CDKL5 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. We 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). Eight 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). The 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. We 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.
Epileptic seizures are generated in cerebral networks that propagate ictal and interictal activity. The structure of cerebral networks underpinning epileptic activity can be inferred from diffusion-weighted magnetic resonance imaging (DWI). However, publicly available DWI data in individuals with epilepsy are scarce, and processing is technically challenging due to scan-specific artifacts, limiting research progress. Here, we release raw DWI data from 216 individuals with epilepsy and 98 healthy controls. Subject identifiers align with our previous data release (IDEAS), which includes T1-weighted and FLAIR magnetic resonance imaging, surgical details, and long-term seizure outcomes after surgery. Preprocessing reduced distortions and artifacts, and fully processed data include diffusion metric maps in native and template space. We also provide parcellated structural connectomes using multiple atlases and connectivity measures. To illustrate the utility of these IDEAS II data, we replicated ENIGMA consortium findings, observing widespread reductions of fractional anisotropy, particularly ipsilateral to the area of seizure onset. We further demonstrate localized abnormality, and network connectivity using streamline tractography in a patient who subsequently underwent temporal lobe resection. This open dataset offers a comprehensive resource to advance research on structural connectivity and surgical outcomes in epilepsy.
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Bridging clinical and basic research is increasingly recognized as a priority in the epilepsy field, yet opportunities for integration remain limited by the time, space, and financial constraints of scientific meetings. To address this gap, the Research Task Force of the Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES) organized a free global webinar series designed to promote translational dialogue and provide accessible research education for early-career clinicians, researchers, and physician-scientists. Based on a preliminary ILAE-YES community survey, eight topics of high interest were selected: (1) epigenetics, (2) EEG biomarkers, (3) ictogenesis, (4) thalamo-cortical network, (5) sudden unexpected death in epilepsy, (6) neurodegeneration and seizures, (7) seizure-related brain damage, and (8) neuromodulation therapy. From March to June 2025, eight live Zoom webinars were held, each featuring expert speakers representing both basic science and clinical perspectives, with recordings made available as unlisted YouTube videos to ensure on-demand access. A total of 1199 individuals from 116 countries registered, 63.2% from low- and middle-income countries. Live attendance averaged 50 participants per session, and the mean session duration was 71.6 min, including an average of 16 min of discussion. Post-session feedback was obtained from 285 respondents; overall satisfaction was high, with 93.3% rating their experience as 4 or 5 on a 5-point Likert scale. Speaker satisfaction was similarly high (95.4%), and 80.0% reported gaining new research ideas. Although access to YouTube and Google Forms may have limited participation in some regions, the series provided an inclusive and globally accessible platform. These findings demonstrated that free, discussion-focused online webinars represent a scalable, low-cost, and reproducible educational model that can effectively promote international engagement and integration between clinical and basic epilepsy research, aligning with the ILAE's global educational mission and complementing WHO IGAP priorities on capacity building and equitable access to knowledge. PLAIN LANGUAGE SUMMARY: Bringing together basic science and clinical research is important for improving epilepsy care, but many researchers have limited opportunities to learn across these fields. We organized a free global webinar series that helped early-career clinicians and researchers learn about epilepsy research by combining scientific talks with clinical perspectives and open discussion. More than 1100 participants from over 100 countries joined, and most reported high satisfaction and gaining new research ideas. These results show that free, discussion-based online webinars can provide an accessible way to support research education and international learning in epilepsy.
Nonconvulsive epileptic activity is common after acute brain injury and contributes to neuronal injury and poor outcomes. Although intracranial electroencephalography (iEEG) improves detection compared with surface EEG (suEEG), it currently relies on focal recordings of epileptic dynamics. We prospectively evaluated multielectrode iEEG strategies designed to achieve large-scale cortical and deep brain coverage in critically ill patients. In a prospective cohort of adults with acute brain injury requiring invasive neuromonitoring, we implemented four depth electrode-based iEEG techniques: three electrocorticographic approaches (open subdural, burr hole subdural, and foramen ovale) and one stereotactic (transcortical) approach. The primary objective was to establish and quantify the extent and durability of cortical recordings. Additional assessments included safety, feasibility, and management impact. Electrode localization was performed in MNI305 space, and recording longevity was assessed using Kaplan-Meier and Cox proportional hazards models. Thirty patients with severe brain injury underwent implantation of 64 electrodes (772 contacts), yielding 361 total iEEG recording days across heterogeneous etiologies and surgical settings. Multielectrode implantation enabled distributed sampling spanning multilobar frontoparietotemporal cortical clusters. Overall, 72% of electrodes sampled cortical convexity alone, whereas 28% incorporated deep targets, including mesial temporal and orbitofrontal regions. Recording durability differed by implantation strategy (log-rank p = .0002), with a mean combined iEEG-suEEG monitoring duration of 14.5 days per patient. Implantation was successful in >95% of electrodes, monitoring started within 24 h postoperatively in 88%, and the per-electrode risk of a causally related adverse event was 3.1%, without hemorrhagic complications. iEEG influenced treatment initiation or escalation in 32% of monitored patients. Multielectrode iEEG strategies enable durable, large-scale cortical sampling in acute brain injury while remaining feasible and safe in the intensive care unit. By shifting from focal to distributed spatial sampling, these approaches provide a conceptual framework for improving detection of epileptic activity in critically ill patients.
Gain-of-function (GoF) variants in the KCNC1 potassium channel subunit gene (Kv3.1) cause motor/cognitive delays and hypotonia and have been associated with seizures. Fluoxetine has inhibitory effects on Kv3.1. However, open-label nonrandomized administration is insufficient to guide clinical decision-making in ultrarare conditions. This 40-week randomized, double-blind, n-of-1 trial evaluated the safety and effectiveness of fluoxetine for motor development in a 2-year, 10-month-old female child with a GoF KCNC1 variant. This study used an ABA phase design (placebo-fluoxetine-placebo), with randomization and blinding of treatment transition moments. The active treatment, fluoxetine powder, was provided at 2.5 mg (low dose) and subsequently 5 mg (target dose) per day. Motor developmental was measured using the parent-reported Early Motor Questionnaire (EMQ), completed weekly. Secondary outcomes included cognitive and adaptive skills and other parent target symptoms (nystagmus, communication, purposeful hand movements). Treatment with fluoxetine was associated with a 6.61-point gain on the EMQ (95% credible interval [CrI] = -.53 to 14.78), beyond the effects of time (.52 points/week, 95% CrI = .28-.91). Treatment was well tolerated; possible withdrawal irritability emerged during the second placebo phase. A higher dose was associated with a larger treatment effect on the EMQ (2.5 mg = 6.81, 95% CrI = -.43 to 14.56; 5 mg = 8.68, 95% CrI = -4.29 to 21.76). Secondary outcomes showed significant improvements in purposeful hand movements (-.65, 95% CrI = -1.27 to -.003, on a 7-point scale), and there were small increases in adaptive behavior and cognitive skills during the trial. Clinical biomarkers suggested a shift toward increased excitation on electroencephalogram and electroretinogram. Fluoxetine treatment was possibly associated with increased motor skill development in a young child with KCNC1-related disorder involving a GoF variant. Trials studying developmental endpoints require innovative designs; this study provides a template for treatment assessment in ultrarare genetic neurodevelopmental disorders.
Appropriate endpoints for daily antiseizure medications may differ from those for intermittent, immediate-use seizure medications (ISMs). The observed interval between seizure clusters over time (SEIzure interVAL [SEIVAL]) has been proposed as a novel effectiveness endpoint for ISMs. SEIVAL was initially identified pragmatically. This post hoc analysis evaluated how the study timeline and participant characteristics could impact the measurement of SEIVAL using data from an open-label study of intermittent treatment with diazepam nasal spray. This analysis includes data from a long-term, phase 3 safety study of diazepam nasal spray, which enrolled patients aged 6-65 years with epilepsy and seizure clusters (NCT02721069). Study timeline and participant characteristic choices were evaluated systematically to determine the impact on effect size, and thereby statistical power, using data regarding individual treated seizure clusters. In this strategy, the date of the first treated seizure cluster constituted day 1 of the baseline period; consecutive 70-day periods were used for analysis. The change in SEIVAL for each patient was calculated using each measured SEIVAL for that patient in the primary outcome period (days 71-140) minus that patient's mean SEIVAL in the baseline period (days 1-70) with mixed effects linear regression. Mean SEIVAL increased from 13 days at baseline (days 1-70) to 24 days in the primary outcome period (days 71-140, p < .0001). SEIVAL lengthening was seen in adults, adolescents (ages 6-17 years), and children (ages 6-12 years), with further lengthening past 140 days in adolescents and children. SEIVAL lengthened more in participants with <1 SEIVAL per 2 weeks at baseline than higher SEIVAL frequency. This systematically planned analysis expands on and reinforces the previous pragmatic analysis that introduced the SEIVAL metric. The present analysis provides a novel framework for future studies of intermittently administered ISMs to treat seizure clusters such as diazepam nasal spray.
Drug-resistant epilepsy (DRE) imposes a significant burden on patients and their caregivers. This study aimed to explore the concerns and perceptions of healthcare providers (HCPs), patients, and caregivers regarding the burden of disease and quality of life (QoL) in patients with DRE. This was a multinational, cross-sectional, online, survey-based study. Participants were HCPs managing at least 30-50 epilepsy patients per month, including ≥10 patients with DRE; patients aged ≥18 years with DRE; and caregivers aged ≥18 years supporting patients with DRE. Data collection was carried out between March and August 2024. In total, 213 stakeholders took part in the survey (146 HCPs, 42 patients, and 25 caregivers); 58% of the HCPs were neurologists and 42% were epileptologists. Caregivers were mainly parents (79%). Patients represented by caregivers were younger (84% vs. 29% aged 18-34 years) and had a higher incidence of seizures (20 vs. 5 seizures per month; p < 0.05) than patient participants. According to all stakeholders, DRE had a significant impact on multiple components of patient QoL, with work capability, psychological well-being, and daily management and logistics the most affected. Significantly fewer HCPs regarded "achieving complete seizure freedom" as of high importance for patients compared with patient participants (p < 0.05) and caregivers (p < 0.05). High satisfaction with current treatment was reported by only 35% of HCPs, 33% of patient participants, and 4% of caregivers. Most stakeholders reported insufficient time during consultations to investigate patients' concerns, and different topics for discussion were prioritized by HCPs and patients/caregivers. This survey highlighted the continued and multifaceted burden of disease among patients with DRE. While seizure freedom is the ultimate goal of treatment, disparities exist among key stakeholders regarding aims and outcomes of treatment as well as management of expectations. Patients with DRE have epileptic seizures despite receiving medicines to reduce their seizures. This survey shows that DRE places a heavy strain on patients and their carers. Satisfaction with current treatments is low, especially among carers. Patients and carers see stopping all seizures as very important, but doctors tend to rate this as less of a priority; patients and carers are also more open than doctors to using digital tools to improve communication with their doctor. Overall, the differences in expectations and approaches between patients, carers, and doctors may create barriers to improving seizure control.
This study was undertaken to evaluate the efficacy and safety of deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) compared with best medical treatment (BMT) in patients with drug-resistant epilepsy (DRE). This randomized, open-label, phase 3 controlled trial was conducted across 14 specialized epilepsy and DBS centers. Eligible participants were adults with focal or multifocal DRE who had previously failed vagus nerve stimulation (VNS). Sixty-one patients were randomized 1:1 either to receive continuous bilateral ANT-DBS (n = 30) or to continue BMT, including VNS (n = 31), for 12 months. Afterward, patients in the BMT group were offered delayed ANT-DBS and followed for an additional year. The primary outcome was the change in monthly severe seizure frequency (defined on the modified Chalfont Scale) at 12 months. Safety outcomes were also recorded. Among 67 screened patients, 61 were enrolled. At 12 months, median seizure reduction was greater in the DBS group (-44%, interquartile range [IQR] = -67 to 0) versus the BMT group (-6%, IQR = -56 to 20; p = .09); 44.5% of patients in the DBS group achieved a ≥50% reduction in seizure frequency compared to 27% in the BMT group. Within-group analyses showed significant seizure reductions in the DBS group at both 12 months (-44%, p < .001) and 24 months (-46%, p < .001), as well as in the delayed DBS group at 12 months (-36%, IQR = -73 to -4; p < .001). No significant differences in quality of life were observed between groups, and no major DBS-related adverse events were reported. Our study suggests a potential benefit rather than demonstrating superiority of ANT-DBS over medical therapy. However, within-group improvements and favorable safety profile support the use of ANT-DBS as a palliative treatment option in patients with DRE who have failed VNS.
Sialidosis type I (ST-1) is an autosomal-recessive, very rare, progressive lysosomal storage disorder caused by pathogenic variants in NEU1. It is clinically characterized by progressive ataxia, myoclonic seizures (MS), bilateral tonic-clonic seizures (BTCS), and distinctive ophthalmological findings. Given the lack of curative options, in this study, we investigated symptomatic treatment strategies, with a particular focus on the efficacy of antiseizure medications (ASMs). We describe the clinical course of a patient followed from diagnosis to 18 years of age, and review seven additional cases from our cohort. In parallel, we conducted a narrative review of the literature (PubMed, January 2010-September 2025) to identify published reports containing therapeutic data. Therapeutic responses were evaluated in a total of 33 cases (8 from our cohort, 25 from published sources). Although available data are insufficient to define standardized treatment guidelines, some ASMs, such as ACZ, PER, LEV, VPA, CZP, and ZNS, demonstrated fairly consistent efficacy in managing MS and BTCS. Sodium oxybate or deep-brain stimulation may be considered in refractory cases. Prospective documentation of clinical course and treatment outcomes-ideally through an international registry-is crucial to improve patient care and inform therapeutic strategies. Sialidosis type I (ST-1) is a very rare genetic disorder causing movement problems and seizures, with no cure available yet. We followed 8 patients and reviewed 25 published cases to assess treatments focusing on myoclonic seizure (MS) control. Some antiseizure medications showed benefit. However, we have too little data to make clear recommendations. To improve patients' treatment and to choose the most appropriate therapy, it would be important to follow patients over a longer period of time, for example, in an international registry.
Treatment selection for infantile epileptic spasms syndrome (IESS) is complex and multifaceted, and currently no electroencephalogram (EEG) biomarkers can guide this decision by predicting treatment response. We tested the predictive value of phase-amplitude coupling (PAC) as IESS patients are known to have elevated PAC. We analyzed retrospective EEG recordings from 40 IESS patients, before and after treatment, and 20 healthy controls. Patients were classified as responders (n = 25) or nonresponders (n = 15) based on short-term treatment outcomes. We measured PAC in each EEG using modulation index (MI) and mean vector length (MVL) and analyzed the relationship between pre- and posttreatment values and the ability of pretreatment values to predict response. MI and MVL values decreased with treatment in almost all subjects. However, nonresponders had significantly higher pretreatment MI than responders (p < 0.05), suggesting utility for predicting treatment response. Logistic regression modeling suggested that a 0.5-unit decrease in ln(MI), which is approximately one IQR of the pretreatment ln(MI) values, results in a 3.5-fold increase in odds of positive treatment response. MI reflects short-term treatment response and is a candidate predictive EEG biomarker for IESS. MI may offer individualized insights for treatment selection and management strategies for IESS. We examined brain activity in infants with infantile epileptic spasms syndrome (IESS) to predict which infants' seizures would stop with standard medication. Specifically, we measured coupling between slow and fast brain waves in both healthy infants and those with IESS. Infants for whom medication failed had stronger coupling, even before the treatment was started, while those with weaker coupling (more similar to healthy infants) were more likely to have their seizures stop after treatment. These findings suggest that brain wave coupling could help doctors predict which infants will need more aggressive treatment.
Human telomerase reverse transcriptase (hTERT) is a key determinant of telomere maintenance and cellular aging. Oxidative stress plays a role in neurodegenerative processes by causing cellular damage through increased reactive oxygen species. Our study aimed to reveal the relationship between hTERT and oxidative stress in the pathophysiology of epilepsy. The study included 45 individuals diagnosed with epilepsy and 55 healthy controls. hTERT concentration, total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase (SOD), and thiol-disulfide homeostasis were measured in serum samples. A significant decrease in hTERT levels, an increase in oxidative stress markers (TOS, OSI), and a decrease in antioxidant levels (TAS, SOD), and total and native thiol levels were determined in epilepsy patients. In addition, a significant and negative correlation was found between hTERT and native thiol. Our study suggested that the interaction between oxidative stress and hTERT levels in the pathophysiology of epilepsy may play an important role in seizure generation and progressive neural damage. This study will form the basis for further research and guide the identification of potential biomarkers for treating epilepsy. We measured the levels of a protective protein that helps preserve chromosomes and several markers of cell stress in people with epilepsy and healthy volunteers. People with epilepsy showed lower levels of this protective protein, weaker antioxidant defenses, and higher oxidative stress. We also found that lower protein levels were linked to fewer molecules that guard cells from damage. These changes may help explain why seizures occur and why the brain can suffer ongoing injury in epilepsy.
National prescribing trends for antiseizure medication (ASM) in children with epilepsy over the past decade are unclear. Despite the 2021 SANAD II trials supporting lamotrigine and valproate for focal and generalized epilepsies, respectively, it is unknown if their use increased. This study evaluated ASM prescriptions in the U.S. before and after publication of high-quality clinical trials. A retrospective cross-sectional cohort study was conducted using the Epic Cosmos Dataset, a national electronic health record repository covering over 300 million patients. Children with epilepsy aged 4-18 years prescribed their first ASM between 2015 and 2024 were included, excluding those with absence epilepsy. The primary outcome was the prescribed ASM, analyzed by year and patient demographics. Among 146 395 children with a single ASM prescription, levetiracetam was most common (58%), increasing from 47% in 2015 to 66% in 2024. Lamotrigine and valproate declined (10%-5.5% and 12%-7.5%, respectively). Females were prescribed less valproate (5% vs. 12% in males). Odds of lamotrigine prescription (OR, 95% CI) were lowest among patients in the highest social vulnerability index quartile (0.71, 0.67-0.75), Black (0.39, 0.36-0.42), Asian (0.49, 0.42-0.57), Hispanic/Latino (0.60, 0.56-0.64), and male (0.60, 0.57-0.62) patients. While a reduction in valproate was anticipated given increasing teratogenic concerns, lamotrigine prescriptions for children in the U.S. declined despite evidence of its superiority over other commonly used ASMs. This trend is more prominent in racial and ethnic minorities and those with higher social vulnerability. Interventions are needed to ensure children receive evidence-based, equitable care. Some seizure medications work better than others, and clinical trials have shown lamotrigine to be among the most effective and best-tolerated first treatments for children with epilepsy. Using a large national database of over 146 000 children, we found that lamotrigine prescriptions declined steadily from 2015 to 2024, while the use of levetiracetam, a less effective alternative, continued to rise. This trend was most pronounced in Black, Hispanic, and socially vulnerable children, suggesting that many children are not receiving evidence-based care and that existing inequities in epilepsy treatment are worsening.
Expanded indications, diagnostic tools, and treatment options have transformed the landscape of modern pediatric epilepsy surgery. Published real-world experiences from large surgical cohorts are still needed. To close this gap, we evaluated access, indications, treatment, and outcomes in a contemporary pediatric epilepsy surgery program. We evaluated data from 100 consecutive diagnostic and therapeutic procedures in 62 pediatric and young adult patients. Data collected included demographics, diagnostics, procedures, 12-month seizure and medication outcomes, and adverse events. Primary outcome for patients who underwent treatment with the goal of cure or resection, along with the intent of palliation, was 12-month postoperative Engel/ILAE scores. For those who underwent RNS-implant (alone or in combination with a second procedure) with the goal of seizure reduction, the primary outcome was proportion seizure reduction in the prior 28 days at 12 months postoperatively. Patients largely matched state and regional demographics. Epilepsy types included unifocal (n = 33, 53.2%), multifocal (n = 15, 24.2%), generalized (n = 12, 19.4%), and combined (n = 2, 3.2%). Of the 100 procedures, 36.0% were diagnostic SEEG (n = 35) and 64.0% were treatment procedures (n = 58; note: n = 4 pending). Among patients who underwent surgical treatment with the goal of cure (n = 33), a 12-month Engel I/ILAE I or III outcome was achieved in 81.8% (n = 27). Among patients who underwent RNS implantation, 79.0% were responders (>50% reduction) and 38.0% were super-responders (>90% reduction), with a median seizure reduction of 78% at 12 months. Three treatment procedures (4.7%, n = 3 patients) had a surgical complication, none permanent. Contemporary pediatric epilepsy surgery, utilizing modern diagnostic and surgical techniques, including off-label use of RNS, provides safe, effective, accessible, and equitable treatment to children across a broad range of indications, many of whom, historically, have not been considered viable surgical candidates. "In this article by McLaren et al, 100 consecutive procedures were examined from a modern pediatric epilepsy surgery program. By utilizing advanced diagnostic and surgical techniques, they've shown that pediatric epilepsy surgery can be safe, effective, and accessible across diverse conditions and demographics. Notably, 82% of patients who underwent surgery aimed at curing their condition achieved seizure-freedom in 12 months and 79% of patients with Responsive Neurostimulation (RNS) implants experienced significant seizure reduction."
Focal epilepsy is characterized by progressive cortical thinning, particularly within limbic structures; however, whether this atrophy reflects acquired seizure-induced damage or shared genetic predisposition remains unresolved. We integrated genome-wide association study (GWAS) summary statistics from the ILAE Consortium (focal epilepsy: 15212 cases; 29 677 controls), ENIGMA (cortical thickness: N = 33 992), and COGENT (cognitive function: N = 257 841) using linkage disequilibrium score regression and genomic structural equation modeling (Genomic SEM). A latent cortical factor (F-EpiCortex) was derived and interrogated through MAGMA gene-based analysis, cell-type-specific Mendelian randomization (csMR) using brain single-cell expression quantitative trait loci, and spatial transcriptomic mapping (gsMap) across mouse embryonic and human cortical datasets. Focal epilepsy exhibited significant negative genetic correlations with cingulate cortical thickness (rg = -0.23 to -0.27; p < 0.05). Genomic SEM identified a well-fitting two-factor model (CFI = 0.916) wherein focal epilepsy genetic liability was associated with reduced cortical thickness (β = -0.30; p = 0.02), while cognitive function showed a protective association (β = 0.10; p = 0.04). GWAS of the F-EpiCortex latent factor identified nine genome-wide significant loci, with DPYSL5 (p = 1.88 × 10-11) as the lead signal. Cell-type-specific analysis revealed oligodendrocytes as the predominant cellular mediator, with DPYSL5 (β = -0.21; p = 1.3 × 10-10) and SLC16A8 (β = -0.28; p = 8.9 × 10-8) exhibiting robust protective effects predominantly within the oligodendrocyte lineage. Spatial transcriptomic validation confirmed oligodendrocyte enrichment across human cingulate and temporal cortices, with 70% concordance between csMR predictions and spatial expression patterns. Experimental validation in human oligodendrocytes under glutamate-induced excitotoxic stress demonstrated significant downregulation of the prioritized protective proteins, providing functional evidence for their susceptibility to epilepsy-associated injury. These findings implicate oligodendrocyte dysfunction as a shared genetic component linking focal epilepsy to cortical atrophy. This extends the "scars of seizures" paradigm by supporting a complementary neurodevelopmental origin model, with implications for neuroprotective therapeutic strategies. Focal epilepsy is often accompanied by a progressive thinning of the brain's cortex, which has traditionally been viewed purely as cumulative damage from repeated seizures. In this study, we investigated whether an underlying genetic predisposition also plays a role. By analyzing large-scale genetic and brain imaging datasets, we discovered a shared genetic link between focal epilepsy and cortical thinning. Furthermore, we traced this genetic vulnerability specifically to oligodendrocytes-the cells responsible for supporting and insulating nerve fibers. Our findings suggest that cortical thinning is not merely a "scar" from seizures, but partly a preexisting structural vulnerability driven by reduced protective functions of specific genes (such as DPYSL5 and SLC16A8) in these support cells. This offers a new perspective on preventing brain structural changes in epilepsy.
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 SUMMARY: This 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.
Despite advancements in "autoimmune epilepsy," more accurately referred to herein as seizures or epilepsy of autoimmune etiology, significant variability exists in its recognition, diagnosis, and management internationally. This study assessed clinicians' understanding, access to diagnostic tools, and treatment practices across global regions. An online survey, "Recognizing Autoimmune Seizures" was disseminated globally through professional networks including the Canadian League Against Epilepsy (CLAE), International League Against Epilepsy (ILAE), Young Epilepsy Section (YES), and American Epilepsy Society (AES). The survey included 157 respondents: adult neurologists (50%), pediatric neurologists (38%), other healthcare professionals (8%), and trainees (6%). Although 69% reported familiarity with updated ILAE definitions for seizures or epilepsy of autoimmune etiology, 43% noted difficulty with clinical identification. Familiarity varied significantly by region (p = 0.024) and was highest in Europe (76%) and Asia/South/Central America (73%) versus North America (50%). In Asia and South/Central America, 66% of respondents reported difficulty accessing neural antibody testing, compared with 22% in North America and 17% in Europe (p < 0.001), largely due to financial barriers in resource-limited regions (87%; p < 0.001). As a result, clinicians in these settings more frequently treated patients empirically with immunotherapy without confirmatory testing (72%; p < 0.001). Further, adult providers more often identified anti-GAD65 (73% vs. 52%), anti-LGI1 (83% vs. 36%), and paraneoplastic antibodies (79% vs. 31%), whereas pediatric clinicians more frequently encountered anti-MOG-associated seizures (84% vs. 58%; all p ≤ 0.015). The survey highlights a clear knowledge-to-practice gap in the recognition and diagnosis of seizures or epilepsy of autoimmune etiology. While many are familiar with conceptual definitions, a substantial proportion lack confidence in clinical identification. Respondents emphasized that both knowledge gaps and limited access to diagnostic resources contribute to ongoing disparities in care. There is a pressing need for regionally tailored international initiatives to facilitate clinician education and improve equitable access to neural antibody testing. This global survey of 157 clinicians found that while familiarity with conceptual definitions of seizures and epilepsy of autoimmune etiology was high, clinical recognition remained limited, revealing a clear knowledge-to-practice gap. Familiarity varied by region, highest in Europe and South/Central America and Asia, and lowest in North America. Access to neural antibody testing was most constrained in Asia and South/Central America, where limited public funding and high out-of-pocket costs were major barriers, leading clinicians to rely more often on empirical immunotherapy. These regional differences highlight the need for context-specific strategies rather than one-size-fits-all solutions to improve equitable care.
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 SUMMARY: The 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.
Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Fifty-three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single-center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non-responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non-responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non-responders (4/17). Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add-on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.