Epilepsia[JOURNAL]
Sun
200 papers
When seizure counts are not seizures: Measurement error and its implications for epilepsy management and driving policy.
Cook MJ, Richardson MP, Schulze-Bonhage A
Epilepsia · 2026 Jun · PMID 42261993 · Publisher ↗
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New-onset refractory status epilepticus/febrile infection-related epilepsy syndrome centers of excellence: A framework for coordinated care, research, and improved outcomes.
Eschbach K, Fisher KS, Haider HA … +14 more , Casas D, Gaspard N, Gilmore EJ, Gofton T, Gopaul MT, Hirsch LJ, Muscal E, Riviello JJ, Sheikh ZB, Stredny CM, Taraschenko O, Wickström R, Wong N, Lai YC
Epilepsia · 2026 Jun · PMID 42257690 · Publisher ↗
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Compensatory rearrangement of parvalbumin interneuron voltage-gated sodium channel subunits in a mouse model of Dravet syndrome.
Dabrowski AK, Somarowthu A, Liebergall SR … +2 more , Lorenzo DN, Goldberg EM
Epilepsia · 2026 Jun · PMID 42257687 · Publisher ↗
Heterozygous loss-of-function variants in the gene SCN1A, which encodes the voltage-gated sodium channel (VGSC) pore-forming (α) subunit Na1.1, lead to a spectrum of neurological disease, including Dravet syndrome. Na1.1...
Heterozygous loss-of-function variants in the gene SCN1A, which encodes the voltage-gated sodium channel (VGSC) pore-forming (α) subunit Na1.1, lead to a spectrum of neurological disease, including Dravet syndrome. Na1.1 is prominently expressed at the proximal portion of the axon initial segment (AIS) of fast-spiking γ-aminobutyric acidergic parvalbumin-expressing inhibitory interneurons (PV+INs). In Dravet syndrome (Scn1a haploinsufficient) mice, action potential firing is impaired in PV+INs during postnatal development; however, in mature animals, PV+IN fast-firing frequency has recovered. We used detailed immunohistochemistry and microscopy to probe the mechanism of this functional recovery, investigating potential upregulation of other brain-expressed VGSC subunits at the PV+IN AIS. We found a specific upregulation of Na1.6 immunofluorescence at the AIS of PV+INs in adult (but not developing) Scn1a mice compared to wild type, with no upregulation of other brain-expressed subunits Na1.2 or Na1.3. These results demonstrate one mechanism through which epilepsy-related gene variants reorganize the developing brain and enact endogenous changes that may be at least partially compensatory.
Individual-specific resting-state networks predict language dominance in drug-resistant epilepsy.
Lim MJR, Zhang S, Pande S … +5 more , Xue A, Kong R, Zaghloul K, Inati S, Yeo BTT
Epilepsia · 2026 Jun · PMID 42257618 · Publisher ↗
OBJECTIVE: This study was undertaken to reliably estimate individual-specific resting-state cortical networks and determine whether language network topography can predict task-based language dominance in drug-resistant...
OBJECTIVE: This study was undertaken to reliably estimate individual-specific resting-state cortical networks and determine whether language network topography can predict task-based language dominance in drug-resistant epilepsy. METHODS: We utilized a multisession hierarchical Bayesian model (MS-HBM) trained on drug-resistant epilepsy patients to map high-quality individual-specific cortical networks in this population (n = 65) with only 6-24 min of resting-state functional magnetic resonance imaging (fMRI). We compared the quality of networks to MS-HBM models trained on healthy participants from the human connectome project (n = 40) and tested the generalizability of the model in an independent cohort of drug-resistant epilepsy participants (n = 26). Resting-state language network topography was then used to predict task-based language dominance. RESULTS: Ninety-one participants with drug-resistant epilepsy (National Institutes of Health, n = 65; University of Iowa, n = 26) were included: 61 (67.0%) temporal lobe epilepsy, 29 (31.9%) extratemporal lobe epilepsy, and one (1.1%) undetermined seizure onset zone. The mean age was 33.0 ± 11.4 years, and 50 (54.9%) were male. There were 40 healthy participants with a mean age of 29.0 ± 4.0 years, and 16 (40.0%) were male. MS-HBM trained on drug-resistant epilepsy estimated individual-specific networks that more accurately capture cortical functional organization than group-average networks or MS-HBM trained on healthy participants. The trained MS-HBM model generalized to an independent cohort of drug-resistant epilepsy participants with concurrent intracranial electrical stimulation and fMRI. Critically, cortical evoked fMRI activity aligned more closely with individual-specific networks than with group-average networks. Furthermore, individual-specific language network topography significantly predicted task-based language dominance, achieving high accuracy for left (area under the curve [AUC] = .82), bilateral (AUC = .72), and right (AUC = .83) dominance. SIGNIFICANCE: These results demonstrate that MS-HBM captures functionally meaningful network reorganization in drug-resistant epilepsy and enables accurate, individual-level prediction of language lateralization, with direct implications for presurgical functional mapping.
Cognitive and behavioral clinical outcome assessments in children with developmental and epileptic encephalopathies: Issues and instruments.
Correale C, Specchio N, Downs J … +7 more , Cross JH, Cappelletti S, Palacio-Navarro A, Geuens S, Valente K, Brunklaus A, Reilly C
Epilepsia · 2026 Jun · PMID 42246937 · Publisher ↗
Children with developmental and epileptic encephalopathies (DEEs) face cognitive and behavioral challenges that may have a greater impact than seizures on their quality of life (QoL). The need to assess these nonseizure...
Children with developmental and epileptic encephalopathies (DEEs) face cognitive and behavioral challenges that may have a greater impact than seizures on their quality of life (QoL). The need to assess these nonseizure outcomes for evaluating treatments is increasingly recognized. Advances in genomic technologies have transformed the diagnostic landscape of rare genetic epilepsies, including DEEs, opening new opportunities for precision medicine. There is also growing interest in drug repurposing, identifying well-tolerated medications for other indications for use in DEEs. Innovative trial designs and the systematic collection of prospective natural history data are essential, given the rarity and heterogeneity of DEEs. The selection of reliable, valid, and meaningful outcome measures of cognition and behavior is crucial for clinical trials and natural history studies. Commonly used tools for assessing cognition and adaptive behavior often exhibit floor effects and may fail to capture subtle, yet clinically significant, changes in functioning that are meaningful for children and their families. There is thus a need to explore a fuller range of clinical outcome assessments (COAs) and scoring methods that could be sensitive to change and suitable for use in rare disease populations. Assessing behavioral and emotional outcomes in children with DEEs is additionally challenging, as many assessment instruments have been developed and validated for use in children without intellectual disability. To fully realize the potential of precision medicine in the DEEs, a robust framework for outcomes assessment is required, one that incorporates sensitive, reliable, and meaningful COAs tailored to this population. Coordinated efforts to identify and adapt existing measures or develop new outcome tools will be crucial for advancing therapeutic strategies that genuinely improve QoL for children with DEEs. This article summarizes the issues faced when selecting outcome measures for DEE trials and reviews commonly used instruments for assessing cognition and behavior in children with DEEs.
Use of artificial intelligence in magnetic resonance imaging across the epileptic patient's journey: A meta-analysis of four clinical applications.
Chen J, Sahlas E, Zhou Y … +11 more , Chen N, Xie J, Wadia F, Caciagli L, Hadjinicolaou A, Weil AG, Dudley RW, Schrader DV, Bernasconi A, Bernasconi N, Bernhardt BC
Epilepsia · 2026 Jun · PMID 42246704 · Publisher ↗
OBJECTIVE: The application of artificial intelligence/machine learning (AI/ML) to magnetic resonance imaging (MRI) promises to enhance and support clinical decision-making in epilepsy. However, there currently lacks an a...
OBJECTIVE: The application of artificial intelligence/machine learning (AI/ML) to magnetic resonance imaging (MRI) promises to enhance and support clinical decision-making in epilepsy. However, there currently lacks an appropriate assessment of clinical utility and study rigor of current AI/ML-driven models that are targeted toward supporting decision-making within the clinical workup in epilepsy. METHODS: We systematically reviewed and examined the ability of current AI/ML-driven models in MRI across four main applications within the clinical workup(s) for epilepsy: (1) diagnosis, (2) temporal lobe epilepsy lateralization, (3) lesion (focal cortical dysplasia) localization, and (4) postsurgical outcome prediction. We additionally assessed the risk of bias for each study model. Studies that employed AI/ML classification models trained on any MRI modality or sequence type were selected for qualitative assessment; those reporting accuracy rates were subsequently included in the meta-analysis. RESULTS: Of 3227 searched articles, we identified 159 studies (n = 26 732 participants) for qualitative evaluation and 127 studies (n = 20 456) for inclusion in the meta-analysis. Our results reveal that AI/ML on MRI could accurately distinguish epilepsy patients from healthy controls (overall accuracy = .87, 95% confidence interval [CI] = .85-.89), lateralize temporal lobe epilepsy (.90, 95% CI = .87-.93), localize epileptogenic lesions (.82, 95% CI = .74-.87), and predict postsurgical seizure freedom (.83, 95% CI = .78-.87). However, systematic assessment indicated a very high risk of bias in the literature, suggestive of overly optimistic performance estimates. SIGNIFICANCE: Although our results support overall high accuracy of AI/ML models in epilepsy diagnostics and prognostics, the literature remains susceptible to bias in participant recruitment and validation methods. Furthermore, most models were limited by study architecture that demands strict adherence to nonstandard, highly specific data acquisition and processing protocols that cannot be easily deployed for clinical implementation. We encourage closer interdisciplinary collaboration between clinical and scientific groups to improve validation studies, and outline suggested recommendations for future study design, analysis, and reporting.
Interictal epileptiform discharges in calcified neurocysticercosis-associated epilepsy: An exploratory study.
Sanchez-Boluarte SS, Nuñez Del Prado LN, Chacon D … +6 more , Huamani M, Callupe-Luna B, Bustos JA, Tatum WO, Garcia HH, Cysticercosis Working Group in Peru
Epilepsia · 2026 Jun · PMID 42246626 · Publisher ↗
The objective of the study was to assess the frequency of interictal epileptiform discharges (IEDs) in calcified neurocysticercosis (NCC) and its relationship with calcification burden. Forty-nine patients with calcified...
The objective of the study was to assess the frequency of interictal epileptiform discharges (IEDs) in calcified neurocysticercosis (NCC) and its relationship with calcification burden. Forty-nine patients with calcified NCC (low-burden, 1-2 calcifications, n = 24; high-burden, ≥15 calcifications, n = 25) and seizure history underwent prolonged (8-h) electroencephalography (EEG), interpreted by epileptologists who were blinded to patient history and calcification category. Clinical seizure outcomes were also assessed. We found that IEDs occurred in 7 of 49 participants (14.3%), with no difference between low-burden (12.5%) and high-burden (16.0%) groups (p = 1.000). All IEDs (spikes and/or sharp waves) in the high-burden group (n = 4) were high-voltage (100-150 μV), whereas those in the low-burden group (n = 3) were low or medium voltage (20-70 μV). Among the participants who had IEDs, 5 (71.4%) had seizures in the last year, compared with 14 (33.3%) in the group without IEDs detected (p = 0.093). Among 19 participants with seizures in the last year, 5 were identified as having drug-resistant epilepsy (DRE). All five cases of DRE occurred in individuals with 15 or more calcifications (5/25, 20%, vs 0/24, p = 0.023). We conclude that IEDs occur frequently in individuals with calcified NCC. Although calcification burden itself was not associated with the presence of IEDs, drug-resistant cases and high-voltage IEDs were concentrated in the high-burden group, supporting the role of calcified parasites as epileptogenic foci.
Localized cortical morphometric and structural covariance differences in adolescents with functional/dissociative seizures.
Dhanik K, Arya A, Agarwal V … +1 more , Kumar U
Epilepsia · 2026 Jun · PMID 42237871 · Publisher ↗
OBJECTIVE: Functional/dissociative seizures (FDS) frequently emerge during adolescence. We examined whether adolescents with FDS show cross-sectional differences in cortical morphometry and structural covariance relative...
OBJECTIVE: Functional/dissociative seizures (FDS) frequently emerge during adolescence. We examined whether adolescents with FDS show cross-sectional differences in cortical morphometry and structural covariance relative to healthy controls. METHODS: High-resolution T1-weighted magnetic resonance imaging data were acquired from 150 adolescents (75 with FDS, 75 healthy controls) recruited between 2021 and 2024. Surface-based morphometry was used to derive cortical thickness, fractal dimension, gyrification index, and sulcal depth. Structural covariance networks were constructed for cortical thickness and fractal dimension across 68 cortical regions from the Desikan-Killiany atlas. Regional analyses were corrected for false discovery rate, and global graph metrics were summarized as area under the curve across a predefined sparsity range with permutation testing. A follow-up region of interest (ROI)-wise analysis additionally included education as a covariate. RESULTS: Adolescents with FDS showed distributed differences involving frontal, insular, cingulate, temporal, parietal, and posterior associative cortices. Strongest effects included increased cortical thickness in the left pars opercularis (t = 3.485, corrected p = .000341, Hedges g = .57), reduced sulcal depth in the left precentral cortex (t = -3.683, corrected p = .000115, g = -.60), and reduced gyrification in the right insula (t = -3.167, corrected p = .000968, g = -.52). Fractal dimension (FD) covariance showed broader descriptive between-group divergence than cortical thickness (CT) covariance. CT-FD consensus analysis identified convergent covariance differences involving frontoparietal, cingulate, and occipitoparietal regions. After education adjustment, no cortical thickness ROI survived false discovery rate correction, whereas six fractal dimension ROIs remained significant: left medial orbitofrontal, left precentral, left banks of the superior temporal sulcus, right rostral middle frontal, left cuneus, and right caudal anterior cingulate cortices (t = -3.6755 to 3.1502, q = .0126-.0487). Global graph analysis did not detect robust differences. SIGNIFICANCE: Adolescent FDS are associated with regional cortical morphometric alterations and modality-specific structural covariance differences, whereas robust differences in global structural covariance topology were not observed.
Comparison of volume- and surface-based magnetic resonance imaging morphometry algorithms in the detection of focal cortical dysplasia.
Bücheler L, Reisert M, Demerath T … +15 more , Mayer F, Moeller C, Reß J, Hegner YL, Altenmüller DM, Antonio-Arce VS, Scheiwe C, Shah M, Beck J, Doostkam S, Bast T, Steinhoff BJ, Schulze-Bonhage A, Urbach H, Heers M
Epilepsia · 2026 Jun · PMID 42233975 · Publisher ↗
OBJECTIVE: Detection of focal cortical dysplasia (FCD) remains a major challenge in presurgical epilepsy diagnostics. Magnetic resonance imaging (MRI) morphometry increasingly improves lesion detection and postsurgical o...
OBJECTIVE: Detection of focal cortical dysplasia (FCD) remains a major challenge in presurgical epilepsy diagnostics. Magnetic resonance imaging (MRI) morphometry increasingly improves lesion detection and postsurgical outcomes. The volume-based Morphometric Analysis Program, version 2018 (MAP18) with integrated artificial neural network and surface-based Multi-centre Epilepsy Lesion Detection (MELD; MELD Graph) MRI morphometry algorithms have demonstrated diagnostic utility, but their performance has not been directly compared within a single cohort of surgically treated patients with histopathologically confirmed FCD. METHODS: We retrospectively analyzed 3-T MRIs of 32 FCD patients who underwent epilepsy surgery. MAP18 was applied to MP2RAGE (magnetization-prepared 2 rapid gradient echo) sequences and MELD to T1MPRAGE (magnetization-prepared rapid gradient echo) and three-dimensional FLAIR (fluid-attenuated inversion recovery) sequences. Binary lesion masks served as ground truth for evaluating detection accuracy, precision, and recall at cluster and voxel levels. Clinical correlation analysis assessed spatial concordance with seizure onset zone (SOZ) and irritative zone (IZ) from video-electroencephalography (EEG) and postoperative outcome. RESULTS: The cohort included 34 histopathologically proven FCD lesions (91.2% FCD II, 5.8% mild malformation of cortical development, 2.9% unspecified). MELD identified 32 of 34 lesions (94.1%), and MAP18 identified 33 of 34 lesions (97.1%), with concordance in 32 of 34 lesions (94.1%). At the cluster level, MELD showed significantly higher precision (p < .001) and fewer false positive clusters per patient (median 0 vs. 3, p < .001). Voxelwise analysis revealed that MELD demonstrated significantly higher precision than MAP18 (.42 vs. .13, p < .0001) and recall (.44 vs. .23, p < .01). Lobar concordance with SOZ reached 90.6% and with IZ reached 87.5%. Among invasive EEG patients, overlap with SOZ and IZ was 100%. Seizure freedom (Engel I) was achieved in 87.5% of patients. SIGNIFICANCE: Under standardized high-resolution 3-T MRI, both algorithms achieved high detection rates with strong concordance. Combined application may enhance presurgical lesion detection, with results limited to surgically treated patients.
Responsive stimulation of the thalamus for idiopathic generalized epilepsy: Results of the randomized controlled NAUTILUS trial through 18 months.
Uysal U, Landazuri P, Burdette DE … +45 more , Patra S, Crudele AN, Englot D, Gavvala JR, Pati S, Kaye LC, Ojemann S, Barnett D, Neimat J, Palade AE, Rahimpour S, Arain AA, Richardson RM, Cash SS, Salanova V, Urban A, Welch WP, Van Gompel JJ, Starnes K, Spencer D, Ernst LD, Amin U, Rivera-Cruz A, Dugan P, Fajardo M, Lallas M, Jobst BC, Odom N, Roland JL, Willie JT, Sheth SA, Goldman AM, Skidmore CT, Wu C, Drees C, Parker J, Ganguly TM, Szaflarski J, Ghatan S, Johnson L, Norman J, Wingeier B, Seale CG, Morrell MJ, Nautilus Study Group
Epilepsia · 2026 Jun · PMID 42233958 · Publisher ↗
OBJECTIVE: This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug-resistant idiopathic generalized epilepsy (IGE) with generalized tonic-cloni...
OBJECTIVE: This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug-resistant idiopathic generalized epilepsy (IGE) with generalized tonic-clonic seizures (GTCSs). METHODS: NAUTILUS is a prospective, multicenter, single-blind, randomized sham-controlled pivotal trial. Patients were ≥12 years of age with drug-resistant IGE and ≥2 GTCSs over a 3-month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open-label active stimulation. The primary safety endpoint was the serious adverse device-related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time-to-second-GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). RESULTS: Eighty-seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed-effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen-month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS-free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. SIGNIFICANCE: NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much-needed option for drug-resistant IGE.
Assessment of the utility of optically pumped magnetometer magnetoencephalography in preoperative localization of refractory epilepsy: A prospective study.
Shen Y, You C, Zhang Y … +17 more , Ji N, Zhao X, Zhang P, Huang S, Kang H, Liu X, Peng Y, Sun C, Yan B, Zhang Y, Zhu S, Zhu W, Lei T, Tang Z, Ding M, Hu F, Shu K
Epilepsia · 2026 Jun · PMID 42227984 · Publisher ↗
OBJECTIVE: Precise localization of the epileptogenic zone (EZ) is crucial for epilepsy surgery success. Optically pumped magnetometer magnetoencephalography (OPM-MEG) is a promising noninvasive technique requiring rigoro...
OBJECTIVE: Precise localization of the epileptogenic zone (EZ) is crucial for epilepsy surgery success. Optically pumped magnetometer magnetoencephalography (OPM-MEG) is a promising noninvasive technique requiring rigorous clinical validation. METHODS: In this prospective diagnostic study, 68 patients with refractory epilepsy underwent 90-min interictal OPM-MEG. Dipoles were fitted to interictal epileptiform discharges for localization. The primary objective was to evaluate the spatial concordance between OPM-MEG and the EZ defined by intracranial electroencephalography (iEEG; stereo-EEG or electrocorticography), assessed at the sublobar level using Gwet AC1. The secondary objective was to evaluate the diagnostic value of OPM-MEG for surgical outcome. This analysis included 51 patients who underwent curative intervention (resection or thermocoagulation). The reference standard was a composite of the treated brain region and seizure freedom (International League Against Epilepsy [ILAE] class 1 or Engel class I) at ≥12-month follow-up, from which sensitivity, specificity, and diagnostic odds ratio (OR) were calculated. RESULTS: OPM-MEG showed almost perfect agreement with iEEG-based EZ localization overall (AC1 = .885, concordance rate = 90.0%), with substantial agreement in temporal (80.1%, AC1 = .723) and almost perfect agreement in extratemporal regions (92.0%, AC1 = .926). The Euclidean centroid distance between OPM-MEG and iEEG localizations was significantly shorter in concordant versus discordant cases. In the assessment of diagnostic value, OPM-MEG demonstrated a sensitivity of 85.7% and specificity of 65.2% (OR = 11.25) under ILAE criteria, and a sensitivity of 73.0% and specificity of 64.3% (OR = 4.86) under Engel criteria. SIGNIFICANCE: OPM-MEG demonstrates high concordance with iEEG for EZ localization and provides robust diagnostic value for predicting postoperative seizure freedom, supporting its utility in the presurgical evaluation of refractory epilepsy.
Pediatric epilepsy surgery: Global survey of referral and presurgical evaluation practices.
Ramantani G, Cross JH, Cserpan D … +44 more , Ahemad E, Aparicio J, Arzimanoglou A, Barba C, Bingaman W, Braun K, Burman RJ, Butler J, Cai L, Cao D, Caraballo R, Chipaux-Raffo M, Cloppenborg T, Cukiert A, Cukiert CM, Dal S, Englot D, Enright N, Fallah A, Ferrand Sorbets S, Feucht M, Gill D, Guio Mahecha L, Hadjinicolaou A, Hallböök T, Harvey AS, Holthausen H, Jiang Y, Kannan L, Katlowitz KA, Kotulska-Jóźwiak K, Kudr M, Lallas M, Valappil AMN, Patil SB, Pieper T, Specchio N, Tripathi M, Vendegh L, Weiner H, Wilmshurst J, Smith ML, Wirrell E, ILAE Pediatric Epilepsy Surgery Task Force and Study Group
Epilepsia · 2026 Jun · PMID 42227967 · Publisher ↗
OBJECTIVE: Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy S...
OBJECTIVE: Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Task Force study provides an updated overview of current trends and regional differences. METHODS: Group-level data were collected from 61 epilepsy surgery programs (49 pediatric-only) across 29 countries and six continents, identified through ILAE networks, and included all children and adolescents treated in 2023 who underwent presurgical evaluation/epilepsy surgery. RESULTS: Group-level data were available for 2427 patients. Mean age at surgery was 9.1 ± 4.9 years; mean epilepsy duration was 5.3. At surgery, 3.2% were <1 year old (highest in Oceania: 5.1%), and 6.1% were nonpharmacoresistant (highest in Europe: 15.0%). Prior neurosurgery was reported in 14.2% (highest in North America: 28.8%), including 8.0% resections (6.1% for epilepsy, 1.5% for tumors; highest in Oceania: 16.5%), 2.3% disconnections (1.3% corpus callosotomy; highest in South America: 4.7%), and 4.2% neuromodulation (3.7% vagal nerve stimulation, .2% responsive neurostimulation, one deep brain stimulation; highest in North America: 12.2%). Developmental and epileptic encephalopathies (DEEs) at surgery included Lennox-Gastaut syndrome (7.4%), infantile epileptic spasms syndrome (5.1%), and DEE with spike-wave activation in sleep (1.5%). Presurgical investigations included fluorodeoxyglucose positron emission tomography (52.6%; highest in Oceania: 79.7%), genetic testing (46.8%; highest in Asia: 54.3%), magnetic resonance imaging (MRI) postprocessing (32.4%; highest in South America: 53.0%), functional MRI (fMRI; 15.2%; highest in North America: 40.3%), magnetoencephalography (11.9%; highest in North America: 39.3%), single photon emission computed tomography (9.6%; highest in North America: 22.2%), high-density electroencephalography (EEG; 1.9%; highest in Europe: 4.7%), source localization (1.6%; highest in Oceania: 7.6%), Wada test (1.2%; highest in North America: 3.5%), and EEG-fMRI (.5%; highest in Europe: 1.1%). SIGNIFICANCE: Despite some early surgeries, including in infancy and before pharmacoresistance, mean epilepsy duration before surgery remains >5 years. Reoperations are common, with resection more frequent than neuromodulation. Genetic testing in nearly half of patients reflects its growing relevance, and the high rate of DEEs underscores the complexity of surgical candidates.
Dynamic limbic-executive decoupling underpins the reciprocal link between drug-resistant state and depression in temporal lobe epilepsy.
Wu Z, Tang H, Huang L … +10 more , Gao Y, Wang M, Chen A, Liu M, Cao H, Caciagli L, Gong Y, Hu J, Yi X, He X
Epilepsia · 2026 Jun · PMID 42227961 · Publisher ↗
OBJECTIVE: Depression is the most common psychiatric comorbidity in temporal lobe epilepsy. It is not merely a psychological reaction to seizures; accumulating evidence supports a bidirectional relationship in which mood...
OBJECTIVE: Depression is the most common psychiatric comorbidity in temporal lobe epilepsy. It is not merely a psychological reaction to seizures; accumulating evidence supports a bidirectional relationship in which mood dysregulation may also precede drug resistance. Here, we tested whether dynamic limbic-executive integration provides an in vivo circuit-level substrate for this reciprocity. METHODS: We cross-sectionally studied 82 patients with temporal lobe epilepsy (33 drug-resistant, 49 drug-responsive) and 50 healthy controls. The drug-resistant state was defined according to International League Against Epilepsy (ILAE) criteria (failure of two appropriate and tolerated anti-seizure medication regimens), and depression severity was indexed by Self-Rating Depression Scale scores. Using resting-state functional magnetic resonance imaging (rs-fMRI), we quantified time-varying large-scale network coupling to characterize limbic interactions with the broader connectome. We then identified specific patterns of limbic disintegration and tested their clinical relevance with mediation models, asking whether limbic integration with executive systems statistically linked drug-resistant state and depression severity bidirectionally. Finally, we spatially correlated network effects with normative positron emission tomography (PET)-derived neurotransmitter receptor/transporter maps and Allen Human Brain Atlas gene-expression profiles, followed by pathway enrichment analyses. RESULTS: The drug-resistant state was characterized by dynamic decoupling of the limbic network from dorsal attention and frontoparietal systems. Reduced limbic-dorsal attention integration tracked depression severity and statistically mediated both the pathway from the drug-resistant state to depression (indirect = 2.18, 95% confidence interval [CI] = 0.20-4.54) and the reverse pathway from depression to the drug-resistant state (indirect = 0.022, 95% CI = 0.006-0.049). The spatial signature of limbic-executive disintegration co-localized with higher serotonin (5-HT) 1B receptor (5-HT1B) and lower dopamine D2 receptor distributions and was transcriptomically enriched for cellular stress adaptation and cell-fate pathways, including translation reinitiation, telomerase activity, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic signaling. SIGNIFICANCE: These convergent multi-scale results propose a dynamic limbic-executive disintegration model of the reciprocity between seizure intractability and depression. Our findings reframe comorbidity as coupled systems-level dysfunction and motivate integrated stratification and target prioritization for dual-burden-focused neuromodulatory intervention.
Hippocampal malformation in Dravet syndrome.
Okutoyi NE, Maru V, Nauen DW
Epilepsia · 2026 Jun · PMID 42227922 · Publisher ↗
In a child with a mutation in SCN1A, hippocampus demonstrates abnormal neuronal architecture. This finding and review of the literature suggest a possible role for the channel in brain formation.
In a child with a mutation in SCN1A, hippocampus demonstrates abnormal neuronal architecture. This finding and review of the literature suggest a possible role for the channel in brain formation.
High-frequency oscillations after acute hemorrhagic traumatic brain injury: insights into posttraumatic epilepsy development.
Kriukova K, Li L, Staba RJ … +11 more , Boswell M, Asifriyaz T, Thomas R, Gugger JJ, Shamas M, Diaz-Arrastia R, Buitrago Blanco M, Engel J, Vespa PM, Duncan D, EpiBios4Rx investigators
Epilepsia · 2026 Jun · PMID 42227921 · Publisher ↗
OBJECTIVE: The development of posttraumatic epilepsy after traumatic brain injury (TBI) is potentially identifiable by measuring biomarkers of epileptogenesis, namely pathological high-frequency oscillations (pHFOs). pHF...
OBJECTIVE: The development of posttraumatic epilepsy after traumatic brain injury (TBI) is potentially identifiable by measuring biomarkers of epileptogenesis, namely pathological high-frequency oscillations (pHFOs). pHFOs are promising candidates, but it remains uncertain whether they can be detected early after TBI in clinical settings. This study was undertaken to determine the incidence and location of pHFOs as recorded from scalp and intracranial electroencephalography (EEG) during the first week after acute TBI and to determine the association of pHFOs with late posttraumatic seizures (PTS). METHODS: We analyzed continuous EEG from 35 TBI patients with acute hemorrhagic TBI (Glasgow Coma Scale = 3-13) enrolled in the multicenter EpiBioS4Rx cohort. Automated pHFO detection was followed by independent experts' verification. The rate of two types of pHFO ripples (70-250 Hz) and fast ripples (250-500 Hz) were computed using scalp and intracranial EEG. Firth logistic regression models estimated associations between pHFOs rates and late PTS occurrence. RESULTS: 16 of 35 patients (45.7%) developed late PTS. Verified scalp ripples were observed in 17 patients (48.6%), whereas no fast ripples were confirmed on expert review. Ripple activity was most frequent over frontal regions (13/17, 76.5%, p = .049, 95% confidence interval [CI] = .50-.93) and similarly frequent in perihemorrhagic locations (13/17, 76.5%, p = .049, 95% CI = .50-.93). Among 10 patients with intracranial EEG, verified ripples occurred in five (50%), including two of two with pericontusional strip electrodes. SIGNIFICANCE: In critically ill patients with acute hemorrhagic TBI monitored in the intensive care unit, both scalp and intracranial EEG can detect pHFOs within the first week after injury, demonstrating the technical feasibility of capturing these signals in a real-world clinical setting. Verified pHFOs were most frequently observed over frontal and perihemorrhagic regions, consistent with early perilesional hyperexcitability. pHFOs appear to be mechanistically grounded markers of perilesional hyperexcitability. Standardized, high-sampling EEG studies with targeted pericontusional coverage are needed to establish prognostic performance for late PTS.
Add-on treatment with vinpocetine reduces seizure frequency and improves comorbidities in patients with loss-of-function γ-aminobutyric acid type A receptor variants.
Gjerulfsen CE, Liao VWY, Mieszczanek TS … +13 more , Jakobsen AV, Gardella E, Olofsson K, Nikanorova M, Bayat A, Ortiz S, Weckhuysen S, Landmark CJ, Devinsky O, Chebib M, Ahring PK, Rubboli G, Møller RS
Epilepsia · 2026 Jun · PMID 42227896 · Publisher ↗
OBJECTIVE: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss-of-function (LoF) variants in γ-aminobutyric acid t...
OBJECTIVE: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss-of-function (LoF) variants in γ-aminobutyric acid type A (GABA) receptor genes. As a positive allosteric modulator of GABA receptors, case reports suggest that vinpocetine can reduce epileptiform activity and seizure frequency, while improving cognitive function in patients with GABA receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS: Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS: Nine patients harboring eight GABA receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE: Adjunctive vinpocetine shows promise as a targeted therapy for patients with GABA receptor LoF variants, decreasing seizure frequency and positively impacting nonseizure factors, with only mild AEs reported. Vinpocetine may be a safe and effective therapy for patients with GABA receptor-related epilepsies, which should be investigated further in future N-of-1 trials.
Region-dependent differences in tonic inhibition underlie epileptic features in Angelman syndrome model mice.
Watanabe M, Goto T, Miyoshi R … +11 more , Nakakubo S, Hiramatsu Y, Nakajima M, Ueda Y, Shiraishi H, Manabe A, Mondal P, Sharmin D, Poe MM, Cook JM, Egawa K
Epilepsia · 2026 Jun · PMID 42227760 · Publisher ↗
OBJECTIVE: Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Epilepsy and abnormal electroencephalographic (EEG) rhythms are key features, but thei...
OBJECTIVE: Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Epilepsy and abnormal electroencephalographic (EEG) rhythms are key features, but their mechanisms and treatment remain unclear. Previous work showed that extrasynaptic γ-aminobutyric acid type A (GABA) receptor-mediated tonic inhibition is reduced in cerebellar granule cells of AS model mice, contributing to motor deficits. Here, we evaluated tonic inhibition across brain regions and tested whether its dysregulation drives epilepsy, EEG abnormalities, and behavioral deficits in AS. METHODS: Tonic inhibition was measured in principal neurons of the neocortex, hippocampus, and thalamus in maternal Ube3a knockout mice. We examined the effects of MP-III-022, an α5-containing GABA receptor-selective positive allosteric modulator, and gaboxadol, a δ-containing GABA receptor agonist, on EEG, seizure threshold, and anxiety-like behavior. RESULTS: Tonic inhibition was reduced in cortical layer 5 and hippocampal CA1 pyramidal neurons but preserved in thalamic relay neurons. This reduction correlated with elevated GAT1 expression in the cortex and hippocampus but not the thalamus. MP-III-022 reduced abnormal slow-wave EEG activity, increased seizure thresholds, and improved anxiety-like behavior. In contrast, gaboxadol enhanced slow-wave activity and lowered seizure thresholds. SIGNIFICANCE: Deficits in tonic inhibition in AS mice are region-specific. These region-dependent differences in tonic inhibition, rather than a global loss, likely underlie EEG abnormalities and heightened seizure susceptibility. α5-containing GABA receptors may offer a promising therapeutic target for adjunctive AS treatment.
Decoding polymorphous low-grade neuroepithelial tumor of the young (PLNTY): Electroclinical features and molecular signatures in epilepsy surgery candidates.
Didato G, Marucci G, Pastori C … +18 more , Doniselli FM, Deleo F, Moscatelli M, Rizzi M, Paterra R, Freri E, Del Sole A, Esposito S, Patanè M, Parente A, Pollo B, Di Giacomo R, Ferrario R, Stabile A, Berlendis A, Silvani A, de Curtis M, Anghileri E
Epilepsia · 2026 Jun · PMID 42227712 · Publisher ↗
OBJECTIVES: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) was recognized as a new histologic entity in the 2021 World Health Organization (WHO) classification of central nervous system tumors. It repr...
OBJECTIVES: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) was recognized as a new histologic entity in the 2021 World Health Organization (WHO) classification of central nervous system tumors. It represents a distinct epileptogenic tumor, with about 80 cases reported to date across all age groups. The aim of this study is to describe the features of a cohort of PLNTY patients with a multimodal approach. METHODS: Patients diagnosed with PLNTY from 2014 to 2023 at our Institute were retrospectively reviewed to collect clinical, EEG, neuroimaging, histopathological, and molecular data. RESULTS: We identified 14 surgically treated patients (median age 21.5 years, range 12-46), with drug-resistant seizures in 78.6%. Seizure onset preceded surgery by a median period of 4 years (range .5-27). Bilateral interictal epileptiform EEG discharges and/or mislateralizing/mislocalizing ictal EEG discharge and/or semiological signs were found in 85.7% of patients, compared to 19.2% in a group of 26 non-PLNTY low-grade epilepsy-associated tumors (LEATs) (p < .001). All PLNTYs were supratentorial solid or solid-cystic cortical mass, involving the temporal (n = 8), temporo-occipital (n = 4), frontal (n = 1), or parietal lobe (n = 1). They featured an infiltrative growth pattern, oligodendroglioma-like cells, strong and often diffuse CD34 immunostaining, and frequent calcifications. Focal cortical dysplasia was associated in 14.3% of cases. Proliferation activity (MIB-1 labeling index) was very low (1%), except for one case (3%). BRAFV600E was found in 50% (n = 6/12) of cases, fibroblast growth factor receptor 3 (FGFR3) protein expression in 7 cases, 30.7% (n = 4/13) carried FGFR3 fusion. No fibroblast growth factor receptor 2 (FGFR2) fusion (n = 0/6) was identified. Postsurgical seizure outcome was excellent (Engel class I) in all cases. SIGNIFICANCE: This study confirms that, despite its name, PLNTY is not limited to pediatric patients. Findings underscore the highly epileptogenic nature of PLNTY and its recognizable electroclinical features, potentially related to its distinctive neuropathology. Most PLNTYs show mitogen-activated protein kinase (MAPK) pathway activating alterations, demonstrated by BRAFV600E mutation and FGFR3 fusion.
Neurodevelopmental trajectories and clinical outcomes following ultra-early epilepsy surgery in infants: A matched cohort study.
Zhao HQ, Wang FP, Wang YY … +11 more , Zhang Q, Xu BJ, Liu YO, Pan L, Zhong HJ, Yao YT, Zhang JY, Cao DZ, Zhou WJ, Yao Y, Zou LP
Epilepsia · 2026 Jun · PMID 42227679 · Publisher ↗
OBJECTIVE: Surgery is increasingly recognized as an effective treatment for drug-resistant epilepsy in children but remains under-utilized. Evidence on its safety and benefits in infants 6 months or younger is very limit...
OBJECTIVE: Surgery is increasingly recognized as an effective treatment for drug-resistant epilepsy in children but remains under-utilized. Evidence on its safety and benefits in infants 6 months or younger is very limited, leaving early surgical decision-making insufficiently supported. METHODS: A matched cohort study included 23 infants with age-dependent epileptic encephalopathy (ADEE) and structural brain abnormalities who underwent epilepsy surgery within 6 months and 115 matched non-surgical controls. Neurodevelopment was assessed using developmental quotient (DQ). Multivariable linear regression and propensity score matching (PSM) were used to examine the association between surgery and neurodevelopmental outcomes, whereas surgical safety and long-term seizure control were also evaluated. RESULTS: Among the 23 surgical infants, the median age at seizure onset was .27 months, and all had congenital brain malformations. Hemimegalencephaly was the most common etiology (n = 13). The mean age at surgery was 3.5 months. Hemispherotomy was the most commonly performed surgical procedure (n = 14). No perioperative death or permanent severe complications were observed. Four (17.4%) infants developed transient unilateral limb weakness and 13.6% had postoperative hydrocephalus. The rate of Engel class Ia was 82.6% at 1 year postoperatively and 78.2% at a mean follow-up of 44.4 months. At last follow-up, 69.6% of the infants had discontinued anti-seizure medications (ASMs). The DQ scores of the control group showed a continuous decline over time, whereas the surgical group showed a more favorable trajectory. Multivariable linear regression analysis revealed that surgery was significantly associated with a higher DQ (β = 30.2, 95% confidence interval [CI]: 19.5-40.9; p < .001). After 1:1 PSM to control confounding variables, the surgical group had significantly higher DQ scores than the control group in all five neurodevelopmental domains (p < .05). SIGNIFICANCE: Epilepsy surgery performed by an experienced team is safe and feasible for very young infants due to congenital brain malformations, without severe perioperative complications. It provides good long-term seizure control, supports ASM withdrawal, and may protect brain development, potentially stabilizing or even improving neurodevelopment in some infants.
Presurgical magnetoencephalography-derived network control metrics distinguish successful hippocampal resection vs sparing in temporal lobe epilepsy.
Seshadri Np G, Kumar H, John NS … +4 more , Alexopoulos AV, Burgess RC, Murakami H, Krishnan B
Epilepsia · 2026 Jun · PMID 42227651 · Publisher ↗
OBJECTIVE: Surgical decision-making in temporal lobe epilepsy (TLE) faces a critical challenge in determining whether the hippocampus can be safely spared during anterior temporal resection, particularly when surgery inv...
OBJECTIVE: Surgical decision-making in temporal lobe epilepsy (TLE) faces a critical challenge in determining whether the hippocampus can be safely spared during anterior temporal resection, particularly when surgery involves the language-dominant hemisphere. We investigated whether presurgical network control metrics derived from magnetoencephalography (MEG) can differentiate patients who achieved seizure freedom with hippocampal resection (HR) from those who achieved seizure freedom with hippocampal sparing (HS). METHODS: We analyzed presurgical spike-free interictal MEG in 25 TLE patients with seizure freedom after anterior temporal resection (19 with hippocampal resection, 6 with sparing). Functional networks constructed from MEG data were partitioned into communities using a Louvain-based consensus clustering algorithm. Within identified hippocampal-related communities from each patient, we applied control centrality analysis to quantify the influence of each node on community synchronizability. Group differences were assessed using Fisher's exact tests with false discovery rate (FDR) correction applied within each frequency band and hemisphere. Leave-one-subject-out (LOSO) sensitivity analysis assessed the robustness of findings to individual subjects. RESULTS: After FDR correction, synchronization of the contralateral anterior superior temporal sulcus (STS) in the HS group at beta band emerged as the primary finding (p = .001, q = .02). This finding showed 100% stability in LOSO and persisted in a subgroup analysis excluding patients with hippocampal seizure onset (p = .004). At p < .05, additional region-frequency differences formed a coherent anatomic pattern: the HR group showed higher synchronization fractions within ipsilateral limbic structures, whereas the HS group showed higher synchronization in the ipsilateral posterior hippocampus and contralateral temporal regions with 100% LOSO stability. SIGNIFICANCE: Presurgical MEG-based network control analysis identified contralateral anterior STS synchronization as a candidate biomarker for hippocampal sparing eligibility in TLE. This proof-of-concept finding warrants prospective validation as potential tools to support individualized surgical planning beyond localization-based approaches.
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