Serum Antiepileptic Drug Research Articles

Antiepileptic-drug tapering and seizure recurrence: Correlation with serum drug levels and biomarkers in persons with epilepsy.

OBJECTIVES:Antiepileptic-drug (AED) serum level and inflammatory biomarkers are primarily monitored/assessed during epilepsy treatment for effective seizure control; however, their correlation with seizure recurrence (SR) following AED-tapering has not been established, and this is being investigated in this study.MATERIALS AND METHODS:This prospective observational study enrolled persons with epilepsy (PWE) on AED monotherapy and going to start tapering after being seizure-free for ≥2 years. Data regarding seizure episodes, AED-treatment, and adverse events (using Liverpool Adverse Event profile [LAEP]-score) were recorded. Serum AED levels using high-performance liquid chromatography and biomarkers levels through enzyme-linked immunosorbent assay kits were estimated at AED-tapering commencement and at 6 months/SR time.RESULTS:Among 129 enrolled PWE (levetiracetam [n = 52], valproate [n = 34], carbamazepine [n = 29], and phenytoin [n = 14]), SR occurred in 23.3% during follow-up (range 12–44 months). PWE with subtherapeutic serum AED level at the onset of tapering had higher SR (P = 0.004) than those with therapeutic or higher levels. Levetiracetam-treated PWEs with SR have significantly low AED levels than PWE with no-SR (P < 0.001). PWE had significantly raised inflammatory biomarkers (interleukin [IL]-1 β, tumor necrosis factor [TNF]-α, IL-6, and high-mobility group box protein 1) and decreased IL-10 than healthy control subjects. SR and no-SR groups did not differ significantly in inflammatory markers except for higher IL-1 β and TNF-α levels in SR group (P = 0.001, 0.02, respectively). Improvement in LAEP score was observed in follow-up visits without any difference between SR and no-SR groups.CONCLUSION:Low serum AED levels (especially levetiracetam) and raised levels of TNF-α and IL-1 β during tapering commencement had a higher association with SR following AED-tapering.

Therapeutic Drug Monitoring of Lamotrigine, Lacosamide, and Levetiracetam in Dried Capillary Blood-Determination of Conversion Factors for Serum-Based Reference Ranges.

Drug concentrations of antiepileptic drugs (AEDs) are routinely determined from blood serum or plasma at trough levels (before intake of morning dose). In capillary blood collection, blood is taken from the fingertip with the aid of a disposable tool and dried on absorbent material. The volumetric absorptive microsampling technique offers several advantages over the use of filter paper cards. The aim of this study was to determine conversion factors for the estimation of AED serum concentrations from capillary blood concentrations. Venous and capillary blood samples were collected from adult inpatients with epilepsy who were treated with lacosamide (LCM, n = 30), lamotrigine (LTG, n = 40), and/or levetiracetam (LEV, n = 36). A validated liquid chromatography-mass spectrometry (LC-MS) method for dried blood samples for these AEDs was compared with routine serum laboratory methods. Method agreement was evaluated using different regression techniques, and the conversion factors were calculated. Regression analyses revealed a linear relationship between serum and capillary blood concentrations for all 3 AEDs (r ≥ 0.95). For LTG, the regression intercept was significantly different from 0, indicating that the relationship was linear, but not necessarily proportional. Although LEV and LCM concentrations tended to be lower in capillary blood than in serum (mean ratio of serum concentration to capillary blood concentration: 1.14 and 1.22, respectively), LTG concentrations were higher in capillary blood (mean ratio = 0.85). The estimation of serum concentrations from measured capillary blood concentrations is feasible for LCM, LTG, and LEV. A simple ratio approach using the mean ratio and Passing-Bablok regression showed the best results for all 3 AEDs. The volumetric absorptive microsampling technique facilitates the quantitative sample collection of capillary blood and overcomes the drawbacks associated with the classical dried blood spot technique.

Significant Association of Antiepileptic Drug Polytherapy with Decreased FT4 Levels in Epileptic Patients.

Epileptic patients have to continue anti-epileptic drugs (AED) over a long period of time which can have deleterious effects on the endocrine system including the thyroid hormones with rare check. Risk factors for the development of thyroid dysfunction are still unclear. Therefore the aim of study was to evaluate thyroid functions in epileptic patients receiving anti-epileptic drugs (AED) as monotherapy and polytherapy and to determine potential risk of low thyroid function in epileptic patients receiving treatment. This cross-sectional study included 100 epilepsy patients more than 12years of age. Serum levels of free thyroxin (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were evaluated in all subjects in addition to serum AED levels. TSH levels were found to be significantly higher in the polytherapy subgroup (p < 0.05) in comparison to the monotherapy group. 44% of the patients in the VPA monotherapy group had raised TSH levels and 41.2% of the patients on CBZ had low FT4. A significant negative correlation was observed between CBZ and FT4 (p < 0.05). Female sex and old age were additional risk factors detected for deranged thyroid function. Female patients with epilepsy, an older age and AED polytherapy were found to be associated with a higher risk of thyroid dysfunction. Thus, Thyroid function in these patients should be monitored closely. In conclusion, we observed significant changes in thyroid hormone levels in patients receiving antiepileptic treatment in both monotherapy and polytherapy. Elevated CBZ levels were significantly associated with decreased FT4 levels.

Intra Nasal Midazolam vs. Rectal Diazepam in Management of Acute Seizures in Pediatrics, Considering the Antiepileptic Drugs Monitoring

Immediate management of children's epilepsy is essential before the patient arrives to the hospital. The purpose of this study was to compare the efficacy of intranasal midazolam vs. rectal diazepam in the management of acute pediatric seizures. In this cross-sectional study, 68 patients having acute seizure were evaluated for response to treatment after receiving intra-nasal midazolam (34 patients) or rectal diazepam (34 patients). Patents were assessed by physicians at the arrival to emergency department for history taking and examination. Blood samples were assessed for valproate, phenobarbital and phenytoin levels in serum to determine previous use of antiepileptic drugs. Seizure duration and response time to treatment were evaluated along with health care utilization and were compared between study groups, by the statistical package for the social sciences software. Mean age of study participants, sex disturbance, age at onset of a seizure, type of seizure and prehospital time had not any significant differences between two groups (p>0.05). The mean response time to diazepam was 8.0±4.9 min and 6.3±2.2 min for midazolam; which had a significant difference between groups (0.001). Linear regression of serum antiepileptic drug levels in association of response time in each group was not significant in all case (p>0.05), expect the lamotrigine serum level in midazolam group (p=0.029). Intranasal midazolam was seen to have a better effect than rectal diazepam in the management and treatment of acute seizures in children; while antiepileptic drugs monitoring want helpful in assessing the absolute effect.

Metabolic syndrome and obstructive sleep apnea syndrome among patients with epilepsy on monotherapy

ObjectivesThe 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). MethodsTwo 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. ResultsMetabolic 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). ConclusionHigher frequency of MetS and OSAS risk should be kept in mind on clinical follow-up of patients with epilepsy receiving monotherapy.

Author response: Clinical utility of therapeutic drug monitoring of antiepileptic drugs.

I appreciated Dr. Sethi's commentary on our recently published article as he raises a number of interesting points.1 Certainly, intraindividual variability is another complicating aspect of therapeutic drug monitoring (TDM) in epilepsy care and, while outside the scope of our review, should be taken into account by all clinicians who choose to incorporate serum antiepileptic drug levels into their clinical decision-making. For my personal practice, I tend to agree that the clinical utility of serum antiepileptic drug levels is limited and that dosing adjustments are best made based on clinical response (seizure control and reported adverse effects). Although our systematic review did identify some studies showing evidence for TDM, the higher quality studies did not show convincing evidence supporting a clinical benefit. In general, we clinicians now have a wealth of diagnostic options available to us, and it is easy to forget that the patient's reported symptoms and clinical examination are almost always the most important outcome measures.

Prevalence of vitamin D deficiency and its relationship with epileptic severity in a pediatric department of tertiary care hospital

Aim To evaluate the prevalence of vitamin D deficiency in pediatric epileptic patients and to assess if there is any correlation between vitamin D level and disease severity in epileptic patients. Objective To estimate vitamin D deficiency and insufficiency as percentage of enrolled patients in pediatric department and to identify if there is any correlation between vitamin D deficiency and factors such as age, sex, BMI, total serum calcium levels, antiepileptic drugs, and types of seizures. Patients and methods A prospective interventional clinical study was carried out in a tertiary care hospital between September 2018 and February 2019. We included 30 pediatric epileptic patients of age group 1–14 years from whom the blood samples were withdrawn and were sent to the laboratory for the estimation of vitamin D levels. Results The data collected was analyzed using statistical method χ2 and analysis of variance in Prism 8.0 version. The prevalence of vitamin D deficiency and its correlation with epilepsy was determined. In this study, we found that there was a high prevalence of vitamin D deficiency in pediatric epileptic patients (23 patients out of 30–73%). The other risk factors for vitamin D deficiency found in this study are children of age group 5–10 years (43%), malnourished patients (40%), hypocalcemic patients (40%), and patients who use antiepileptic drugs for more than 2 years (57%). Conclusion Based on the aforementioned scientific analysis, it can be concluded that there is a high prevalence of vitamin D deficiency in pediatric patients with epilepsy. So, vitamin D3 supplements should be given for all epileptic children even before the initiation of antiepileptic therapy. Patients’ parents were educated on the importance of vitamin D.

Pharmacokinetic interaction between modified Atkins diet and antiepileptic drugs in adults with drug-resistant epilepsy.

The aim was to examine the influence of modified Atkins diet on serum concentration of antiepileptic drugs (AEDs). Prospective data from 63 adult patients with either focal or generalized drug-resistant epilepsy recruited to 12-week dietary treatment as add-on to AEDs are analyzed. AED serum concentrations, ketones, glucose, and hemoglobin A1c were measured before and after the dietary intervention. Paired t test was used and Spearman correlation coefficient, r, was estimated. Mean age was 37years (range 16-65years). Mean serum concentrations of carbamazepine, clobazam, and valproate were significantly reduced after 4 and 12weeks of the diet period (<.001≤P≤.02). Levels of lacosamide, lamotrigine, and topiramate were less reduced (.02≤P≤.08), whereas the serum concentrations of oxcarbazepine, zonisamide, and levetiracetam were unchanged (.06≤P≤.90). The largest reduction in serum concentration was found for clobazam: mean reduction after 12weeks was 1.5μmol/L (34%). Percent change in serum concentration after 4 and 12weeks of all drugs analyzed was -10.5% (95% confidence interval [CI] -14.1 to -6.8; n=60; P<.001) and -13.5% (95% CI -18.8 to -8.3; n=56; P<.001), respectively. Percent change in serum concentration of AEDs was not significantly correlated to percent change in seizure frequency after 12weeks of dietary treatment (r=.14, P=.33, n=53) but negatively correlated to urine ketosis (r=-.43; P=.003; n=46). A reduction in AED serum concentrations may counteract a seizure-reducing effect of the diet, and in patients without such an effect, it may cause seizure aggravation. Thus, we recommend that clinicians who are treating patients with ketogenic diets monitor serum concentrations of the concomitant AEDs.

Kumaraswamy Distribution in Analyzing the Health-related Quality of Life and Effective Factors in Elderly Patients with Epilepsy

Background: Epilepsy, which develops in the elderly, is recognized as a major health burden. Although health-related quality of life (HRQoL) is an essential element in the medical treatment of elderly patients with epilepsy, it is a question whether epilepsy and its treatment effectively influence the quality of life (QoL) in the elderly. Objectives: The current study aimed at evaluating the relationship between demographic and clinical aspects of epilepsy in HRQoL of elderly patients. Since HRQoL scores are bounded, the Kumaraswamy (Kum) regression model was used to analyze the data. Methods: The current study was conducted on 766 elderly patients diagnosed with epilepsy taking at least one antiepileptic drug (AED) selected from six neurologic clinics in Iran. In addition to demographic information, the Liverpool seizure severity scale (LSSS), medication adherence report scale (MARS-5), and quality of life in epilepsy (QoLIE-31) questionnaire were completed for patients. Data were analyzed using multiple linear regression (MLR) and the Kum regression models. Results: Most of the patients included in the study had focal (70.2%) epilepsy. Mean duration of disease was 17.71 ± 4.56 years and the average number of seizures was 3.4 ± 3.2 episodes per month. The Kum regression model indicated that seizure frequency (β = -0.157, P < 0.0001) and LSSS score (β = -0.003, P = 0.009) were significant and negative predictors of overall QoLEI-31 score; MARS-5 score was a positive predictor of overall QoLEI-31 score (β = 0.014, P = 0.002). However, disease duration and serum AED level had no significant effects on overall QoLEI-31 score. Conclusions: The findings suggested that increased seizure frequency and severity were associated with lower QoL and medication adherence was directly associated with HRQoL. The Kum regression could be a suitable alternative to the methods currently used in the analysis of HRQoL data.

Health-related quality of life and medication adherence in elderly patients with epilepsy.

Considering the high prevalence of epilepsy in the elderly and the importance of maximising their quality of life (QoL), this study aimed to investigate the relationship between medication adherence and QoL, and the mediating effects of medication adherence on the association between serum antiepileptic drug (AED) level and seizure severity with QoL in elderly epileptics. In a longitudinal study, 766 elderly patients with epilepsy who were prescribed a minimum of one antiepileptic drug were selected by convenience sampling method. A Medication Adherence Report Scale (MARS-5) questionnaire was completed at the baseline. Seizure severity and QoL were assessed after six months using the Liverpool Seizure Severity Scale (LSSS) and the QoL in Epilepsy (QOLIE-31) questionnaires respectively. Serum level of AED was also measured at six-month follow-up. Medication adherence was significantly correlated with both seizure severity (β = -0.33, p < 0.0001) and serum AED level (β = 0.29, p < 0.0001) after adjusting for demographic and clinical characteristics. Neither QoL nor its sub-classes were correlated with seizure severity. In addition, a significant correlation was not observed between serum AED level and QoL. However, medication adherence was significantly correlated with QoL (β = 0.30, p < 0.0001). The mediating effects of medication adherence on the association between serum AED level (Z = 3.39, p < 0.001) and seizure severity (Z = -3.47, p < 0.001) with QoL were supported by the Sobel test. This study demonstrates that medication adherence has a beneficial impact on QoL in elderly epileptics. Therefore, adherence to treatment should be monitored to improve their QoL.

Changes in Serum Valproate and Levetiracetam Levels Related to Sex Steroids in Adolescent Girls

Abstract Background The goal of this study was to explore the changes in serum antiepileptic drug levels and their relation with sex steroid levels during the menstrual cycles of adolescent girls. In addition, valproate and levetiracetam were compared in terms of their effects on body mass index, ovulation, and sex steroid levels. Methods Adolescent girls using valproate (n = 16) and levetiracetam (n = 9) were included in the study. Serum antiepileptic drug, progesterone, and estradiol levels were analyzed in two periods, when the levels of sex hormones might be the highest (midluteal phase) and the lowest (early follicular phase). Results Serum antiepileptic drug levels were not significantly different between the two periods in both antiepileptic drug groups. Serum antiepileptic drug levels during menstruation increased in 69.2% of the valproate group, whereas they decreased in 88.9% of the levetiracetam group ( P = 0.011). A positive correlation between serum valproate and progesterone levels ( r = 0.767, P = 0.001) and between levetiracetam and estradiol levels ( r = 0.259, P > 0.05) was present in the menstrual phase. Body mass index, body mass index percentile, z score, and ovulation rates were not different between the two groups. Conclusions This study indicates a strong correlation between valproate and progesterone levels in the early follicular phase of the menstrual cycle. The findings of this study also suggest that valproate and levetiracetam have different relationships with sex steroid levels, during menstrual cycle. Especially in catamenial seizures, taking this interaction into account may be beneficial.

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine.

SummaryObjectiveTo ascertain the clinical and genetic factors contributing to carbamazepine‐ and oxcarbazepine‐induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy.MethodsWe collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ‐diol to unchanged drug precursor substrate as measured in serum.ResultsClinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome‐wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome‐wide significant associations with CBZ metabolic ratio were found.SignificanceAlthough we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

Randomized Controlled Trial of Melatonin for Sleep Disturbance in Dravet Syndrome: The DREAMS Study

Dravet syndrome is a severe developmental and epileptic encephalopathy, in which 75% of patients have sleep disturbance. Melatonin is often used for sleep problems in childhood; however, there is no quality evidence supporting its use in Dravet syndrome. We hypothesized that melatonin would increase total sleep and quality of life for patients with Dravet syndrome. A double-blind crossover randomized placebo-controlled trial was conducted, comparing 6 mg regular-release melatonin to placebo for patients with Dravet syndrome and sleep disturbance. The primary outcome measure was total sleep measured by actigraphy, with secondary outcomes including wakefulness after sleep onset (WASO), Sleep Disturbance Scale in Children and Quality of Life in Children with Epilepsy 55 questionnaires, caregiver reports of clinical change, seizure diary and serum antiepileptic drug levels. We also compared actigraphy data of patients with Dravet syndrome to an age-matched healthy control group. A total of 13 patients completed the study. There was no difference in total sleep or WASO between melatonin and placebo. However, of the 11 patients for whom caregivers reported a clear clinical difference between treatments (blinded), 8 reported improvement on melatonin (P < .05). Interestingly, when compared to patients in the control group, patients with Dravet syndrome had significantly increased total sleep (P = .002). Melatonin did not increase total sleep; however, blinded caregiver reports indicate treatment with melatonin provided considerable clinical benefit for some patients with Dravet syndrome and sleep disturbance. Registry: Australian Government Department of Health, Therapeutic Goods Administration under the Clinical Trials Notification Scheme (protocol number 2241).

Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.

To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency. Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without. AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05). AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.

Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. Fewer women than the original target were recruited. There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. Current Controlled Trials ISRCTN01253916. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

Specific Patient Features Affect Antiepileptic Drug Therapy Decisions: Focus on Gender, Age, and Psychiatric Comorbidities.

Patient features, apart from the type of seizures/epilepsy, affect markedly antiepileptic drug (AED) choice and dosage. The present review focuses on gender, age and psychiatric comorbidities which play a leading role in influencing antiepileptic treatment. Reviews with large population of patients, controlled clinical trials, observational investigations, experimental studies and experimental reviews of experimental data, where appropriated, were analysed and illustrated to produce the most homogeneous indications possible. Different and also contradictory observations have been highlighted to stimulate a critical approach to specific aspects. Women of childbearing age should avoid valproic (VPA), acid, since this drug doubles the risk of major malformations and causes in the exposed offspring reduced intellectual development and disorders of autistic spectrum. The drug is also associated with hormonal disorders, polycystic ovary and reduced fertility. Children treated with valproic acid or phenobarbital can exhibit hyperactivity, nervousness and attention disorders. As a consequence of increased drug elimination, younger children require higher doses as compared to adults and older patients. Elderly patients treated with phenobarbital may face the risk of cognitive disorders and/or falls resulting in bone fractures. Fractures are also facilitated by carbamazepine-induced osteoporosis. Psychiatric disorders are frequently associated with epilepsy and evidence has been gained that common pathological steps underlie these conditions. Depressed patients should avoid drugs like phenobarbital, topiramate, levetiracetam, zonisamide and perampanel since these drugs can induce mood disorders. Although not conclusive, literature data indicate that topiramate and levetiracetam and also tiagabine and vigabatrin, are associated with suicidal thought/behaviour. Conversely, lamotrigine, carbamazepine, VPA and oxcarbazepine exert beneficial effects on mood. Bupropion, clomipramine, amoxapine and maprotyline among antidepressants, and clozapine, olanzapine and quietapine among antipsychotics have been observed to lower seizure threshold. Serum AED concentration monitoring is of help in dosage adjustments, especially in very young children, in patients with cognitive decline and in patients with psychiatric comorbidities. A careful evaluation of the patient variables analysed in the present review is useful to personalize and optimize AED therapy.

Cannabidiol and Serum Antiepileptic Drug Levels: The ABCs of CBD With AEDs.

Cannabidiol and Serum Antiepileptic Drug Levels: The ABCs of CBD With AEDs.

Effects of religiosity and religious coping on medication adherence and quality of life among people with epilepsy

The epidemiologic information demonstrates the importance of caring people with epilepsy (PWE). Indeed, the impaired quality of life (QoL) and medication nonadherence rate among PWE have been reported. However, religiosity and religious coping could be potential factors for clinicians to foster appropriate intervention on epileptic care. This study investigated two models to further understand the relationships between religiosity, religious coping (including positive and negative coping), medication adherence, and QoL in an Iranian sample with epilepsy. Eligible PWE (n=760) completed the religiosity scale (Duke University Religion Index; DUREL) at baseline; the religious coping scale (Brief Religious Coping Scale; Brief RCOPE) one month later; the medication adherence scale (Medication Adherence Report Scale; MARS-5) two months later; and the QoL scale (Quality of Life in Epilepsy; QOLIE-31) twelve months later. Their antiepileptic drug serum level was measured during the period they completed the MARS. Through structural equation modeling (SEM), we found that religiosity directly correlated with negative religious coping and medication adherence, and indirectly correlated with medication adherence through negative religious coping. Both positive and negative religious coping directly correlated with medication adherence and QoL. Therefore, religiosity and religious coping may be determinants of medication adherence and QoL in PWE; health professionals may consider asking PWE if religion is important to them and how they use it to cope with their epilepsy.

Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients.

Patients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations. A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p < 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Interactions between cannabidiol and commonly used antiepileptic drugs.

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.