 and .82) and N3 (r = .84 and .80), with the strongest contributors being 2-4-Hz synchrony and bistability in 2-4-Hz and 15-200-Hz bands. Correlations between interictal spikes and canonical covariates of bistability and PAC (r = .62 for N2 and .56 for N3) validated their relevance to epileptogenicity. SIGNIFICANCE: δ-Band synchrony and β-γ-band bistability are not isolated epileptogenic mechanisms but likely act synergistically, playing a pivotal role in seizure generation through the coupling of δ phases and β-γ amplitudes across large networks, with significant contributions from nonepileptogenic tissues.
Sleep magnetoencephalography enhances detection and source imaging of seizures and fast oscillations in focal cortical dysplasia.
Heers M, Afnan J, Braun C … +11 more , Grova C, Altenmüller DM, Steinhoff BJ, Dümpelmann M, Demerath T, Urbach H, Ethofer S, Siegel M, Schulze-Bonhage A, Lerche H, Li Hegner Y
Epilepsia · 2026 Jun · PMID 41804684 · Full text
OBJECTIVE: Focal cortical dysplasia (FCD) causes drug-resistant epilepsy requiring presurgical evaluation. Invasive electroencephalographic (EEG) studies demonstrate that sleep modulates epileptic activity, including int...
OBJECTIVE: Focal cortical dysplasia (FCD) causes drug-resistant epilepsy requiring presurgical evaluation. Invasive electroencephalographic (EEG) studies demonstrate that sleep modulates epileptic activity, including interictal epileptiform discharges (IEDs), fast oscillations (FOs) in the beta (14-40 Hz) and gamma (40-80 Hz) frequency bands, and seizures. This study aimed to quantify sleep-associated changes in IEDs, FOs, and seizures in FCD patients using noninvasive magnetoencephalography (MEG). METHODS: Nineteen patients with FCD were prospectively recruited and underwent simultaneous MEG/EEG recordings lasting 89 ± 19 min during daytime sleep. Sleep stages were classified from the EEG. Beamformer source signals were computed from the MEG signal to enhance sensitivity for visual detection of IEDs, FOs in the beta and gamma frequency bands, and seizures. Magnetic source imaging (MSI) was performed using the Maximum Entropy on the Mean (MEM) method, which is particularly sensitive to the spatial extent of sources, enabling accurate localization of epileptic activity. RESULTS: N1 sleep was reached in 17 of 19 patients and N2 sleep in 14 of 19 patients. Compared to wakefulness, sleep recordings showed significantly higher rates of FOs and seizures (both p < .05), whereas IED rates showed nonsignificant trends. Ten patients demonstrated FOs or seizures, and 12 showed IEDs. MSI of IEDs demonstrated consistent accuracy across vigilance states, with median Euclidean distances of 12.74 mm (interquartile range [IQR] = 22.74) in wake and 8.34 mm (IQR = 27.58) in sleep, and no systematic amplitude or spatial extent changes. Wavelet-MEM enabled frequency-specific source imaging, with FOs and seizures localizing concordantly to FCD lesions in five of seven and seven of eight patients, respectively. SIGNIFICANCE: Daytime sleep MEG recordings are clinically feasible and significantly enhance the detection of seizures (37% of patients) and FOs compared to wakefulness. Sleep protocols enable noninvasive capture of ictal patterns-the gold standard for epileptogenic zone localization-alongside increased FO rates. These findings support incorporating sleep into standard MEG protocols for presurgical epilepsy evaluation.
Contralateral language network integration predicts and protects against naming decline after temporal lobe resection.
Nenning KH, Trimmel K, Bartha-Doering L … +6 more , Berger M, Koepp MJ, Langs G, Kasprian G, Duncan JS, Bonelli SB
Epilepsia · 2026 Jun · PMID 41804632 · Full text
OBJECTIVE: Anterior temporal lobe resection (ATLR) is an effective treatment for drug-resistant temporal lobe epilepsy (TLE) but carries a substantial risk of language impairment, particularly in naming. Understanding an...
OBJECTIVE: Anterior temporal lobe resection (ATLR) is an effective treatment for drug-resistant temporal lobe epilepsy (TLE) but carries a substantial risk of language impairment, particularly in naming. Understanding and predicting the impact of ATLR on language functions remains a major clinical challenge. METHODS: In this study, we used functional magnetic resonance imaging (fMRI) to investigate the short-term effects of ATLR on the organization of the functional language connectome with a focus on the role of the nondominant hemisphere. We studied 44 patients with TLE due to unilateral hippocampal sclerosis (24 left, 20 right) who underwent language fMRI and neuropsychological testing preoperatively and 4 months after ATLR. We examined functional connectivity changes pre- and postsurgery and their relationship with neuropsychological performance. RESULTS: ATLR induced widespread alterations in functional connectivity, with distinct ipsilateral disruptions and contralateral compensatory changes. Left ATLR reduced mainly interhemispheric temporal connectivity, whereas right ATLR primarily affected bilateral frontal connections. Postoperatively, left ATLR showed increased intrahemispheric frontotemporal connectivity, and right ATLR exhibited more widespread intra- and interhemispheric increases. In left TLE, better preoperative naming was associated with stronger connectivity of the right (nondominant) temporal lobe and between the left inferior frontal cortex and bilateral posterior hippocampi. Postoperatively, reduced right frontotemporal integration was linked to greater naming decline, underscoring a compensatory role of the nondominant hemisphere. Finally, a machine learning model using preoperative functional connectivity fingerprints outperformed demographic and clinical variables in predicting clinically significant naming decline following ATLR. SIGNIFICANCE: Our findings highlight the critical role of the right temporal lobe in supporting naming function after left ATLR and suggest that preoperative assessment of its connectivity may improve prediction of postoperative language outcomes.
Did the French pregnancy pictogram change antiseizure medication use during pregnancy?
Araujo M, Damase-Michel C, Denuelle M … +5 more , Boulogne S, Delteil L, Saucedo M, Deneux-Tharaux C, Lacroix I
Epilepsia · 2026 Jun · PMID 41804083 · Full text
OBJECTIVE: The aim of this study was to assess the impact of introducing a pregnancy pictogram on medication packaging on the prescription and dispensation of antiseizure medications and on the maternal and neonatal outc...
OBJECTIVE: The aim of this study was to assess the impact of introducing a pregnancy pictogram on medication packaging on the prescription and dispensation of antiseizure medications and on the maternal and neonatal outcomes for women exposed to these medications. METHODS: This is a national retrospective cohort study, based on the French National Health Data System, with a "before/after the introduction of the pictogram" design. Women aged between 15 and 55 years who had a pregnancy outcome between 2014 and 2017 ("before pictogram" period) and between 2018 and 2021 ("after pictogram" period) and who had received at least two antiseizure medication dispensations before their pregnancy were included. We compared the rates of antiseizure medication discontinuation and continuation during pregnancy, the average doses used, and maternal and neonatal outcomes between the two periods. RESULTS: The rate of women who had received at least two dispensations of a medication indicated for epilepsy before their pregnancy remained stable between the two periods (.7%). There was a significant decrease in valproic acid prescriptions (5.4% vs. 1.3%) during pregnancy and, conversely, an increase in lamotrigine (29.9% vs. 31.5%) and levetiracetam (10.9% vs. 14.5%) prescriptions. Prescriptions by specialists such as neurologists increased significantly (22.8% vs. 28%) between the two periods. There was an increase of more than 2.7% in the continuation of antiseizure medication (37.6% vs. 40.3%, p < .0001) and conversely a decrease in the rate of women who stopped their antiseizure treatment before or during pregnancy in the "after pictogram" period (59.4% vs. 56.7%, p < .0001). Rates of maternal and neonatal outcomes remained similar between the two periods. SIGNIFICANCE: The introduction of a pregnancy pictogram in France in 2017 was not associated with an increase in discontinuation of antiseizure medications, less adequate treatment, or poorer maternal or neonatal outcomes in pregnant women receiving these medications before pregnancy.
Response: Neuropsychological outcome in open resection and laser interstitial thermal therapy for mesial temporal lobe epilepsy: Meta-analysis and selective review.
Stavrogianni K, Tsalouchidou PE
Epilepsia · 2026 May · PMID 41804078 · Full text
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