The SCN1A gene is implicated in a broad spectrum of epilepsy phenotypes, ranging from self‐limited genetic epilepsy with febrile seizures plus (GEFS+) to severe developmental and epileptic encephalopathies such as Dravet syndrome (DS). While fenfluramine (FFA) has demonstrated strong efficacy in DS, its role in SCN1A‐related epilepsies beyond DS has not been thoroughly investigated. We conducted a multicenter observational study including 11 patients with SCN1A‐related GEFS+ who received FFA as adjunctive therapy. All patients had previously failed to achieve adequate seizure control with valproate and, in most cases, additional antiseizure medications. FFA was introduced following the DS titration protocol, with a mean dose of 0.39 mg/kg/day. FFA addition led to a mean seizure frequency reduction of 91%, with more than half of the patients achieving complete seizure freedom. Reduced EEG abnormalities were documented in 5/11 patients of the cohort, including complete normalization in 3/11 patients. Furthermore, subjective caregiver reports indicated perceived improvements in patients' alertness and behavioral responses. FFA was well tolerated, with only mild and transient adverse events reported. These findings support the potential role of FFA as an effective and well‐tolerated treatment option in patients with SCN1A‐related GEFS+.Plain Language SummaryGEFS+ is a genetic epilepsy frequently caused by changes in the SCN1A gene. In a multicenter real‐world study of 11 people with SCN1A‐related GEFS+, adding fenfluramine to usual care substantially reduced seizures, with several becoming seizure‐free. EEG recordings improved, and caregivers reported better alertness in some patients. Treatment was generally well tolerated, with only mild, temporary side effects.

ObjectivePostimplantation assessment of the position of depth EEG electrodes for intracerebral recordings in patients with refractory focal epilepsy can be performed with MRI or with CT after coregistration to a preimplantation MRI. While both methods offer risks and advantages, postimplantation MRI risks depend on the electrode heating profile under different MRI conditions. We aimed to assess the MRI‐related heating of Dixi microdeep electrodes at 1.5T in multiple electrode configurations and with varying levels of radiofrequency (RF) power.MethodsIn vitro tests of heating due to RF power deposition were performed according to the F2182‐19e2 standard from the ASTM (American Society for Testing and Materials International). A 10‐contact Dixi microdeep electrode was inserted into the gel within the ASTM head–torso phantom, and the temperature was recorded from selected electrode contacts during MRI. Tests were performed with the electrode positioned in various locations in straight and coiled configurations, with coil diameters from 6 to 25 cm. MRI was conducted on a 1.5T Philips Achieva scanner using the transmit–receive body coil.ResultsSignificant heating was observed for all configurations where more than 12 cm of the electrode was in the RF coil, apart from those with an applied specific absorption rate (SAR) ≤0.16 W/kg and with additional coiling of the electrode lead using a diameter of ≤6 cm. The worst‐case configurations, reaching a maximum temperature of 70°C (temperature rise 48°C), occurred where the electrode end was straight or looped with a large‐diameter (25 cm) loop. Heating was greatest in the contact furthest from the tip.SignificanceDixi microdeep electrodes demonstrate heating levels capable of causing serious injury during MRI, but using a conservative SAR limit of 0.1 W/kg and coiling the electrode lead to a diameter of ≤6 cm appears to reduce the heating risk.Plain Language SummaryElectrodes positioned within the brain for planning epilepsy surgery can heat up during MRI. Using a standard test object mimicking the electrical properties of the human body, we measured heating of Dixi microdeep depth electrodes in different positions and orientations and with varying levels of radiofrequency power. We found substantial heating apart from when the radiofrequency power was greatly restricted or when the lead was tightly coiled. Different electrode contacts showed drastically different heating, and heating levels capable of causing serious injury were measured during MRI.

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early‐onset, treatment‐resistant epilepsy. Mice lacking CDKL5 display several clinically relevant phenotypes, but spontaneous seizures are not consistently reported, and it is unknown if CDD model mice are susceptible to sensory stimulus‐triggered seizures, a well‐documented clinical feature of CDD. Here, we tested the hypothesis that CDKL5 deficiency confers susceptibility to audiogenic seizures (AGS). We exposed adult male Cdkl5 knockout, female heterozygous, and wildtype littermates (P80‐217) to audiogenic challenges and, in a separate cohort, monitored for spontaneous seizures. Audiogenic stimulation triggered severe, lethal (80%) seizures in Cdkl5 knockout mice. In contrast, heterozygous mice were largely resistant to audiogenic stimulus (92% survival). These findings establish susceptibility to AGS as a highly penetrant phenotype in a CDD mouse model. Furthermore, spontaneous seizures were detected in a subset of Cdkl5 knockout mice during chronic video‐EEG monitoring. AGS may provide a translationally relevant screen for investigating hyperexcitability and for evaluating potential therapeutics to prevent seizures in CDD.Plain Language SummaryCDKL5 deficiency disorder (CDD) is a severe genetic condition causing early‐onset seizures. Mice with the same mutation are useful models but don't consistently have epilepsy. We tested if these mice in our lab are sensitive to sound‐triggered seizures. We discovered that male CDD mice are highly vulnerable to sound, which triggered severe seizures in most of them. Female CDD mice and normal mice were resistant. This is the first report of sound‐triggered seizures in a CDD model and provides a useful new method to study epilepsy in CDD and screen for antiseizure treatments.

Neonates have a high incidence of seizures that are frequently difficult to control with conventional first-line anti-seizure medications, which are gamma-aminobutyric acid (GABA) agonists. The reasons for this clinical problem are multifold but are likely related to the unique physiology of the immature nervous system. Specifically, the early and transient neuronal expression of ion transporters that lead to higher concentrations of chloride inside the cell creates an electrochemical gradient that is depolarizing when chloride channels open, as they do when the GABAA receptor is activated. The later expression of chloride exporting transporters eventually leads to a chloride gradient that is hyperpolarizing, but this does not occur uniformly across the brain. The early depolarizing effect of GABAA receptor activity may have important functions in normal brain development but could theoretically impact therapies designed to enhance GABAergic transmission in neonates. In several studies, neonatal status epilepticus induced in the first 2 weeks of rodent life produces no or minimal brain injury in otherwise normal rodents. However, in certain settings, injury may ensue. A model of pilocarpine-induced seizures induced by higher doses of lithium and pilocarpine in P7 rats has demonstrated that widespread cell death can be seen in unmedicated animals experiencing severe seizures. Injury is further enhanced by treatment with either midazolam or phenobarbital. The effect is separate from the enhancement of apoptosis that has been reported with higher doses of the same drugs. Though limited, these data align with other basic studies and clinical reports that raise questions as to whether enhancement of GABA activity is the best approach for treating all neonatal seizures. GABAA receptor agonists are still used in the clinical setting for the treatment of neonatal seizures. Further basic and clinical research studies are needed to understand the short- and long-term effects of common first-line anti-seizure drugs and to investigate viable alternatives. PLAIN LANGUAGE SUMMARY: In the newborn brain, the neurotransmitter GABA, acting through GABAA receptors, which inhibits neurons in the adult brain, can be depolarizing. Status epilepticus has been reported to cause less severe injury in immature rats compared to adults. In certain settings, however, severe neonatal status epilepticus injury could be observed, and drugs that activate GABAA receptors, like phenobarbital and midazolam, can make seizure-associated brain damage worse in newborn rats. More studies are needed to better understand this problem and create better and safer treatments for neonatal seizures.

Sudden unexpected death in epilepsy (SUDEP) affects more than 3000 individuals annually, yet objective and scalable biomarkers to assess risk remain limited. Postictal generalized electroencephalogram suppression (PGES) has been proposed as a potential biomarker, but its quantification is often subjective and variable. Here, we developed and validated an automated Cumulative Sum (CuSUM)‐based algorithm to objectively quantify PGES duration in traumatic brain injury (TBI) mouse models of epilepsy. The algorithm was tested across three cohorts: 1 mm TBI, 2 mm TBI, and 2 mm TBI with HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) treatment. Although SUDEP occurred in only a subset of animals in both TBI groups, injury severity influenced the timing of SUDEP onset. More severe injury was associated with earlier SUDEP events and shorter PGES durations, whereas less severe injury was characterized by longer PGES durations (1 mm TBI: ~110 s; 2 mm TBI: ~40 s) and delayed SUDEP onset. SAHA treatment further reduced PGES duration (~30 s), suggesting potential translational relevance for SUDEP. Bland–Altman analysis demonstrated strong agreement between automated and expert measurements. Together, these findings demonstrate that automated PGES quantification provides a reproducible and objective framework for assessing postictal EEG dynamics and their relationship to SUDEP timing in epilepsy models. This approach offered a scalable tool for mechanistic studies and treatment evaluation, supporting future efforts toward multimodal and clinically translatable SUDEP research.Plain Language SummaryThis study developed a simple, automated method to measure postictal generalized electroencephalogram suppression (PGES) in mouse models of brain injury to estimate the risk of SUDEP. It matched expert ratings and showed that injury severity, PGES length, and SUDEP risk relate in unexpected ways. While an epigenetic inhibitor drug shortened PGES, further studies are needed to validate its efficacy in epilepsy models.

ObjectivesPredicting seizure recurrence following a first unprovoked seizure (FUS) remains a significant clinical challenge, especially when routine clinical magnetic resonance imaging (MRI) and EEG do not reveal abnormalities diagnostic of epilepsy. Here, we incorporate quantitative structural MRI‐derived biomarkers into prediction models for seizure recurrence at 12 months and identify brain structural features that are predictive of seizure recurrence.MethodsWe analyzed a retrospective, multicenter cohort of 197 adult patients with FUS, comprising 83 with seizure recurrence and 114 with no seizure recurrence at 12 months. All participants had normal or nondiagnostic MRI and EEG findings. Morphometric features were extracted from clinical 3 T T1‐weighted MRI using FreeSurfer. Machine learning algorithms were trained on combined imaging and clinical features using nested cross‐validation for model selection. Performance was compared with a logistic regression model based on clinical features only.ResultsThe best‐performing model, a support vector machine (SVM) trained on a combination of imaging features and clinical factors, achieved an AUC of 0.65 (95% CI: 0.57–0.73), significantly better than chance (p = 0.01 when compared with an AUC of 0.5). In contrast, the logistic regression model trained on clinical factors alone yielded an AUC of 0.57 (95% CI: 0.49–0.65), not statistically different to chance (p = 0.28). Direct comparison between the SVM and the logistic regression clinical factor‐only model was not statistically significant (95% CI for the difference in AUC: −0.019 to 0.173, p = 0.11). The most important imaging features for prediction were inter‐hemispheric asymmetry of subcortical and cortical gray matter volumes and regional gyral curvatures, particularly in fronto‐parietal and limbic regions.SignificanceQuantitative structural MRI contributes additional information beyond clinical factors for machine learning models predicting seizure recurrence. Changes to cortical folding and gray matter asymmetries in cortical and subcortical regions show potential as prognostic biomarkers of seizure recurrence risk after a FUS.Plain Language SummaryIdentifying individuals who will have another seizure after their first unprovoked seizure is difficult when routine brain scans and EEG appear normal. We developed a tool that combines MRI‐derived markers with clinical information to predict seizure recurrence. Subtle structural differences in the brain, especially asymmetries between left and right hemispheres and changes to cortical folding, were associated with a higher chance of another seizure within a year. This approach has potential in identifying individuals at risk of seizure recurrence earlier.

Seizure forecasting models require long‐term, high‐quality data collected in real‐life settings using noninvasive or minimally invasive devices, yet, the lack of such systems remains a major barrier to their clinical translation. Here, we aimed to evaluate the signal quality of self‐applied at‐home EEG monitoring using a wearable system in patients with epilepsy to assess its reliability for future seizure forecasting applications. All EEG recordings were reviewed to identify non‐usable data and interictal epileptiform discharges (IEDs). We analyzed power spectral density and the temporal evolution of a signal‐to‐noise ratio, and applied composite quality criteria for each patient based on spectral profile and the proportion of EEG data discarded. Twelve patients with drug‐resistant epilepsy performed self‐applied resting‐state EEG recordings twice daily over a median period of 173.5 days (min. 12, max. 235). Two‐thirds of patients had data of good or moderate quality (N = 3 and 5, respectively), which remained overall stable over time with cap replacement every 2–3 months. IEDs were found in four patients and were concordant with prior in‐hospital recordings. Self‐applied at‐home EEG monitoring can yield clinically relevant insights and may support future seizure forecasting strategies in selected patients, provided patient adherence and the feasibility of regular maintenance follow‐up are addressed.Plain Language SummaryTwelve people whose epilepsy was hard to control with medication recorded a short brain‐wave test (electroencephalography, or EEG) at home twice a day for several months. In 8 of the 12 people, most recordings were clear enough to use and stayed steady over time, although some EEG caps needed replacement. In four people, the home EEG showed abnormal spikes between seizures that matched earlier hospital EEGs. This suggests that long‐term, self‐recorded EEG at home is possible for some patients and may help clinicians track brain activity outside the hospital.

Polymicrogyria (PMG) is a rare malformation of cortical development (MCD) characterized by abnormal neuronal architecture, often associated with epilepsy. Neurosurgical interventions have been explored, but their effectiveness remains a subject of ongoing research and debate. This systematic literature review aims to provide a comprehensive analysis of surgical interventions for epilepsy in PMG individuals, their outcomes, complications, and factors influencing surgical decision‐making. This systematic review, conducted according to PRISMA guidelines and registered on PROSPERO (CRD420251010221), analyzed studies on individuals with PMG and epilepsy undergoing neurosurgical treatment. A structured search across five databases was performed. Two reviewers independently selected and extracted data on clinical characteristics, surgical techniques, and outcomes, with seizure control assessed through Engel and ILAE classifications. Statistical analyses included Chi‐square and Mann–Whitney U tests. Study quality was evaluated. A total of 47 studies involving 225 patients were included, mostly consisting of case reports or series. The majority of patients underwent resective surgery or hemispherotomy. Postsurgical outcomes were evaluated using Engel or ILAE classifications in 178 cases: 64.61% achieved seizure freedom (Engel/ILAE I). A shorter epilepsy duration was significantly associated with better outcomes. Only a minority received neuropsychological assessments, with cognitive improvements observed mainly in patients operated at a younger age. Postoperative complications were discussed. This review highlights the potential effectiveness of neurosurgical interventions in selected patients with PMG and drug‐resistant epilepsy. Despite the overall encouraging seizure outcomes, the limited and heterogeneous reporting of cognitive and quality‐of‐life measures underscores the need for more comprehensive and standardized pre‐ and postsurgical assessments to better inform clinical decision‐making and long‐term management.Plain Language SummaryThis study looked at the effects of brain surgery in people with epilepsy caused by polymicrogyria, a condition where the brain does not form properly before birth and develops an unusual surface. Many patients became seizure‐free or had fewer seizures after surgery, especially when performed at an earlier stage. More research is needed to understand how surgery affects mental functions (e.g., memory, attention) and quality of life of these patients.

The FBXW7 gene encodes a substrate‐recognition component of the Skp1‐Cul1‐F‐box (SCF) E3 ubiquitin ligase complex, which targets key regulatory proteins for proteasomal degradation. Recently, loss‐of‐function FBXW7 variants have been associated with a novel neurodevelopmental disorder characterized by heterogeneous clinical features. Most reported pathogenic variants cluster within the WD40 domains, while variants in other regions, such as the F‐box domain, remain poorly characterized. In this study, we performed trio‐exome sequencing on a 3‐year‐old girl with Early‐Onset Childhood Absence Epilepsy. We analyzed the identified FBXW7 variant using multiple in silico tools for pathogenicity prediction and structural modeling. Clinical phenotype was compared with previously reported cases. We identified a novel de novo missense variant in FBXW7, c.926G>C; p.(Arg309Pro), affecting a highly conserved residue in the F‐box domain. Notably, unlike prior cases predominantly associated with WD40 domain variants and severe phenotypes, our patient exhibited a much milder clinical presentation consisting of isolated, drug‐responsive absence seizures without intellectual disability. Structural modeling predicted significant impairment in protein–protein binding affinity, particularly with the SCF complex component SKP1, supporting a potentially disruptive effect of the p.(Arg309Pro) substitution on complex assembly. Overall, our findings expand the genotypic and phenotypic spectrum of FBXW7‐related disorders. Variants in the F‐box domain may result in milder neurological phenotypes compared to those in the WD40 domains, suggesting domain‐specific effects and potentially distinct pathogenic mechanisms.Plain Language SummaryThe FBXW7 gene helps regulate the stability of many proteins essential for brain development and function. Changes in this gene have recently been linked to neurodevelopmental disorders with epilepsy. We identified a new FBXW7 variant in a 3‐year‐old girl with early‐onset absence epilepsy. Computer‐based modeling suggests that this change weakens the protein's normal interactions. Our findings broaden the spectrum of FBXW7‐related disorders and indicate that variants in different gene regions may result in variable clinical severity.

ObjectiveCDKL5 deficiency disorder (CDD) is an early‐onset developmental and epileptic encephalopathy characterized by frequent drug‐resistant seizures, cerebral visual impairment, motor dysfunction, and sleep and gastrointestinal disturbances. Preliminary evidence suggests that highly purified cannabidiol (CBD) may reduce seizure frequency, but data on its effects on comorbidities are lacking. This study aimed to evaluate the efficacy and safety of CBD in individuals with CDD.MethodsWe conducted a prospective, open‐label, single‐center study including patients with CDD aged >1 year. Outcomes included motor seizure frequency, caregiver‐ and clinician‐rated Clinical Global Impression (CGI), and changes in sleep, motor abilities, and EEG at 3, 6, and 12 months. CBD plasma levels were measured with High‐Performance Liquid chromatography–Mass Spectrometry (HPLC‐MS).ResultsEight of nine patients (all females; median age 10 years, range 1–24) completed the study, with a retention rate at 12 months of 8/9 (89%). One discontinued at 6 months due to a skin rash. A > 50% seizure reduction was observed in 8/9 patients at 3 months, 6/9 at 6 months, and 1/8 at 12 months. Seven patients showed some degree of vigilance improvements, three in motor performance, and two in sleep and constipation. All caregivers reported at least minimal overall improvement (CGI score 3) at 3 months, and three reported marked improvement (CGI score 2), with a peak at 3 months. Five patients showed adverse events during the trial, but none were considered serious. The median CBD dose at all time‐points was 15.6 mg/kg/day (IQR 10.0–18.9) corresponding to a plasma dose of 69.9 ng/mL (IQR 29.8–114.6) and the median concentration/dose ratio was 4.7 (IQR 2.7–6.8).SignificanceThe safety and efficacy of highly purified CBD in CDD were consistent with previous reports in the literature, with possible benefits beyond seizure control. Further studies are warranted to assess non‐seizure outcomes and compare long‐term efficacy across treatment options.Plain Language SummaryWe studied nine girls with CDKL5 deficiency disorder who had frequent, hard‐to‐treat seizures. They received cannabidiol for up to 1 year, added to their usual medicines. Most children had fewer seizures in the first months of treatment. Some families also noticed better alertness, eye contact, movement, sleep, or constipation. Side effects were usually mild and manageable. Although seizure frequency often returned to baseline by the end of the study, most families chose to continue cannabidiol. Because this was a small study without a placebo group, these results are preliminary, and larger controlled trials are needed.