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Background: The use of antiseizure medication in patients with epilepsy is one of the significant risk factors associated with abnormal vitamin D status. We aimed to identify risk factors related to hypovitaminosis D in pediatric patients treated with antiseizure medications., Method: A cross-sectional retrospective cohort study was conducted on 127 pediatric epilepsy patients who received antiseizure drugs from December 2021 to December 2022. Demographic data, seizure types, diet, physical activity, duration, and types of antiseizure medications were analyzed., Results: Among the 127 patients in this study, 53% were male, and the mean age was 9,1 ± 4,6 years (range: 2-17). The mean serum 25(OH)D level at baseline in winter/autumn was 24,2 ± 14,2 ng/mL; 47.0% of the patients were 25(OH) D deficient, 23% were 25(OH)D insufficient, and 30% had a vitamin D level within the normal range. The vitamin 25(OH) D level was 27,6 ± 12,2 in the epilepsy group with non-enzyme-induced antiseizure drugs, 21,76 ± 19,7 in the group with enzyme-induced antiseizure drugs, and 13,96 ± 7,9 in the group with combined antiseizure drugs (p < 0.001)., Conclusion: The number of antiseizure drugs, treatment with enzyme-induced antiseizure drugs, duration of epilepsy, abnormalities in magnetic resonance imaging, and etiology play important roles in determining the vitamin D level., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the ethical standards established in the Declaration of Helsinki and its later amendments or comparable ethical standards and approved by the Clinical Research Ethics Committee of Gazi YşargilEducation & Research Hospital (2023:2023/353). Written informed consent was obtained from all the participants and/or legal guardians. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Objective: To assess the alterations of endogenous sex hormone profiles in patients with epilepsy (PWE) on different antiepileptic drug (AED) monotherapies compared to healthy controls and drug naïve PWE (DNPWE)., Methods: Four databases MEDLINE, EMBASE, SCOPUS, and CENTRAL were searched for analytical observational/intervention studies on the assessment of endogenous sex hormones in PWE compared to healthy controls and DNPWE. Two researchers reviewed the title/abstract, and full-text articles for the selection of the studies independently. Extracted data included information on study details, participant demographics, interventions, method of assessment and study results. The study outcomes were used to calculate the standard mean differences (SMD) and 95% confidence interval (CI) as effect size for assessing differences in the endogenous sex hormone levels between the treatment group and control/DNPWE., Results: Among 5888 publications retrieved, 33 studies were included. Enzyme-inducing AEDs (EIAEDs) such as phenytoin (men: SMD = 1.36; 95%CI = 1.06,1.66) and carbamazepine (men: SMD = 0.71; 95%CI = 0.39, 1.04 and women: SMD = 0.54; 95%CI = 0.25, 0.83) and weak-EIAED oxcarbazepine (men: SMD = 0.62; 95%CI = 0.26,0.99) increased the SHBG levels in PWE compared to control. The same trend was observed when comparing it to DNPWE. No significant changes in SHBG were observed for non-EIAEDs valproic acid, lamotrigine and levetiracetam in men. Lamotrigine significantly reduced SHBG in women (SMD = -0.50; 95%CI = -0.85, -0.16) compared to controls. Testosterone (T) levels were significantly reduced for both carbamazepine (SMD = -0.39; 95%CI = -0.67, -0.11) and valproic acid (SMD = -0.48; 95%CI = -0.74, -0.21) treated men compared to control., Significance: Our findings emphasize the importance of screening the endogenous sex hormonal profile in PWE on AED monotherapies to evaluate the associated endocrine-related perturbations which may impact reproductive functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Epilepsy causes a heavy disease burden, and the gut microbiota (GM) influences the progression of epilepsy, while plasma metabolites directly or indirectly associated with GM may play a mediating role. However, the causal relationships between epilepsy, GM, and potential metabolite mediators are lack of investigation., Methods: Mendelian randomization (MR) analysis was applied to estimate the effects of GM and plasma metabolites on epilepsy. Genetic instruments were obtained from large-scale genome-wide meta-analysis of GM (n = 5959), plasma metabolites (n = 136,016), and epilepsy (Cases/controls = 12891/312803) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy and focal epilepsy from the Finn Gen R10 database. And two-step MR (TSMR) to discover the potential mediating metabolites., Results: In total, we found 19 gut microbial taxa to be causally associated with the risk of epilepsy, among which Omnitrophota phylum had the strongest association (OR, 2.3; P = 0.009) with promoting effect. We also identified 21 plasma metabolites associated with epilepsy, the strongest ones of which are eastotal fatty acids (OR, 1.12; P = 0.001) that exhibited a facilitating effect. We observed indirect effects of free cholesterol to total lipids ratio in large LDL in associations between Fournierella massiliensis species and epilepsy, with a mediated proportion of -3.64% (95%CI, -7.22%∼-0.06%; P = 0.046)., Conclusion: This study supports a causal link between Fournierella massiliensis species, free cholesterol to total lipids ratio in large LDL and epilepsy, as well as a mediating effect of free cholesterol to total lipids ratio in large LDL in epilepsy., Competing Interests: Declaration of competing interest The authors declared no disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Childhood epilepsy is a major health concern posing a significant burden and having disastrous consequences for cognitive function. High Mobility Group Box1 (HMGB1) is an activator of neuroinflammation, and it is possibly involved in the initiation and progression of epilepsy. We aimed to investigate circulating HMGB1 in children with epilepsy and its connection to cognitive function and drug responsiveness., Methods: Case-control research included 100 epileptic youngsters and 100 healthy matched controls. Serum HMGB1 was measured using a commercially available ELISA assay. Cognitive functions were evaluated by the Stanford-Binet test 5th edition., Results: Drug-resistant epilepsy (DRE) was found in 37% of the investigated patients. Epileptic children have lower cognitive function parameter levels versus the control group and lower cognitive function in the DRE group compared to the drug-responsive group (P-value < 0.0001). HMGB1 levels were significantly higher in the patients' group (6.279 µg/L) compared to the control group (2.093 µg/L) and in the drug-resistant group (14.26 µg/L) versus the drug-responsive group (4.88 µg/L). A significant negative correlation was detected between HMGB1 with Full-scale IQ (r = - 0.547, P = 0.000), Visual-spatial reasoning (r = - 0.501, P = 0.000), fluid reasoning (r = - 0.510, P = 0.000), and working memory (r = - 0.555, P = 0.000). Serum HMGB1 cut-off levels > 6.85 µg/L differentiate drug-responsive from resistant patients., Conclusion: Elevated HMGB1 levels, especially in patients with drug-resistant epilepsy, correlate negatively with cognitive performance, emphasizing its importance as a potential marker for early prediction of drug resistance and impairment of cognitive function., Competing Interests: Declarations. Ethics approval and consent to participate: Cases were collected correspondingly with the guidelines established in the Declaration of Helsinki. This study was approved by the ethics committee of South Valley University (Ethical approval code: SVUMEDPED0254245849). Informed written consent was taken from the parents of the participants for participation in the study and publication. Consent for publication: Not applicable. Competing interests: The authors declare that they have no conflict of interest., (© 2024. The Author(s).)

Background: Vitamin D deficiency has been associated with headaches in adults, but data for children with headaches are sparse., Objective: To describe vitamin D levels in children with headaches., Methods: We retrospectively analyzed serum 25(OH)D concentrations in children aged 2-17 years with headaches compared to children with epilepsy at the Children's Hospital of Eastern Ontario between October 1, 2014, and August 19, 2021. Serum 25(OH)D <50 nmol/L was classified as insufficient., Results: Vitamin D concentrations of 353 children (117 with headaches; 236 with epilepsy) were analyzed. The median age in years was 10 (interquartile range [IQR] 5, 14); 50.4% of subjects were female. The median serum 25(OH)D was 56 nmol/L (IQR 41, 69) in children with headaches and 70 nmol/L (IQR 50, 95) in children with epilepsy. Vitamin D insufficiency was present in 42% of children with headaches and 25% of children with epilepsy ( P  = .002). In a multivariable linear regression model adjusting for age, sex and seasonality, children with headaches had serum 25(OH)D concentrations that were on average 9 nmol/L (95% CI-16.76, -0.96) lower compared to children with epilepsy ( P  = .029)., Conclusion: The prevalence of vitamin D insufficiency is higher in children with headaches compared to children with epilepsy. Prospective studies are needed to assess if vitamin D supplementation may have a therapeutic effect on pediatric headaches., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pyridoxine-dependent epilepsy (PDE) is a rare inborn error of lysine metabolism. To date, diagnosis of PDE relies on the quantification of α-AminoAdipic SemiAldehyde (α- AASA), Piperideine-6-Carboxylate (P6C) and Pipecolic acid (PA) in urine or plasma from patients with overt symptoms. However, these biomarkers are not specific, and their biochemical analysis is challenged by their instability and technical limitations. We set-up and validated a method for the quantification of two new biomarkers of PDE (2S,6S- and 2S,6R-oxopropylpiperidine-2-carboxylic acid, 2-OPP, and 6-oxopiperidine2-carboxylic acid, 6-oxoPIP) on human urine and plasma by LC-MS/MS, to overcome the diagnostic and technical challenges of old biomarkers., Methods: We analysed urine and plasma samples by LC-MS/MS, and validated the method in both biological matrices., Results: We performed the biomarkers extraction from a 10 µL aliquot of urine or plasma in around 15 min using water 100 % for urine, and a solution of water/methanol 50 % for plasma, respectively. The analytical method was validated and gave good linearity (r 2  > 0.999) in the range 0-15 µmol/L for 2-OPP and 0-25 µmol/L for 6-oxoPIP. In both matrices, the biomarkers were stable at different storage temperatures tested., Conclusions: We set-up and validated a reliable method and confirmed its clinical applicability on real samples from PDE patients. This method could be used as routine test for the diagnosis and monitoring of PDE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nitric oxide (NO) is an important gas signaling molecule, and endoplasmic reticulum (ER) stress induced by NO may be related to the pathogenesis of many diseases. Therefore, the development of ER-targeted fluorescent probes for NO is of great significance to investigate the relationship between ER stress and NO concentration changes in related diseases. Herein, an ER-targeted fluorescent probe (ER-Np) for sensing NO was constructed. ER-Np was served as an excellent tool for detection NO with high selectivity, sensitivity and ER-targetable ability. Moreover, fluorescence imaging experiments indicated that ER-Np is capable of imaging NO in living cells. Impressively, visualization of endogenous NO production during dithiothreitol (DTT)-induced ER stress in living cells was successfully observed. In addition, we found that serum NO levels were upregulated in epilepsy children, which opens up a new avenue for further understanding the relationship between the diagnostic of epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The ability to differentiate epileptic- and non-epileptic events is challenging due to a lack of reliable molecular seizure biomarker that provide a retrospective diagnosis. Here, we use next generation sequencing methods on whole blood samples to identify changes in RNA expression following seizures., Methods: Blood samples were obtained from 32 patients undergoing video electroencephalogram (vEEG) monitoring. Blood samples were collected in PaxGene tubes at baseline (admission) and following a seizure event (4-6 h and 24 h later or discharge). EEG and video of clinical events were reviewed by the clinical team and study epileptologist and were classified as epileptic seizure, psychogenic nonepileptic spell (PNES), or other. RNA was extracted from blood and RNA expression was determined using RNA-sequencing., Results: We show significant differences in RNA profiles between patients that did or did not experience an epileptic seizure. Compared to baseline patients with PNES show large increases in RNA expression 4-6 h and 24 h post seizure. Conversely, genes that changed following epileptic seizure showed more modest changes associated with a decrease in immune system function. Transcript usage was changed between patients with PNES and epileptic seizure at all three time points examined. Lists of genes differentially expressed following PNES or epileptic seizure vs. all baseline samples were used as classifiers for prediction. Models generated using random forest and radial support vector machine algorithms were 100% accurate at predicting both PNES and epileptic seizures., Significance: These data suggest that blood gene expression changes may have utility to retrospectively identify patients who have suffered a seizure or seizure-like event as a cause of transient loss of consciousness., Competing Interests: Declarations. Conflicts of interest: None to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Monica Dhakar is an employee at Xenon Pharmaceuticals Inc. and has consulted for Ceribell Inc, none of which are relevant to this work. None of the other authors has any conflict of interest to disclose. Ethical approval: Included- see Methods. Patient consent: Included-see Methods., (© 2024. The Author(s).)

Background : Epilepsy is a group of disorders characterized by a cluster of clinical and EEG signs leading to the formation of abnormal synchronous excitation of neurons in the brain. It is one of the most common neurological disorders worldwide; and is characterized by aberrant expression patterns; both at the level of matrix transcripts and at the level of regulatory RNA sequences. Aberrant expression of a number of microRNAs can mark a particular epileptic syndrome; which will improve the quality of differential diagnosis. Materials and Methods : In this work; the expression profile of six microRNAs was analyzed: hsa-miR-106b-5p; hsa-miR-134-5p; hsa-miR-122-5p; hsa-miR-132-3p; hsa-miR-155-5p; and hsa-miR-206-5p in the blood plasma of patients suffering from temporal lobe epilepsy (n = 52) and juvenile myoclonic epilepsy (n = 42); n-amount of participants; in comparison with healthy volunteers. The expression analysis was carried out using RT-PCR. Mathematical processing of the data was carried out according to the Livak method. Results : A statistically significant change in the expression of hsa-miR-106b-5p; hsa-miR-134-5p; hsa-miR-122-5p; and hsa-miR-132-3p was found. An increase in the expression of hsa-miR-134-5p and hsa-miR-122-5p was registered in the group of patients with temporal lobe epilepsy compared to the control; as well as an increase in the expression of hsa-miR-132-3p and hsa-miR-106b-5p in the juvenile myoclonic epilepsy group compared to the control. hsa-miR-122-5p; 106b-5p; 132-3p are also able to discriminate groups with different syndromes. Additionally; a number of microRNAs are able to discriminate patients with drug-resistant and drug-sensitive forms of epilepsy from the control; as well as patients with hippocampal sclerosis and patients without hippocampal sclerosis from the control. Conclusion. Our data allow us to propose these microRNAs as plasma biomarkers of various epileptic syndromes.

Background: Epilepsy has a genetic predisposition, yet causal factors and the dynamics of the immune environment in epilepsy are not fully understood., Methods: We analyzed peripheral blood samples from epilepsy patients, identifying key genes associated with epilepsy risk through Mendelian randomization, using eQTLGen and genome-wide association studies. The peripheral immune environment's composition in epilepsy was explored using CIBERSORT. An epilepsy mouse model was established to validated the expression of key genes at the transcriptomic and proteomic levels through single-cell analysis. Relevant pathways were verified. Finally, we developed a predictive model for antiepileptic drug response in epilepsy patients., Results: We found that CDC25B, DNMT1, GZMA, MTX1, and SSH2 expression decreases epilepsy risk, whereas FGD3, RAF1, and SH3BP5L increase it. Epilepsy patients exhibited an altered peripheral immune profile, notably with increased activated mast cells and decreased CD4 memory activated T cells and γδ T cells. Eight genes were significantly related to this immune environment. In the animal model, FGD3, SSH2, and DNMT1 were upregulated at both mRNA and protein levels in the hippocampus. FGD3 and SSH2 are specifically elevated in microglia and are primarily associated with actin regulation. The trained predictive model was deployed on an online platform., Conclusions: This study elucidates key genes linked to epilepsy, delineates the epilepsy immune landscape, and highlights the interaction between these domains, providing insights into potential epilepsy mechanisms and treatments., (© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Context.—: New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce., Objective.—: To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy., Design.—: Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on an Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiple-reaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed., Results.—: The method was linear with limit of detection less than 0.05 μg/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within ±15% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53% (244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals for all 6 ASMs., Conclusions.—: A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. These large-scale TDM data could help establish an effective monitoring strategy for these drugs., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2025 College of American Pathologists.)

Background: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy historically characterized by seizures that are resistant to antiseizure medications. Treatment with pyridoxine and lysine reduction therapies are associated with seizure control and improved developmental outcomes. In rare circumstances, patients have died prior to diagnosis and treatment with pyridoxine, and many patients are diagnosed after six months of age when lysine reduction therapies have limited efficacy. Recently two new metabolites were identified (2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid, 2-OPP and 6-oxo-pipecolate, 6-oxo-pip), and we evaluated these metabolites as potential newborn screening biomarkers., Methods: We recruited participants with a confirmed diagnosis of PDE-ALDH7A1 and retrieved their residual dried blood spots from state-sponsored newborn screening programs. We evaluated the dried blood spots for 2-OPP using commercially available newborn screening kits and equipment, and developed a second-tier test for 6-oxo-pip using LC-MS/MS., Results: We received eight residual dried blood spots collected before the onset of seizures and the diagnosis of PDE-ALDH7A1. In our newborn screening experiments, 2-OPP was elevated in 7 of 8 samples from affected participants with a mean of 3.08 μmol/L (95 % CI 2.17-3.99) compared to a mean of 0.09 μmol/L (95 % CI 0.09-0.10) in controls (p < 0.001). Second tier testing demonstrated elevated 6-oxo-pip in all samples from affected participants with a mean of 5.66 μmol/L (95 % CI 1.51-9.81) and was undetectable in controls (p < 0.001)., Conclusion: Patients with PDE-ALDH7A1 can be identified using neonatal dried blood spots prior to the onset of symptoms. The use of commercially available newborn screening approaches demonstrates the feasibility of newborn screening for this treatable condition., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aimed to establish an optimal model based on machine learning (ML) to predict Valproic acid (VPA) trough concentrations in Chinese adult epilepsy patients., Methods: A single-center retrospective study was carried out at the Jinshan Hospital affiliated with Fudan University from January 2022 to December 2023. A total of 102 VPA trough concentrations were split into a derivation cohort and a validation cohort at a ratio of 8:2. Thirteen ML algorithms were developed using 27 variables in the derivation cohort and were filtered by the lowest mean absolute error (MAE) value. In addition, feature selection was applied to optimize the model., Results: Ultimately, the extra tree algorithm was chosen to establish the personalized VPA trough concentration prediction model due to its best performance (MAE = 13.08). The SHapley Additive exPlanations (SHAP) plots were used to visualize and rank the importance of features, providing insights into how each feature influences the model's predictions. After feature selection, we found that the model with the top 9 variables [including daily dose, last dose, uric acid (UA), platelet (PLT), combination, gender, weight, albumin (ALB), aspartate aminotransferase (AST)] outperformed the model with 27 variables, with MAE of 6.82, RMSE of 9.62, R 2 value of 0.720, relative accuracy (±20%) of 61.90%, and absolute accuracy (±20 mg/L) of 90.48%., Conclusion: In conclusion, the trough concentration prediction model for VPA in Chinese adult epileptic patients based on the extra tree algorithm demonstrated strong predictive ability which is valuable for clinicians in medication guidance., Competing Interests: Declarations. Ethics Statement: The study involving humans was approved by the Hospital Ethics Committee of the Jinshan Hospital affiliated with Fudan University (Approval No. JIEC 2024-S67). The study was performed in accordance with the Declaration of Helsinki. Written informed consent from patients was waived by the Hospital Ethics Committee. Conflict of Interest: The authors declare no competing interests in this work., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dipeptides (DPs), composed of two amino acids (AAs), hold significant therapeutic potential but remain underexplored. Given the crucial role of AAs in central nervous system (CNS) function, this study investigated the presence of DPs in cerebrospinal fluid (CSF) and their correlation with corresponding AAs, potentially indicating their role as AA donors. Plasma and CSF samples were collected from 43 children with neurological or metabolic conditions of unknown origin, including 23 with epilepsy. A panel of 33 DPs was quantified using UPLC-MS/MS. Out of 33 DPs, 18 were detectable in CSF and 20 in plasma, displaying high inter-individual variance. Gly-Asp, Gly-Pro, and Ala-Glu were consistently found in all CSF samples, while only Gly-Asp was universally detectable in plasma. Anserine and carnosine were prominent in CSF and plasma, respectively, with no other histidine-containing DPs observed. Generally, DP concentrations were higher in plasma than in CSF; however, anserine and Gly-Pro had similar concentrations in both fluids. Significant correlations were observed between specific DPs and their corresponding AAs in CSF (Gly-Glu, Gly-Pro and Ser-Gln) and plasma (Glu-Glu and Glu-Ser). Notably, patients with epilepsy had elevated medium anserine concentrations in CSF. This study is the first to demonstrate the presence of numerous DPs in CSF and plasma. Further research is needed to determine if DP patterns can support the diagnosis of neurological diseases and whether DP administration can modulate amino acid availability in the brain, potentially offering new therapeutic options, such as for defects in the amino acid transporter., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: This study was approved by the ethic committee of the University Heidelberg (S-554/2018)., (© 2024. The Author(s).)

To evaluate the effects of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms on the plasma concentrations, efficacy, and safety of lacosamide (LCM) among pediatric patients with epilepsy. This prospective study was conducted at two institutions. It included 215 pediatric patients with epilepsy who were under LCM. LCM plasma concentrations were quantified using validated ultra-performance liquid chromatography. CYP2C9 and CYP2C19 polymorphisms were analyzed in all pediatric patients in our hospital's Institute of Clinical Pharmacy research laboratory through polymerase chain reaction, agarose gel electrophoresis detection, gel recovery, and other steps. Seizure frequencies were recorded 3, 6, and 12 months after initiating LCM therapy and compared with the baseline monthly frequency. Clinical information, including efficacy, toxicity, and concomitant drugs, was collected. A total of 158 pediatric patients (73.5%) responded to LCM therapy. Of them, 77 patients reported adverse events while under LCM. The LCM plasma concentration was linearly correlated with its daily dose (r = 0.26, p < 0.001). Patients with adverse events reported higher LCM plasma concentrations (7.9 ± 4.0 µg/mL) than patients without adverse events (6.8 ± 3.0 µg/mL; p < 0.05). The poor metabolizer (PM) group demonstrated the highest concentration-to-dose ratio (1.7 ± 0.7 μg·mL -1 ·kg·mg -1 ) than the extensive metabolizer, intermediate metabolizer, and ultra-rapid metabolizer groups (0.8 ± 0.4, 1.0 ± 0.5, and 0.8 ± 0.4 μg·mL -1 ·kg·mg -1 , respectively). The PM group comprised the highest proportion of patients with effective LCM (9/11, 81.8%) and adverse events (7/11, 63.6%)., Conclusion: LCM plasma concentrations were strongly associated with its clinical efficacy and toxicity. CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in pediatric patients with epilepsy. CYP2C19 PMs with two no-function alleles are likely to have higher LCM plasma concentrations., What Is Known: • LCM is metabolized by CYP2C19, CYP2C9, and CYP3A4 into pharmacologically inactive O-desmethyl-lacosamide; it primarily undergoes renal elimination. • Plasma LCM concentrations in patients treated with the recommended dose vary widely between and within individuals variability., What Is New: • CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in Chinese pediatric patients with epilepsy. • CYP2C19 PMs with two no-function alleles are likely to have higher plasma LCM concentrations., Competing Interests: Declarations. Ethics approval: This study was conducted in accordance with the Declaration of Helsinki’s principles. This study was authorized by the Medical Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region (No. KY2019120614), and informed consent was obtained from individual participants and their parents. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Previous studies suggest potential associations between epilepsy, anti-epileptic drugs (AEDs), and levels of vitamin D and vitamin D-binding protein (VDBP). This study aims to investigate the causal relationships among these variables using Mendelian Randomization (MR) methods., Methods: Using summary data from genome-wide association studies on serum 25-hydroxyvitamin D [25(OH)D] levels (N = 417,580), VDBP concentrations (N = 65,589), and various types of epilepsy (Ncases = 27,559), MR analyses were conducted to determine bidirectional causal relationships among these variables. Additionally, eQTL data from eQTLGen (N = 31,684) were employed to model the effects of AEDs and evaluate their causal impact on both biomarkers., Results: No causal relationships were found between serum 25(OH)D or VDBP levels and epilepsy. Although genetically predicted focal epilepsy risk was potentially associated with increased serum 25(OH)D levels (OR 1.031, 95% CI: 1.006-1.058, p = 0.017), and a higher genetic risk of juvenile myoclonic epilepsy was linked to lower VDBP levels (OR 0.977, 95% CI: 0.961-0.993, p = 0.004), both associations lost significance after multiple correction. Furthermore, significant associations were observed between serum 25(OH)D levels and AED target genes SCN4A, GABBR1, CA13, ALDH5A1, and CA8. No significant associations were found between AED target genes and VDBP levels after correction., Conclusion: No causal relationships were found between genetically determined serum 25(OH)D levels, VDBP, and epilepsy or its subtypes. Furthermore, the use of AEDs, such as Carbamazepine, Oxcarbazepine, Progabide, and Valproic Acid, reduces serum 25(OH)D levels, while not affect VDBP levels., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: This study was undertaken to test whether the postinjury plasma concentration of phosphorylated neurofilament heavy chain (pNF-H), a marker of axonal injury, is a prognostic biomarker for the development of posttraumatic epilepsy., Methods: Tail vein plasma was sampled 48 h after traumatic brain injury (TBI) from 143 rats (10 naïve, 21 controls, 112 with lateral fluid percussion injury) to quantify pNF-H by enzyme-linked immunosorbent assay. During the 6th postinjury month, rats underwent 30 days of continuous video-electroencephalographic monitoring to detect unprovoked seizures and evaluate epilepsy severity. Somatomotor (composite neuroscore) and spatial memory (Morris water maze) testing and quantitative T 2 magnetic resonance imaging were performed to assess comorbidities and lesion severity., Results: Of the 112 TBI rats, 25% (28/112) developed epilepsy (TBI+) and 75% (84/112) did not (TBI-). Plasma pNF-H concentrations were higher in TBI+ rats than in TBI- rats (p < .05). Receiver operating characteristic curve analysis indicated that plasma pNF-H concentration distinguished TBI+ rats from TBI- rats (area under the curve [AUC] = .647, p < .05). Differentiation was stronger when comparing TBI+ rats exhibiting severe epilepsy (≥3 seizures/month) with all other TBI rats (AUC = .732, p < .01). Plasma pNF-H concentration on day 2 (D2) distinguished TBI+ rats with seizure clusters from other TBI rats (AUC = .732, p < .05). Higher plasma pNF-H concentration on D2 after TBI correlated with lower neuroscores on D2 (p < .001), D6 (p < .001), and D14 (p < .01). Higher pNF-H concentration on D2 correlated with greater T 2 signal abnormality volume on D2 (p < .001) and D7 (p < .01) and larger cortical lesion area on D182 (p < .01). Plasma pNF-H concentration on D2 did not correlate with Morris water maze performance on D37-D39., Significance: Plasma pNF-H is a promising clinically translatable prognostic biomarker for the development of posttraumatic epilepsy with frequent seizures or seizure clusters., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To explore the longitudinal association between blood count-derived immunoinflammatory markers and the risk of epilepsy in a large population cohort., Methods: We used data from the UK Biobank (UKB) to investigate the association between pre-diagnostic peripheral immunoinflammatory cells and their derived ratios, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and the risk of epilepsy. This was a longitudinal cohort study in which multivariate Cox proportional hazards models and a series of sensitivity and subgroup analyses were performed to explore the nature of these associations., Results: We examined these associations in a prospective UKB cohort of 497,291 participants. During a median follow-up of 12.43 years, 2,715 participants developed epilepsy. After adjusting for all covariates, the results showed that higher monocyte counts and some blood count-derived immunoinflammatory metrics (monocyte counts, hazard ratio [HR]=1.093, 95 % confidence interval [CI] 1.052-1.136, P<0.001; NLR, HR=1.062, 95 % CI 1.022-1.103, P=0.002; PLR, HR=1.096, 95 % CI 1.055-1.139, P<0.001; SII, HR=1.041, 95 % CI 1.003-1.082, P=0.036) were associated with an increased risk of epilepsy. Conversely, we found that higher lymphocyte counts and LMR were negatively associated with the risk of epilepsy (lymphocyte count, HR=0.889, 95 % CI 0.856-0.923, P < 0.001; LMR, HR=0.85, 95 % CI 0.82-0.881, P < 0.001)., Conclusions: Monocyte count, NLR, PLR, and SII increased the risk of epilepsy, whereas lymphocyte count and LMR decreased it. Further studies will help translate these findings into clinical practice or targeted treatments., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Thromboelastography (TEG) is an effective technique to assess the efficiency of coagulation. Phenobarbital (PB) can induce hematological and coagulation disorders in both animals and humans, but its effects on hemostasis have been little investigated and are poorly understood in dogs., Objectives: The aim of this article was to assess coagulation using TEG in a population of dogs with idiopathic epilepsy treated with PB., Material and Methods: Prospective observational study. TEG was performed in blood samples from dogs with idiopathic epilepsy that were divided in three groups: Two groups of treated dogs that were on phenobarbital treatment for less or more than 6 months, and a control group of healthy dogs. Duration of treatment, dose, phenobarbital serum concentration and selected hematological and biochemical parameters were evaluated and correlated with the TEG results., Results: No statistically significant differences were found between groups. None of the animals appeared to be in a hypo- or hypercoagulable state, however 9/19 (47,4%) dogs were classified as hyper-fibrinolytic. A statistically significant negative relationship between MA and G values and increased fibrinolytic activity (LY30) were found. No statistically significant relationship was found between PB dose or PB blood levels and TEG parameters in either group. No bleeding complications were observed., Discussion: The rise in fibrinolysis might be due to hepatic damage from PB, as indicated by elevated liver enzymes in many dogs with abnormal fibrinolytic patterns. Although TEG showed hyperfibrinolysis in some dogs, the presence of primary or secondary hyperfibrinolysis could not be confirmed due to the lack of D-dimer measurements and liver biopsy. TEG's sensitivity compared to other fibrinolysis biomarkers like PAP might also affect results., Conclusions: TThe cause of hyperfibrinolysis in epileptic dogs treated with phenobarbital remains unclear, with potential links to hepatic effects or handling, and further research is needed to assess its clinical significance., (© 2024 The Author(s). Veterinary Clinical Pathology published by Wiley Periodicals LLC on behalf of American Society for Veterinary Clinical Pathology.)

Epilepsy is a major disease affecting millions of people worldwide. Carbamazepine is on the World Health Organization's list of essential medicines and is one of the most prescribed medicines for treating epilepsy. It has a narrow therapeutic range (4-12 μg/mL). Due to this narrow therapeutic range, toxic and adverse reactions are likely to be observed in the clinic. Therefore, therapeutic drug monitoring (TDM) should be routinely performed in the clinic for epilepsy patients treated with carbamazepine. Considering that an antiepileptic drug produces an antiepileptic effect only when its free (non-protein bound) concentration crosses the blood-brain barrier and reaches the brain, knowing and measuring the free drug fraction is important. In this study, a GC-MS method was developed for TDM of total and free carbamazepine, and carbamazepine epoxide in plasma. Free carbamazepine and carbamazepine epoxide were collected by ultra-filtrate, and analytes were extracted in plasma using salt-assisted liquid-liquid extraction (SALLME). The method was validated according to the European Medicines Agency (EMA) bioanalytical method validation guidelines. In the developed method, calibration curves were constructed for total carbamazepine, free carbamazepine, total carbamazepine epoxide, and free carbamazepine epoxide with calibration ranges of 1-20 µg/mL, 0.25-20 µg/mL, 0.4-8 µg/mL, and 0.1-8 µg/mL, respectively. The corresponding LLOQ values were 1, 0.25, 0.4, and 0.1 µg/mL. The correlation coefficient for both molecules was > 0.99 and the developing technique was applied to TDM for carbamazepine profile for plasma of patient samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: There is a lack of actual and comprehensive data on the detection rate of neuronal surface antibodies in patients with unexplained epilepsy in China. Thus, we attempted to analyze the differences in clinical manifestations, cerebrospinal fluid (CSF) characteristics, seizure types and other aspects of antibody-positive and negative patients, to identify suspected antibody-positive epilepsy patients., Methods: In total, 137 inpatients with unexplained epilepsy were consecutively included, and neuronal surface antibodies (NSAbs) were detected by serological and/or CSF evaluations. The clinical features and seizure characteristics were analyzed between the NSAb-positive and negative patients. In addition, patients were divided into four groups based on CSF and blood antibody titers. CSF cell count and protein content were analyzed in relation to antibody titers., Results: There were 45 (32.8%) patients tested positive for antibodies. Multivariate analyses revealed that age, mental status changes or memory deterioration, CSF protein, CSF cell count, treatment, days of hospitalization, outcome, duration of symptoms before hospitalization, status epilepticus, and number of antiepileptic drugs were significantly associated with the NSAb-positive group and changes in inflammatory indicators in routine CSF analysis were associated with antibody titers., Conclusions: A relatively high proportion of patients with unexplained epilepsy have positive NSAbs. Patients with the above clinical characteristics need to be highly suspected of NSAbs positivity and should be tested for antibodies in time to assist treatment. The decrease of CSF cell count and protein content has suggestive value for the decrease of antibody titer, which should be evaluated in the follow-up.

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Sunnerdahls Handikappfond, Stockholm County Council Research Funds, and Linnea & Josef Carlssons Foundation., Competing Interests: Declaration of interests None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult., Methods: Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long-term video-electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers., Results: Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05)., Significance: Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: In this study, we aimed to assess main factors influencing the Valproic Acid (V.Acid) plasma trough levels (C0) and to determine their degree of influence on V.Acid C0 in children with epilepsy who had Therapeutic Drug Monitoring (TDM)., Methods: We conducted an observational study in the Department of Clinical Pharmacology including patients with generalized seizures' epilepsy aged between two and 18 years. Only the children that had benefited from at least two V.Acid C0 determinations were included. First, we assessed daily dose optimization, performed by the practitioners. Then we divided our population into two groups: group A with a final V.Acid C0 in the therapeutic range (TR) and group B with a final V. Acid C0 outside the TR to find out factors influencing V.Acid C0 journey., Results: We included 805 patients (2537 V.Acid C0). The median age was 6.24 years and the sex ratio (M/F) was 1.45. The median V.Acid normalized daily dose was 27.27mg/kg/day and the median V.Acid C0 was 57µg/mL. The children's first V.Acid C0 was in the TR in 59.4% and V.Acid daily dose optimization was performed by the practitioners in 72.3%. Comparing GroupA and B, we found that age and the number of V.Acid C0 determinations increases the chance to reach the TR by respectively 3.79% and 7.39%., Conclusion: Older children who benefit from higher number of performed V.Acid C0 were more likely to reach the TR. In children who beneficiate from a TDM of V.Acid, close follow-up is mandatory to reach and maintain therapeutic V.Acid C0.

Epilepsy remains a disease that affects many people around the world. With the development of new drugs to treat this condition, the importance of therapeutic drug monitoring continues to rise and remains a challenge for the medical community. This review article explores recent advances in the detection of antiepileptic drugs across various sample types commonly used for drug monitoring, with a focus on their applications and impact. Some of these new methods have proven to be simpler, greener, and faster, making them easier to apply in the context of therapeutic drug monitoring. Additionally, besides the classic use of blood and its derivatives, there has been significant research into the application of alternative matrices due to their ease of sample collection and capacity to reflect drug behavior in blood. These advances have contributed to increasing the efficacy of therapeutic drug monitoring while enhancing its accessibility to the population.

Purpose: To detect possible neuronal damage due to recurrent isolated seizures in patients with epilepsy in a clinical routine setting., Methods: We measured the serum concentrations of neurofilament light chain (sNfL) in 46 outpatients with an at least monthly occurrence (self-reported) of generalized tonic-clonic seizures in the six months prior to the study and in 49 patients who had been seizure free (self-reported) for at least one year. We assigned the patients with seizure activity into groups with moderate and high seizure frequency. We measured sNfL with a highly sensitive single molecule array (Simoa)., Results: The majority (94 %) of all patients with epilepsy had sNfL values within the age adjusted reference ranges of our laboratory. Three patients with and three patients without seizure activity (each 3 %) showed elevated sNfL concentrations. Age adjusted sNfL concentrations did not differ significantly between patients with and without seizure activity in the total sample or in the female subgroup. In contrast, NfL concentrations were significantly higher in male patients with seizure activity and highest in the subgroup of those with high seizure activity, but were only above the reference range in two patients. sNfL concentrations did not differ between focal and generalized epilepsies and between genetic and structural etiologies., Conclusions: The sNfL concentrations in patients with epilepsy and healthy patients did not differ significantly. The finding of higher sNfL concentrations in males with self-reported seizure activity should be viewed with utmost caution because the difference was small and only two male patients showed sNfL concentrations above the reference range., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest concerning this study., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Uric acid (UA) serves as a crucial endogenous antioxidant in the body, offering protection against oxidative stress, whichmaycontributetoepilepsypathogenesis. The association between serum UA levels and epilepsy remains uncertain. This study aimed to examine the potential connections between serum UA levels and epilepsy in US adults., Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018, a cross-sectional analysis was conducted. Weighted logistic regression analyses were employed to assess the potential link between serum UA levels and the risk of epilepsy. Additionally, sensitivity analyses were conducted to evaluate the reliability of the results., Results: We included 15,373 participants, of whom 136 (0.79 %) had epilepsy. Following adjustment for multiple variables, participants with serum UA levels <4.1 mg/dl had an odds ratio of 2.24 (95 % CI: 1.12-4.47, P = 0.023) for epilepsy compared to those with serum UA levels of 5.8-6.5 mg/dl. The results of the sensitivity analyses corroborated the initial findings., Conclusions: Our study revealed a significant association between lower serum UA levels and heightened risks of epilepsy, suggesting that low UA levels may serve as an independent risk factor for epilepsy. A marginal increase in UA levels within the normal range may act as a protective factor against epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration., Methods: A retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations., Results: The inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R 2 (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables., Conclusions: Our model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To evaluate the incidence of insulin resistance and its association with change in serum anti-seizure medication (ASM) level and their pharmacokinetic, body composition and metabolic hormones after six months of levetiracetam (LEV) exposure in persons with epilepsy (PWE) in comparison to valproate (VPA)., Methods: This prospective-longitudinal study included clinically diagnosed PWE on VPA or LEV monotherapy (for<3 months). At enrolment, body weight/composition, BMI were measured and blood samples were collected for assessing metabolic dysfunctions by estimation of serum insulin, insulin resistance [in terms of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], leptin, adiponectin, lipid profile along with ASMs level. Subjects were followed up for six months and all the above parameters were reassessed., Results: A total of 150 PWE were screened based on inclusion and exclusion criteria, and 105 number of subjects were enrolled (n = 35 in VPA and n = 70 in LEV group). Out of them, 92 subjects (n = 32 in VPA; n = 60 in LEV) completed six months follow-up. After six months, serum insulin level increased significantly in VPA group compared to baseline p < 0.001). Insulin resistance (HOMA-IR>2.5) was observed in 14.28 % of PWE in VPA group. Significantly higher percentage-change in body-weight (p = 0.003), leptin and decreased adiponectin were found in VPA-group compared to baseline ((p = 0.003, 0.02, 0.001, <0.001, respectively). These changes were independent of serum level or pharmacokinetic of VPA. On the other hand, no such changes were observed in LEV-group despite increased serum LEV level and altered pharmacokinetic parameters after six months., Conclusion: Six months treatment with VPA resulted in insulin resistance and metabolic dysfunctions in PWE. These alterations were not correlated with change in VPA serum level. These changes were not observed in LEV therapy suggesting its better safety profile. This may be considered while prescribing the ASM like VPA and LEV in adult patients with obesity or insulin resistance and diabetes., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy., Methods: Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed., Results: In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001)., Conclusions: The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We aimed to assess the serum levels of caspase-3 as a marker of apoptosis and microtubule-associated protein 1A/1B-light chain 3 (MAP1-LC3) as an autophagy marker in epileptic children with various clinical and pharmacological types., Methods: This case-control study was carried out on 90 participants (50 pediatric patients with epilepsy and 40 healthy matched children), the patients were categorized into three groups: Group (A): 25 pharmacosensitive epilepsy, Group (B): 25 pharmacoresistant epilepsy, and Group (C): 40 (age, sex, and body mass index) matched healthy children selected as controls. Serum caspase-3 and MAP1-LC3 were measured in all study groups, using commercially available ELISA kits., Results: Serum caspase-3 was significantly higher among epileptic children, especially in the pharmacoresistant group, cases managed with multiple antiepileptic drugs, and cases with abnormal EEG findings. Conversely, circulating MAP1-LC3 levels showed a significant reduction in epilepsy cases, particularly in pharmacoresistant cases, in cases treated with multiple antiepileptic drugs, and in cases with abnormal EEG data. A significant negative correlation between serum caspase-3 and MAP1-LC3 was found among epileptic children ( r  =  -0.369, p  = 0.0083). Serum caspase-3 was a more valid biomarker in helping diagnose childhood epilepsy, while serum MAP1-LC3 was more valid in predicting pharmacoresistant type., Conclusion: The study reveals that serum caspase-3 levels were significantly elevated, particularly in pharmacoresistant cases and those managed with multiple drugs. Conversely, MAP1-LC3 levels were significantly reduced in epilepsy cases, suggesting potential involvement of altered apoptosis and autophagy in childhood epilepsy., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Inflammation plays an important role in epilepsy. There is evidence for the relationship between proinflammatory cytokines and epilepsy. We aimed to detect the serum levels of multiple cytokines in epilepsy patients, looking for biological indicators, and providing a theoretical basis for the clinical diagnosis, treatment, and prognosis of epilepsy., Materials and Methods: In this study, 30 patients with drug-resistant epilepsy (DRE), 30 patients with well-controlled epilepsy (WCE), and 29 healthy controls (HC) were enrolled. Multi-proinflammatory cytokines were measured by LUMINX multi-factor detection., Results: The levels of IL-1β, IL-7, IL-12, and IL-17 were significantly elevated, and the levels of CX3CL1 and ITAC were significantly decreased in epilepsy patients compared with healthy controls. Furthermore, the level of IL-17 was significantly higher in the DRE group compared to WCE. We also found the ratio of IL-7/CX3CL discriminates accurately between patients and controls, with a ROC Area Under the Curve (AUC) of 0.963 (P<0.001). The levels of IL-1β, IL-7, IL-12, and IL-17 in the DRE group were positively correlated with the National Hospital Seizure Severity Scale (NHS3) scores (IL-1β, P = 0.029; IL-12, P = 0.039; IL-17, P = 0.004). IL-17 was positively correlated with seizure frequency (P = 0.050), while ITAC was negatively correlated with seizure frequency (P = 0.012) and Sudden Unexpected Death in Epilepsy-3 (SUDEP-3) scores (P = 0.023)., Conclusions: IL-1β, IL-12, and IL-17 may be used to predict seizure severity and the IL-7/CX3CL1 ratio may be a candidate biomarker for predicting epileptic seizures. While CX3CL1 and ITAC play anti-epileptic effects, ITAC may be used to assess the risk of SUDEP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate changes in proportions of peripheral blood lymphocyte subsets, the correlation between the lymphocyte subsets and cytokine levels in patients with GluR3B antibody-positive epilepsy, analyze the role of GluR3B antibodies and cytokines in the progression of epilepsy. In addition, the immunotherapeutic effect in patients with GluR3B antibody-positive epilepsy will be evaluated., Methods: Patients with epilepsy hospitalized in the Department of Neurology of the affiliated Hospital of Xuzhou Medical University from December 2016 to May 2023 were recruited. GluR3B antibody levels were measured by enzyme-linked immunosorbent assay (ELISA). Lymphocyte subset proportions were determined using flow cytometry, and serum concentrations of 12 cytokines were measured using cytometric beads array. Differences in T lymphocyte subsets and inflammatory factors were analysed between GluR3B antibody positive and negative patients. Structural equation modeling (SEM) was used to analyse the role of GluR3B antibodies and inflammatory factors in drug-resistant epilepsy (DRE). Finally, the therapeutic effect of immunotherapy on epilepsy patients with GluR3B antibodies was assessed., Results: In this study, sixty-four cases of DRE, sixty-six cases of drug-naïve epilepsy (DNE), and forty-one cases of drug-responsive epilepsy were recruited. (1) DRE patients with positive GluR3B antibody were characterized by a significant increase in the proportion of cluster of differentiation (CD)4 + T lymphocytes, a decrease in CD8 + T lymphocytes, and an increase of CD4 + /CD8 + ratio. Similar alterations in T lymphocyte subsets were observed in GluR3B antibody-positive patients with DNE. GluR3B antibody levels correlated positively with CD4 + T lymphocytes (r = 0.23) and negatively with CD8 + T lymphocytes (r=-0.18). (2) In patients with DRE, the serum concentrations of interleukin-1β (IL-1β), IL-8, and interferon-gamma (IFN-γ) were significantly higher in those with positive GluR3B antibody compared to those with negative GluR3B antibody. Serum IL-1β levels were also higher in GluR3B antibody-positive DNE patients compared to antibody-negative DNE patients. In drug-responsive epilepsy patients with GluR3B antibody-positive, both serum IL-1β and IFN-γ levels were higher than those with GluR3B antibody-negative. Moreover, the concentrations of serum GluR3B antibody were positively correlated with the levels of IL-1β, IL-8, and IFN-γ. (3) SEM analysis indicated that GluR3B antibody may be a direct risk factor for DRE (direct effect = 4.479, 95%CI 0.409-8.503), or may be involved in DRE progression through affecting IFN-γ and IL-8 levels (total indirect effect = 5.101, 95%CI 1.756-8.818). (4) Immunotherapy significantly decreased seizure frequency and serum GluR3B antibody levels, and the seizure frequency was positively correlated with the levels of GluR3B antibody levels in patients receiving immunotherapy., Conclusions: This study demonstrates that GluR3B antibody may influence the progression of epilepsy through altering the proportion of CD4 + and CD8 + lymphocyte subsets and increasing proinflammatory cytokines. The seizure suppression of immunotherapy is associated with the decrease of GluR3B antibody levels. Thus, the present study contributes to a better understanding of the immunoregulatory mechanisms of autoimmune-associated epilepsy and provides a potential target for DRE., (© 2024. The Author(s).)

Background: Previous studies have suggested that gut microbiota (GM) may be involved in the pathogenesis of epilepsy through the microbiota-gut-brain axis (MGBA). However, the causal relationship between GM and different epilepsy subtypes and whether circulating inflammatory proteins act as mediators to participate in epileptogenesis through the MGBA remain unclear. Therefore, it is necessary to identify specific GM associated with epilepsy and its subtypes and explore their underlying inflammatory mechanisms for risk prediction, personalized treatment, and prognostic monitoring of epilepsy., Methods: We hypothesized the existence of a pathway GM-inflammatory proteins-epilepsy. We found genetic variants strongly associated with GM, circulating inflammatory proteins, epilepsy and its subtypes, including generalized and partial seizures, from large-scale genome-wide association studies (GWAS) summary data and used Multivariate Mendelian Randomization to explore the causal relationship between the three and whether circulating inflammatory proteins play a mediating role in the pathway from GM to epilepsy, with inverse variance weighted (IVW) method as the primary statistical method, supplemented by four methods: MR-Egger, weighted median estimator (WME), Weighted mode and Simple mode., Results: 16 positive and three negative causal associations were found between the genetic liability of GM and epilepsy and its subtypes. There were nine positive and nine negative causal associations between inflammatory proteins and epilepsy and its subtypes. Furthermore, we found that C-X-C motif chemokine 11 (CXCL11) levels mediated the causal association between Genus Family XIII AD3011 group and epilepsy., Conclusion: Our study highlights the possible causal role of specific GM and specific inflammatory proteins in the development of epilepsy and suggests that circulating inflammatory proteins may mediate epileptogenesis through the MGBA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Liu, Gao, Liu, Zhang, Liu, Ma, Zhang, Shi, Duan, Ma, Zhang, Cheng, Qu, Chen and Zhan.)

Objective: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders., Methods: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy., Results: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03)., Significance: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In this study, we investigated the effects of peripheral nesfatin-1 on basal brain activity and 4-aminopyridine (4-AP)-induced epileptiform activity, and its relationship with the electrocorticogram (ECoG) power spectrum and EEG bands. Forty-nine male Wistar rats were divided into seven groups: control sham, 4-AP (2.5 mg/kg i.p.), Nesfatin-1 (1, 2, and 4 μg/kg i.p.), Nesfatin-1 (2 μg/kg) post-treatment, and Nesfatin-1 (2 μg/kg) pre-treatment. Recordings were conducted for 70 min under ketamine/xylazine (90/10 mg/kg) anesthesia. In the post-treatment group, nesfatin-1 was injected 20 min after 4-AP induction. In the pre-treatment groups, nesfatin-1 was administered following basal recordings and before 4-AP injection. 4-AP induced epileptiform activity in all animals, peaking at 30 min. Nesfatin-1 (2 μg/kg) reduced basal brain activity (p < 0.05) and decreased alpha, delta, and theta bands in ECoG. Post-treatment of nesfatin-1 did not affect 4-AP-induced activity (p > 0.05) but increased gamma band activity (p > 0.05). Pre-treatment of nesfatin-1 reduced epileptiform activity between 50 and 60 min (p < 0.05), decreased delta bands, and increased gamma bands (p > 0.05). We conclude that peripheral nesfatin-1 modulates normal brain activity but has limited effects on abnormal discharges.

Epilepsy is a chronic neurological disorder that causes a major threat to public health and the burden of disease worldwide. High-performance diagnostic tools for epilepsy need to be developed to improve diagnostic accuracy and efficiency while still missing. Herein, we utilized nanoparticle-enhanced laser desorption/ionization mass spectrometry (NELDI MS) to acquire plasma metabolic fingerprints (PMFs) from epileptic and healthy individuals for timely and accurate screening of epilepsy. The NELDI MS enabled high detection speed (∼30 s per sample), high throughput (up to 384 samples per run), and favorable reproducibility (coefficients of variation <15 %), acquiring high-performed PMFs. We next constructed an epilepsy diagnostic model by machine learning of PMFs, achieving desirable diagnostic capability with the area under the curve (AUC) value of 0.941 for the validation set. Furthermore, four metabolites were identified as a diagnostic biomarker panel for epilepsy, with an AUC value of 0.812-0.860. Our approach provides a high-performed and high-throughput platform for epileptic diagnostics, promoting the development of metabolic diagnostic tools in precision medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: In addition to clinical factors, blood-based biomarkers can provide useful information on the risk of developing post-stroke epilepsy (PSE). Our aim was to identify serum biomarkers at stroke onset that could contribute to predicting patients at higher risk of PSE., Patients and Methods: From a previous study in which 895 acute stroke patients were followed-up, 51 patients developed PSE. We selected 15 patients with PSE and 15 controls without epilepsy. In a biomarker discovery setting, 5 Olink panels of 96 proteins each, were used to determine protein levels. Biomarkers that were down-regulated and overexpressed in PSE patients, and those that showed the strongest interactions with other proteins were validated using an enzyme-linked immunosorbent assay in samples from 50 PSE patients and 50 controls. A ROC curve analysis was used to evaluate the predictive ability of significant biomarkers to develop PSE., Results: Mean age of the PSE discovery cohort was 68.56 ± 15.1, 40% women and baseline NIHSS 12 [IQR 1-25]. Nine proteins were down-expressed: CASP-8, TNFSF-14, STAMBP, ENRAGE, EDA2R, SIRT2, TGF-alpha, OSM and CLEC1B. VEGFa, CD40 and CCL4 showed greatest interactions with the remaining proteins. In the validation analysis, TNFSF-14 was the single biomarker showing statistically significant downregulated levels in PSE patients ( p  = 0.006) and it showed a good predictive capability to develop PSE (AUC 0.733, 95% CI 0.601-0.865)., Discussion and Conclusion: Protein expression in PSE patients differs from that of non-epileptic stroke patients, suggesting the involvement of several different proteins in post-stroke epileptogenesis. TNFSF-14 emerges as a potential biomarker for predicting PSE., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: L. Abraira has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals, EISAI Inc, Neuraxpharm, Exeltis, Angelini Pharma and Esteve Laboratorios. E. Fonseca has received funding and speaker fees from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals, EISAI Inc, Neuraxpharm, Sanofi Genzyme, Angelini Pharma and Esteve Laboratorios. M. Toledo has received research funding and speaking fees from UCB Pharma, Angelini, Arvelle, Jazz Pharma, BIAL Pharmaceutical, EISAI Inc and Esteve Laboratorios. E. Santamarina has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc and Esteve Laboratorios. D. Campos has received travel support from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals and Angelini Pharma S. Lallana has received travel support from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals and Angelini Pharma. The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Objective: To analyze the correlation between the level of 25(OH)D in peripheral blood and cognitive function in patients with epilepsy, and to find the biomarkers of epilepsy complicated with cognitive dysfunction., Methods: 68 patients with epilepsy and 30 healthy subjects were included in this study. The 25(OH)D level in peripheral blood of all subjects was detected and the score of the Montreal Cognitive Assessment Scale was performed. The patients with epilepsy were divided into a cognitively normal group (36 cases) and a cognitively impaired group (32 cases) according to the scale score. The inter-group scale score and 25(OH)D level were compared, and the correlation was analyzed., Results: The levels of 25(OH)D and MOCA in epileptic group were significantly lower than those in healthy control group. The 25(OH)D and MOCA of the cognitively impaired group were significantly lower than those of the cognitively normal group. Logistic regression analysis indicated that serum 25(OH)D level was an independent risk factor for epilepsy combined with cognitive impairment (OR = 0.704, P = 0.014). The area under ROC curve of serum 25(OH)D for diagnosis of epilepsy combined with cognitive impairment was 0.924 (95 %CI 0.866,0.981), the critical value was 34.50 nmol/L, the sensitivity was 0.778, and the specificity was 0.906., Conclusion: Decreased levels of vitamin D are associated with cognitive impairment associated with epilepsy, and it may be a biomarker for early screening of cognitive impairment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The existing diagnostic methods of epilepsy have great limitations, and more reliable and less difficult diagnostic methods are needed. We collected serum samples of adult patients with first-diagnosed epilepsy (EPs) and seizure control patients (EPRs) for non-targeted metabolomics detection and found that they were both significantly altered, with increased expression of nicotine addiction, linoleic acid metabolism, purine metabolism, and other metabolic pathways. The diagnostic model based on 4 differential metabolites achieved a diagnostic efficiency of 99.4% in the training cohort and 100% in the validation cohort. In addition, the association analysis of oral flora, serum metabolism, and clinical indicators also provided a new angle to analyze the mechanism of epilepsy. In conclusion, this study characterized the serum metabolic characteristics of EPs and EPRs and the changes before and after epilepsy control based on a large cohort, demonstrating the potential of metabolites as non-invasive diagnostic tools for epilepsy., (© 2024. The Author(s).)

Background and Objectives: Oxidative stress resulting from a disturbance of the endogenous redox system is suspected in numerous diseases of the central nervous system, including epilepsy. In addition, antiseizure medications (ASMs), especially those of the old generation, may further increase oxidative stress. To evaluate the effects of ASM generation on oxidative stress, we conducted a cross-sectional study in patients with epilepsy treated with old, new, and polytherapy. Materials and Methods : The antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, as well as the concentrations of malondialdehyde, protein carbonyl, nitrate, nitrite, and glutathione in reduced and oxidized forms, were measured in 49 patients with epilepsy and 14 healthy controls. In addition, the plasma concentrations of ASMs and metabolites of carbamazepine and valproic acid were measured in the patients. Results : Patients with epilepsy showed increased activities of superoxide dismutase and catalase ( p < 0.001), concentrations of glutathione disulfide and markers of nitric oxide metabolism ( p < 0.001), and decreased activities of glutathione peroxidase, glutathione reductase, glutathione, and nitrite concentrations ( p ≤ 0.005) compared to healthy controls. A comparison of ASM generations revealed increased levels of superoxide dismutase and catalase ( p ≤ 0.007) and decreased levels of glutathione peroxidase and glutathione reductase ( p ≤ 0.01) in patients treated with old ASMs compared to those treated with new generation ASMs. In addition, an increase in protein carbonyl and nitric oxide metabolites ( p ≤ 0.002) was observed in patients treated with old generation ASMs compared to those treated with new generation ASMs. Most oxidative stress parameters in patients receiving polytherapy with ASMs were intermediate between the results of patients treated with the old and new generations of ASMs. Conclusions : An increase in oxidative stress markers and modulation of antioxidant enzyme activities was observed in patients with epilepsy compared to controls. The results of our study showed significantly higher oxidative stress in patients treated with old ASMs compared to those treated with new generation ASMs.

Purpose: Executive function (EF) impairment and vitamin D deficiency are common clinical features among children with epilepsy (CWE). Recently, vitamin D has become a potential modification factor that affects cognitive status in individuals with neurological disorders. In this study, we investigated the association between EF status and vitamin D levels in patients with CWE., Methods: In total, 79 CWE patients and 39 healthy controls (HCs) were recruited in this study. Each participant's EF was assessed using the Behavior Rating Inventory of Executive Function-Parent form (Brief-P), and the serum level of 25-OH vitamin D was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: Compared with those in the HC group, the CWE group had higher T scores of Brief-P scale, including global executive composite (GEC) (51.01(45.12, 60.69) vs. 44.08(39.24, 49.96), p＜0.001), behavioral regulation index (BRI) (51.29(45.67, 59.13) vs. 45.67(40.06, 51.29), p＜0.001), metacognition index (MI) (51.83(46.77, 59.43) vs. 46.13(40.44, 51.83), p＜0.001), and lower serum vitamin D (14.85(10.24,23.2) vs. 22.5(16.91,30), p＜0.001) levels. After adjustment for covariates, multivariate linear regression models suggested that for every 1 ng/ml increase in vitamin D, the GEC, BRI, and MI would decrease by 0.52 (Coeff = -0.48; 95 % CI = -0.69, -0.26; p = 0.000), 0.45 (Coeff = -0.45; 95 % CI = -0.69, -0.20; p = 0.000), and 0.47 (Coeff = -0.45; 95 % CI = -0.67, -0.22; p = 0.000), respectively., Conclusion: There may be an association between decreased vitamin D levels and EF impairment in CWE. Future research should consider longitudinal variations in EF related to improving vitamin D deficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and -20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing., Methods: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR., Results: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV., Conclusions: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous research has demonstrated that neuroinflammation is a key element in the progress of epilepsy. Nevertheless, it is currently unidentified which inflammatory factors and proteins increase or decrease the risk of epilepsy., Methods: We adopted Mendelian randomization techniques to explore the causal relationship between circulating inflammatory factors and proteins and various epilepsy. Our principal approach was inverse variance weighting, supplemented by several sensitivity analyses to guarantee the robustness of our findings., Results: Studies have identified associations between epilepsy and specific inflammatory factors and proteins: three inflammatory factors and six proteins are linked to epilepsy in general; one inflammatory factor and four proteins are associated with focal epilepsy with no documented lesions; two inflammatory factors and three proteins are related to focal epilepsy, excluding cases with hippocampal sclerosis; two inflammatory factors and two proteins are connected to juvenile myoclonic epilepsy; two inflammatory factors and five proteins are linked to juvenile absence epilepsy; four inflammatory proteins are associated with childhood absence epilepsy; two inflammatory factors are related to focal epilepsy overall; two inflammatory factors and two proteins are connected to generalized epilepsy; and two inflammatory proteins are linked to generalized epilepsy with tonic-clonic seizures. Additionally, six inflammatory factors may play a downstream role in focal epilepsy., Conclusion: Our study uncovers various inflammatory factors and proteins that influence the risk of epilepsy, offering instructive insights to the diagnosis and therapy of the condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization., Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes., Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions., Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis., Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant., Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers., Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Background: Lamotrigine as a broad-spectrum antiepileptic drug, is widely applied and its clinical efficacy is highly recognized. However, significant differences are observed in blood drug concentration of lamotrigine among individuals, which may have an impact on its efficacy. UGT1A4 is the main metabolic enzyme. However, it was inconsistent for the influence of UGT1A4 genetic polymorphism on concentration and efficacy of lamotrigine therapy. This study aimed to evaluate the influences of UGT1A4*3 genetic polymorphisms on lamotrigine concentration and therapeutic effect through meta-analysis., Methods: The literature search was conducted in Medline, Embase, PubMed, Web of Science, Wan Fang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database until January 2024. The primary outcome included the mean serum concentration, concentration-to-dose-ratio by body weight (CDR), or efficacy related to different UGT1A4*3 genotype for lamotrigine therapy. Data were collected to access the Mean Difference or odds ratio with 95% confidence interval. Meta-analysis was performed by RevMan 5.2., Results: A total of eleven studies were enrolled. The meta-analysis for mean serum concentration of lamotrigine showed no significant difference between patients carrying TT genotypes and TG and GG genotypes group (MD: 0.12, 95% [-0.35, 0.58], P = 0.62). There was significant difference in CDR (MD: 0.49, 95% [0.03, 0.94], P = 0.04) and therapeutic efficacy (OR: 7.18, 95% [4.01, 12.83], P<0.00001) of lamotrigine, however no significant difference was found in subgroup analysis of CDR of children (MD: 0.03, 95% [-0.35, 0.42], P = 0.87) between patients carrying TT genotypes and TG and GG genotypes group., Conclusions: Polymorphism of UGT1A4*3 influenced the CDR and therapeutic efficacy of lamotrigine for antiepileptic therapy. Genotype analysis provided reference for personalized medication in the future. However, more high-quality evidences are necessary for precise and definitive conclusion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics., Methods: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines., Results: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10 -3 , 95%CI = -16.08 to -8.58 × 10 -3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 -3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10 -3 , p = 0.10). The quality of studies was acceptable with an average rating score of 11.5., Conclusions: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes., Competing Interests: Declaration of competing interest Dr. Deligiannidis reported grants from the National Institutes of Health (Grant R01MH120313) during the conduct of study, nonfinancial support and personal fees from Sage Therapeutics Inc. (i.e., travel reimbursement, consulting), and Brii Biosciences (i.e., consulting); Dr. Kittel-Schneider has received speaker's and author's fee from Medice Arzneimittel Pütter GmbH & Co KG and Takeda; Dr. Paulzen has received speaker fees from Neuraxpharm, Langenfeld, Germany, and Lundbeck, Hamburg, Germany; Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, Saladax and Thermo Fisher and has received speaker fees from HLS Therapeutics and Saladax; All other authors declare no conflicts of interest. The research study did not receive funds or support from any source., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The hypothalamic-pituitary-adrenal axis is known to be involved in the pathogenesis of epilepsy and psychiatric disorders. Epileptic seizures (ESs) and psychogenic non-epileptic seizures (PNESs) are frequently differentially misdiagnosed. This study aimed to evaluate changes in serum cortisol and prolactin levels after ESs and PNESs as possible differential diagnostic biomarkers. Patients over 18 years with ESs (n = 29) and PNESs with motor manifestations (n = 45), captured on video-EEG monitoring, were included. Serum cortisol and prolactin levels as well as hemograms were assessed in blood samples taken at admission, during the first hour after the seizure, and after 6, 12, and 24 h. Cortisol and prolactine response were evident in the ES group (but not the PNES group) as an acute significant increase within the first hour after seizure. The occurrence of seizures in patients with ESs and PNESs demonstrated different circadian patterns. ROC analysis confirmed the accuracy of discrimination between paroxysmal events based on cortisol response: the AUC equals 0.865, with a prediction accuracy at the cutoff point of 376.5 nmol/L 0.811 (sensitivity 86.7%, specificity 72.4%). Thus, assessments of acute serum cortisol response to a paroxysmal event may be regarded as a simple, fast, and minimally invasive laboratory test contributing to differential diagnosis of ESs and PNESs.

Aims: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy., Methods: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy., Results: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 μg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 μg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007., Conclusion: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)