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Background: Neurofilament light chain (NfL) is released into the peripheral circulation by damaged axons., Objectives: To evaluate the diagnostic value of serum NfL concentration in dogs with intracranial diseases., Animals: Study included 37 healthy dogs, 31 dogs with idiopathic epilepsy (IE), 45 dogs with meningoencephalitis of unknown etiology (MUE), 20 dogs with hydrocephalus, and 19 dogs with brain tumors., Methods: Cohort study. Serum NfL concentrations were measured in all dogs using single-molecule array technology., Results: Serum NfL concentration in dogs with each structural disease was significantly higher than in healthy dogs and dogs with IE (P = .01). The area under the receiver operating characteristic curve of NfL for differentiating between dogs with structural diseases and IE was 0.868. An optimal cutoff value of the NfL 27.10 pg/mL had a sensitivity of 86.67% and a specificity of 74.19% to differentiate the dogs with IE from those with structural brain diseases. There were significant correlations between NfL concentrations and lesion size: (1) MUE, P = .01, r = 0.429; (2) hydrocephalus, P = .01, r = 0.563., Conclusions and Clinical Importance: Serum NfL could be a useful biomarker for distinguishing IE from structural diseases in dogs and predicting the lesion sizes of MUE and hydrocephalus., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy., Hypothesis/objectives: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs., Animals: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam., Methods: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction., Results: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R 2  = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R 2  = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified., Conclusion and Clinical Importance: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Inflammatory cytokines participate in the pathology of epilepsy and the development of drug resistance. In this study, we combined a cytokine array and enzyme-linked immunosorbent assay to identify new cytokines in the plasma from children on early stage of the onset of epilepsy (EOE) and children with drug-resistant epilepsy (DRE). Compared with healthy controls, a broad up-regulation of cytokines was observed in patients with EOE, and many of the cytokines were not previously reported. In patients with DRE, most of these up-regulated cytokines maintained at relatively low levels close to those in controls; only a few of them, including CCL5, Serpin E1, and IGFBP2, remained at high levels. The dramatic difference in cytokine profile could be a strong clue for the incidence of DRE, and DRE-associated cytokines appeared to have the potential to be new biomarkers for epilepsy prognosis and therapeutic targets., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Epilepsy is a chronic disease that requires long-term monitoring and treatment. It is suspected that there is a interaction between the use of anti-seizure medications and the risk of cardiovascular disease. The aim of the study is to investigate the association between the intake of phenobarbital, carbamazepine and valproic acid and their serum drug concentrations (SDC) with various cardiovascular risk parameters (homocysteine, folic acid, vitamin B12, total cholesterol (TC), triglycerides, high- and low-density lipoprotein (LDL))., Methods: This is a cross-sectional study. Data (demographic characteristics and laboratory results) of patients treated for epilepsy in a tertiary care hospital between January 2020 and February 2022 were analyzed retrospectively (n = 2014). Kruskal Wallis, Mann-Whitney U, correlation analysis was used, p < 0.05 was considered statistically significant., Results: The median age of patients was 15 years (IQR:8-31) and 48.3 % were women. The highest homocysteine level was found in patients receiving valproic acid, but it was not statistically significant. Patients receiving phenobarbital had the highest levels of folic acid and B12 and the lowest levels of total cholesterol and low-density lipoprotein cholesterol, which was statistically significant. In patients receiving carbamazepine, a moderately negative significant association was found between serum drug concentration and folic acid levels and a moderately positive significant association was found between TC and LDL levels., Conclusion: In our study, the majority of patients were children and adolescents. Regular monitoring of drug serum concentrations and metabolic parameters may be useful to select the safest drug in terms of cardiovascular disease risk. Randomized controlled trials on the long-term effects of anti-seizure treatment are needed., 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.)

Objectives: To measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with antiseizure medications and compare these to MPA concentrations in those without epilepsy., Study Design: For this multisite cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various antiseizure medications (n = 18) within the week before their next depot medroxyprogesterone injection. Among the participants without epilepsy (n = 20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay., Results: MPA concentrations were similar among those with epilepsy and controls and between groups with and without the use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing antiseizure medications, one of 10 using noninducing medications, and one of 19 controls had concentrations below 0.2 ng/mL., Conclusions: In this exploratory study, lower MPA concentrations in some participants using enzyme-inducing antiseizure medications suggest a potential interaction that could reduce depot medroxyprogesterone efficacy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents., (© 2024 International League Against Epilepsy.)

Background: Although there are models predicting epilepsy recurrence under different clinical conditions, few studies have examined blood biomarkers. Inflammation plays a crucial role in the occurrence and development of epilepsy. We analyzed inflammatory mediators in a regional hospital-based epilepsy cohort and investigated their relationship with subsequent epilepsy recurrence., Methods: Interictal inflammatory mediators were measured in 128 patients diagnosed with epilepsy participating in a prospective study. Inflammatory mediators were compared during the follow-up period between patients who experienced epilepsy recurrence and those who did not. We also assessed the correlation between inflammatory mediators and the time interval until the next recurrence., Results: Over a median 4-month follow-up period, 41 patients experienced seizure recurrence. Differences in interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were observed between seizure recurrence and non-recurrence groups. After adjusting for covariates through multivariate Cox regression analysis, the patients in the third IL-6 tertile (>2.31 pg/mL; HR: 2.49; 95 % CI: 1.00-6.16; P = 0.049) and in the third TNF-α tertile (>0.74 pg/mL; HR: 2.80; 95 % CI: 1.13-6.92; P = 0.026) had higher risk of seizure recurrence. The time until the next recurrence was negatively correlated with IL-6 level (ρ =  - 0.392, P = 0.011)., Conclusion: High levels of IL-6 and TNF-α are associated with a higher possibility of seizure recurrence. Future predictive models should also include inflammatory mediators in addition to clinical variables., 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.)

Epidemiological research has shown that a variety of circulating bioactive factors are associated with epilepsy, including macrophage colony-stimulating factor, interleukin-1β, and tumor necrosis factor-α. To further investigate the associations between epilepsy and 41 inflammatory cytokines, this Mendelian randomization was performed. This study presents genome-wide association study summary data on 41 inflammatory cytokines and epilepsy. Epilepsy incorporates generalized and focal epilepsy. A two-sample Mendelian randomization method was used. In order to analyze causal relationships between exposures and outcomes, the inverse variance-weighted method was mainly used. The findings suggested that increased levels of interleukin-1 receptor antagonists and interleukin-5 may be significantly associated with increased risks of focal epilepsy (beta: 0.080, P = .043; beta: 0.083, P = .015). In addition, regulated upon activation normal T cell expressed and secreted factor and Macrophage colony-stimulating factor may be significantly associated with generalized epilepsy (beta: 0.110, P = .042; beta: -0.114, P = .024). Furthermore, inflammatory cytokines such as interleukin-10, interleukin-1β, interleukin-1Ra, interleukin-7, tumor necrosis factor-α, and interferon-γ may be identified as the result of focal epilepsy (beta: 0.152, P = .031; beta: 0.214, P = .037; beta: 0.214, P = .047; beta: 0.222, P = .031; beta: 0.224, P = .025; beta: 0.161, P = .018). This study suggests that interleukin-5 and interleukin-1 receptor antagonists are potentially correlated factors with focal epilepsy etiology, macrophage colony-stimulating factor and regulated upon activation normal T cell expressed and secreted factor are potentially correlated factors with generalized epilepsy etiology, while several inflammatory cytokines possibly contribute to focal epilepsy development downstream., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women., Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance., Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester., Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period., (© 2024 International League Against Epilepsy.)

Background: Neurofilament light chain (NfL) is a frequently used biomarker in humans for both diagnostic and therapeutic monitoring purposes in various neurologic diseases., Hypothesis/objectives: It was hypothesized that dogs with diagnosed structural epilepsy (SE) would have a significantly higher serum NfL concentrations compared to dogs with idiopathic epilepsy (IE). The secondary hypothesis was that dogs would have a significantly higher serum NfL concentrations when measured within 7 days after a seizure compared to being seizure-free for at least 30 days., Animals: Fifty client-owned dogs presented to the neurology service for evaluation of seizures were enrolled. Fourteen dogs had SE and 36 dogs had IE., Methods: Prospective cohort study performed on 52 serum samples obtained for NfL concentration measurement using single molecule array technology., Results: The median serum concentration of NfL in dogs with SE was significantly higher (109 pg/mL; range, 11.4-741.3 pg/mL) than in dogs with IE (17.7 pg/mL; range, 5.8-188 pg/mL; Wilcoxon rank sum test, P = .001). No significant relationship was found between serum NfL concentration and time of sampling in relation to the most recent seizure in dogs with IE., Conclusions and Clinical Importance: Serum NfL may serve as an adjunctive biomarker for the differentiation of SE and IE., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Purpose: Drug-resistant epilepsy (DRE) poses a significant challenge in epilepsy management, and reliable biomarkers for identifying patients at risk of DRE are lacking. This study aimed to investigate the association between serum uric acid (UA) levels and the conversion rate to DRE., Methods: A retrospective cohort study was conducted using a common data model database. The study included patients newly diagnosed with epilepsy, with prediagnostic serum UA levels within a six-month window. Patients were categorized into hyperUA (≥7.0 mg/dL), normoUA (<7.0 and >2.0 mg/dL), and hypoUA (≤2.0 mg/dL) groups based on their prediagnostic UA levels. The outcome was the conversion rate to DRE within five years of epilepsy diagnosis., Results: The study included 5,672 patients with epilepsy and overall conversion rate to DRE was 19.4%. The hyperUA group had a lower DRE conversion rate compared to the normoUA group (HR: 0.81 [95% CI: 0.69-0.96]), while the hypoUA group had a higher conversion rate (HR: 1.88 [95% CI: 1.38-2.55])., Conclusions: Serum UA levels have the potential to serve as a biomarker for identifying patients at risk of DRE, indicating a potential avenue for novel therapeutic strategies aimed at preventing DRE conversion., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA., Methods: We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group., Results: The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 μg/mL) compared with that before co-administration (88.8 ± 13.6 μg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 μg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291)., Conclusions: In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted., Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020., (© 2024 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM)., Materials and Methods: This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC)., Results: The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018)., Conclusion: There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Aim: Valproic acid (VPA) is a classic broad-spectrum antiepileptic drug, with significant pharmacokinetic variability. Genetic polymorphisms contribute to this variability, influencing both VPA trough serum concentration (VPA concentration) and VPA-induced liver injury. Our study aims to investigate the association between polymorphisms of uridine diphosphate glucuronyl transferase ( UGT ) 1A6 , UGT2B7 and VPA concentration and screen for potential genetic loci affecting VPA-induced liver injury. Methods: This study included epilepsy patients treated with VPA. PCR-RFLP method was used to determine the genotypes of UGT1A6 and UGT2B7 . Chemiluminescent microparticle immunoassay was used to measure VPA concentration. Multiple linear regression and logistic regression were employed to analyze factors influencing VPA concentration and VPA-induced liver injury, respectively. Results: The correlation between UGT polymorphism and VPA concentration was analyzed in 133 samples. For VPA-induced liver injury, 105 patients were analyzed, with 29 in the liver injury group and 76 in the control group. Our finding showed patients with the UGT1A6-T19G variant had significantly lower VPA concentrations compared with wild-type patients and UGT1A6-T19G, A541G, A552C and UGT2B7-C802T, G211T, A268G polymorphisms showed no impact on VPA-induced liver injury. Conclusion: This study demonstrated UGT1A6-T19G polymorphisms affected the VPA concentration, providing a theoretical basis for the individualized clinical use of VPA.

Previous studies show changes in lipid metabolism in epilepsy. The aim of this study was to investigate the association between lipid profile and clinical variables in adult patients with epilepsy (APE). Seventy-two APE participated in this pilot study at an outpatient neurology service. The lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoproteins (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides), age at disease onset, disease duration, seizures frequency, and the number of antiseizure medications (ASM) used were investigated. Data were analyzed using the Chi-square, Fisher, Mann-Whitney, Spearman coefficient, and logistic regression tests. There were significant differences in HDL (p = 0.0023) and total cholesterol (p = 0.0452) levels in connection with the number of ASM used. There was a significant difference in seizure control among the different numbers of ASM used (p = 0.0382). Higher HDL values were found in females (p = 0.0170). The logistic regression showed that only the number of ASM used was associated with seizure control (p = 0.0408; OR = 2.800; 95% CI = 1.044; 7.509). The number of ASM taken and not the lipid profile was associated with seizure control in APE., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Anti-seizure drugs have long been known to affect thyroid hormone levels in epilepsy patients. The current study is a network meta-analysis designed to produce a systematic review and comprehensive evaluation of thyroid hormone changes to inform future research and clinical treatment., Method: A systematic search of databases, PubMed, EMBASE, Web of Science, and the Cochrane Library, was conducted and all observational studies reporting thyroid hormone levels in epilepsy patients receiving monotherapy and controls were included. Stata MP.14 was used for analysis., Results: A total of 35 studies, including 4135 participants and 8 anti-seizure drugs, were analyzed. TSH levels were elevated following use of topiramate [mean = 1.86; 95%CI: 0.83 to 2.90], levetiracetam [mean = 1.08; 95%CI: 0.07 to 2.09], and valproic acid [mean = 1.54; 95%CI: 0.58 to 2.50]. FT4 levels may be lowered by oxcarbazepine [mean =  - 6.13; 95%CI: - 8.25 to - 4.02] and T4 was lowered by carbamazepine [mean =  - 1.55; 95%CI: - 2.05 to - 1.05] and phenytoin [mean =  - 1.33; 95%CI: - 1.80 to - 0.85]. No significant changes were reported for FT3, although use of phenobarbital resulted in a non-significant decrease [mean =  - 0.31; 95%CI: - 0.99 to 0.37]. T3 levels were lowered by carbamazepine [mean =  - 0.52; 95%CI: - 0.81 to - 0.24]. Lamotrigine had no significant effect on thyroid hormone levels., Conclusion: Carbamazepine and phenytoin were the drugs most strongly associated with decreases in T4 and T3 levels while topiramate had the greatest elevating effect on TSH. Oxcarbazepine may lead to decreased serum FT4 and FT3, an effect relevant to central hypothyroidism. Phenobarbital appeared to significantly lower FT3. Use of levetiracetam and valproic acid may result in subclinical hypothyroidism. The anti-seizure drug with the least disruptive effect on thyroid hormone levels was found to be lamotrigine., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Valproic acid (VPA) is a broad spectrum anticonvulsant drug, which could be partially metabolised by cytochrome P450 (CYP) 2C9 and 2C19 enzymes. This study was designed to investigate the relationship between CYP2C19 and CYP2C9 gene polymorphisms and the plasma concentrations of VPA in subjects with epilepsy., Methods: Eighty-three subjects with epilepsy aged 18-92 years were enrolled in this study. All were treated with sustained-release VPA monotherapy. Based on the genotypes of CYP2C19 and the ability to metabolise substrates, the subjects were divided into poor metabolisers, intermediate metabolisers and extensive metabolisers. Sanger sequencing was used to detect the genotypic and allelic frequencies of CYP2C19 (*1, *2 and *3) and CYP2C9 (*13) of the patients. Automatic immunity analysis was used to find steady-state trough plasma concentrations of VPA. By adjusting the plasma concentrations of VPA with body weight and total daily dose of VPA, the concentration-to-dose ratio of VPA (CDRV) was obtained. Data were analysed using SPSS software., Results: The genetic frequencies of CYP2C19*2, CYP2C19*3 and CYP2C9*13 were 33.1%, 3.0% and 5.4%, respectively, among patients with epilepsy from Yunnan province, China who used VPA therapy. The CDRV was significantly lower in the CYP2C19 extensive metabolisers (3.33±1.78) than it was in the CYP2C19 intermediate metabolisers (4.45±1.42) and the CYP2C19 poor metabolizers (6.64±1.06). The CYP2C19*2 and CYP2C19*3 alleles were correlated with the plasma VPA concentration, while the CYP2C9*13 allele had no effect on the plasma VPA concentration (p=0.809)., Conclusions: The genetic polymorphisms of CYP2C19 significantly affect the VPA plasma concentration, and the dosage of VPA for intermediate and poor metabolisers could be lower than for extensive metabolisers. CYP2C9*13 carrier was not closely related to plasma concentrations of VPA in patients with epilepsy., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The relationship between treatment efficacy/tolerability and the dose/blood concentration of lacosamide (LCM) was investigated in a clinical cohort of Japanese pediatric patients with epilepsy., Methods: This retrospective analysis reviewed the medical records of patients treated with LCM for >6 months at the Department of Pediatrics, Hiroshima University Hospital, from September 2017 to January 2021. The collected data included age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events leading to LCM discontinuation, dose at any evaluation point, serum concentration, and concomitant antiepileptic drugs (AEDs)., Results: The study included 51 patients (31 male patients) between the ages of 2 and 19 years. All patients were Japanese. Epilepsy was classified as focal in 44 patients, generalized in six patients, and combined generalized and focal in one patient. The 50% responder rate for LCM treatment was 56.9%. Seven patients experienced complete seizure control (absence of seizures for 6 months before the follow-up visit). A relationship between dose and blood concentration was identified. Although the blood LCM concentration was higher in the responders than in the nonresponders (7.86 vs. 6.16 μg/mL; p = 0.028), there was no significant difference in dose between the two groups. Lacosamide showed efficacy at a dose >5 mg/kg/day in more than half of the 50% responders. The treatment-emergent adverse events (TEAEs) included seizure aggravation in five patients, irritability in two patients, and somnolence and drug eruption in one patient each. In six patients with TEAEs, the TEAEs developed within 1 month after treatment initiation and led to LCM discontinuation., Conclusion: In Japanese pediatric patients with epilepsy, LCM treatment is effective, particularly at higher doses. The blood concentration may be related more to efficacy than to dose. Lacosamide is generally well-tolerated by pediatric patients, and should be used at the maximum tolerable dose (needed to be gradually increased) in patients with otherwise insufficient seizure control. As TEAEs leading to discontinue treatment likely occur in early phase, it is needed to monitor patients carefully if TEAEs would happen in that phase., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In the present study we investigated the levels of proapoptotic caspase-9 and antiapoptotic Bcl-2 proteins in the sera of children and adolescents with idiopathic epilepsy and tried to relate the findings to the patients' clinical parameters., Methods: This retrospective study consisted of 118 children and adolescents with idiopathic epilepsy, categorized according to type and number of seizures, duration of the disease and the control of seizures and 30 age- and sex-matched controls. The relapse of seizures was taken into consideration., Results: Mean serum level between Bcl-2 and caspase-9 was significantly higher only in Bcl-2 patients, compared to controls (P≤0.0001) and (P=0.987) respectively. Significant difference in Bcl-2 level was found among the different types of focal seizures. Caspase-9 level was statistically different in patients with two or more seizures per month compared to those with one seizure per month (P=0.048). No correlation was found between Bcl-2 and caspase-9 levels and age, gender, seizure frequency, total number of seizures and the duration of epilepsy. No significant difference was found in patients with and without drug treatment., Conclusions: Bcl-2 displays an association with apoptosis and highlights the potential of being a surrogate biomarker for active seizures and epilepsy. There is a significant difference in Bcl-2 serum level among the different types of focal seizures. Proapoptotic caspase-9 cannot act as a marker of active seizures and epilepsy. Caspase-9 serum level is increased acutely in controlled cases after a single relapse.

We aimed to explore the relationships between the plasma expression levels of microRNA (miR)-146a and miR-132 in epileptic patients and cognitive, mental and psychological disorders. Eighty epileptic patients and seventy healthy subjects as controls were evaluated with Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Rating (HAMA) and Hamilton Depression Rating (HAMD) scales, and plasma samples were collected. MiR-146a and miR-132 levels were detected by real-time quantitative PCR. The total incidence rate of cognitive dysfunction, anxiety and depression in epilepsy group was 62.5%. Cognitive dysfunction was correlated positively with educational level, but negatively with disease course, duration and type of administration. The frequency and duration of seizures were positively correlated with anxiety. Depression was correlated negatively with educational level, whereas positively with course of disease and number of used drugs. Epileptic patients had significantly higher miR-146a and miR-132 levels than those of healthy controls. The miR-146a and miR-132 levels of patients with complications were significantly higher than those of cases without complications. Their expressions were correlated negatively with total MoCA scale score, but positively with type of complications. MiR-132 expression was positively correlated with the total scores of HAMA and HAMD scales. Plasma miR-146a and miR-132 expressions increased in epileptic patients, and miR-132 expression reflected the severity of epilepsy and predicted the risks of complications.

Pyridoxine-dependent epilepsy (PDE) is a recessive genetic disease characterized by epileptic encephalopathy with therapeutic response to pharmacological doses of pyridoxine and resistance to anti-epileptic treatments. The recent discovery in 2006 of the genetic defect antiquitin (ALDH7A1, OMIM #266100) has helped to understand the underlying mechanism, which is the accumulation of neurotoxic intermediates in the lysine catabolic pathway. The goal of the new therapeutic approach, termed triple therapy (TT) (pyridoxine, lysine-restricted diet and arginine supplementation), is to improve epilepsy control and neurocognitive development in patients with PDE. We present the 3-year treatment outcome for a child with PDE on pyridoxine treatment (started at age 5 months), lysine-restricted diet (started at age 17 months) and arginine supplementation therapy (started at age 19 months). The TT was well-tolerated with good compliance. No adverse events were reported. We observed a neurodevelopmental improvement, significantly fewer seizures, and a reduction of pipecolic acid (PA) as a biomarker of the illness. Our results show an improving clinical evolution, supporting and extending previous studies reporting efficacy of TT., (© 2020. Belgian Neurological Society.)

The present study focuses on the investigation of the dynamic thiol-disulphide homeostasis in patients with epilepsy and understanding the effects of antiepileptic drugs on thiol levels. A total of 148 participants, 75 of whom had epilepsy and 73 were healthy volunteers, were included in the study. Total thiol and native thiol levels of all epilepsy patients and healthy volunteers were measured. Disulphide level, disulphide/native thiol, disulphide/total thiol and native/total thiol ratios were calculated from these values. The results were compared between epilepsy patients and healthy volunteers. A statistically significant difference was found between native thiol level, total thiol level, disulphide level, disulfide/total thiol, disulphide/native thiol and native/total thiol ratios between patients with epilepsy and healthy volunteers (p = 0.002, p = 0.035, p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). The drugs used had a significant effect on disulphide, disulphide/total thiol, native/total thiol levels (p values 0.004, 0.009, 0.009, respectively). Decreased levels of serum native, total thiol and increased disulfide levels as parameters of oxidative stress may be considered as parameters to explain the pathogenesis or consequences of epilepsy., (© 2020. Belgian Neurological Society.)

Antiepileptic drugs may cause systemic and metabolic side effects. The aim of our study was to investigate the effects of valproic acid and carbamazepine monotherapy used in the treatment of epilepsy patients on serum adiponectin and carnitine levels. The study included 60 patients, of which 30 patients receiving valproic acid monotherapy and 30 patients receiving carbamazepine monotherapy, who were followed up by the epilepsy outpatient clinic with the diagnosis of idiopathic epilepsy, and 30 healthy volunteers. Patients, who used drugs for at least 6 months, were selected. Venous blood samples were collected from the patients and healthy volunteers after their consent was obtained. Serum carnitine and adiponectin levels in the collected samples were measured using the ELISA method. Serum carnitine levels were 5166.55 ng/ml (± 1954.92) in patients receiving carbamazepine, 4224.56 ng/ml (± 2055.54) in patients using valproic acid, and 5802.64 ng/ml (± 3422.57) in the control group. Serum adiponectin levels were 13,606.51 ng/ml (± 5915.92) in patients using carbamazepine, 11,986.58 ng/ml (± 5367.82) in patients receiving valproic acid, and 14,033.43 ng/ml (± 5646.34) in the control group. In both groups, both serum carnitine and serum adiponectin levels were lower than the control group. There was a negative but insignificant correlation between the duration and dose of carbamazepine and valproic acid drug use and serum adiponectin and carnitine levels. There is a need for more extensive studies with larger sample size to investigate the effect of antiepileptic drugs used on serum adiponectin and carnitine levels., (© 2020. Belgian Neurological Society.)

BACKGROUND We aimed to explore the risk factors that affect the serum concentration of sodium valproate (VPA-Na) in patients with epilepsy and to provide references for the rationale of the use of VPA-Na. MATERIAL AND METHODS The enzyme-multiplied immunoassay technique was used to determine the serum VPA-NA concentrations of 109 patients, and the results were retrospectively analyzed and summarized. A multivariate logistic regression model was used to analyze substandard serum VPA-Na concentrations. RESULTS Fifty-six patients (51.38%) treated with VPA-Na tablets were within the effective treatment range of 50-100 μg/mL, while 53 patients (48.62%) were out of the treatment range. The results indicated that the standard-reaching rate of serum drug concentration in the juvenile group was higher than that in the adult and elderly groups; the standard-reaching rates of serum drug concentrations in the low-dose group and the intermediate-dose group were lower than that in the high-dose group; and the standard-reaching rate of serum drug concentration in the group receiving carbapenems in combination was lower than that in the non-combination group; all differences were statistically significant. The combination with carbapenems and enzyme inducers was an independent risk factor for VPA-Na serum concentration below the target level in hospitalized patients. CONCLUSIONS To improve clinical efficacy and reduce the occurrence of adverse reactions, there is a need for therapeutic drug monitoring of VPA-Na. Moreover, individual administration should be implemented when VPA-Na tablets are used in the treatment of epilepsy because of the significant fluctuation in VPA-Na blood concentration.

Despite the years of research, epilepsy remains uncontrolled in one-third of afflicted individuals and poses a health and economic burden on society. Currently available anti-epileptic drugs mainly target the excitatory-inhibitory imbalance despite targeting the underlying pathophysiology of the disease. Recent research focuses on understanding the pathophysiologic mechanisms that lead to seizure generation and on possible new treatment avenues for preventing epilepsy after a brain injury. Various signaling pathways, including the mechanistic target of rapamycin (mTOR) pathway, mitogen-activated protein kinase (MAP-ERK) pathway, JAK-STAT pathway, wnt/β-catenin signaling, cAMP pathway, and jun kinase pathway, have been suggested to play an essential role in this regard. Recent work suggests that the mTOR pathway intervenes epileptogenesis and proposes that mTOR inhibitors may have antiepileptogenic properties for epilepsy. In the same way, several animal studies have indicated the involvement of the Wnt signaling pathway in neurogenesis and neuronal death induced by seizures in different phases (acute and chronic) of seizure development. Various studies have also documented the activation of JAK-STAT signaling in epilepsy and cAMP involvement in epileptogenesis through CREB (cAMP response element-binding protein). Although studies are there, the mechanism for how components of these pathways mediate epileptogenesis requires further investigation. This review summarises the current role of various signaling pathways involved in epileptogenesis and the crosstalk among them. Furthermore, we will also discuss the mechanical base for the interaction between these pathways and how these interactions could be a new emerging promising target for future epilepsy therapies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Epilepsy is a frequent chronic disorder of the brain characterized by intermittent epileptic seizures caused by hypersynchronous discharge of neurons in the brain. Studies have reported the role of cytokines in the pathogenesis of epilepsy, and a number of investigations have shown decreased levels of omega-3 fatty acids in epileptic patients. We investigated differences in serum levels of two cytokines, transforming growth factor (TGF)-β and interferon (IFN)-γ, in 40 epileptic cases prior to and after treatment with omega-3 fatty acids. IFN-γ levels were significantly increased after the 16-week treatment period (P < 0.001). However, TGF-β levels remained unchanged (P = 0.14). Omega-3 fatty acid treatment may alter the immune response in epileptic patients. This should be considered in prescription of omega-3 fatty acid supplements in these patients. Future studies with larger sample sizes should verify the results of the current study., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

The blood-brain barrier (BBB) is dysfunctional in temporal lobe epilepsy (TLE). In this regard, microvascular changes are likely present. The aim of this review is to provide an overview of the current knowledge on microvascular changes in epilepsy, and includes clinical and preclinical evidence of seizure induced angiogenesis, barriergenesis and microcirculatory alterations. Anatomical studies show increased microvascular density in the hippocampus, amygdala, and neocortex accompanied by BBB leakage in various rodent epilepsy models. In human TLE, a decrease in afferent vessels, morphologically abnormal vessels, and an increase in endothelial basement membranes have been observed. Both clinical and experimental evidence suggests that basement membrane changes, such as string vessels and protrusions, indicate and visualize a misbalance between endothelial cell proliferation and barriergenesis. Vascular endothelial growth factor (VEGF) appears to play a crucial role. Following an altered vascular anatomy, its physiological functioning is affected as expressed by neurovascular decoupling that subsequently leads to hypoperfusion, disrupted parenchymal homeostasis and potentially to seizures". Thus, epilepsy might be a condition characterized by disturbed cerebral microvasculature in which VEGF plays a pivotal role. Additional physiological data from patients is however required to validate findings from models and histological studies on patient biopsies.

Abstract: It is important to diagnose epilepsy in a timely and accurate manner, and also to distinguish it from non-epileptic conditions. The present study was aimed at determining postictal serum prolactin levels and lactate dehydrogenase (LDH) activities in patients with new-onset seizure admitted to the emergency department in order to assess whether they could be used in the differentiation of epileptic seizure (ES) from nonepileptic seizure (NES).Eighty-five patients were included prospectively in this study. Patients were divided into 2 groups with respect to epilepsy diagnosis, and the final groups were comprised of 36 patients with ES and 49 patients with NES. Blood samples were obtained within 1 hour of seizure.No significant differences between groups were observed in prolactin levels and in the percentage of patients with abnormal prolactin level (P = .569 and .239, respectively). The median LDH activity was significantly higher in those with ES compared with those with NES (P = .031). The percentage of patients with elevated LDH levels was similar between 2 groups (P = .286).This was the first study to examine LDH activities in terms of its role in differentiation of seizure origin in the postictal period in patients hospitalized with seizure. Our study demonstrated that serum LDH activities within 1 hour after the seizure appear to be increased in patients with ES compared with those with NES, suggesting the potential role of LDH activities as a diagnostic tool in distinction of seizure types. Our study supports the hypothesis that LDH-antagonists may have a role in the management of seizure and epilepsy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α ), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE., Competing Interests: The authors declare there are any potential conflicts of interest. The authors declare they have no actual or potential competing financial interests., (Copyright © 2021 Mengke Liang et al.)

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Objective: There is a major unmet need for a molecular biomarker of seizures or epilepsy that lends itself to fast, affordable detection in an easy-to-use point-of-care device. Purines such as adenosine triphosphate and adenosine are potent neuromodulators released during excessive neuronal activity that are also present in biofluids. Their biomarker potential for seizures and epilepsy in peripheral blood has, however, not yet been investigated. The aim of the present study was to determine whether blood purine nucleoside measurements can serve as a biomarker for the recent occurrence of seizures and to support the diagnosis of epilepsy., Methods: Blood purine concentrations were measured via a point-of-care diagnostic technology based on the summated electrochemical detection of adenosine and adenosine breakdown products (inosine, hypoxanthine, and xanthine; SMARTChip). Measurements of blood purine concentrations were carried out using samples from mice subjected to intra-amygdala kainic acid-induced status epilepticus and in video-electroencephalogram (EEG)-monitored adult patients with epilepsy., Results: In mice, blood purine concentrations were rapidly increased approximately two- to threefold after status epilepticus (2.32 ± .40 µmol·L -1 [control] vs. 8.93 ± 1.03 µmol·L -1 [after status epilepticus]), and levels correlated with seizure burden and postseizure neurodegeneration in the hippocampus. Blood purine concentrations were also elevated in patients with video-EEG-diagnosed epilepsy (2.39 ± .34 µmol·L -1 [control, n = 13] vs. 4.35 ± .38 µmol·L -1 [epilepsy, n = 26])., Significance: Our data provide proof of concept that the measurement of blood purine concentrations may offer a rapid, low-volume bedside test to support the diagnosis of seizures and epilepsy., (© 2021 International League Against Epilepsy.)

The purpose of this study was to prevent anaemia caused on long-term phenytoin treatment among Epileptic patients. Therefore, two groups were categorised based on the duration of phenytoin namely, cases and control. The duration of Phenytoin treatment for case was > 2 years while control had < 1 year. The estimation of serum Folate and Vitamin B12 was carried out and the association between the deficiency of Vitamins with the duration of treatment were evaluated using Linear Regression Analysis. The statistical results shown that the mean value of Folate (2.61 ± 1.81) and the mean value of Vitamin B12 (284.68 ± 110.12) were considered to be low as the duration of Phenytoin treatment increases (> 2 years) compare to control with the Folate concentration of (7.01 ± 4.40) which was statistically significant (p < 0.000). The experimental results have proved that a long-term phenytoin treatment significantly affects the concentration of Folate and Vitamin B12 among the Epileptic patients vigorously.

Objectives: Epilepsy is one of the most common neurological disorders, diagnosis of which is challenging as many unrelated conditions may mimic seizure. Epilepsy impairs the quality of life of patients due to associated physical and psychological trauma. Epileptic patients are also at increased risk of premature death due to autonomic disturbance and fatal accidents. The aim of the present research work was to study ischemia modified albumin (IMA) as an early biomarker of epilepsy in the adolescent population., Methods: Twenty-five diagnosed cases of epilepsy and 25 healthy volunteers as control of adolescent group were recruited as study subjects. The study subjects were age and sex matched. Clinical evaluation, routine biochemical parameters and IMA estimation were carried out. Serum IMA was measured by spectrophotometric method., Results: The mean serum IMA levels were significantly raised in epileptic patients (0.69  ±  0.1 absorbance units [ABSU]) as compared to the healthy control group (0.52  ±  0.24 ABSU) (p=0.004). ROC curve of IMA predicted that at cut off of 0.59 ABSU, the IMA has 96% sensitivity and 52% specificity for diagnosing epilepsy., Conclusions: IMA may be used as a biomarker for early diagnosis of epilepsy as well as to differentiate epileptic seizure from various non epileptic disorders in the adolescent population., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

SLC13A5/NaCT is a sodium-coupled citrate transporter expressed in the plasma membrane of the liver, testis, and brain. In these tissues, SLC13A5 has important functions in the synthesis of fatty acids, cholesterol, and neurotransmitters. In recent years, patients homozygous for recessive mutations in SLC13A5, known as SLC13A5 deficiency [early infantile epileptic encephalopathy-25 (EIEE-25)], exhibit severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting tooth development. Although the pathogenesis of SLC13A5 deficiency remains not clearly understood, cytoplasmic citrate deficits, decreased energy status in neurons, and citrate-zinc chelation are hypothesized to explain the neurological deficits. However, no study has examined the possibility of specific pharmacological drugs and/or lifestyle changes synergizing with heterozygosity of SLC13A5 deficiency to increase the risk of EIEE-25 clinical phenotype. Here, we report on a heterozygous SLC13A5-deficient patient who demonstrated evidence of pharmaco-synergistic heterozygosity upon administration of metformin, valproic acid, and starvation. The report illustrates the importance of careful consideration of the potential adverse effects of specific pharmacological treatments in patients with heterozygosity for disease-causing recessive mutations in SLC13A5., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

We investigated the metabolic profile, reactive species production, and inflammatory parameters in patients with epilepsy. Furthermore, we investigated whether there is any relationship between these parameters and seizure type. Patients with epilepsy (n=43) and healthy subjects (control group; n=41) were recruited to participate in the study. Initially, the participants were submitted to a clinical questionnaire and patients with epilepsy were classified according to seizure type. Metabolic markers and inflammatory and oxidative factors were also measured in specific blood samples. We compared these results with data from the control subjects. Statistical analyses showed that patients with epilepsy presented with higher levels of glycolipid, oxidative stress, and inflammatory parameters compared to the control subjects. Interestingly, patients with generalized seizures presented with higher MnSOD activity and metabolic parameters (total cholesterol, low-density lipoprotein, glucose and triglyceride levels) compared to the partial seizure and control groups. Furthermore, patients with generalized epilepsy demonstrated a significant correlation between TNF-α and caspase 8 (p<0.05), caspase 3 (p<0.05), and Picogreen (p<0.001). This study supports evidence that the levels of inflammatory, glycolipid, and oxidative factors are higher in epilepsy patients, especially those with generalized epilepsy.

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

Objective: The effects of anticonvulsants on lipids are the subject of considerable concern and investigation, but there are almost no data on this issue from randomized trials. We evaluated serum lipid profiles in adults with newly diagnosed epilepsy, following randomization to lacosamide (LCM) or carbamazepine (CBZ) monotherapy., Methods: We analyzed data from a Phase 3, international, randomized, double-blind trial of LCM vs CBZ for the initial treatment of focal epilepsy. Serum lipid profiles in patients not taking lipid-lowering agents and providing blood samples under fasting conditions before treatment, and following 3 or 12 months of treatment with LCM or CBZ at various doses were analyzed., Results: At 12 months, 271 patients satisfied the inclusion criteria for the analysis. No change was observed in LCM-treated patients for total cholesterol, cholesterol fractions, or triglycerides. CBZ-treated patients showed an increase of 21.1 mg/dL in total cholesterol, 12.6 mg/dL in low-density lipoprotein (LDL) cholesterol, 12.5 mg/dL in non-high density lipoprotein (non-HDL) cholesterol, and 8.5 mg/dL in HDL cholesterol; triglycerides remained unchanged. The proportion of patients with elevated total cholesterol levels (above the upper limit of the reference range) did not change in the LCM treatment group (37.0% at Baseline; 34.8% at 12 months), but increased from 30.8% (at Baseline) to 49.6% (at 12 months) in the CBZ treatment group., Significance: This study provides Class II evidence that CBZ elevates serum lipids, whereas LCM has no effect on lipids. It supports LCM as an appropriate choice for new-onset focal epilepsy., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To evaluate first trimester screening test parameters in epileptic patients using anti-epileptic drugs., Materials and Methods: We retrospectively evaluated first trimester screening test results of 23 epileptic pregnant women using anti-epileptic drugs with a control group consisting of 92 healthy pregnancies. The anti-epileptic drugs used in this study were carbamazepine, levatiracetam, valproic acid and lamotrigine. Single drug or multi-drug regimens were used according to the clinical conditions. Patients with any known chronic or acute disease and drug usage were excluded from the study. Comparisons were performed via Mann-Whitney U test., Results: First trimester screening test biochemical markers were compared and maternal serum PAPP-A MoM values were found to be similar in study and control groups while β-hCG MoM values were significantly higher in pregnancies using epileptic drugs (p: 0,737 and p < 0.001, respectively)., Conclusion: Biochemical first trimester screening test results may be affected by anti-epileptic drug usage, which may lead to misinterpretation of the risk level. Thus, validation of MoM values should be necessary in order to obtain optimal results., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Although many neurologists are familiar with the clinical presentations of anti-N-methyl-d-aspartate receptor or limbic encephalitides, there remains much mystery surrounding autoimmune etiologies of subacute and chronic epilepsies. In addition, the subtleties and differences in presentation in the pediatric population limit diagnosis and challenge clinicians. In the absence of an acute encephalitic picture, it is likely that many clinicians do not test for autoimmune disorders due to the uncertainty surrounding the selection of appropriate candidates for testing and immunomodulation. Recent developments have expanded the definition of epilepsy related to autoimmune mechanisms. Based on current knowledge, autoimmune epilepsy can best be thought of as a subset of autoimmune encephalitis where seizures and epilepsy are the primary presenting factor. Autoimmune epilepsy has been increasingly recognized as a contributor to drug-resistant epilepsies; however, identification of affected individuals remains challenging, particularly in the pediatric population. Our understanding of autoimmune epilepsy continues to evolve as more individuals with epilepsy are tested for antibodies to neuronal proteins and as additional antibodies are being identified. This article provides an overview of the clinical features most commonly associated with positive antibody testing in epilepsy and the scales that are currently available to screen patients for antibody testing and response to immunotherapy. Literature-based recommendations are presented for the modification and validation of current scales to increase applicability to children., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 ( PHF6 ) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6 - /Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Purpose: Valproic acid (VPA) is not only an antiepileptic drug but also a mood stabilizer for patients with bipolar disorder. Long-term VPA therapy can cause carnitine deficiency, which may result in an increase in the blood ammonia level, in patients with epilepsy. However, information about this effect in patients with bipolar disorder is limited. The aim of this study was to investigate the associations between the serum VPA level and the carnitine and ammonia levels in psychiatric adult patients with epilepsy., Methods: The subjects were 182 consecutive Japanese adult patients (mean age 54.3 ± 19.5 years) diagnosed with bipolar disorder and treated with VPA. The serum VPA level, carnitine fraction, and plasma ammonia level were measured. Furthermore, the free carnitine and acylcarnitine fractions were measured using an enzyme cycling method., Results: Sixty-nine patients (38%) had a low free carnitine level. There were significant differences in sex, height, VPA dose, serum VPA level, total carnitine level, acylcarnitine level, and acylcarnitine/free carnitine ratio between patients with a low free carnitine level and those with a normal range of free carnitine. The simple and multiple regression analyses revealed that the VPA dose and the serum VPA level were inversely and significantly correlated with the free carnitine level. The plasma ammonia level was correlated with the VPA dose, serum VPA level, and acylcarnitine level but not with the free carnitine level., Conclusions: These findings suggest that carnitine deficiency is associated with the VPA dose and the serum VPA level in patients with bipolar disorder. However, it is unlikely that carnitine deficiency is associated with hyperammonemia in patients with bipolar disorder.

Background: The aim of the study was to investigate how age and genetic polymorphisms of UGT1A6 and UGT2B7 contribute to the concentrations of valproic acid (VPA) and its hepatotoxic metabolites in Chinese pediatric patients with epilepsy., Methods: A total of 122 children with epilepsy were genotyped at 19T>G, 541A>G, and 552A>C in UGT1A6 and -161C>T and 802C>T in UGT2B7 using the polymerase chain reaction-restriction fragment length polymorphism method or direct sequencing method. The concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA were simultaneously determined using ultra-performance liquid chromatography-tandem mass spectrometry., Results: Significant association was observed between the UGT2B7 802C>T genotype and dose-adjusted concentrations of VPA, 4-ene-VPA, and 2,4-diene-VPA. The younger children had increased concentrations of the hepatotoxic metabolites and decreased levels of VPA. The allele status of UGT2B7 802C>T had no influence on the metabolite ratios within age groups, but showed a significant difference among the age groups., Conclusions: The present study suggests that UGT2B7 802C>T polymorphism and age are factors affecting the concentrations of dose-adjusted VPA and its metabolites. No genotype-related differences were noted in the metabolite ratios of 4-ene-VPA and 2,4-diene-VPA within age-assigned groups. Therefore, careful administration is particularly necessary for younger patients who are UGT2B7 802C>T poor metabolizers.

Objective: Alteration of bone strength is an adverse effect of antiepileptic drug treatment. We investigated the effects of zonisamide (ZNS) monotherapy on bone mineral density (BMD) and biomarkers of bone metabolism after 13 months of treatment in drug-naive epileptic patients., Methods: Fifty-nine patients with new onset drug-naive epilepsy were enrolled (29 women, 30 men; mean age = 31.5 ± 11.5 years). The BMD and T scores were measured at the lumbar spine and femoral neck by using dual-energy X-ray absorptiometry. Biomarkers specific for bone metabolism (bone-specific alkaline phosphatase, parathyroid hormone, osteocalcin, insulinlike growth factor-1, C-telopeptide, and vitamin D3 levels) were measured before and after long-term ZNS monotherapy. Analysis of covariance (ANCOVA) was used to estimate BMD and biomarkers of bone metabolism before and after ZNS therapy. Age, sex, treatment duration, and ZNS dosage were included as covariates for adjustment in the ANCOVA model. Furthermore, subgroup analyses were performed for each sex, and the effect size was calculated., Results: After 13 months of ZNS treatment, the BMD and T scores at the lumbar spine (L1-L4 level) and femoral neck were not significantly different. Moreover, the biochemical markers showed no significant differences after ZNS monotherapy. Women showed significantly decreased baseline BMD at the femoral neck compared to men (P = .026), although the mean age and body mass index were not significantly different between the sexes. No significant changes in BMD or biomarkers of bone metabolism were seen in either sex after 13 months of ZNS treatment., Significance: The results suggest that long-term ZNS monotherapy does not affect bone health in drug-naive patients with epilepsy negatively., (© 2020 International League Against Epilepsy.)

Background: The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients., Methods: Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated., Results: Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P < 0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P < 0.05). Younger age also contributed to pharmacokinetic variability., Conclusions: Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.

Objective: Blood biomarkers have not been widely investigated in poststroke epilepsy. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and analyze their association with the development of epilepsy at long term., Methods: A panel of 14 blood biomarkers was evaluated in patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z-scores. Stroke and epilepsy-related variables were also assessed: stroke severity, determined by National Institutes of Health Stroke Scale (NIHSS) score, stroke type and cause, time from stroke to onset of late seizures, and type of seizure. Multiple Cox regression models were used to identify clinical variables and biomarkers independently associated with epilepsy., Results: From a cohort of 1115 patients, 895 patients were included. Mean ± standard deviation (SD) age was 72.0 ± 13.1 years, and 57.8% of patients were men. Fifty-one patients (5.7%) developed late seizures, with a median time to onset of 232 days (interquartile range [IQR] 86-491). NIHSS score ≥8 (P < .001, hazard ratio [HR] 4.013, 95% confidence interval [CI] 2.123-7.586) and a history of early onset seizures (P < .001, HR 4.038, 95% CI 1.802-9.045) were factors independently associated with a risk of developing epilepsy. Independent blood biomarkers predictive of epilepsy were high endostatin levels >1.203 (P = .046, HR 4.300, 95% CI 1.028-17.996) and low levels of heat shock 70 kDa protein-8 (Hsc70) <2.496 (P = .006, HR 3.795, 95% CI 1.476-9.760) and S100B <1.364 (P = .001, HR 2.955, 95% CI 1.534-5.491). The risk of epilepsy when these biomarkers were combined increased to 17%. The area under the receiver-operating characteristic (ROC) curve of the predictive model was stronger when clinical variables were combined with blood biomarkers (74.3%, 95% CI 65.2%-83.3%) than when they were used alone (68.9%, 95% CI 60.3%-77.6%)., Significance: Downregulated S100B and Hsc70 and upregulated endostatin may assist in prediction of poststroke epilepsy and may provide additional information to clinical risk factors. In addition, these data are hypothesis-generating for the epileptogenic process., (© 2020 International League Against Epilepsy.)

Objective: The objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy., Background: Previous studies demonstrate that oral hormonal contraceptives containing synthetic estrogen increase lamotrigine clearance through induction of glucuronidation. This leads to variable lamotrigine serum concentrations throughout monthly cycles in women who are on combined oral contraceptives (COCs). The effects of estrogen-containing nonoral hormonal contraceptive methods, including the vaginal ring and transdermal patch, on lamotrigine pharmacokinetics are not well described., Methods: Retrospective chart review was performed to identify serum lamotrigine levels drawn from women with epilepsy while on the active phase of vaginal ring or transdermal patch and while off contraception. Wilcoxon signed-rank tests for paired data were used to compare the difference in dose-corrected lamotrigine concentration in plasma between values while on hormonal contraception to those while off contraception in patients using a vaginal ring., Results: Six patients were using the vaginal ring, and one patient was using the transdermal patch. Lamotrigine dose-corrected concentrations were decreased during the active phase of the vaginal ring compared with concentrations during the period off contraception (p = .04). There was one patient without a decrease in concentration, but the other five patients on the vaginal ring had a decrease in dose-corrected lamotrigine concentration ranging from 36 to 70% while on the vaginal ring. Similarly, one patient using the transdermal patch had a decrease of 37% in dose-corrected lamotrigine concentration while on the patch., Conclusions: The findings support that the vaginal ring contraceptive method decreases lamotrigine concentrations during the active phase of treatment. This has important implications for contraceptive counseling and maintaining therapeutic levels in women of childbearing age with epilepsy., Competing Interests: Declaration of competing interest The authors have no conflicts of interested related to this publication. Elizabeth E. Gerard has received research support from Xenon, Sunovion, and SAGE pharmaceuticals and from the following NIH/NINDS grants: U01-NS038455, 2U01-NS038455. She has received speaker/travel fees from UCB Pharma. Micheal P. Macken received research support and consulting fees from Liva Nova and UCB Pharma, as well as consulting fees from Sunovion. Alexa King, Elizabeth Bachman, and Jungwha Lee have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated the effects of cannabidiol (CBD; 21-day maintenance dose) on the pharmacokinetics (PK) of clobazam (CLB) and monitored the safety of CBD (or placebo) plus CLB in 20 patients with uncontrolled epilepsy on stable doses of CLB. Blood samples collected until 24 hours postdose were evaluated by liquid chromatography tandem mass spectrometry. PK parameters of CLB and major metabolite N-desmethylclobazam (N-CLB), valproic acid, stiripentol, levetiracetam, topiramate, plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/mL oral solution) and its major metabolites were derived using noncompartmental analysis. There was no evidence of a drug-drug interaction (DDI) between CBD and CLB: geometric mean ratio (GMR) of day 33:day 1 CLB was 1.0 (90%CI, 0.8-1.2) for C max and 1.1 (90%CI, 0.9-1.2) for AUC tau . There was a significant DDI between CBD and N-CLB: the GMR of day 33:day 1 N-CLB was 2.2 (90%CI, 1.4-3.5) for C max and 2.6 (90%CI, 2.0-3.6) for AUC tau . Placebo had no effect on CLB or N-CLB; CBD had no effect on levetiracetam. Data were insufficient regarding DDIs with other antiepileptic drugs. The safety profile of CBD (20 mg/kg/day) with CLB was acceptable; all but 1 adverse events (AEs) were mild or moderate. One serious AE (seizure cluster) led to CBD discontinuation. One patient withdrew after intolerable AEs. Although there was no evidence of a CBD and CLB DDI, there was a significant DDI between CBD and N-CLB. The safety profile of GW Pharmaceuticals' CBD formulation with CLB was consistent with other GW-sponsored trials., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

It has been speculated that patients with epilepsy in elderly is increasing. The effect of enzyme-inducing antiepileptic drugs (EIAED) on lipid metabolism is well known. However, the study in elderly subjects has been rarely conducted. Furthermore, it has not been directly assessed whether EIAED use causes the change of lipid levels from normal range to abnormal range. Adult patients with epilepsy (235 on EIAED, 213 on non-EIAED) were divided by age (20-64, 65-74 and 75 over years old). Longitudinal change (before starting AED, in 3 and 6 months after starting AED) of serum total cholesterol (TC), triglyceride (TRIG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were retrospectively analyzed using mixed models. The risk of change of lipid levels from normal range to abnormal range was also assessed by logistic regression analysis. Comparison between patients with EIAED use (EIAED group) and patients with non-EIAED use (non-EIAED group) revealed significant differences. non-EIAED group was set as reference. Differences in least square mean (LSM), 95 % confidence interval (CI) and P value in analysis of LDL-C and non-HDL-C levels (1 × 10 -2 ) were as follows: 0.23 (0.10 ∼ 0.36), P < 0.001, 0.22 (0.09 ∼ 0.33), P = 0.001 in patients with age 65-74. In patients of age over 75, those were 0.08 (0.01 ∼ 0.15), P = 0.038, 0.17 (0.07 ∼ 0.26), P < 0.001, respectively. In patients with age 65-74, odds ratios (ORs) (95 % CI) in change of TC, LDL and non-HDL-C level from normal range to abnormal range were 32.28 (1.83-567.05), 48.43 (2.69-869.05), 12.04 (1.29-111.88), respectively. In patients with age 75 over, odds ratios (ORs) (95 % CI) in change of TC, LDL and non-HDL-C level from normal range to abnormal range were 46.02 (2.77-762.89), 5.53 (1.27-23.94), 2.38 (1.01-10.76), respectively. EIAED use had significant impact on changes in lipid levels in elderly patients. Furthermore, we could assess the impact of switching AED from EIAED to levetiracetam (LEV) in 36 patients including elderly. Switching AED from EIAED to LEV had significant impact in reducing TC, TRIG, LDL-C and non-HDL-C in both younger adult and elderly patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Limbic encephalitis (LE) forms a spectrum of autoimmune diseases involving temporal lobe epilepsy and memory impairment. Imaging features of LE are known to depend on the associated antibody and to occur on the brain network level. However, first studies investigating brain networks in LE have either focused on one distinct antibody subgroup or on distinct anatomical regions. In this study, brain graphs of 17 LE patients with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE), four LE patients with autoantibodies against leucine-rich glioma-inactivated 1, five LE patients with autoantibodies against contactin-associated protein-like 2, 26 age- and gender-matched healthy control subjects, and 20 epilepsy control patients with hippocampal sclerosis were constructed based on T1-weighted structural magnetic resonance imaging scans and diffusion tensor imaging. GAD-LE showed significantly altered global network topology in terms of integration and segregation as compared to healthy controls and patients with hippocampal sclerosis (P < .01, analysis of variance with Tukey-Kramer post hoc tests). Linear regression linked global network measures with amygdala volume and verbal memory performance (P < .05). Alterations of local network topology show serotype dependence in hippocampus, amygdala, insula, and various cortical regions. Our findings reveal serotype-dependent patterns of structural connectivity and prove the relevance of in silico network measures on clinical grounds., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objectives: The study aimed to determine the frequency of metabolic syndrome (MetS) and obstructive sleep apnea syndrome (OSAS) in patients with epilepsy receiving monotherapy and the relationship between these syndromes and antiepileptic drugs (AEDs)., Methods: Two hundred and ninety-seven patients with epilepsy between the ages of 18-65 years receiving monotherapy for at least one year and 50 healthy participants were enrolled. Body mass indices and waist circumferences were measured. Serum fasting glucose levels, high-density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), triglyceride, and serum AED concentrations were noted. The frequency of MetS in patients with epilepsy was calculated. The snoring, tiredness, observed apnea, high blood pressure, body mass index, age, neck circumference, and male gender (STOP-Bang) questionnaire was used to determine the risk of OSAS. The relationship between these two syndromes and seizure type, disease duration, AED dosage, and treatment duration was analyzed., Results: Metabolic syndrome was more frequent in patients with epilepsy compared with healthy participants (32.6% vs. 12.0%), and it was diagnosed in 37.8% of patients receiving valproic acid (VPA), 36.1% of patients receiving carbamazepine (CBZ), 34.9% of patients receiving oxcarbazepine (OXC), and 30.5% of patients on levetiracetam (LEV). There was a positive correlation between VPA treatment duration and MetS existence (p < 0.05). However, MetS frequency did not change because of seizure type, disease duration, or AED dosages in patients with epilepsy receiving monotherapy. The risk for OSAS was higher in patients with epilepsy compared with healthy participants (24.6% vs. 12%), and it was calculated high in 27.7% of patients receiving CBZ, 32.2% of patients receiving LEV, and 30.2% of patients receiving OXC. The OSAS risk was higher in patients who have focal seizures than generalized seizures (p = 0.044). There was no relationship between OSAS risk and duration of epilepsy, duration of treatment, drug doses, and serum drug levels (p > 0.05)., Conclusion: Higher frequency of MetS and OSAS risk should be kept in mind on clinical follow-up of patients with epilepsy receiving monotherapy., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)