Therapy For Epilepsy Research Articles

Association between seizure reduction during ketogenic diet treatment of epilepsy and changes in circulatory metabolites and gut microbiota composition

The ketogenic diet (KD) is a high fat, sufficient protein, and low carbohydrate dietary therapy for drug-resistant epilepsy. The underlying mechanisms of action of the KD remain unclear. In mice, the microbiota is necessary for the anti-seizure effect and specific microbes influence circulatory levels of metabolites that are linked to seizure reduction. However, it remains unclear which changes are linked to seizure reduction in patients with epilepsy. We analysed the serum metabolome of children with drug-resistant epilepsy (n=14) before and after three months on KD. Metabolomic changes were correlated to the gut microbiome and treatment outcome, i.e., seizure reduction. In this prospective observational study, we uncovered associations between microbial species and serum metabolites that correlated with seizure reduction. Plasmalogens were most strongly linked to seizure reduction and had significant positive correlations with several gut microbes (e.g., Faecalibacterium prausnitzii, Alistipes communis, Alistipes shahii, and Christensenella minuta) while significant negative correlations were found for five strains of Escherichia coli. Infant-type Bifidobacteria correlated negatively with other metabolites associated with seizure reduction. The microbes and metabolites identified here may contribute to the therapeutic effect of the KD in children with drug-resistant epilepsy. Several of these metabolites (e.g., plasmalogens) play important roles in neurobiology and may influence seizures. Based on our findings, anti-seizure therapeutic strategies could be developed involving the targeted manipulation of the gut microbiota and/or its metabolites. This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Sunnerdahls Handikappfond, Stockholm County Council Research Funds, and Linnea & Josef Carlssons Foundation.

Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.

Developmental and epileptic encephalopathies (DEEs) can result from dominant, gain of function variants of neuronal ion channels. More than 450 de novo missense variants of the sodium channel gene SCN8A have been identified in individuals with DEE. We studied a mouse model carrying the patient Scn8a variant p.Asn1768Asp. An AAV-PHP.eB virus carrying an allele-specific single guide RNA (sgRNA) was administered by intracerebroventricular injection. Cas9 was provided by an inherited transgene. Allele-specific disruption of the reading frame of the pathogenic transcript generated out-of-frame indels in 1/4 to 1/3 of transcripts throughout the brain. This editing efficiency was sufficient to rescue lethality and seizures. Neuronal hyperexcitability was reduced in cells expressing the virus. The data demonstrate efficient allele-specific editing of a dominant missense variant and support the feasibility of allele-specific therapy for DEE epilepsy. ANN NEUROL 2024;96:958-969.

Effectiveness and safety analysis of ketogenic diet therapy for drug-resistant epilepsy caused by structural pathology

ObjectiveTo explore the effectiveness and safety of the ketogenic diet (KD) in children with drug resistant epilepsy (DRE) caused by structural etiology.MethodsThe children were categorized into acquired brain injury group and malformations of cortical development (MCD) group based on the etiology. Follow-up assessments were performed at 1, 3, and 6 months after KD treatment to observe seizure reduction, behavioral and cognitive improvements, adverse reactions events, and reasons for discontinuation withdrawal. Statistical analysis was conducted on the results.ResultsWe found the seizure-free rates at 1, 3, and 6 months were 4.8% (2/42), 19% (8/42), and 21.4% (9/42), respectively. The seizure control effective rates were 42.9% (18/42), 52.4% (22/42), and 54.8% (23/42) at the corresponding time points. Compared to the acquired brain injury group, the MCD group showed a higher seizure control effective rate. Further analysis within the MCD group revealed the highest efficacy in focal cortical dysplasia (FCD). At the 3-month follow-up, cognitive and behavioral improvements were observed in 69% (29/42) of children. The main reasons for discontinuation were lack of efficacy and poor compliance.SignificanceFinally, we get that KD is a safe and effective treatment for drug resistant epilepsy caused by structural etiology, with the added benefit of improving behavioral and cognitive abilities in children. The efficacy is higher in children with MCD, particularly in cases of FCD. Early intervention with KD is recommended for this population.

Efficacy and safety of traditional Chinese medicine for the treatment of epilepsy by wind quenching and phlegm resolving: A systematic review and meta-analysis.

Using wind-quenching and phlegm-resolving (WQPR) therapy for epilepsy has yielded beneficial results in various clinical studies. However, a comprehensive analysis of the WQPR approach to epilepsy has not yet conducted to date. This study aimed to evaluate the effectiveness and safety of the WQPR method in traditional Chinese medicine (TCM) for epilepsy. Eight databases, including The Cochrane Library, Web of Science, PubMed, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), and WanFang Database, were comprehensively searched to include randomized controlled trials (RCTs) investigating the WQPR approach in epilepsy. Quality was evaluated by the Cochrane Handbook for Systematic Reviews of Interventions, and meta-analysis was conducted using the RevMan 5.4 and Stata 14.0 software. For the outcome indicators with the number of studies ≥ 10, funnel chart and Egger test were used to evaluate the bias, and the evidence quality was evaluated according to GRADEpro system. We included 19 randomized controlled trials with 1475 participants. Compared to the control group, the WQPR approach showed clinical efficacy for epilepsy (odds ratio = 3.23, 95% confidence interval [CI] [2.19, 4.77], Z = 5.90, P < .00001), reduced seizure frequency (standardized mean differences = -1.24, 95% CI [-1.62, -0.85], Z = 6.26, P < .00001), shortened seizure duration (standardized mean differences = -2.07, 95% CI [-2.99, -1.14], Z = 4.39, P < .0001), improved patient's quality of life (mean difference = 2.60, 95% CI [2.16, 3.03], Z = 11.62, P < .00001), and ameliorated TCM syndromes (mean difference = -4.37, 95% CI [-6.19, -2.56], Z = 4.72, P < .00001). The reduced rate of adverse reactions (odds ratio = 0.56, 95% CI [0.37, 0.85], Z = 2.71, P = .007). WQPR therapy appears to be an effective and safe approach for treating epilepsy, increasing clinical efficacy, reducing seizures' frequency and duration, improving patients' quality of life, ameliorating TCM syndromes, and reducing adverse reaction rates.

Пути оптимизации антропометрических параметров у детей с фармакорезистентной эпилепсией, получающих кетогенную диетотерапию

Ketogenic diet (KD) whilst being an effective method of diet therapy for drug-resistant epilepsy (DRE) is nevertheless accompanied by a significant number of side effects that include the possibility for the delayed physical development in pediatric patients. The problem is multifactorial and is primarily associated with the non-physiological nature of the ketogenic diet itself. Foreign studies on the KD effect on the physical development in children are contradictory and there are none domestic ones. The purpose of this research was to study the dynamics of anthropometric parameters in children with DRE against the background of KD and to assess the possibilities of the alimentary factor in its improvement. Materials and methods used: single-center retrospective cohort study had been carried out on the basis of the Russian Federal Research Centre for Nutrition, Biotechnology and Food Safety (Moscow, Russia) in 2016-2024. The study included patients with an established diagnosis of DRE against the background of KD aged 1 to 18 y/o. Patients were monitored for 24 months as follows: quarterly during the first year and semiannually during the second year of observation, using anthropometric, clinical-laboratory and clinical-instrumental research methods. Results: by the 3rd month of KD, out of 174 pediatric patients, the diet was effective in 105 (60%); by 12th month, 100% control over attacks was achieved in 11 (6%). Analysis of anthropometric parameters made it possible to establish that at the initial point of observation, in accordance with the z-score of the body mass index (BMI), 108 (64%) had normal nutritional status, 22 (13%) had malnutrition and 40 (24%) were overweight/obese. When studying the dynamics of weight and height indicators of children who were on KD throughout the observation period, it was found that the median BMI z-score statistically significantly changed upward (p=0.047), which was largely due to growth retardation, with a decrease in the height/age z-score throughout the observation period (p&lt;0.001). It was found that the protein component of the diet, as well as the level of ketonemia, have a significant impact on the dynamics of the BMI z-score in KD patients. The amount of protein in the diet at 6% to 7% of the energy value contributed to the maintenance of optimal growth parameters in children within this research. Conclusion: the significance of the BMI indicator in assessing the nutritional status over KD decreases against the background of growth retardation. Taking into account the value of the protein/energy indicator when calculating nutrition helps in maintaining of the physical development rate in such patients.

Nano-formulations for the Management of Epilepsy: Synthetic and Herbal Drug Perspectives

Introduction: Epilepsy is a multifaceted neurological disorder impacting many individuals globally. Although the main treatment method is through medicines, many patients do not respond to existing drugs. This has spurred extensive research for new therapeutic targets and drug delivery methods. Inflammation and oxidative stress have been associated with the development and progression of epilepsy. Nanomedicine-based treatments focussing on these pathways could provide a promising way to enhance treatment results. Objective: This review aims to provide insights into enhancing antiepileptic therapy through the development of nanoformulations of synthetic and herbal drugs. Methods: A comprehensive review of existing literature was conducted to evaluate the potential of nanoformulations in improving the delivery and efficacy of antiepileptic drugs. The review covers the pathophysiological hypotheses of epilepsy, including the glutamatergic, GABAergic, oxidative stress, and neuroinflammation hypotheses, and examines the role of neurotransmitter imbalances in seizure activity. Results: Nanoformulations offer promising advantages for epilepsy treatment by enhancing drug delivery across the blood-brain barrier, reducing required dosages, and minimizing side effects. The utilization of nanoparticles can improve the bioavailability and targeting of AEDs, potentially leading to better seizure control. However, challenges such as ensuring biocompatibility and optimizing nanoparticle characteristics remain. Conclusion: While significant progress has been made in understanding epilepsy and developing treatments, the disorder continues to pose challenges. Nanoformulations represent a promising area of research that could lead to more effective and targeted therapies for epilepsy, although further studies are needed to address the associated challenges and fully realize their potential.

Low-frequency stimulation of corpus callosum suppresses epileptiform activity in the cortex through γ-aminobutyric acid type B receptor and slow afterhyperpolarization-mediated reduction in tissue excitability.

Deep brain stimulation, particularly low-frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug-resistant epilepsy (DRE) and for generalized epilepsy, both of which pose significant treatment challenges. LFS diffusely suppresses seizures in the cortex when applied to fiber tracts like the corpus callosum (CC). Nevertheless, the specific processes responsible for suppressing epileptic activity in the cortex induced by LFS remain unclear. This study investigates the mechanisms underlying the antiepileptic effect in the cortex of LFS of the CC in coronal rodent brain slices. An invitro 4-aminopyridine (4-AP) seizure model of cortical seizures was generated. LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in artificial cerebrospinal fluid, 4-AP, and in the presence of various specific and nonspecific γ-aminobutyric acid type B (GABAB) and slow afterhyperpolarization (sAHP) antagonists. LFS significantly suppressed seizure activity in the cortex, with an optimal frequency of 5 Hz (76.5%). Tissue excitability during LFS reduces across a wide range of interstimulus intervals, with a maximum reduction at 200 ms. Notably, the tissue excitability remains depressed at 1000 ms. LFS, in the presence of GABAB antagonists, had diminished seizure reduction (<15%) and failed to reduce tissue excitability in the 50-400-ms range. Tissue excitability measured with paired pulses in the 600-1000-ms range was depressed in the presence of GABAB antagonists, suggesting a different antiepileptic mechanism was active. Upon administering sAHP antagonists, seizure reduction was once again diminished (<15%). Upon administration of both sAHP and GABAB antagonists, LFS failed to provide any meaningful seizure reduction (<5%). LFS of the CC provides an antiepileptic effect in the cortex with well-understood mechanisms and could be an alternative to surgical intervention for patients suffering from DRE.

Vagus nerve stimulation for epilepsy: A narrative review of factors predictive of response.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality-specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1-weighted MRI morphometrics and EEG may provide better strategies for treatment optimization.

Overcoming Graft Rejection in Induced Pluripotent Stem Cell-Derived Inhibitory Interneurons for Drug-Resistant Epilepsy.

Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson's disease (PD) and Huntington's disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Non-systematic literature review. While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity.

Unraveling Epilepsy: Investigating stem cell approaches for innovative treatment and future cure

Epilepsy is a persistent neurological disorder characterized by repeated, spontaneous seizures that arise without a specific cause. These seizures result from abnormal electrical activity in the brain, leading to a range of symptoms, from brief periods of unconsciousness or minor sensory disturbances to severe convulsions. The management of epilepsy remains a significant challenge, as current treatment modalities, primarily involving antiepileptic drugs and surgical interventions to remove seizure foci, often provide adequate control for a substantial portion of patients. For this reason, stem cell therapies have become a hopeful approach because of their ability to potentially restore and renew impaired neural networks, which is particularly relevant for neurological disorders like epilepsy. This review investigates the present state of stem cell therapies in epilepsy, analyzing distinct types of stem cells, their mode of action, preclinical and clinical trials, as well as future research prospects.

Recent advances and current status of gene therapy for epilepsy.

Epilepsy is a common neurological disorder with complex pathogenic mechanisms, and refractory epilepsy often lacks effective treatments. Gene therapy is a promising therapeutic option, with various preclinical experiments achieving positive results, some of which have progressed to clinical studies. This narrative review was conducted by searching for papers published in PubMed/MEDLINE with the following single and/or combination keywords: epilepsy, children, neurodevelopmental disorders, genetics, gene therapy, vectors, transgenes, receptors, ion channels, micro RNAs (miRNAs), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9 (CRISPR/Cas9), expression regulation, optogenetics, chemical genetics, mitochondrial epilepsy, challenges, ethics, and disease models. Currently, gene therapy research in epilepsy primarily focuses on symptoms attenuationmediated by viral vectors such as adeno-associated virus and other types. Advances in gene therapy technologies, such as CRISPR/Cas9, have provided a new direction for epilepsy treatment. However, the clinical application still faces several challenges, including issues related to vectors, models, expression controllability, and ethical considerations. Here, we summarize the relevant research and clinical advances in gene therapy for epilepsy and outline the challenges facing its clinical application. In addition to the shortcomings inherent in gene therapy components, the reconfiguration of excitatory and inhibitory properties in epilepsy treatment is a delicate process. On-demand, cell-autonomous treatments and multidisciplinary collaborations may be crucial in addressing these issues. Understanding gene therapy for epilepsy will help clinicians gain a clearer perception of the research progress and challenges, guiding the design of future clinical protocols and research decisions.

One-year follow-up of neurobehavioral therapy in functional seizures or epilepsy with traumatic brain injury: A nonrandomized controlled trial.

Patients with traumatic brain injury (TBI) often present with seizures (functional and/or epileptic), but treatments for patients with TBI and seizures are limited. We examined treatment phase and 1-year post-enrollment outcomes following neurobehavioral therapy (NBT) for patients with TBI + functional seizures (FS) and TBI + epilepsy. In this multicenter, prospective, three-group, nonrandomized, controlled trial, with 1-year post-enrollment follow-up, three cohorts of adults were recruited: TBI + video-electroencephalography (EEG)-confirmed FS (n = 89), TBI + EEG-confirmed epilepsy (n = 29), and chart/history-confirmed TBI without seizures (n = 75). Exclusion criteria were recent psychotic or self-injurious behavior, current suicidal ideation, pending litigation or long-term disability, active substance use disorder, and inability to participate in study procedures. TBI + FS and TBI + epilepsy groups completed NBT for seizures, an evidence-based, 12-session, multimodal psychotherapy, whereas TBI without seizures participants received standard medical care. The primary outcome was change in seizure frequency; secondary outcomes were changes in mental health, TBI-related symptoms, disability, and quality of life. Reductions in average monthly seizures occurred during treatment in TBI + FS participants (p = .002) and were significant from baseline (mean = 16.75; 95% confidence interval [CI] = 11.44-24.53) to 12 months post-enrollment (mean = 7.28, 95% CI = 4.37-12.13, p = .002, d = .38). Monthly seizures decreased during treatment in TBI + epilepsy participants (p = .002); reductions were not statistically significant from baseline (mean = 2.38, 95% CI = 1.12-5.04) to 12-month postenrollment (mean = .98, 95% CI = .40-2.42, p = .07, d = .22). Regarding treatment-phase changes in secondary outcome measures, TBI + FS participants improved significantly on 10 of 19 variables (52.6%), TBI + epilepsy participants improved on five of 19 (26.3%), and TBI-onlycomparisons improved on only one of 19 (5.3%). NBT benefited patients with TBI + FS and TBI + epilepsy. Improvements were demonstrated at 1 year post-enrollment in those with TBI + FS. NBT may be a clinically useful treatment for patients with seizures.

Responsive neurostimulation of the frontal lobe for the detection and treatment of seizures in intractable epilepsy due to tuberous sclerosis complex: illustrative case.

Responsive neurostimulation (RNS) is often considered to be a palliative therapy for drug-resistant epilepsy (DRE) and is generally not considered to be a treatment for patients with tuberous sclerosis complex (TSC). Here, the authors present the case of a 24-year-old male with TSC who obtained seizure freedom following RNS device implantation. Prior to RNS device implantation, the patient underwent tuberectomies, subependymal giant cell astrocytoma resection, vagus nerve stimulator placement, and left frontal lobe resection but continued to have frequent seizures. An RNS device was implanted, which initially led to a decrease in seizures, but he continued to have 12 seizures per month. He then underwent lead revision for stimulation via a different electrode. After that lead change, he had no seizures for almost 3 years. In the following 3 years, he had two episodes of breakthrough seizures, both of which occurred with medication weans. Although the patient still requires antiseizure medication, he has had years of seizure freedom with RNS therapy. This study exhibits the potential effectiveness of RNS therapy for patients with TSC and DRE. RNS should be considered for patients with TSC when other therapies have not sufficiently treated their epilepsy. https://thejns.org/doi/10.3171/CASE23411.

Advancing Pediatric Epilepsy Care: Efficacy and Mechanisms of Melatonin Intervention

Seizures and epilepsies pose significant challenges in pediatric populations, necessitating precise classification and effective management. The International League Against Epilepsy updated its classification system in 2017 to standardize epilepsy care. This study investigated melatonin, a neurohormone known for its role in circadian rhythm regulation, and its potential to enhance the diagnosis, management, and quality of life of pediatric epilepsy patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted to explore the relationship between melatonin and pediatric epilepsies. PubMed searches were performed using specific search terms, with eligibility criteria including studies on melatonin’s pathophysiological, biochemical, and therapeutic effects in pediatric epilepsy. Studies involving patients aged 0-18 years were published between 2003 and 2023. Four-teen studies with 898 pediatric patients were included. Melatonin was administered as an adjunct to antiepileptic therapy with the aim of alleviating disorders associated with epileptic encephalopathies or assisting electroencephalogram procedures. Findings were varied: Some studies indicated a reduction in seizure frequency with melatonin, while others provided inconclusive results. Improvements in sleep disorders related to epilepsy were noted with melatonin supplementation, which indirectly enhanced the overall quality of life. Melatonin has potential as an adjunctive therapy for pediatric epilepsy, with positive effects on seizure frequency and sleep quality. However, methodological limitations in some studies and inconclusive data underscore the need for further research to determine the efficacy of melatonin in pediatric epilepsy management. The diverse potential of melatonin in treating neurological disorders highlights the importance of continued, comprehensive research into its therapeutic application.

A VAMS‐based LC–MS/MS method for precise cenobamate quantification in epilepsy (patients)

AbstractObjectiveCenobamate (CNB), a recently approved antiseizure medication by the European Medicines Agency (EMA), serves as an adjunctive therapy for focal‐onset seizures in adult patients unresponsive to at least two other treatments. Administered in polytherapy, CNB can potentially interact with co‐administered drugs in epilepsy patients, necessitating dose adjustments and the need for effective therapeutic drug monitoring (TDM).MethodsIn this study, we introduce a novel LC–MS/MS method for precise CNB quantification using Volumetric Absorptive Microsampling (VAMS), following validation according to ICH guidelines M10. VAMS samples are efficiently extracted with 200 μL of methanol, with chromatographic separation achieved using an Acquity UPLC HSS PFP column. The method's efficacy was confirmed through its application to real samples from adult CNB‐treated patients.ResultsOur results demonstrate that the method exhibits linearity within the range of 0.05–30 mg/L, with intra‐ and inter‐run precision ranging from 1% to 8% and accuracy from 1% to 10% based on 30 μL of sample. Furthermore, CNB stability in VAMS is confirmed for up to 15 days at 25°C and −20°C. Importantly, no significant difference was observed between CNB concentrations in VAMS samples and those in plasma obtained from venous blood.SignificanceThis VAMS‐based LC–MS/MS method presents a robust alternative for TDM in CNB‐treated patients. Future investigations should explore CNB concentrations in capillary blood and assess their correlation with plasma levels to further enhance its clinical utility.Plain Language SummaryCenobamate is an antiepileptic drug and used for treatment of focal‐onset seizures in adult patients (≥18 age). TDM can prevent drug interactions and minimize drug toxicity. The aim of this work is to evaluate volumetric absorptive microsampling (VAMS) from capillary blood as an alternative strategy for TDM in patients treated with the newly antiepileptic drug. Our method is suitable for TDM, and this study suggests that VAMS allows monitoring of cenobamate concentration and can offer valuable support for personalized therapy in refractory epilepsy.

Clinical efficacy and safety of perampanel monotherapy as primary anti-seizure medication in the treatment of pediatric epilepsy: A single-center, prospective, observational study.

To assess the efficacy and safety of perampanel (PER) as primary monotherapy in patients aged 4-18 years old with epilepsy. A single-center, prospective, observational study was conducted from October 2021 to October 2023, to evaluate PER monotherapy's efficacy and safety as initial therapy for pediatric epilepsy. Changes in seizure frequency, safety, and retention rate were observed at 3, 6, 9, and 12 months after initiating PER primary monotherapy. A total of 124 children aged 4-15 years (mean age = 8.25 ± 2.50 years) were included in the Analysis Sets. The retention rates at 3, 6, 9, and 12 months were 88.71% (110/124), 84.68% (105/124), 78.26% (90/115), and 71.58% (68/95), respectively. Seizure freedom rates at 3, 6, 9, and 12 months were 85.45%, 79.09%, 76.24%, and 75.31%, respectively. The responder rates (≥50% but <100%) at the same endpoints were 9.09%, 14.55%, 12.87%, and 7.41%, respectively. Seizure freedom rate of PER was independent of age at PER initiation, seizure onset age, gender, baseline frequency, seizure types, and family history of epilepsy (p > 0.05) but associated with duration of treatment (p = 0.001) and maintenance dose (p = 0.022). Additionally, 124 patients were included in the safety analysis set. The overall adverse event rate was 38.71% (48/124), with irritability (19 cases, 15.32%) and dizziness (18 cases, 14.52%) being the most common adverse effects. One patient discontinued PER monotherapy within 1 month due to unbearable itching of the skin. PER monotherapy as the primary anti-seizure medication (ASM) for pediatric epilepsy demonstrates high efficacy and safety in real-world clinical treatment. Patients who respond well to this drug and adhere to long-term treatment can achieve favorable seizure control. Furthermore, patients achieving seizure freedom with a relatively lower dose can opt for the same dose as the maintenance dose. This study provided the efficacy and safety of PER monotherapy as the primary ASM for Chinese pediatric epilepsy. In total, 124 patients took part. The seizure freedom rates were over 70% at different observation points (OPs), along with a retention rate of 71.58% at the 12-month OP. Most of adverse effects observed were mild to moderate.

Correlation between prescription volumes of generic antiepileptic drugs and the number of clinical epileptologists across prefectural regions in Japan: A descriptive study using a national claims database

PurposeAlthough generic drugs are essential in reducing medical costs, their use in epilepsy therapy remains a subject of ongoing debate. In this study, we analysed prescription trends of generic drugs using data from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. MethodsThe number of generic drug prescriptions from 2017–2021 was extracted from the NDB Open Data Japan, with data for each medication stratified by prefectural region, sex, and age, allowing for the analysis of the impact of each factor. We analysed the correlation between the prescription volumes of generic antiseizure medications (ASMs) and the number of clinical epileptologists registered with the Japan Epilepsy Society per 100,000 population. ResultsIn 2021, the prescription volume of generic ASMs was 49 %, whereas that for other pharmacological agents was between 70–80 %. Notably, for children < 15 years of age, generics made up approximately 20 % of prescriptions, which was significantly less than that in other age groups. Analysis by prefecture revealed a negative correlation between prescription volumes of ASMs and the number of clinical epileptologists across prefectural regions in Japan (R = −0.47, p < 0.01). ConclusionOur findings indicate that the higher the proportion of clinical epileptologists in each prefecture, the lower the number of prescribed generic ASMs. Clinical epileptologists in Japan therefore prescribe antiseizure agents in accordance with the Japanese epilepsy treatment guidelines that do not recommend the use of generic agents.

A randomized, double-blind, placebo-controlled, dose-escalating phase IIa trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of multiple oral doses of Pynegabine tablets as add-on therapy in patients with focal epilepsy.

This study aims to investigate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine as an add-on therapy in the treatment of focal epilepsy. This is a protocol phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in patients with focal epilepsy from multiple centers in China who have been treated with at least 2 ASMs without effective control. The study involves an 8-week run-in period with stable use of previous medications. Patients are then randomized to receive either Pynegabine or a placebo. Sentinel administration is performed initially, and subsequent patients are randomized based on safety assessments. Three dose cohorts (15, 20, and 25 mg/d) are established. Efficacy is assessed through various measures, including seizure frequency, CGI score, PGI score, HAMA score, HAMD score, MoCA scale score, QOLIE-31 scale score, and 12 h-EEG score. Safety evaluations, PK blood samples, concomitant medications, and adverse events are also recorded. Data from the study will be used to evaluate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine tablets as add-on therapy for focal epilepsy.

Danish population based study of familial epilepsy and childhood cancer.

Results from studies investigating the association between maternal or child epilepsy, use of anticonvulsants in pregnancy, and childhood cancer are inconsistent and at times contradictory. Linking Danish national databases, we obtained epilepsy and childhood cancer diagnoses, and anticonvulsant use data. We estimated adjusted odds ratios of all or specific childhood cancers in relation to maternal or child epilepsy and anticonvulsant therapies using conditional logistic regression. Maternal epilepsy was positively associated with all childhood cancers in offspring, specifically, with acute lymphoblastic leukemia (Odds Ratio (OR) = 1.68, 95% Confidence Interval (CI) = 1.16, 2.43) and Wilms tumor (OR = 2.13, 95% CI = 0.97, 4.68). When considering maternal ever (lifetime) ingestion of anticonvulsants, a positive association was found with all cancers (OR = 1.14, 95% CI = 1.00, 1.30), and central nervous system tumors (CNS) (OR = 1.36, 95% CI = 1.04, 1.76) as well as neuroblastoma (OR = 1.76, 95% CI = 1.06, 2.90) among offspring. Maternal anticonvulsant use before or during the index pregnancy was related to CNS tumors in offspring (OR = 1.99, 95% CI = 0.99, 4.00).

Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.

Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients. Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data. Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses. We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.