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.
暂无摘要（点击查看详情）
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.
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.
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.
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.
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.
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.
Convulsive status epilepticus (CSE) is a major neurological emergency in childhood, but population-based data from low- and middle-income countries remain limited. We estimated the incidence, mortality, neurological outcomes, and predictors of adverse outcomes among children with CSE in Kano, northern Nigeria. We conducted a review of one-year surveillance data on childhood CSE across eight hospitals and a random sample of eight primary health centers in the Kano metropolis. Cases were identified using standardized definitions and weighted to account for sampling at primary health centers. Demographic and clinical data were collected at presentation and during hospitalization. Logistic regression analysis was used to identify predictors of mortality and new-onset neurological deficits. A total of 972 children with CSE were identified at participating hospitals, with additional cases detected at primary health centers. After weighting, an estimated 1921 CSE cases occurred during the study period, corresponding to an annual incidence of 98 per 100 000 children aged 1 month-14 years. Incidence was highest among infants (175 per 100 000). Among hospitalized children, in-hospital mortality was 24.7%, with more than half of the deaths occurring within 24 h of admission. New-onset neurologic deficits were observed in 9.6% of hospitalized survivors. In multivariable analysis, hypoglycemia at presentation, presumed meningoencephalitis, and CSE lasting longer than 30 min were independently associated with increased odds of death. Neurological deficits were associated with multiple CSE episodes, prolonged seizures, and presumed meningoencephalitis. Childhood CSE in Kano is associated with a high incidence and substantial mortality, particularly among infants. Hypoglycemia, central nervous system infections, and prolonged seizures are key predictors of adverse outcomes. These findings highlight the need for improved early recognition and strengthened emergency seizure management in resource-limited settings. Convulsive status epilepticus is a dangerous type of prolonged seizure in children. In this study from Kano, Nigeria, many children developed this condition and about one in four hospitalized patients died. Low blood sugar, suspected brain infections, and long seizures increased the risk of poor outcomes. Improving early treatment and emergency care may help reduce these deaths.
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.
This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10-22.5) years, with a median (IQR) follow-up of 21 (14-33) months. All dup15q and two AS patients presented with a Lennox-Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7-72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression-Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q-DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. PLAIN LANGUAGE SUMMARY: Epilepsy secondary to 15q11.2-q13.1 duplication or deletion syndromes (15q-DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q-DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q-DDS.
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.
Epicranial focal cortex stimulation (FCS) is a new CE-certified treatment for pharmacoresistant focal epilepsy. In a multicenter observational trial, we report cognitive tolerability in 11 patients with pharmacoresistant epilepsy undergoing epicranial focal cortex stimulation (eFCS) over the predominant seizure focus (left temporal (N = 4), central (N = 2 right, N = 1 left), left frontal (N = 2), left temporoparietal (N = 1), and left frontoparietal (N = 1)). Extensive cognitive assessment focused on domains represented in the stimulated areas and was compared between baseline and first and last follow-up (after a median 35 months of stimulation). Based on the reliable change index, the majority of patients remained cognitively stable; 3/11 patients showed improvements in more than one cognitive parameter at both follow-up assessments. Isolated task parameters deteriorated exclusively at one time point; no patient revealed consistent worsening. Cognitive changes did not correspond to stimulation site or seizure outcome. Overall, the results from this case study provide preliminary evidence of stable cognitive functioning under focal cortical stimulation even if performed over eloquent brain regions. These findings are limited by the patient sample size and medication changes in part of the patients and need corroboration in larger patient cohorts. PLAIN LANGUAGE SUMMARY: We report on preliminary results of a new brain stimulation treatment for epilepsy that doesn't respond to medication. Over about 3 years, 11 patients showed stable cognitive performance, some even improved, and no patient had lasting declines. These results provide preliminary evidence that the treatment is generally safe for brain function. However, larger studies are needed to confirm these findings.
Glut1 deficiency syndrome (Glut1DS) leads to neurological and cognitive symptoms and is primarily treated using carbohydrate-restricted ketogenic diets. However, a recent clinical trial of a less restrictive, non-ketogenic, medium chain triglyceride (MCT) diet with a high decanoic acid content suggests efficacy in Glut1DS treatment. Here, we employ human Glut1DS-derived iPSCs to investigate a role for these medium chain fatty acids in the regulation of gene expression as a proxy for metabolic reprogramming. We show that the new high decanoic blend reproduces many therapeutic changes in energy metabolism-related gene expression seen during glucose-restricted ketogenic diets, including enhanced expression of β-oxidation, TCA cycle, and oxidative phosphorylation-related genes, but under high glucose conditions. These treatments also unexpectedly regulate transcription of adenosine signaling and synaptic transmission-related genes. This study thus identifies potential molecular mechanisms of decanoic acid that may underlie its clinical benefit in Glut1DS and expands its role to other genetic epilepsies. PLAIN LANGUAGE SUMMARY: Ketogenic diets provide the first-choice treatment for glucose transporter type 1 deficiency syndrome (Glut1DS), where reduced carbohydrate intake triggers the production of ketones as the therapeutic mechanism. Alternatively, a new, flexible medium chain triglyceride diet has been developed that does not involve reduced carbohydrate restriction nor ketone production. This study investigates the metabolic mechanisms underlying this diet in Glut1DS patient-derived stem cells. Interestingly, the diet mimicked the beneficial effects of ketogenic diets to improve energy metabolism, and surprisingly indicated new ways that the diet may provide therapeutic benefit in Glut1DS treatment.
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 objective of this study was to assess feasibility of a remotely delivered physical activity intervention in adults with epilepsy. Adults with epilepsy and at least one seizure in the prior six months were randomized 2:1 to either a physical activity intervention or a healthy living education control arm. The intervention group received a 12-week program led by a trained health coach aimed to progressively increase daily steps while the control group received biweekly telephone education on healthy living. Sustainability was assessed at 12 weeks post-intervention. Daily steps and activity intensity were continuously measured by a Garmin Forerunner 45. A total of 21 participants were randomized (15 intervention; 6 control), and 17 completed the full study (14; 3). There was high retention (93%), attendance (80%), and acceptability in the intervention group. While the proportion of the intervention group who strictly adhered to their daily step goal was low (26.67%; 95% CI 0.076 - 0.581), there was a significant increase in mean daily steps (3495 (95% CI 2,170-4,821) to 5591(4,271-6,911), p < 0.001) and mean daily moderate-to-vigorous intensity activity minutes (17.98 (5.55-30.41) to 30.11 (17.93-42.28), p < 0.001) in the intervention group compared to the control group. Both measures remained elevated at follow-up (4,758 (3,437-6,079) and 35.26 (23.03-47.49), respectively) while the control group showed no statistically significant changes over time. A remotely delivered daily steps-based physical activity intervention is feasible for people with epilepsy and shows promising immediate and sustainable effects on physical activity behaviors.
The interplay between chronic sleep deprivation and drug-resistant epilepsy (DRE) has gained increasing attention. Brain and muscle Arnt-like protein 1 (BMAL1), which is implicated in sleep disturbance, has an unclear role in DRE. We aimed to investigate the role of BMAL1 in sleep deprivation-induced DRE. A pentylenetetrazole (PTZ) kindling epilepsy model was established to explore the impact of chronic sleep deprivation on pharmacoresistance and related molecular expression. BMAL1 was either overexpressed or knocked down in epileptic rats using adeno-associated viral vectors, and pharmacoresistance together with hippocampal protein levels were assessed. Complementary in vitro experiments in brain endothelial cells and astrocytes further evaluated the effects of BMAL1 on Per2, P-S6, and P-gp. Chronic sleep deprivation significantly increased pharmacoresistance, accompanied by reduced BMAL1 and Per2, elevated P-S6, and increased P-glycoprotein (P-gp) expression in the hippocampus. In vitro experiments confirmed that BMAL1 regulates P-gp through the mTOR pathway. In vivo, BMAL1 overexpression attenuated chronic sleep deprivation-induced pharmacoresistance, restoring Per2, inhibiting the mTOR pathway, and reducing P-gp levels. Conversely, BMAL1 knockdown promoted pharmacoresistance in epileptic rats with normal sleep, with decreased Per2, increased P-S6, and elevated P-gp. These findings indicate that BMAL1 is an important mediator linking chronic sleep deprivation to pharmacoresistance in epilepsy, and suggest the BMAL1-mTOR-P-gp axis as a potential therapeutic target for drug-resistant epilepsy. Drug-resistant epilepsy remains a major clinical challenge, and sleep loss increases its risk. We found that chronic sleep loss reduces BMAL1, a protein that helps regulate sleep. In experiments with rats and brain cells, altering BMAL1 levels changed P-glycoprotein via the mTOR pathway. These changes in P-glycoprotein then influenced the response to anti-seizure medicines. The study showed that targeting BMAL1 may be a new treatment for drug-resistant epilepsy.