Anticonvulsant Levels Research Articles

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).

Single antiepileptic drug levels do not predict adherence and nonadherence.

To investigate the significance of "subtherapeutic" vs "therapeutic" antiepileptic drug (AED) plasma levels with respect to treatment adherence. One hundred and seventy patients with refractory temporal lobe epilepsy who underwent video-EEG monitoring in view of a surgical indication had their AEDs (carbamazepine, phenobarbital, phenytoin, and valproate) rapidly withdrawn following a standardized schedule. Plasma levels were measured at admission, and during the 2days of drug withdrawal. Adherence and nonadherence were identified by the development of plasma levels from day 1 through day 3. Frequencies of an initial level below the reference range in both groups were compared. Adherence was found in 73.2% of cases, and nonadherence in 26.8%. Low levels were seen equally often (about 1/4 of cases) in adherent and nonadherent cases. The vast majority (73.7%) of low levels had another explanation than nonadherence (eg low-dose treatment or enzyme induction). Of 42 nonadherent cases, the vast majority of 76.2% had unsuspicious plasma levels at admission. "Subtherapeutic" AED plasma levels only rarely are caused by nonadherence whereas levels in the "therapeutic range" by no means prove that the patient is adherent to treatment. For meaningful interpretation, any level needs to be compared with other levels of the same patient. Our findings strongly emphasize the principle of individualized therapeutic AED monitoring as promoted by the Therapeutic Strategies Commission of the ILAE.

Systematic review of the screening, diagnosis, and management of ADHD in children with epilepsy. Consensus paper of the Task Force on Comorbidities of the ILAE Pediatric Commission

Attention-deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large-population prospective studies.

Predictors of nonadherence in children and adolescents with epilepsy: A multimethod assessment approach

BackgroundThere is a lack of a standardized tool for adherence measurement in patients with epilepsy. Studies in children with epilepsy have reported adherence in 50–96.5%. The primary objective of this study was to identify predictors of nonadherence to antiepileptic drugs (AEDs) using two different methods in Jordanian children and adolescents with epilepsy. MethodsParticipants included 63 children and adolescents with epilepsy and their primary caregivers. Adherence measures included a subjective approach (using parent and child self-reports via Medication Adherence Report Scale (MARS)) and an objective method (measuring plasma levels of AEDs coupled with the application of population pharmacokinetic models to predict AED concentrations in the children). The Beliefs about Medicines Questionnaire (BMQ) was used to examine the association beliefs about medicines with nonadherence in the participating patients. ResultsMeasuring AEDs in plasma samples captured the highest percentage of nonadherence (36.2%). No significant agreement was found between the AED plasma level method and both the MARS (parent) and MARS (child). The overall nonadherence (combined methods) to AED therapy in children with epilepsy was 44.4%. Logistic regression analysis indicated that children with longer duration of disease were more likely (odds ratio [OR]: 1.54, 95% confidence interval [CI]: 1.16–2.04) to be classified as nonadherent as were children whose parents have lower AED Necessity scores (OR: 0.68, 95% CI: 0.53–0.87) and higher AED Concerns (OR: 1.6, 95% CI: 1.26–2.04) as measured by the BMQ. ConclusionThe use of a multimethod approach for assessing adherence increases sensitivity for detection of nonadherence to AEDs. Disease duration and parental necessity beliefs and concerns assessed by the BMQ-specific questionnaire were significant predictors of nonadherence to the AED therapy. The need for the development and implementation of interventions that can be employed to improve adherence within this pediatric population has been highlighted by the high levels of nonadherence identified.

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.

Prescribing antiepileptic drugs to women of reproductive age

The notion that use of antiepileptic drugs by pregnant women increases the risk for major congenital malformations is not new, but the oversimplification of grouping all antiepileptic drugs together into the same risk category is outdated. Data have accumulated to show the differential risks for major congenital malformations, with the highest risk consistently associated with in-utero valproate exposure. 1 Hernandez-Diaz S Smith CR Shen A et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012; 78: 1692-1699 Crossref PubMed Scopus (399) Google Scholar The Neurodevelopmental Effects of Antiepileptic Drugs study also concluded that the highest risk for impaired cognitive function at 6 years of age occurs in the children of women who took valproate during pregnancy compared with other antiepileptic drug monotherapies. 2 Meador KJ Baker GA Browning N et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013; 12: 244-252 Summary Full Text Full Text PDF PubMed Scopus (526) Google Scholar Reports from pregnancy registries have also revealed that the teratogenic risk for valproate is dose dependent, 3 Harden CL Meador KJ Pennell PB et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73: 133-141 Crossref PubMed Scopus (274) Google Scholar and it was tempting for physicians to not worry about the level of the so-called safe antiepileptic drugs, such as lamotrigine. However, a landmark paper in 2011 by the investigators of the EURAP international registry, 4 Tomson T Battino D Bonizzoni E et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011; 10: 609-617 Summary Full Text Full Text PDF PubMed Scopus (549) Google Scholar reporting on 3909 pregnancies exposed to the four most common antiepileptic drug monotherapies (carbamazepine, valproate, lamotrigine, and phenobarbital), showed that not only did the antiepileptic drug choice matter in determining the relative risk of major congenital malformations, but also the dose at conception, even for lamotrigine despite having the lowest risk. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registryDifferent antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Full-Text PDF

Prise en charge d’une épilepsie nouvellement diagnostiquée

The diagnosis of de novo epilepsy is complex. An accurate diagnostic approach has to be followed based on specific key steps. Epileptic seizure or non-epileptic malaise: risk of diagnosis error around 20%. Facing a first unprovoked seizure, the practitioner has to know the risk factors specifically linked to an increase risk of seizure recurrence. In presence of these factors, an antiepileptic drug would be indicated. The first antiepileptic drug has to be highly selected according to the epilepsy type and causes but also to the patient characteristics (sex, age, comorbidities, associated drugs, profession, and way of life…) An exhaustive patient Education needs to support the first antiepileptic drug prescription: (sleep and nutritional advices, benefit of observance, antiepileptic drugs features and side effects, follow-up, prognosis…) A regular follow-up is essential to control the observance, tolerability and efficacy of the antiepileptic drug, and to control also the good acceptance of the disease. A systematic research of common comorbidities may be also performed. Electroencephalogram and antiepileptic drugs levels are unnecessary in the classical follow up of known epileptic patients (except specific cases).

Understanding variability in driving recommendations for patients with seizures

BackgroundThere is lack of consensus regarding driving restrictions for patients with epilepsy. Regulations vary by state. New York State (NYS) recommends driving restrictions for one year in a person with an episode of loss of consciousness (LOC), with physician discretion. Often, providers make recommendations to permit their patients to drive after a shorter seizure-free period than proposed guidelines. The prevalence and reasons behind more lenient recommendations have not been elucidated. MethodsForty-one neurologists were surveyed anonymously in Nassau County, New York. They were questioned about the length of recommended driving restrictions (≤1, 3, 6, or ≥12months) that they typically provide to patients with suspected seizures in different clinical scenarios and overall reasons for doing so. Data about level of training, setting of practice, use of antiepileptic drug (AED) levels, and electroencephalogram (EEG) were also collected. ResultsOf the 41 neurologists surveyed, 72% reported recommending driving restrictions <12months for patients who experienced LOC, without a confirmed diagnosis of seizure. The majority also recommended driving restriction of <12months for other scenarios including acute symptomatic seizure, exclusively simple partial seizures, nocturnal seizures, psychogenic nonepileptic seizures (PNES), and seizures occurring with or during AED reduction. The most common rationale was to improve patient autonomy and independence. Less than a third of neurologists estimated that the majority of their patients were noncompliant with driving recommendations. ConclusionWe found that many neurologists' recommendations for limiting driving for patients with seizure-related episodes are shorter than those recommended by NYS. Furthermore, as there are no specific guidelines for questionable epileptic scenarios and seizures occurring nocturnally or without LOC, this appears to contribute to substantial variability in the duration of recommended driving restrictions. This opens a broad discussion about approaches towards advising driving limitations in order to protect public and patient safety while maintaining patient autonomy.

Correlation Between Serum Level of Antiepileptic Drugs and their side-effects

Phenytoin can cause a range of dose-related and idiosyncheratic adverse effects.

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.

An LC-MS/MS based candidate reference method for the quantification of carbamazepine in human serum

A validated LC-MS/MS-based candidate reference measurement procedure for the quantification of carbamazepine is presented in order to be used for standardization and harmonization of routine assays applied for therapeutic drug monitoring. Sample preparation was based on protein precipitation using acetonitrile followed by sample dilution. Since the previously listed certified reference material (CRM) SRM 1599 (anticonvulsant drug level assay standard) is no longer available, an ISO certified calibration material was used in this assay. As internal standards deuterated analyte congeners were applied. The method allows the measurement of carbamazepine, carbamazepine-10,11-epoxide and 10-hydroxy-10,11-dihydrocarbamazepine in the concentration range of 0.1 to 22.0μg/ml with LODs and LOQs of <0.1μg/ml and 0.1μg/ml, respectively. Comparative measurement of 105 native patient samples using the here presented method showed a good agreement between two independent laboratories with a mean bias of 0.6%.

Interacciones medicamentosas de los anticonvulsivantes de primera línea con antipsicóticos y/o antidepresivos

ObjectiveIdentify drug interactions of old antiepileptic drugs with antidepressants and antipsychotics and its impact on the patient with epilepsy at the Hospital de San José in outpatient appointment from June 1st, 2015 to the april 30th, 2016. Material and methodsA descriptive study was conducted to identify drugs interactions in patients diagnosed with epilepsy. The study involved patients over 18 years old with a diagnosis of epilepsy according to the International League Against Epilepsy criteria in therapy with first line antiepileptic drugs associated with antipsychotic drugs or/and antidepressants, excluded pregnant women, patients with hepatic and renal impairment. The statistic analysis of qualitative variables was performed using absolute and relative frequencies. Quantitative variables were analysed using medians and interquartile ranges. ResultsWe included 26 patients with a median age of 49 years (IQR: 33-57), 14 were women (53.8%). The most relevant conditions on past medical history were perinatal hypoxia and brain trauma, both diagnosed on 5 patients (19.2%). The most frequently anticonvulsant monotherapy used was carbamazepine, which was prescribed on 8 patients (30.8%). Only two patients receiving carbamazepine presented leucopenia. None of the patients presented elevated liver enzymes. Anticonvulsant serum levels in most therapies were within the therapeutic range. Discussion and conclusionsWe described multiple combinations of anticonvulsants with antipsychotics and/or antidepressants. No liver toxicity or serious hematologic abnormalities that could suggest a change on the therapy was documented. Furthermore, most anticonvulsants serum concentration remained within the therapeutic range.

Magnitude and factors associated with nonadherence to antiepileptic drug treatment in Africa: A cross‐sectional multisite study

SummaryObjectivesThe epilepsy treatment gap is large in low‐ and middle‐income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross‐sectional studies conducted in five African countries.MethodsWe approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily. Participants were asked if they were taking AEDs, and plasma drug concentrations were measured using a fluorescence polarization immunoassay analyzer. Information about possible risk factors was collected using questionnaire‐based clinical interviews. We determined factors associated with nonadherence to AED treatment in children and adults, as measured by detectable and optimal levels, using multilevel logistic regression.ResultsIn 1,303 samples assayed (43.7% were children), AEDs were detected in 482, but only 287 had optimal levels. Of the 1,303 samples, 532 (40.8%) were from people who had reported they were on AEDs. The overall prevalence of nonadherence to treatment was 63.1% (95% confidence interval [CI] 60.5–65.6%) as measured by detectable AED levels and 79.1% (95% CI 73.3–84.3%) as measured by optimal AED levels; self‐reported nonadherence was 65.1% (95% CI 45.0–79.5%). Nonadherence was significantly (p < 0.001) more common among the children than among adults for optimal and detectable levels of AEDs, as was the self‐reported nonadherence. In children, lack of previous hospitalization and learning difficulties were independently associated with nonadherence to treatment. In adults, history of delivery at home, absence of burn marks, and not seeking traditional medicine were independently associated with the nonadherence to AED treatment.SignificanceOnly about 20% of people with epilepsy benefit fully from antiepileptic drugs in sub‐Saharan Africa, according to optimum AEDs levels. Children taking AEDs should be supervised to promote compliance.

Appropriateness of Antiepileptic Drug-Level Monitoring at a Childrens’ Hospital in Mexico

Introduction In Mexico, plasma drug monitoring is being used to check toxicity, compliance, and dose titration in treatment with antipileptic drugs (AEDs), but without taking into account the principles of pharmacokinetics due to the absence of a clinical pharmacokinetic service with specialized

An Analytical Study to Correlate Serum Levels of Levetiracetam with Clinical Course in Patients with Epilepsy.

Introduction:With the advancement of therapeutics, newer antiepileptic drugs (AEDs) like Levetiracetam (LEV), with good therapeutic efficacy and tolerability are available. But unfortunately, therapeutic drug monitoring is not routinely done in India for these drugs.Objectives:The objective of this study is to determine the range of serum levels of LEV in patients at stabilized doses and correlate them with their clinical course.Materials and Methods:Patients with epilepsy and started on LEV were enrolled from the Neurology Department after the Ethics Committee approval. Serum levels of LEV were estimated using high-performance liquid chromatography and correlated with patient demographics, dosage, dosage forms, concomitant AEDs, compliance of the patient, therapeutic effect, adverse drug reactions (ADRs), and suspected toxicity.Results:Serum levels of LEV ranged from 0.4 to 102.2 μg/ml at different time points and demonstrated a negligible positive correlation with age of the patients (r = 0.12) but negligible negative correlation with bodyweight (r = −0.19). No conclusive relationship could be established for dose, gender, dosage forms, clinical efficacy (seizure frequency), ADRs, and toxicity. Compliance was verified in all the patients. Levels were found to reduce with the use of concomitant enzyme inducer drugs (56.78%) whereas increase with valproic acid (7.8%).Conclusion:These findings emphasize the need for monitoring the serum levels of newer AEDs like LEV considering the various parameters studied here, so as to maintain the therapeutic efficacy by preventing under or over dosage and to generate a broader database of serum levels of LEV in the Indian population to help appropriate prescribing with more confidence.

Pharmacokinetic-pharmacodynamic influence of N-palmitoylethanolamine, arachidonyl-2′-chloroethylamide and WIN 55,212-2 on the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice

We evaluated the effects of ACEA (selective cannabinoid (CB)1 receptor agonist), WIN 55,212-2 mesylate (WIN; non-selective CB1 and CB2 receptor agonist) and N-palmitoylethanolamine (PEA; an endogenous fatty acid of ethanolamide) in DBA/2 mice, a genetic model of reflex audiogenic epilepsy. PEA, ACEA or WIN intraperitoneal (i.p.) administration decreased the severity of tonic-clonic seizures. We also studied the effects of PEA, WIN or ACEA after co-administration with NIDA-41020 (CB1 receptor antagonist) or GW6471 (PPAR-α antagonist) and compared the effects of WIN, ACEA and PEA in order to clarify their mechanisms of action. PEA has anticonvulsant features in DBA/2 mice mainly through PPAR-α and likely indirectly on CB1 receptors, whereas ACEA and WIN act through CB1 receptors. The co-administration of ineffective doses of ACEA, PEA and WIN with some antiepileptic drugs (AEDs) was examined in order to identify potential pharmacological interactions in DBA/2 mice. We found that PEA, ACEA and WIN co-administration potentiated the efficacy of carbamazepine, diazepam, felbamate, gabapentin, phenobarbital, topiramate and valproate and PEA only also that of oxcarbazepine and lamotrigine whereas, their co-administration with levetiracetam and phenytoin did not have effects. PEA, ACEA or WIN administration did not significantly influence the total plasma and brain levels of AEDs; therefore, it can be concluded that the observed potentiation was only of pharmacodynamic nature. In conclusion, PEA, ACEA and WIN show anticonvulsant effects in DBA/2 mice and potentiate the effects several AEDs suggesting a possible therapeutic relevance of these drugs and their mechanisms of action.

Correlation between adherence to antiepileptic drugs and quality of life in patients with epilepsy: A longitudinal study.

This study aimed to investigate whether the score of self-reported medication adherence using the Medication Adherence Report Scale (MARS-5) correlates with the serum level of antiepileptic medication, as well as whether the MARS-5 score can predict the quality of life (QoL) in patients with epilepsy. A longitudinal study was carried out. The patients with epilepsy who were prescribed a minimum of one antiepileptic drug were recruited (n=807). Each participant completed a background information sheet and the MARS-5 at baseline, followed by the Liverpool Seizure Severity Scale (LSSS) and Quality of Life in Epilepsy (QOLIE-31) questionnaire at 18-month follow-up. In addition, the serum level of antiepileptic medications was measured at the follow-up. The MARS-5 score was negatively associated with the LSSS score (B=-0.089, SE=0.009, p<0.001) and positively correlated with the serum level of antiepileptic medications (B=3.200, SE=0.416, p<0.001), after adjusting for demographics and clinical characteristics. The serum level of antiepileptic drugs was significantly correlated with the overall QOLIE-31 score (B=3.118, SE=1.417, p=0.03). The MARS-5 score was significantly correlated with the overall QOLIE-31 scores and all the scores in the subcategories. In addition, the MARS-5 score was in line with the correlation between the LSSS and QOLIE-31 scores (Z=4.20, p<0.001) and between serum antiepileptic medication levels and QOLIE-31 score (Z=3.98, p<0.001). The MARS-5 score can predict the QoL in patients with epilepsy for up to 18months. Therefore, healthcare providers may predict the QoL and drug adherence using the MARS-5 score, in order to design personalized interventions.

Increasing adherence to treatment in epilepsy: what do the strongest trials show?

Patient non-adherence to prescribed anti-epileptic drugs (AEDs) remains a challenge to successful treatment of patients with epilepsy. However, the literature on epilepsy does not document a comprehensive review of interventions to improve adherence as a means to improve clinical outcomes. This study systematically reviews existing literature on interventions to enhance AED adherence and clinical outcomes, and the measures of adherence included in these studies. We selected randomized controlled trials (RCTs) of interventions to enhance adherence with AEDs, which also measured clinical outcomes, with at least 80% follow-up of participants for at least 6months, from a comprehensive Cochrane review of adherence interventions for medications, complete to January 2013, and updated searches for additional AED studies in multiple bibliographic databases to January 2016. Two review authors independently extracted all data and a third author resolved disagreements. The present update included one trial from the Cochrane review and three RCTs published since, bringing the total number of RCTs on this topic to four. Two types of intervention were tested: educational (e.g., providing information to the patient or carer about treatment characteristics, duration, dosage regime, and how to use the AED) and behavioral (activity in order to remind the patient to take a medicine). Methods of measuring adherence included a combination of direct (plasma AED levels) and indirect measures (prescription refill frequency and appointment keeping) or use alone of self-report adherence on standardized scales. Despite the importance of the problem, evidence is limited concerning enhancement of adherence among people with epilepsy. However, the trials available to date show that medication adherence in epilepsy can be improved, leading to better seizure control.

Associations between MDR1 C3435T polymorphism and drug-resistant epilepsy in the Polish population.

Epilepsy is a common neurological disorder. About one-third of epileptic patients demonstrate multidrug resistance (MDR) phenotype and develop drug-resistant epilepsy (DRE). Single nucleotide polymorphism (SNP) C3435T (rs1045642), identified in the MDR1 gene, is associated with an increased intestinal expression of P-glycoprotein (P-gp) which affects the levels of anti-epileptic drugs in plasma. The reported study was designed to explore associations between the MDR1-C3435T gene SNP and the risk of DRE in the Polish population. The C3435T polymorphism of MDR1 gene was investigated by the PCR-RFLP technique in 74 patients with DRE and 70 age- and sex-matched non-DRE controls. Blood samples were obtained from patients with drug-resistant epilepsy, treated at the Department of Neurological Surgery, Medical University in Warsaw between the years 2011 and 2012. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. Genotype distribution of C3435T polymorphism of MDR1 gene was compared between the DRE patients and controls with significant differences (p<0.05) between the two investigated groups. A possible association was observed between DRE and the presence of 3435C allele. The 3435C allele was found in 69% of DRE cases and in 48% of the used controls. The variant 3435T allele of MDR1 decreased the risk of drug-resistant epilepsy [odds ratio (OR) 0.41; 95% confidence interval (CI) 0.26-0.67]. The results indicate that the C3435T polymorphism of MDR1 gene may be associated with the incidence of DRE observed in the Polish population.

Towards an implantable bio-sensor platform for continuous real-time monitoring of anti-epileptic drugs.

The need of continuous real-time monitoring device for in-vivo drug level detection has been widely articulated lately. Such monitoring could guide drug posology and timing of intake, detect low or high drug levels, in order to take adequate measures, and give clinicians a valuable window into patients' health and their response to therapeutics. This paper presents a novel implantable bio-sensor based on impedance measurement capable of continuously monitoring various antiepileptic drug levels. This portable point-of-care microsystem replaces large and stationary conventional macrosystems, and is a one of a kind system designed with an array of electrodes to monitor various anti-epileptic drugs rather than one drug. The micro-system consists of (i) the front-end circuit including an inductive coil to receive energy from an external base station, and to exchange data with the latter; (ii) the power management block; (iii) the readout and control block; and (iv) the biosensor array. The electrical circuitry was designed using the 0.18-um CMOS process technology intended to be miniature and consume ultra-low power.