The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

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.

Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study.

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.

Innovative LC-MS/MS method for therapeutic drug monitoring of fenfluramine and cannabidiol in the plasma of pediatric patients with epilepsy.

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.

Interictal interleukin-6 and tumor necrosis factor α levels are associated with seizure recurrence in adults with 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.

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

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.

Evaluation of anti-seizure medications and their serum concentration with regard to cardiovascular risk parameters: A cross-sectional study.

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.

Association between pre-diagnostic serum uric acid levels in patients with newly diagnosed epilepsy and conversion rate to drug-resistant epilepsy within 5 years: A common data model analysis.

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.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

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.

Depot medroxyprogesterone acetate concentrations in patients with and without the use of antiseizure medications.

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.

Evaluation of neurofilament light chain as a biomarker in dogs with structural and idiopathic 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.

Therapeutic drug monitoring in pregnancy: Levetiracetam.

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.

Side effects of long-term oral anti-seizure drugs on thyroid hormones in patients with epilepsy: a systematic review and network meta-analysis.

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.

Clinical impact of the dose and blood concentration of lacosamide in Japanese pediatric patients with epilepsy: A cohort study.

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.

Relationships between plasma expression levels of microRNA-146a and microRNA-132 in epileptic patients and their cognitive, mental and psychological disorders.

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.

Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy.

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.

Bcl-2 and caspase-9 serum levels in children and adolescents with idiopathic epilepsy and active seizures.

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.

Factors Influencing Sodium Valproate Serum Concentrations in Patients with Epilepsy Based on Logistic Regression Analysis.

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.

Serum prolactin level and lactate dehydrogenase activity in patients with epileptic and nonepileptic seizures: A cross-sectional study.

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.

An insight into crosstalk among multiple signaling pathways contributing to epileptogenesis.

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/ß-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.

Advances in the Development of Biomarkers for Poststroke Epilepsy.

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.