Epilepsia Open

ObjectiveVagus nerve stimulation (VNS) is an established neuromodulation therapy used in the management of drug-resistant epilepsy (DRE), or when other intracranial surgical modalities have not reduced seizure burden. We evaluated whether prior intracranial surgery for epilepsy influences safety and effectiveness outcomes with adjunctive VNS, using real-world data from the CORE-VNS study. MethodsCORE-VNS (NCT03529045), a prospective, multicenter, international observational study, was designed to collect data on seizure and non-seizure outcomes in patients with DRE treated with VNS. Participants were identified as having or not having undergone prior intracranial brain surgery for epilepsy (ICSE) and received an initial VNS implant. Baseline seizure frequency data and patient-reported outcome measures were collected at 3, 6, 12, 24, and 36 months. This analysis compared the baseline data for VNS therapy and safety outcomes at 36 months. ResultsAmong 531 participants implanted with VNS, prior ICSE was performed in 84. Median percentage seizure reductions at 36 months for all seizures (76.6% and 76.3%), all focal seizures (83.3% and 71.8%), and all generalized seizures (77.8% and 76.2%) were found to be similar between those without and with a history of ICSE, respectively. The 50% responder rate for all seizures reported at baseline was similar, 64.8% and 61.8%, in both groups and complete seizure freedom was reported by 17.9% and 8.8%, respectively. Implant-related adverse events (AE) and serious AE rates were similar between groups. ConclusionVNS was associated with clinically meaningful seizure reductions and showed a consistent safety profile irrespective of the history of ICSE. Prior ICSE should not be a contraindication to the consideration of VNS.

Purpose: DNM1-related disorder is a rare developmental and epileptic encephalopathy. The current understanding of the clinical spectrum is based on sparse patient descriptions. Here, we compile the largest DNM1 cohort to date, to characterize the genotypic and phenotypic landscape of the disorder. Methods: Phenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework. Results: Disease-causing variants in DNM1 cluster in mutational hotspots within the gene, which achieve Strong and Moderate evidence for pathogenicity based on ACMG guidelines. The overall DNM1 phenotype was homogeneous compared to other genetic epilepsy conditions: SCN2A, SCN8A, STXBP1, and SYNGAP1. The p.R237W (n=15) variant was associated with bilateral tonic-clonic seizures, infantile spasms, and dystonia. The p.I398_R399insCR (n=14) variant was associated with severe hypotonia, profound global delay, and cortical visual impairment. Five individuals with homozygous loss-of-function variants were clinically similar to dominant-negative DNM1-related disorder, but microcephaly and brain MRI abnormalities were more common in this group. Conclusion: A harmonized cohort of individuals with DNM1-related disorder was analyzed to define mutational hotspots and reveal novel genotype-phenotype correlations. Due to the homogeneous phenotype, disease mechanism, and high proportion of recurrent variants, DNM1 represents an attractive target for targeted therapy development.

BackgroundGenetic testing is increasingly used in presurgical evaluation, but the yield of resection across germline genetic epilepsies remains uncertain. MethodsWe conducted a systematic review of MEDLINE (PubMed) and Scopus and added cases from three institutional cohorts and the Pediatric Epilepsy Research Consortium (PERC) databases, including individuals with pathogenic/likely pathogenic germline variants besides tuberous sclerosis and neurofibromatosis who underwent resection or laser ablation. Etiologies were grouped into biologically informed categories (GATORopathies, vascular, overgrowth, CNVs, channelopathies, synaptopathies, other). Primary outcome was seizure freedom (Engel I) at last follow-up. Group comparisons used Fishers exact and Kruskal-Wallis tests (=0.05; Bonferroni when applicable). Prespecified sensitivity analyses stratified by lesional status, excluded GATORopathies, and restricted to literature-only cases. ResultsWe included 223 literature cases (64 studies), 35 institutional cases, and 11 PERC cases (n=269). Median follow-up was 24 months (IQR 12-48.0). Seizure freedom was achieved in: vascular disorders 14/19 (73.6%), GATORopathies 79/120 (67.5%), CNVs 18/31 (66.7%), overgrowth 7/13 (53.8%), other 16/25 (41.7%), channelopathies 13/43 (33.3%), and synaptopathies 4/18 (22.2%) (overall p<0.001). Among cases with known imaging, 208/253 (82.2%) had epileptogenic MRI lesions, including 64% of channelopathies and 80% of the synaptopathies. In univariate contrasts (each category vs all others), odds of seizure freedom were higher for vascular disorders (2.66-fold, 95% CI 0.87-9.72) and GATORopathies (2.46-fold, 95% CI 1.46-4.18), and lower for synaptopathies ([~]4.2-fold lower, OR 0.24, 95% CI 0.05- 0.78) and channelopathies ([~]4.5-fold lower, OR 0.22, 95% CI 0.09-0.48). Direction and magnitude were consistent across prespecified sensitivity analyses (lesional-only, literature-only, exclusion of GATORopathies). ConclusionsResective surgeries can be effective in germline genetic epilepsies, but outcomes vary by pathway. Disorders with discrete, lesional substrates (GATORopathies, vascular) show the highest likelihood of seizure freedom, whereas channelopathies and synaptopathies, despite the presence of MRI lesions, have substantially lower yields even in lesional cases. Prospective, genotype-aware surgical registries with standardized reporting (EEG, imaging, pathology) and time-to-event outcomes are needed to refine the selection of surgical candidates and quantify seizure and non-seizure-related outcomes.

ImportanceEpilepsy is one of the most common neurological disorders globally. A significant proportion of patients fail to achieve effective seizure control with medication and ultimately develop drug-resistant epilepsy, particularly mesial temporal lobe epilepsy (MTLE). While surgical resection and laser interstitial thermal therapy (LITT) are effective treatments for drug-resistant MTLE, these procedures may be associated with severe adverse events. In contrast, allogeneic induced pluripotent stem cell (iPSC)-based therapy is expected to offer a novel, potentially safer therapeutic approach with fewer side effects for patients with drug-resistant MTLE. ObjectiveTo evaluate the safety and preliminary efficacy of a single intracranial injection of ALC05 (iPSC-derived GABAergic interneurons) in patients with unilateral MTLE, and to assess the therapeutic effects of different dosage levels. Design, Setting, and ParticipantsThis single-center, randomized, double-blind, Phase 1 clinical trial will enroll 12 subjects with unilateral MTLE. All subjects will be randomly assigned to either the low-dose or high-dose group in a 1:1 ratio. To minimize risks at each dose level, the first subject in each dose group will be monitored for safety for at least 3 months following ALC05 injection and must demonstrate acceptable safety and tolerability before the remaining subjects are enrolled. The primary outcome will be the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes include cell engraftment and survival, responder rate, and seizure frequency. The follow-up period for this study is 1 year. After completing the follow-up period within this study, subjects will enter a 15-year long-term safety follow-up. DiscussionMTLE remains a significant challenge in neurology. The results of this study will provide critical data regarding the feasibility and preliminary efficacy of ALC05 in treating MTLE and may offer a transformative therapeutic option for this condition.

Temporal lobe epilepsy (TLE) is a heterogeneous disorder with most clinical presentations involving unilateral or bilateral hippocampal seizure onsets. Antiseizure medications are often ineffective for TLE, and epilepsy surgery can have variable outcomes. Risk factors for TLE are readily identifiable and typically precede chronic epilepsy, providing a window of opportunity for preventative treatments. However, there are currently no clinically approved anti-epileptogenic therapies. In this study, we investigate the role of Wnt signaling in epileptogenesis using two mouse TLE models, the intrahippocampal kainate model of unilateral TLE (IHK), and the intraperitoneal kainate model of bilateral TLE (IPK). We specifically examined adult-born immature dentate granule cells as these cells have been heavily implicated in the pathogenesis of TLE and clinical TLE is typically initiated in adulthood. We observed that adult-born immature dentate granule cells undergo pathological morphological changes during epileptogenesis in both the IHK and IPK models of TLE. When compared across epileptogenic zones, however, these changes differed between the two models. Wnt signaling also decreased in these cells in epileptic mice during the epileptogenic period. When mice were treated with SB415286, a highly selective Wnt activator, Wnt signaling in immature dentate granule cells was restored to baseline levels and pathological remodeling changes were reduced in both models. These data therefore suggest that a reduction in Wnt signaling in immature dentate granule cells plays an etiological role in epileptogenesis, and that restoring Wnt signaling using Wnt activating drugs or alternative agents may have therapeutic potential as an anti-epileptogenic strategy in TLE.

Objective: The postictal state is a major yet underrecognised component of epilepsy burden. We aimed to develop a structured patient-reported instrument to quantify postictal recovery, characterise its multidimensional burden and identify demographic, clinical, psychiatric and treatment-related factors associated with postictal severity and duration. Methods: We conducted a prospective, single-centre observational cohort study (Timone Hospital, Marseille, February 2025 - March 2026). Consecutive patients aged >=15 years admitted for scalp or stereo-EEG video-monitoring were included. Patients completed the Postictal Recovery Scale (PRS), an 11-domain questionnaire assessing fatigue, mood, sensory, motor, language, orientation, time perception and postictal amnesia. Items were rated from 0 (severe impairment) to 3 (no symptoms), yielding a total score of 0-33. Internal consistency was assessed using Cronbach alpha. Associations between PRS scores, subjective postictal duration and covariates were analysed using group comparisons, correlations and regression models. Results: Of 107 enrolled patients, 96 were included. PRS showed good internal consistency (Cronbach alpha; = 0.79). 96% of patients reported experiencing postictal symptoms, with fatigue (80%) and postictal amnesia (79%) being the most frequent and severe manifestations. Recovery exceeded one hour in 21% of patients. Greater postictal impairment was associated with higher interictal anxiety (Spearman {rho} = -0.32, p = 0.0018) and depressive symptoms (Spearman {rho} = -0.40, p = 0.0001), whereas demographic, epilepsy-related and treatment variables showed no significant associations. Altered postictal time perception was reported by 40% of patients and was associated with disorientation, but not psychiatric symptoms. Subjective postictal duration was longer than subjective ictal duration (Wilcoxon test, p < 0.0001). Significance: The postictal state is a frequent and multidimensional patient-reported experience. Greater postictal severity, particularly concerning anxiety and depression, is associated with interictal psychiatric comorbidity, while altered temporal experience emerges as a distinct dimension of postictal dysfunction. These findings support integrating postictal measures into clinical practice and trials.

Background and Purpose: Drug resistant epilepsy (DRE) affects approximately 15 million people worldwide, and surgery remains the only curative option. A key challenge in predicting outcomes is the lack of standardized, quantitative tools to help distinguish seizure driver regions from responder regions during stereoelectroencephalography (sEEG) recordings. We validated the CN Suite, a computational platform that uses causal network mapping and machine learning to assign criticality scores to sEEG contacts, testing whether higher scores correspond to surgically treated tissue in patients with favorable outcomes. Methods: We analyzed deidentified clinical data from 60 patients (aged 2 years and older) with focal or multifocal DRE who underwent sEEG monitoring and proceed to surgery at four U.S. Level 4 epilepsy centers. The algorithm was trained on an independent cohort (N=37) and locked prior to validation. The primary outcome was the standardized effect size (Cohens d) of the patient level surgical zone enrichment ratio between more favorable (Engel I or II) and less favorable (Engel III or IV) outcome groups. Contact level sensitivity, specificity, PPV, and NPV were evaluated at a prelocked threshold. Results: The findings support our hypothesis: the algorithm results showed significantly higher criticality values for surgically treated tissue in favorable outcome patients (d=0.74, 95% CI: 0.39 to 1.06, p=0.003). Three potentially clinically actionable findings emerged. First, high-criticality contacts formed spatially compact clusters (~9 mm nearest-neighbor distance vs. 17mm expected by chance), consistent with focal targets amenable to minimally invasive ablation. Second, sensitivity was highest in small focal procedures (80% at 10 or fewer treated contacts) and decreased with resection size. Third, in patients whose surgery failed, high-critical tissue remained outside the resection boundary, suggesting incomplete treatment coverage of the epileptogenic zone rather than mislocalization. Prediction specificity was 84% at the contact level. For adult and pediatric cases (n=28), 88% of contacts that were identified as seizure free were in fact seizure free. Conclusions: Causal network mapping of sEEG identifies compact epileptogenic targets that correspond to surgically treated tissue in patients with more favorable outcomes. CN-Suite performed best in focal procedures and may be best suited for LITT and other minimally invasive approaches. In addition, low-criticality regions were infrequently associated with seizure-generating tissue, particularly in the pediatric cohort although our sample size was small. When surgery failed, residual high-critical tissue outside the resection boundary offered both a mechanistic explanation for less favorable surgical outcome as well as a potential target for reoperation.

ImportanceImplantable sub-scalp EEG systems with a small number of channels have emerged as promising solutions for long-term seizure monitoring in patients with epilepsy. How seizure detection performance varies by montage configuration is unknown. ObjectiveTo quantify how automated seizure detection performance differs between full and reduced montages, and how these differences vary by epilepsy characteristics. DesignRetrospective cross-sectional study. SettingSingle-center at the Hospital of the University of Pennsylvania Epilepsy Monitoring Unit (EMU). ParticipantsEEG data from 2281 consecutive EMU admissions between January 2017 and December 2024 were screened. Admissions with at least one annotated seizure and one interictal clip [&ge;]20 minutes from any seizure were included. ExposureComputational simulation of published sub-scalp device montages using standard 10-20 EEG channels. Main Outcomes and MeasuresThe primary outcome was event-based F1 scores evaluated for three published seizure detectors--a one-class support vector machine (SVM), a convolutional neural network (SPaRCNet), and a long short-term memory autoregressive model (NDD)--across montages. ResultsA total of 466 admissions from 436 patients (mean [SD] age, 39.0 [14.4] years; 54.4% female) met inclusion criteria, comprising 1683 seizures and 1527 interictal clips. SPaRCNet achieved the highest performance (mean [SD] F1, 0.61 [0.30]), followed by NDD (0.56 [0.28]) and SVM (0.39 [0.25]). Performance decreased by at most 0.09 with reduced montages, depending on detectors. Patient factors accounted for the largest proportion of performance variance (29.2%), followed by detector choice (10.3%). Montage effects were minimal (0.4%), despite variation in optimal montage across detectors. Reduced-montage performance correlated moderately to highly with full-montage performance ({rho}=0.29-0.73), suggesting full-montage performance could help identify patients suitable for sub-scalp devices. Missed seizures were associated with lower amplitude and bandpowers than detected seizures, though they remained distinguishable from interictal data. Conclusions and RelevanceAutomated seizure detection achieved comparable accuracy, with only modest reductions, under simulated reduced montages. Performance differences were driven primarily by detector- and patient-level factors rather than montage. These findings support the feasibility of accurately detecting seizures with published sub-scalp devices and highlight the need for improved algorithms to optimize performance. Key FindingsO_ST_ABSQuestionC_ST_ABSHow do automated seizure detection algorithms perform with reduced-channel montages simulating published sub-scalp devices? FindingsIn this retrospective cross-sectional study, seizure detection performance decreased only modestly on reduced montages relative to the full montage (absolute F1 change -0.09 to 0.014), whereas patient- and algorithm-level factors accounted for most of performance variance (29.2% and 10.3%, respectively). Algorithm performance on full montage recordings was moderately correlated with performance on reduced channel montages ({rho}=0.29-0.73). MeaningReduced-montage sub-scalp devices are promising for ultra-long-term monitoring, but best performance requires selecting the right patients. Patient-specific seizure detectors will likely be required to optimize long-term performance.

Objective: Electrical brain stimulations (EBS) are central to epileptic network identification and functional mapping during stereo-electroencephalography (SEEG), yet stimulation frequencies remain empirical, and standardized across patients and brain regions, producing false negatives and false positives, and potentially compromising surgical outcome. We investigated theta-range EBS (7 Hz) in the temporal lobe, a prominent physiological frequency band in this region, and compared it with conventional 1-Hz and 50-Hz protocols. Methods: We analyzed 1,408 temporal EBS in 25 patients with drug-resistant epilepsy. Epileptic responses (afterdischarges, seizures) and clinical signs were assessed across the epileptic network and temporal structures (amygdala, hippocampus, neocortex, parahippocampal gyrus, white matter), and analyzed according to stimulation parameters (frequency, intensity, duration, total charge). Results: At matched intensity and duration, 7-Hz EBS were associated with a higher occurrence of afterdischarges and clinical signs than 1-Hz EBS in several temporal structures (e.g., parahippocampal epileptogenic zone: p=0.014). Effects on usual seizure induction were less consistent. Comparisons with 50 Hz showed no systematic significant differences, with responses observed at one or both frequencies depending on structure and outcome. When controlling for total charge, frequency-related differences were attenuated. Some effects were sporadically observed at both intermediate frequency and charge quantity. No adverse events occured. Significance: Theta-range stimulation modulates electrophysiological and clinical responses during SEEG mapping and may provide complementary information to conventional frequencies. These findings support exploring a broader range of stimulation frequencies, rather than relying solely on standard protocols.

ObjectiveSeizure dogs are service animals trained to respond supportively to seizures in people with epilepsy; some are also trained to detect seizure-specific scents, particularly ictal volatile organic compounds (VOCs). This survey study examines feasibility and safety of incorporating a seizure service dog (SSD) into an inpatient setting, as well as patient perceptions of having an SSD in the Epilepsy Monitoring Unit (EMU). MethodsOur SSD underwent specialized training for seizure response and seizure recognition based on seizure-specific VOCs, and accompanied his epileptologist owner in the EMU on rounds for over four years prior to the study. We administered surveys to patients hospitalized in the EMU before and after interactions with a trained seizure dog. The surveys assessed the patients comfort with the dog, perceived usefulness of service dogs, safety, and tolerability. Select case examples are also presented in which seizure dog spontaneously alerted prior to epileptic seizures; seizures later confirmed by independent EEG review. ResultsPatient responses underscored overall high enthusiasm for seizure dog therapy, with 93% of participants reporting feeling "very comfortable" or "extremely comfortable" with a seizure dog present. No adverse concerns or negative experiences were reported by participants. 91% reported personally experiencing benefits of working with the seizure dog, citing emotional and comfort benefits during their hospitalization. 94% of participants were comfortable with physical contact with the dog or had no proximity preference. ConclusionThese findings suggest that seizure service dogs can be safely integrated into the inpatient EMU setting and have potential to enhance patient care and emotional well-being during EMU monitoring. Summary PointsO_LITotal of 98 patients admitted to EMU were surveyed about opinions regarding seizure dogs and comfort with integration of seizure dog in EMU setting, with 35 patients completing post-test surveys after interacting with the seizure dog. C_LIO_LI93% of surveyed EMU patients completing post-test surveys felt very or extremely comfortable with the seizure dog; no negative experiences or safety concerns were reported. C_LIO_LI91% reported personally experiencing emotional benefits of working with the seizure dog. C_LIO_LISelect case examples demonstrate that the trained seizure dog in our study may be able to spontaneously identify epileptic seizures. C_LI

AIM: STXBP1-related disorder (STXBP1-RD) is a severe developmental and epileptic encephalopathy characterized by early-onset seizures and persistent cognitive and motor impairments. With disease-modifying trials emerging, a disorder-specific severity scale is needed. To address this, we adapted a validated clinician-reported measure from CDKL5 Deficiency Disorder to develop the STXBP1 Clinical Severity Assessment (S-CSA) and evaluated its psychometric properties. METHOD: The S-CSA was adapted from the CDKL5 Clinical Severity Assessment through expert consensus sessions with STXBP1 clinicians. Revisions addressed gaps in motor and vision domains, adding tremor and vision items. The measure was administered to 123 individuals with STXBP1-RD. Psychometric evaluation included confirmatory factor analysis, internal consistency, composite reliability, average variance extracted, and distinctiveness, compared with recommended thresholds. RESULTS: Analyses supported a three-domain structure (motor, communication, vision) with factor loadings >0.5 and strong internal consistency (Cronbachs alpha >0.7; composite reliability >0.88). Model fit and variance metrics met recommended standards, and domains demonstrated distinctiveness. No ceiling or floor effects were observed. Minimal skew was seen in motor (0.34) and communication (0.16) domains; positive skew in vision (2.2) was seen, identifying patients with and without cortical visual impairment. INTERPRETATION: The S-CSA demonstrates strong validity and reliability in STXBP1-RD and may show utility in clinical trials for STXBP1-RD and potentially other severe DEEs. Key Words: STXBP1-Related Disorder, Developmental and Epileptic Encephalopathies, Clinical Outcome Assessments

Background: The detection of subtle epileptogenic lesions such as focal cortical dysplasias (FCDs) is a clinical challenge in the management of drug-resistant focal epilepsy (DRFE). Ultra-high field (UHF) MRI offers increased signal-to-noise ratios and spatial resolution compared to 3Tesla (T) MRI and may improve diagnostic yield. Here, we present a 9.4T MRI cohort study of patients with DRFE. Methods: We recruited n=21 DRFE patients (with 3T-MRI findings: 2 positive, 3 equivocal, 16 negative) undergoing presurgical workup, and n=20 healthy controls for 9.4T MRI (0.8 mm isotropic MP2RAGE, slabs of 0.375 x 0.375 x 0.8 mm T2*-weighted GRE) and 3T MRI (MP2RAGE, FLAIR) acquisitions. Visual review for possible epileptogenic lesions was performed by clinical experts. For histopathologically confirmed FCD lesions, we extracted surface-based quantitative features (cortical thickness, qT1, FLAIR, T2*, and QSM values) across cortical depths and distances from the lesion centre and performed high-resolution cortical profiling of 9.4T T2* values. Results: No new epileptogenic lesions were visually identified at 9.4T in 3T MRI negative patients. In the two patients with histopathologically confirmed lesions, the FCD IIb lesions were visible with distinct qualitative and quantitative features at both field strengths. One of these FCD IIb showed a focal cortical T2* reduction at 9.4T that could here be quantified via automated cortical profiling, consistent with the previously described "black line sign". Conclusion: 9.4T MRI findings in epileptogenic lesions underlying DRFE are consistent with those on 3T MRI. While additional lesions were not identified in patients with negative 3T MRI, higher resolution T2*-weighted sequences can reveal a feature not seen at 3T: Cortical profiling of FCDs highlights the black line sign and can possibly help refine surgical or ablation targeting for some FCDs. Further optimization of UHF protocols and analysis methods on larger cohorts may reveal clinically applicable diagnostic benefits.

Mutations in DOCK7 have been identified in individuals with epileptic encephalopathies. Given that epileptic encephalopathies are a set of disorders that result in seizure activity and associated cognitive and behavioral impairments, we investigated the role of Dock7 in seizure susceptibility and flurothyl kindling using the repeated flurothyl seizure model in mice. Male and female Dock7+/+ and Dock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 mice were subjected to 8 daily flurothyl exposures (kindling, induction phase) followed by a 28-day incubation period and a subsequent flurothyl rechallenge (retest). No significant differences were observed in baseline myoclonic jerk or generalized seizure thresholds between genotypes or sexes. However, over the kindling period, male Dock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 mice exhibited slightly higher myoclonic jerk and generalized seizure thresholds compared to Dock7+/+ males across trials. Female mice showed similar trends, but the differences were only significant for generalized seizure thresholds. Following the 28-day incubation period and flurothyl retest, male mice of both genotypes maintained their seizure thresholds upon retest. Dock7+/+ female mice showed increased myoclonic jerk and generalized seizure thresholds during retest, while Dock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 females maintained their thresholds. A key finding was the emergence of more severe forebrain[-&gt;]brainstem seizures upon flurothyl retest in a significant percentage of mice across all groups. However, the proportion of mice developing these seizures did not differ significantly between genotypes. Although DOCK7 mutations have been linked to human epileptic encephalopathies and neurodevelopmental dysfunction, we find that Dock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 male and female mice do not show heightened excitability or seizure susceptibilities using the repeated flurothyl seizure model. HighlightsO_LIDock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 mice show slightly higher seizure thresholds during flurothyl kindling C_LIO_LIDock7{bigtriangleup}ex3-4/{bigtriangleup}ex3-4 mice do not exhibit heightened seizure susceptibility upon retest. C_LIO_LIForebrain-brainstem seizures emerged upon retest regardless of Dock7 genotype. C_LI

ObjectiveThe ketogenic diet (KD) is a high-fat, low-carbohydrate intervention widely used to treat drug-resistant epilepsy, thought to reduce seizures through a combination of metabolic, neuronal, and microbiota-dependent mechanisms. Additionally, recent studies suggest that the anticonvulsant effects of KD require the gut microbiota, with taxa such as Akkermansia and Parabacteroides contributing to seizure protection by modulating host neurotransmitter balance and neural excitability. While KD has been shown to be effective in reducing seizure burden across different epilepsies, its antiseizure effect on infection-driven seizures, which are often driven by acute neuroinflammation, has not been evaluated. Here, we evaluated the effects of KD on seizure burden, neuroimmune responses, and gut microbiota composition in the Theilers murine encephalomyelitis virus (TMEV) model of virus-induced epilepsy. MethodsMice were maintained on either a KD or a normal diet prior to intracerebral TMEV infection. Seizures were induced by handling and scored twice daily from day 3 to 7 post-infection. Neuroimmune responses were assessed by flow cytometry, and fecal microbial composition was analyzed using 16S rRNA gene sequencing. ResultsDespite achieving ketosis, KD did not reduce seizure incidence, seizure burden, or seizure severity during acute TMEV infection. KD also did not significantly alter overall immune cell infiltration into the central nervous system, indicating limited effects on global neuroinflammation. However, KD significantly reshaped the gut microbiota, reducing alpha diversity (richness, Shannon diversity, and evenness) and strongly altering community structure with clear separation between diet groups, including enrichment of taxa such as Akkermansia, Acetatifactor, Dorea, and Flintibacter, and depletion of fiber-associated taxa including Bifidobacterium and Roseburia. However, these microbial shifts were insufficient to mitigate inflammation-driven seizures. SignificanceThese results demonstrate that KDs anticonvulsant efficacy is highly context-dependent, and that KD-driven changes in microbiota- and metabolite-mediated mechanisms may be ineffective against infection-associated epilepsy, suggesting that inflammation-driven seizures require distinct therapeutic approaches. Key pointsO_LIThe ketogenic diet (KD) does not reduce acute seizure incidence and severity during TMEV infection despite achieving ketosis C_LIO_LIKD does not induce neuroinflammatory changes associated with seizure outcomes C_LIO_LIKD strongly reshapes gut microbiota, reducing diversity and altering community structure. C_LIO_LIMicrobiota changes are insufficient to protect against inflammation-driven seizures C_LIO_LIKD anticonvulsant effects are context-dependent and ineffective in infection-driven epilepsy C_LI

AbstractO_ST_ABSBackgroundC_ST_ABSInvasive neuromodulation may be used in patients if seizure medications fail and surgery is not an option. However, moderate success is achieved and improved paradigms are required. The medial septum has been considered a suitable target for the treatment of temporal lobe epilepsy due to its location and connectivity. ObjectiveTo assess the effect of medial septum low-frequency deep brain stimulation to inhibit pentylenetetrazole (PTZ)-induced seizures. MethodsMale Sprague-Dawley rats were stereotaxically implanted in the medial septum and left dorsal hippocampus one week prior to the experimental protocols. Then, the animals were assigned to three experimental groups: 1) 10 Hz + PTZ (n=3); 2) 5 Hz + PTZ (n=7); and 3) 5 Hz (n=7). The stimulation consisted of a 30 min train of biphasic square-wave pulses at a current of 150 {micro}A and a pulse duration of 1 ms. Rats were subjected to the experimental protocol every 24 h for seven consecutive days. ResultsSubjects exposed to the 10 Hz died after the first PTZ injection. The 5 Hz stimulation not only prevented the animals death, but also induced a protective effect against generalization. Surprisingly, in both 5 Hz groups, septal and hippocampal spike-wave-like discharges were detected (mainly integrated by theta oscillations). This phenomenon was correlated with the generalization avoidance. ConclusionsWhile this study is preclinical in nature, our findings underscore the potential of using low-frequency medial septum stimulation for future clinical applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/720729v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@53482org.highwire.dtl.DTLVardef@1ba5d7corg.highwire.dtl.DTLVardef@4f999aorg.highwire.dtl.DTLVardef@1ed6744_HPS_FORMAT_FIGEXP M_FIG C_FIG

1.PurposeSYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is characterized by high rates of both epilepsy and autism spectrum disorder (ASD). While the clinical spectrum is well-documented, the link between specific seizure semiologies and caregiver-reported autistic behaviors is not well understood. This study analyzed the correlation between ten distinct seizure types, their frequencies, and a caregiver-reported autistic behavior score. MethodClinical data were extracted from the PATRE (PATient-based phenotyping and evaluation of therapy for Rare Epilepsies) Registry for SYNGAP1, in the framework of the EURAS project (Grant No. 101080580, Horizon Europe). This study employed a retrospective cross-sectional analysis of caregiver-reported registry data. Analysis was restricted to an analytic cohort of N=337 participants with complete data for both the epilepsy questionnaire (including epilepsy status, seizure semiology, and peak seizure frequency items) and the behavior questionnaire (from a total N=522 registry participants). Caregiver-reported autistic behaviors were quantified using a standardized caregiver-reported scale (Likert 1-5). Statistical associations were evaluated using the Wilcoxon rank-sum test to compare caregiver-reported autistic behavior scores across different seizure semiologies and Spearmans rank correlation to assess the impact of seizure frequency (9-point scale). ResultsWithin the analytic cohort (N=337), epilepsy was reported in 259 patients. Eyelid myoclonia was the most prevalent semiology, affecting 64.9% (n=168) of the epilepsy-positive group. Atypical absences (n=77) demonstrated the most profound and statistically robust association with higher caregiver-reported autistic behavior scores (FDR-adjusted p = 0.001). Significant associations were also observed for typical absences (n=70, FDR-adjusted p = 0.018), eyelid myoclonia (FDR-adjusted p = 0.018), myoclonic-atonic seizures (n=40, FDR-adjusted p = 0.019), and atonic seizures (n=72, FDR-adjusted p = 0.025). Focal and tonic-clonic seizures showed weaker associations (FDR-adjusted p = 0.026 and p = 0.047, respectively). Crucially, quantitative analysis revealed no significant correlation between ordinal caregiver-reported peak seizure frequency ratings and caregiver-reported autistic behavior scores across all semiologies (e.g., Eyelid Myoclonia: p=0.096; Atypical Absences: p=0.744), indicating no detectable association between peak-frequency ratings and caregiver-reported autistic behavior scores. ConclusionHigher caregiver-reported autistic behavior scores in SYNGAP1-DEE were most strongly associated with the presence of atypical absences, representing a generalized, thalamocortical seizure network dysfunction. In contrast, no detectable association was observed between caregiver-reported autistic behavior scores and the ordinal caregiver-reported peak seizure frequency metric. Atypical absences and related semiologies may serve as clinical "red flags" for increased neurodevelopmental comorbidity severity, regardless of reported peak seizure frequency. Abstract SummaryThis study investigates the relationship between ten seizure semiologies, seizure frequency, and severity of caregiver-reported autistic behaviors in a large-scale international cohort of N=337 patients with SYNGAP1-DEE. We identify a robust association between elevated caregiverreported autistic behavior scores and specific thalamocortical seizure patterns, most prominently atypical absences. Notably, our analysis reveals that this association is independent of seizure frequency, demonstrating no detectable association between this ordinal, caregiver-reported seizure frequency metric and caregiver-reported autistic behaviors.

Objective Memory impairment is a frequent comorbidity of focal epilepsy, incompletely explained by seizure frequency or structural pathology. Ictal and postictal hippocampal dysfunction disrupt memory processes, but their cumulative impact remains poorly quantified. This study introduces cumulative hippocampal seizure-related burden metrics and examines their association with long-term memory consolidation. Methods Twenty consecutive patients undergoing stereo-EEG in Marseille (2016-2018) were prospectively included. Continuous stereo-EEG recordings between two memory assessments (30 minutes and one week post-encoding) were analysed. Hippocampal ictal involvement and durations were assessed using epileptogenicity markers and visual stereo-EEG analysis. The postictal period was quantified using permutation entropy. Cumulative hippocampal seizure-related burden metrics (ictal, postictal and combined: c-HipSZB) were computed across hippocampus-involving ictal events. Verbal and visual memory were assessed using standardized recall and recognition tasks. Associations were examined using univariate and multivariate analyses. Results Higher dominant-hemisphere hippocampal burden was associated with poorer one-week verbal memory (performance and retention), independently of most covariates. Higher c-HipSZB was associated with lower total recall performance (RT; free + cued) and RT retention ({beta} = -25.04 and -23.88; R2 = 0.57 and 0.53; p < 0.05) and accounted for the greatest variance in both outcomes (adjusted R2= 0.59 and 0.53; {beta} = -25.45 and -24.27; p < 0.01), particularly when adjusting for epilepsy duration. No robust associations were observed between non-dominant-hemisphere hippocampal seizure-related burden metrics and visual memory. Effects predominantly involved recall. Interpretation Cumulative ictal-postictal hippocampal dysfunction is a major determinant of impaired long-term verbal memory consolidation in focal epilepsy.

BackgroundAttributional bias, a tendency to overinterpret others intentions as hostile (rather than situational or accidental), represents a component of social cognition and may affect everyday functioning. Neural models link attributional processing to fronto-temporal circuits and the default mode network, which are frequently altered in epilepsy. Difficulties in social participation and employment are common in people with epilepsy, and maladaptive attributional styles may contribute to these challenges. Attributional bias has not been systematically compared across epilepsy syndromes. MethodsWe examined attributional bias in 96 participants comprising 26 individuals with genetic generalised epilepsy (GGE), 27 with temporal lobe epilepsy (TLE), and 43 healthy controls (HC). Attributional style was assessed using the Ambiguous Intentions Hostility Questionnaire. Depressive symptoms were evaluated using the Neurological Disorders Depression Inventory in Epilepsy. Group differences were analysed, and potential clinical and demographical correlates were explored. ResultsThe GGE group exhibited higher hostility bias scores than HC (95% CI: 0.12-0.38, adjusted p = 0.014), whereas the difference between TLE and HC groups was moderate and not statistically significant (95% CI: 0.12-0.58, adjusted p = 0.059). Higher blame scores were positively associated with depressive symptoms (p = 0.016). Disease duration, seizure frequency, and antiseizure medication were not significantly associated with attributional bias. ConclusionsThese findings suggest that some individuals with genetic generalised epilepsy are more likely to interpret ambiguous situations as hostile. Altered attributional style may represent an under-recognised factor contributing to social difficulties in people with epilepsy and warrants further investigation as a potential target for psychosocial interventions. HighlightsO_LISome people with epilepsy are more prone to interpret social situations as hostile. C_LIO_LIHigher depression scores correlate with a tendency to blame external factors for misfortunes. C_LIO_LIDisease duration, antiseizure medication, and seizure frequency do not seem to influence the attributional bias. C_LI

Objective: Interictal spikes have been proposed as a biomarker for both localizing seizure onset zones (SOZ) and tracking changes in seizure risk with neurostimulation in patients with drug-resistant epilepsy. Electrical stimulation can modulate spike rates acutely, and it has been proposed that measuring this modulation can help localize the SOZ. However, it is unclear whether stimulation-induced spike rate changes reflect epilepsy-specific pathology in the stimulated network or simply intrinsic regional excitability, which limits our understanding of their utility in epilepsy surgery planning. Methods: We analyzed low-frequency stimulation (LFS; 1 Hz) applied during a clinical seizure-induction protocol systematically targeting multiple brain regions in 43 patients with drug-resistant epilepsy undergoing intracranial EEG monitoring. A validated, automated spike detector was used to quantify pre-, during-, and post-stimulation spike rates. We tested whether the stimulation-evoked spike rate response (i) tracks the expected change in seizure risk from a seizure induction protocol, (ii) varies with anatomical stimulation site and epilepsy localization, (iii) localizes the SOZ beyond baseline spike rate, and (iv) is accompanied by changes in spike morphology. Results: Nearby LFS acutely increased spike rates in high-spiking channels (inter-stimulation median 2.25 vs. during-stimulation 4.25 spikes/min; p < 0.001), with effects attenuating with distance and resolving within approximately 30 seconds of stimulation offset. Mesial temporal lobe stimulation produced the largest increase in nearby spike rates relative to temporal neocortex and other cortex (Kruskal-Wallis p = 0.003), but this effect did not differ between patients with and without mesial temporal lobe epilepsy. A random forest classifier incorporating stimulation-evoked modulation features achieved an AUC of 0.787, comparable to a resting-state spike model (AUC 0.747; DeLong p = 0.81), indicating that stimulation-evoked spike changes do not add localizing information beyond resting-state spike rates. Stimulation produced a small but significant shift in spike morphology toward broader, higher-amplitude discharges (PERMANOVA p < 0.001), consistent with recruitment of a broader neuronal population. Significance: LFS-evoked increases in interictal spike rates reflect intrinsic regional excitability, greatest in the mesial temporal lobe, rather than epilepsy-specific pathology, and do not improve SOZ localization over resting-state spike rates. These results argue against using the change in spikes with stimulation to localize the SOZ. On the other hand, the transient spike rate increase induced by a pro-epileptic protocol supports the acute change in spike rate as a biomarker of the effect of stimulation on seizure risk, with potential to guide parameter selection for epilepsy neuromodulation.

Gain-of-function variants (GOF) in SCN8A, which encodes the NaV1.6 sodium channel, lead to epilepsy syndromes ranging from drug-responsive self-limited (SeLIE) and intermediate epilepsy to drug-resistant developmental and epileptic encephalopathy (DEE). It is currently unclear why individuals with SCN8A GOF variants show variable responses to sodium channel blockers (SCBs). Here, we compared the clinical characteristics of 173 individuals with 25 different SCN8A GOF variants following the hypothesis that carriers of variants affecting activation gating respond less well to SCBs than those with variants affecting fast inactivation gating, given that use-dependent SCBs preferentially target inactivated channel states. We found that individuals with variants altering channel activation gating were more severely affected than those with variants altering inactivation properties: They had an earlier age at onset (3 vs. 5 months, P < 0.0001), higher prevalence of DEE (75% vs. 39%; P < 0.0001), and poorer response to SCBs (20% vs. 69% seizure free; P < 0.0001). We performed pharmacological studies on representative and recurrent variants from each group: two variants (F846S and M1760I) causing hyperpolarizing shifts of the voltage-dependent activation curves, and two variants (G1475R and N1877S) causing depolarizing shifts of the voltage-dependent fast inactivation curves. Phenytoin failed to suppress neuronal firing in neurons expressing activation-related variants, but showed good suppressing effects in neurons expressing inactivation-related variants. In contrast, PRAX-330, a new SCB, which showed much faster binding rates than phenytoin, was effective for both groups of variants by markedly reducing neuronal firing through rapidly and persistently stabilizing NaV1.6 in the inactivated state. Our findings provide new insights into the mechanism of drug-resistance in SCN8A-DEE and support PRAX-330 and compounds with similar pharmacological properties as a promising preclinical candidate for targeted therapies.