The correlation of GluR3B antibody with T lymphocyte subsets and inflammatory factors and their role in the progression of epilepsy.

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

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.

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.

Association of Lamotrigine Plasma Concentrations With Efficacy and Toxicity in Patients With Epilepsy: A Retrospective Study.

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

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Dysregulated Apoptosis and Autophagy in Childhood Epilepsy: Correlation to Clinical and Pharmacological Patterns.

OBJECTIVES: We aimed to assess the serum levels of caspase-3 as a marker of apoptosis and microtubule-associated protein 1A/1B-light chain 3 (MAP1-LC3) as an autophagy marker in epileptic children with various clinical and pharmacological types. METHODS: This case-control study was carried out on 90 participants (50 pediatric patients with epilepsy and 40 healthy matched children), the patients were categorized into three groups: Group (A): 25 pharmacosensitive epilepsy, Group (B): 25 pharmacoresistant epilepsy, and Group (C): 40 (age, sex, and body mass index) matched healthy children selected as controls. Serum caspase-3 and MAP1-LC3 were measured in all study groups, using commercially available ELISA kits. RESULTS: Serum caspase-3 was significantly higher among epileptic children, especially in the pharmacoresistant group, cases managed with multiple antiepileptic drugs, and cases with abnormal EEG findings. Conversely, circulating MAP1-LC3 levels showed a significant reduction in epilepsy cases, particularly in pharmacoresistant cases, in cases treated with multiple antiepileptic drugs, and in cases with abnormal EEG data. A significant negative correlation between serum caspase-3 and MAP1-LC3 was found among epileptic children (r = -0.369, p = 0.0083). Serum caspase-3 was a more valid biomarker in helping diagnose childhood epilepsy, while serum MAP1-LC3 was more valid in predicting pharmacoresistant type. CONCLUSION: The study reveals that serum caspase-3 levels were significantly elevated, particularly in pharmacoresistant cases and those managed with multiple drugs. Conversely, MAP1-LC3 levels were significantly reduced in epilepsy cases, suggesting potential involvement of altered apoptosis and autophagy in childhood epilepsy.

Assessing the impact of circulating inflammatory cytokines and proteins as drivers and therapeutic targets in epilepsy: A Mendelian randomization study.

BACKGROUND: Previous research has demonstrated that neuroinflammation is a key element in the progress of epilepsy. Nevertheless, it is currently unidentified which inflammatory factors and proteins increase or decrease the risk of epilepsy. METHODS: We adopted Mendelian randomization techniques to explore the causal relationship between circulating inflammatory factors and proteins and various epilepsy. Our principal approach was inverse variance weighting, supplemented by several sensitivity analyses to guarantee the robustness of our findings. RESULTS: Studies have identified associations between epilepsy and specific inflammatory factors and proteins: three inflammatory factors and six proteins are linked to epilepsy in general; one inflammatory factor and four proteins are associated with focal epilepsy with no documented lesions; two inflammatory factors and three proteins are related to focal epilepsy, excluding cases with hippocampal sclerosis; two inflammatory factors and two proteins are connected to juvenile myoclonic epilepsy; two inflammatory factors and five proteins are linked to juvenile absence epilepsy; four inflammatory proteins are associated with childhood absence epilepsy; two inflammatory factors are related to focal epilepsy overall; two inflammatory factors and two proteins are connected to generalized epilepsy; and two inflammatory proteins are linked to generalized epilepsy with tonic-clonic seizures. Additionally, six inflammatory factors may play a downstream role in focal epilepsy. CONCLUSION: Our study uncovers various inflammatory factors and proteins that influence the risk of epilepsy, offering instructive insights to the diagnosis and therapy of the condition.

Association of serum uric acid levels with risk of epilepsy: A national population-based study.

BACKGROUND: Uric acid (UA) serves as a crucial endogenous antioxidant in the body, offering protection against oxidative stress, whichmaycontributetoepilepsypathogenesis. The association between serum UA levels and epilepsy remains uncertain. This study aimed to examine the potential connections between serum UA levels and epilepsy in US adults. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018, a cross-sectional analysis was conducted. Weighted logistic regression analyses were employed to assess the potential link between serum UA levels and the risk of epilepsy. Additionally, sensitivity analyses were conducted to evaluate the reliability of the results. RESULTS: We included 15,373 participants, of whom 136 (0.79 %) had epilepsy. Following adjustment for multiple variables, participants with serum UA levels <4.1 mg/dl had an odds ratio of 2.24 (95 % CI: 1.12-4.47, P = 0.023) for epilepsy compared to those with serum UA levels of 5.8-6.5 mg/dl. The results of the sensitivity analyses corroborated the initial findings. CONCLUSIONS: Our study revealed a significant association between lower serum UA levels and heightened risks of epilepsy, suggesting that low UA levels may serve as an independent risk factor for epilepsy. A marginal increase in UA levels within the normal range may act as a protective factor against epilepsy.

Executive function impairment is associated with low serum vitamin D levels in children with epilepsy.

PURPOSE: Executive function (EF) impairment and vitamin D deficiency are common clinical features among children with epilepsy (CWE). Recently, vitamin D has become a potential modification factor that affects cognitive status in individuals with neurological disorders. In this study, we investigated the association between EF status and vitamin D levels in patients with CWE. METHODS: In total, 79 CWE patients and 39 healthy controls (HCs) were recruited in this study. Each participant's EF was assessed using the Behavior Rating Inventory of Executive Function-Parent form (Brief-P), and the serum level of 25-OH vitamin D was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Compared with those in the HC group, the CWE group had higher T scores of Brief-P scale, including global executive composite (GEC) (51.01(45.12, 60.69) vs. 44.08(39.24, 49.96), p＜0.001), behavioral regulation index (BRI) (51.29(45.67, 59.13) vs. 45.67(40.06, 51.29), p＜0.001), metacognition index (MI) (51.83(46.77, 59.43) vs. 46.13(40.44, 51.83), p＜0.001), and lower serum vitamin D (14.85(10.24,23.2) vs. 22.5(16.91,30), p＜0.001) levels. After adjustment for covariates, multivariate linear regression models suggested that for every 1 ng/ml increase in vitamin D, the GEC, BRI, and MI would decrease by 0.52 (Coeff = -0.48; 95 % CI = -0.69, -0.26; p = 0.000), 0.45 (Coeff = -0.45; 95 % CI = -0.69, -0.20; p = 0.000), and 0.47 (Coeff = -0.45; 95 % CI = -0.67, -0.22; p = 0.000), respectively. CONCLUSION: There may be an association between decreased vitamin D levels and EF impairment in CWE. Future research should consider longitudinal variations in EF related to improving vitamin D deficiency.

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.

Correlation analysis of 25(OH)D with cognitive function in epilepsy patients: A cross-sectional study.

OBJECTIVE: To analyze the correlation between the level of 25(OH)D in peripheral blood and cognitive function in patients with epilepsy, and to find the biomarkers of epilepsy complicated with cognitive dysfunction. METHODS: 68 patients with epilepsy and 30 healthy subjects were included in this study. The 25(OH)D level in peripheral blood of all subjects was detected and the score of the Montreal Cognitive Assessment Scale was performed. The patients with epilepsy were divided into a cognitively normal group (36 cases) and a cognitively impaired group (32 cases) according to the scale score. The inter-group scale score and 25(OH)D level were compared, and the correlation was analyzed. RESULTS: The levels of 25(OH)D and MOCA in epileptic group were significantly lower than those in healthy control group. The 25(OH)D and MOCA of the cognitively impaired group were significantly lower than those of the cognitively normal group. Logistic regression analysis indicated that serum 25(OH)D level was an independent risk factor for epilepsy combined with cognitive impairment (OR = 0.704, P = 0.014). The area under ROC curve of serum 25(OH)D for diagnosis of epilepsy combined with cognitive impairment was 0.924 (95 %CI 0.866,0.981), the critical value was 34.50 nmol/L, the sensitivity was 0.778, and the specificity was 0.906. CONCLUSION: Decreased levels of vitamin D are associated with cognitive impairment associated with epilepsy, and it may be a biomarker for early screening of cognitive impairment.

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.

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.

Peripheral nesfatin-1 reduces basal brain activity but has limited effect on epilepsy-like conditions.

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

Dissimilar Changes in Serum Cortisol after Epileptic and Psychogenic Non-Epileptic Seizures: A Promising Biomarker in the Differential Diagnosis of Paroxysmal Events?

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

Determination of Antiepileptics in Biological Samples-A Review.

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

A Cross-Sectional Study Comparing Oxidative Stress in Patients with Epilepsy Treated with Old and New Generation Antiseizure Medications.

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

Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome.

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.

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.

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.