Individual Antiepileptic Drugs Research Articles

Risk of out-of-hospital cardiac arrest in patients with epilepsy and users of antiepileptic drugs.

AimsA few studies suggested that epilepsy and antiepileptic drugs with sodium channel‐blocking properties were independently associated with out‐of‐hospital cardiac arrest (OHCA). However, these findings have not yet been replicated.MethodsUsing Danish registries, we conducted a nested case–control study in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were defined as OHCA from presumed cardiac causes, and were matched with non‐OHCA‐controls based on sex, and age on the date of OHCA. Exposure of interest was epilepsy or antiepileptic drug use. To study the association between individual antiepileptic drug use and the rate of OHCA, we compared each antiepileptic drug with valproic acid. Cox regression with time‐dependent covariates was conducted to calculate hazard ratio (HR) and 95% confidence interval (CI).ResultsWe identified 35 195 OHCA‐cases and 351 950 matched non‐OHCA controls. Epilepsy (cases: 3.58%, controls: 1.60%) was associated with increased rate of OHCA compared with the general population (HR: 1.76, 95%CI: 1.64–1.88) when common OHCA risk factors were taken into account. When we studied antiepileptic drug use, we found that 2 antiepileptic drugs without sodium channel blockage, clonazepam (HR: 1.88, 95%CI: 1.45–2.44) and pregabalin (HR: 1.33, 95%CI: 1.05–1.69), were associated with OHCA, whereas none of the antiepileptic drugs with sodium channel blockage were associated with OHCA.ConclusionEpilepsy is associated with increased rate of OHCA. Our findings do not support a possible association between antiepileptic drugs with sodium channel‐blocking properties and OHCA.

Management of Medication-Induced Psychiatric Disorders.

Management of Medication-Induced Psychiatric Disorders.

Antiepileptic drugs for seizure control in people with neurocysticercosis.

Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the most common clinical presentation, though people may also present with headache, symptoms of raised intracranial pressure, hydrocephalus, and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, antiepileptic drugs (AEDs), and anti-oedema drugs, such as steroids, form the mainstay of treatment. This is an updated version of the Cochrane Review previously published in 2019. To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis. For the question of primary prevention, we examined whether AEDs reduce the likelihood of seizures in people who had neurocysticercosis but had not had a seizure. For the question of secondary prevention, we examined whether AEDs reduce the likelihood of further seizures in people who had had at least one seizure due to neurocysticercosis. As part of primary prevention studies, we also aimed to examine which AED was beneficial in people with neurocysticercosis in terms of duration, dose, and side-effect profile. For the 2021 update of this review, we searched the Cochrane Register of Studies (CRS Web), MEDLINE, and LILACS to January 2021. CRS Web includes randomised or quasi-randomised, controlled trials from CENTRAL, the Specialised Registers of Cochrane Review Groups, including Epilepsy, PubMed, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform. We also checked the reference lists of identified studies, and contacted experts and colleagues in the field to search for additional and ongoing studies. Randomised and quasi-randomised controlled trials. Single-blind, double-blind, or unblinded studies were eligible for inclusion. We followed standard methodological procedures expected by Cochrane. Two review authors independently selected trials for inclusion and extracted the relevant data. The primary outcomes of interest were: proportion of individuals experiencing seizures, and time to first seizure post randomisation. Secondary outcomes included: seizure freedom, number of withdrawals, side effects, number of people seizure free with short or long durations of treatment, quality of life, therapy costs, hospitalisations, and mortality. We used an intention-to-treat analysis for the primary analysis. We calculated odds ratio (OR) for dichotomous data (proportion of individuals who experienced seizures, were seizure free for a specific time period (12 or 24 months), withdrew from treatment, developed drug-related side effects or complications, were seizure-free with each treatment policy, mortality), and planned to use mean difference (MD) for continuous data, if any continuous data were identified (quality of life, cost of treatment). We intended to evaluate time to first seizure after randomisation by calculating hazard ratios (HRs). We assessed precision using 95% confidence intervals (CIs). We stratified the analysis by treatment comparison. We also considered the duration of drug usage, co-medications, and the length of follow-up. We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures. We did not find any trials that directly compared individual AEDs for primary prevention in people with neurocysticercosis. We included four trials that evaluated the efficacy of short-term versus longer-term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) who presented with seizures. In total, 466 people were enrolled. These studies compared AED treatment durations of 6, 12, and 24 months. The risk of seizure recurrence with six months of treatment compared with 12 to 24 months of treatment was inconclusive (odds ratio (OR) 1.34, 95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence). The risk of seizure recurrence with six to 12 months of treatment compared with 24 months of treatment was inconclusive (OR 1.36, 95% CI 0.72 to 2.57; three studies, 385 participants; very low-certainty evidence). Two studies compared seizure recurrence with CT findings, and suggested that persistent and calcified lesions had a higher recurrence risk, and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of the drugs. None of the studies addressed the quality of life of the participants. These studies had methodological deficiencies, such as small sample sizes, and a possibility of bias due to lack of blinding, which affect the results of the review. Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. Therefore, there is a need for large scale randomised controlled trials to address these questions.

Sociodemographic factors associated with the first administration of anti-seizure medication in patients with focal epilepsy in Western China

BackgroundEpilepsy is a severe chronic neurologic disease with a prevalence of 0.7% worldwide; anti-seizure medications (ASMs) are the mainstay of epilepsy treatment. The effects of sociodemographic factors on the characteristics of initial treatment in patients with newly diagnosed focal epilepsy in Western China are unknown. This study was conducted to explore sociodemographic factors associated with initial treatment characteristics.MethodsPatients with focal epilepsy on continuous ASM treatment who visited to our epilepsy center at Sichuan Provincial People’s Hospital between January 2018 and December 2019 were recruited. Data on initial treatment status and sociodemographic variables were obtained from the patients with a questionnaire designed by our researchers. We examined whether sociodemographic factors were associated with epileptic patients’ access to neurologists and prescriptions of individual ASMs.ResultsA total of 569 patients completed this study. We found that patients with a higher education level, aged < 16 years, and with a higher household disposable income were more likely to receive treatment from a neurologist than their counterparts. Patients with a lower personal income level and who were treated at a junior hospital were more likely to receive prescriptions for carbamazepine, and those who were younger than 16 years were less likely to receive prescriptions for carbamazepine and oxcarbazepine. Patients with a higher education level, with a higher household disposable income level, who were younger than 16 years, and who were treated at a senior hospital were more likely to receive prescriptions for levetiracetam than their counterparts. Adult, female patients with focal epilepsy treated at a senior hospital were more likely to receive prescriptions for lamotrigine.ConclusionsThis observation suggests that sociodemographic characteristics are associated with access to neurologists and prescriptions of individual antiepileptic drugs. These data may help public health officials establish guidelines for doctors and distribute resources according to the needs of different patient groups.

Сучасний підхід до діагностики та лікування судом у новонароджених та дітей раннього віку

The article is devoted to the topical problem of neonatology and pediatric neurology — the diagnosis and treatment of seizures in newborns and young children. The work presents an algorithm for the diagnosis and treatment of epileptic seizures in children. It is indicated that the therapeutic effect of most antiepileptic drugs consists of modulation of voltage-gated and ligand-gated channels of membranes of neurons of the cerebral cortex, enhancement of inhibitory synaptic transmission or inhibition of activating synaptic transmission. The issues of the pharmacokinetics and pharmacodynamics of antiepileptic drugs are considered, taking into account the age characteristics of the child's body, in particular, newborns and early age children. The problems of drug interaction were discussed. The properties of individual antiepileptic drugs, which are used in newborns and young children, are considered. Emphasized are «polar» differences in the work of phenobarbital, which depend on the stage of epileptogenesis, namely: suppression of epileptiform activity at the early stage of epileptogenesis and its enhancement in the already formed epileptic focus (epileptic system). The literature data on the differentiated treatment of certain epileptic syndromes are presented. The issues on the prospects for the treatment of genetically determined diseases, which are accompanied by seizures associated with metabolic disorders, are considered. The modern high-tech methods of treatment of these diseases are noted. The role of diet therapy, co-factor therapy in the treatment of hereditary metabolic disorders, in particular, the ketogenic diet as a method of alternative treatment for drug-resistant epilepsy in children, is shown. No conflict of interest was declared by the authors. Key words: newborn, epilepsy, epileptic encephalopathy, treatment, antiepileptic drugs, review.

Editors' note: Antiepileptic drugs are not independently associated with cognitive dysfunction

In “Antiepileptic drugs (AEDs) are not independently associated with cognitive dysfunction,” Foster et al. studied cognitive function in 331 patients admitted to an inpatient epilepsy unit and found that although age, seizure frequency, depression, anxiety, and diagnosis of both epilepsy and psychogenic nonepileptic seizures were related to cognitive dysfunction identified by the Neuropsychiatry Unit Cognitive Assessment Tool and the Quality of Life in Epilepsy inventory, individual antiepileptic drugs (AEDs) were not. Witt et al. commented that these results erroneously—and, perhaps, dangerously—suggest AEDs do not impact cognitive function because the tests used did not assess for specific cognitive deficits, which are known to be associated with both AED selection and dosing. Foster agreed that other tests may be more sensitive to these subdomains of cognitive dysfunction and acknowledged that some patients may be more likely to experience cognitive changes related to AEDs, but reiterated that the intent of the study was to assess global cognitive function and that their findings demonstrate factors other than AEDs are associated with cognitive impairment in patients with epilepsy. They also noted that clinicians must, of course, thoughtfully apply these findings to clinical practice and recognize that these results do not preclude the potential for AEDs to impact attention and executive function. In “Antiepileptic drugs (AEDs) are not independently associated with cognitive dysfunction,” Foster et al. studied cognitive function in 331 patients admitted to an inpatient epilepsy unit and found that although age, seizure frequency, depression, anxiety, and diagnosis of both epilepsy and psychogenic nonepileptic seizures were related to cognitive dysfunction identified by the Neuropsychiatry Unit Cognitive Assessment Tool and the Quality of Life in Epilepsy inventory, individual antiepileptic drugs (AEDs) were not. Witt et al. commented that these results erroneously—and, perhaps, dangerously—suggest AEDs do not impact cognitive function because the tests used did not assess for specific cognitive deficits, which are known to be associated with both AED selection and dosing. Foster agreed that other tests may be more sensitive to these subdomains of cognitive dysfunction and acknowledged that some patients may be more likely to experience cognitive changes related to AEDs, but reiterated that the intent of the study was to assess global cognitive function and that their findings demonstrate factors other than AEDs are associated with cognitive impairment in patients with epilepsy. They also noted that clinicians must, of course, thoughtfully apply these findings to clinical practice and recognize that these results do not preclude the potential for AEDs to impact attention and executive function.

Therapeutic Monitoring of Lacosamide in Japanese Patients With Epilepsy: Clinical Response, Tolerability, and Optimal Therapeutic Range.

Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 μmol/L) and 8.4 mcg/mL (33.6 μmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 μmol/L) and 7.5 mcg/mL (30 μmol/L), respectively. Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.

Understanding the challenge of comparative effectiveness research in focal epilepsy: A review of network meta‐analyses and real‐world evidence on antiepileptic drugs

ObjectiveHead‐to‐head randomized controlled trials (RCTs) are the gold standard for assessing comparative treatment effects. In the absence of direct comparisons between all possible antiepileptic drugs (AEDs), however, clinical decision‐making in focal (partial onset) epilepsy relies on alternative evidence borne from indirect comparisons including network meta‐analyses (NMAs) and from real‐world evidence (RWE) studies. We review NMAs and observational RWE studies comparing AEDs in the adjunctive setting to compare the robustness of these methods and to formulate recommendations for future evidence development.MethodsA literature review identified NMAs and RWE studies comparing AEDs for the adjunctive treatment of focal seizures published between January 2008 and October 2018. NMAs were evaluated for robustness using a framework based on guidelines from the National Institute for Health and Care Excellence Decision Support Unit and the International Society for Pharmacoeconomics and Outcomes Research. RWE studies were evaluated using the GRACE checklist.ResultsFrom a total of 1993 records, 11 NMAs and six RWE studies were eligible. Key limitations identified in the NMAs include nonsystematic selection of RCTs, unexplored heterogeneity between included RCTs in terms of study and patient characteristics, and selection of AEDs and AED doses or dosing strategies that are not reflective of clinical practice. The main limitations of RWE studies concern sample size, design, and analysis methods. Approximately 90% of comparisons between individual AEDs were nonsignificant in the NMAs. None of the RWE studies adjusted for baseline differences between comparator groups; therefore, they lack the validity to make comparative conclusions.SignificanceCurrent NMAs and RWE studies provide only nominal comparative evidence for AED treatments in focal epilepsy, and should be used with caution for decision‐making due to their methodological limitations. To overcome these hurdles, adherence to methodological guidelines and concerted efforts to collect relevant outcome data in the real world are needed.

Effects of Antiepileptic Drug Tapering on Episodic Memory as Measured by Virtual Reality Tests.

Antiepileptic drugs impair episodic memory in patients with epilepsy, but this effect has so far only been examined with tests that do not provide first-person experience—an aspect that is crucial for episodic memory. Virtual reality techniques facilitate the development of ecologically valid tests. In the present study, we measure the effect of antiepileptic drug changes in a within-subject design using a virtual reality test in order to provide direct evidence for effects of antiepileptic drugs on episodic memory. Among 106 recruited patients, 97 participated in a virtual reality test up to six times during a 4-day hospitalization, and 78 patients underwent changes in drug load during this period. There were six parallel versions of a virtual town test, with immediate recall and delayed recall after about 12 h. The test requires recall of elements, details, sequence of experience, and egocentric and allocentric spatial memory. We determined drug load by defined daily dose, and compared test performance at lowest antiepileptic drug load to highest antiepileptic drug load. Across the six towns, performance was lower in delayed compared to immediate recall. There was an overall effect of medication when comparing patients taking vs. not taking antiepileptic drugs and/or psychoactive drugs (p = 0.005). Furthermore, there was a within-subject effect of antiepileptic drug load (p = 0.01), indicating lower test performance at higher drug load. There was no effect of gender, daytime, circadian type, depression, seizures, lesions, and epilepsy. For patients with temporal lobe epilepsy, there was no effect of lateralization. The present study provides direct evidence for episodic memory impairment due to antiepileptic drugs, suggesting that a small change in drug load can matter. This study can serve as a proof of principle for the methodology, but a larger sample is needed to examine the differential effects of individual antiepileptic drugs.

Antiepileptic drugs are not independently associated with cognitive dysfunction.

To test the hypothesis that individual antiepileptic drugs (AEDs) are not associated with cognitive impairment beyond other clinically relevant factors, we performed a cross-sectional study of patients admitted to an inpatient video-EEG monitoring unit. We prospectively enrolled patients admitted to an inpatient specialist epilepsy program between 2009 and 2016. Assessments included objective cognitive function, quality of life subscales for subjective cognitive function, and questionnaires for anxiety and depressive symptoms. Bayesian model averaging identified predictors of cognitive function. Bayesian model selection approach investigated effect of individual AEDs on cognition. Conventional frequentist analyses were also performed. A total of 331 patients met inclusion criteria. Mean age was 39.3 years and 61.9% of patients were women. A total of 45.0% of patients were prescribed AED polypharmacy, 25.1% AED monotherapy, and 29.9% no AED. Age, seizure frequency, and a diagnosis of concomitant epilepsy and psychogenic nonepileptic seizure were predictors of objective cognitive function. Depression, anxiety, and seizure frequency were predictors of subjective cognitive function. Individual AEDs were not independently associated with impaired cognitive function beyond other clinically relevant variables. This study found that no AED was independently associated with cognitive dysfunction. Significant determinants of objective and subjective cognitive dysfunction included seizure frequency and depression, respectively. These findings suggest that optimizing therapy to prevent seizures is not likely to occur at the expense of cognitive function.

ATP1A3-related epilepsy: Report of seven cases and literature-based analysis of treatment response

ATP1A3 related disease is a clinically heterogeneous condition currently classified as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Recently, it has become apparent that a remarkably large subgroup is suffering from often difficult-to-treat epilepsy. The aim of the present study was to assess the prevalence and efficacy of commonly used anti-epileptic-drugs (AEDs) in patients with ATP1A3 related seizures. Therefore, we performed a retrospective study of patients in combination with a systematic literature-based review. Inclusion criteria were: verified ATP1A3 mutation, seizures and information about AED treatment. The literature review yielded records for 188 epileptic ATP1A3 patients. For 14/188 cases, information about anti-epileptic treatment was available. Combined with seven unpublished records of ATP1A3 patients, a sample size of 21 patients was reached. Most used AED were levetiracetam (n = 9), phenobarbital (n = 8), valproic acid (n = 7), and topiramate (n = 5). Seizure reduction was reported for 57% of patients (n = 12). No individual AEDs used (either alone or combined) had a success rate over 50%. There was no significant difference in the response rate between various AEDs. Ketogenic diet was effective in 2/4 patients. 43% of patients (n = 9) did not show any seizure relief. Even though Epilepsy is a significant clinical issue in ATP1A3 patients, only a minority of publications provide any information about patients’ anti-epileptic treatment. The findings of treatment effectiveness in only 57% (or lower) of patients, and the non-existence of a clear first-line AED in ATP1A3 related epilepsy stresses the need for further research.

Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008-2017.

BackgroundSevere and life-threatening drug eruptions include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). One class of medications that has been highly associated with such drug eruptions is antiepileptic drugs (AEDs). We attempt to investigate drug eruptions associated with AEDs as a class, as well as with individual AEDs, in Korea.MethodsWe used the Korea Institute of Drug Safety and Risk Management - Korea Adverse Event Reporting System (KIDS-KAERS) database, a nationwide database of adverse events reports, between January 2008 and December 2017 to investigate the reporting count of all drug eruptions and calculated the ratio of DRESS/SJS/TEN reports for each AED.ResultsAmong a total of 2,942 reports, most were of rash/urticaria (2,702, 91.8%), followed by those of DRESS (109, 3.7%), SJS (106, 3.6%), and TEN (25, 0.85%). The common causative AEDs were lamotrigine (699, 23.8%), valproic acid (677, 23%), carbamazepine (512, 17.4%), oxcarbazepine (320, 10.9%), levetiracetam (181, 6.2%), and phenytoin (158, 5.4%). In limited to severe drug eruptions (DRESS, SJS, and TEN; total 241 reports), the causative AEDs were carbamazepine (117, 48.8%), lamotrigine (57, 23.8%), valproic acid (20, 8.3%), phenytoin (15, 6.3%), and oxcarbazepine (10, 4.2%). When comparing aromatic AED with non-aromatic AED, aromatic AEDs were more likely to be associated with severe drug eruption (aromatic AEDs: 204/1,793 versus non-aromatic AEDs: 37/1,149; OR, 3.86; 95% CI, 2.7–5.5). Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5).ConclusionAlthough most cutaneous drug eruptions in this study were rash or urticaria, approximately 8% of reports were of severe or life-threatening adverse drug reactions, such as SJS, TEN, or DRESS. When hypersensitivity skin reactions occurred, aromatic AEDs were associated with 4 fold the risk of SJS/TEN/DRESS compared with non-aromatic AEDs. Our findings further emphasize that high risk AEDs should be prescribed under careful monitoring, and early detection and prompt interventions are needed to prevent severe complications.

Antiepileptic drugs for seizure control in people with neurocysticercosis.

Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the most common clinical presentation, though it may also present with headache, symptoms of raised intracranial pressure, hydrocephalus and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, anti-oedema drugs, such as steroids, and antiepileptic drugs (AEDs) form the mainstay of treatment.This is an updated version of the original Cochrane Review published in 2015, Issue 10. To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis.For the question of primary prevention, we examined whether AEDs reduce the likelihood of seizures in patients who have neurocysticercosis but have not had a seizure.For the question of secondary prevention, we examined whether AEDs reduce the likelihood of further seizures in patients who have had at least one seizure due to neurocysticercosis.As part of primary prevention studies, we also aimed to examine which AED has been found to be beneficial in people with neurocysticercosis in terms of duration, dose and side-effect profile. For the latest update of this review, we searched the following databases on 8 July 2019: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to July 05, 2019) and LILACS (1982- ). CRS Web includes the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised or quasi-randomised, controlled trials from Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We also checked the references lists of identified studies, and contacted experts in the field and colleagues to search for additional studies and for information about ongoing studies. Randomised and quasi-randomised controlled trials.Single-blind, double-blind or unblinded studies were eligible for inclusion. Two review authors screened all citations for eligibility (MS screened the initially identified 180 citations, MF and BDM screened the 48 citations identified for the purpose of this update).Two review authors independently extracted data and evaluated each study for risk of bias. We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures.We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis.We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality.We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) presenting with seizures. In total, 466 people were enrolled. These studies compared various AED treatment durations, six, 12 and 24 months. The risk of seizure recurrence with six months treatment compared with 12 to 24 months treatment was not statistically significant (odds ratio (OR) 1.34 (95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence)). The risk of seizure recurrence with six to 12 months compared with 24 months treatment was not statistically significant (OR 1.36 (95% CI 0.72 to 2.57; three studies, 385 participants; low-certainty evidence)).Two studies co-related seizure recurrence with CT findings and suggested that persistent and calcified lesions had a higher recurrence risk and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of drugs. None of the studies addressed the quality of life of the participants.These studies had certain methodological deficiencies such as a small sample size and a possibility of bias due to lack of blinding, which affect the results of this review. Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. There is therefore a need for large scale randomised controlled trials to address these questions.

Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth.

BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996–2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference as lamotrigine-exposed infants. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had a head circumference 0.1 SDs smaller (-0.1 [-0.3 to 0.1]). Valproic acid–exposed infants had, on average, the same duration of gestation and birth weight z-score as lamotrigine-exposed infants, but had a head circumference 0.2 SDs smaller (-0.2 [-0.2 to -0.1]). Associations between carbamazepine exposure and pregnancy duration and between valproic acid exposure and pregnancy duration and birth weight z-score were more negative at the left than at the right tails of the outcome distributions. Effect-measure modification and dose-response relations were noted for some of the associations.ConclusionsRelative to lamotrigine, valproic acid and carbamazepine were associated with smaller head circumference.

Association of Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs in pediatric patients: Subgroup analysis based on a Japanese spontaneous database.

Antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous disorders; however, real-world data remain limited, especially on pediatric patients. The objective of this study was to investigate the association of AEDs with SJS and TEN in pediatric patients based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Adverse event reports submitted to the JADER database between 2004 and 2017 were analysed. We performed a retrospective pharmacovigilance disproportionality analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). A total of 159605 adverse events were reported in pediatric patients. Significant SJS signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine, zonisamide, clonazepam and lamotrigine. TEN signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine and zonisamide, but the signal was strongest for gabapentin (ROR, 24.76; 95% CI, 11.4-53.9). Severe cutaneous disorders were associated with multiple AEDs, but individual AEDs were associated with variable signals. These results may be useful for minimizing the risk of SJS or TEN during treatment of children with AEDs.

Cutting the Losses of Pregnant Women With Epilepsy.

If unintended pregnancy is common among women with epilepsy and is associated with increased risk of spontaneous fetal loss (SFL), it is important to develop guidelines for safe and effective contraception for this community. To assess whether planned pregnancy is a determinant of SFL in women with epilepsy. The Epilepsy Birth Control Registry conducted this web-based, retrospective survey between 2010 and 2014. It gathered demographic, epilepsy, antiepileptic drug (AED), contraceptive, and reproductive data from 1144 women with epilepsy in the community between ages 18 and 47 years. Data were analyzed between March 2018 and May 2018. Main outcomes and measures The primary outcome was the risk ratio (RR) with 95% confidence intervals (CIs) for SFL in unplanned versus planned pregnancies. The secondary outcome was the identification of some potentially modifiable variables (maternal age, pregnancy spacing, and AED category) of SFL versus live birth using binary logistic regression. The participants were proportionally younger (mean [standard deviation] age, 28.5 [6.8] years), and 39.8% had household incomes of $25 000 or less. Minority women represented only 8.7% of the participants. There were 530 (66.8%) of 794 unplanned pregnancies and 264 (33.2%) of 794 planned pregnancies. The risk of SFL in 653 unaborted pregnancies in women with epilepsy was greater for unplanned (n = 137 of 391; 35.0%) than planned (n = 43 of 262; 16.4%) pregnancies (RR: 2.14; 95% CI: 1.59-2.90; P < .001). Regression analysis found that the risk of SFL was greater when planning was entered alone (odds ratio [OR], 2.75; 95% CI: 1.87-4.05; P < .001) and more so when adjusted for maternal age, interpregnancy interval, and AED category (OR: 3.57; 95% CI: 1.54-8.78; P = .003). Interpregnancy interval (OR: 2.878; 95% CI: 1.8094-4.5801; P = .008) and maternal age (OR: 0.957; 95% CI: 0.928-0.986 for each year from 18 to 47 years; P = .02), but not AED category, were also associated. The risk was greater when interpregnancy interval was less than 1 year (n = 56 of 122; 45.9%) versus greater than 1 year (n = 56 of 246; 22.8%; RR: 2.02; 95% CI: 1.49-2.72; P < .001). Relative to the younger than 18 years cohort (n = 15 of 29; 51.7%), the risks were lower for the intermediate older cohort aged 18 to 27 years (n = 118 of 400; 29.5%; RR: 0.57; 95% CI: 0.39-0.84; P < .004) and the cohort aged 28 to 37 years (n = 44 of 212; 20.8%; RR: 0.40; 95% CI: 0.26-0.62; P < .001) but not significantly different for the small number of participants in the aged 38 to 47 years cohort (n = 3 of 12; 25.0%). No individual AED category's SFL frequency differed significantly from the no AED category. The Epilepsy Birth Control Registry retrospective survey finding that unplanned pregnancy in women with epilepsy may double the risk of SFL warrants prospective investigation with outcome verification.

Update on Antiepileptic Drugs 2019.

This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug's efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

Teratogenicity of antiepileptic drugs.

We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure. Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation. The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

Making Rash Decisions in Epilepsy: Evaluating Hypersensitivity Reactions to Anti-seizure Medications.

The Frequency and Clinical Features of Hypersensitivity Reactions to Antiepileptic Drugs in Children: A Prospective Study Guvenir H, Dibek Misirlioglu E, Civelek E. J Allergy Clin Immunol Pract. 2018;6(6):2043-2050. doi:10.1016/j.jaip.2018.02.018Background:Antiepileptic drugs (AEDs) can cause hypersensitivity reactions during childhood. Studies report a wide clinical spectrum of reactions with AED use, ranging from a mild rash to severe cutaneous reactions.Objective:To determine the prevalence and clinical features of AED hypersensitivity reactions during childhood.Methods:Patients in our pediatric neurology clinic who were prescribed an AED for the first time between November 2015 and November 2016 were monitored and those who developed skin rash during this period were evaluated.Results:A total of 570 patients were evaluated. The median age of the patients was 8.86 (interquartile range, 4.2-13.7) years, and 55.8% (318) of patients were male. The most frequently used AEDs were valproic acid (42%, n = 285) and carbamazepine (20.4%, n = 116). Hypersensitivity reactions to AEDs developed in 5.4% of patients. Of these patients, 71% (29) had cutaneous drug reactions and 29% (9) had severe cutaneous drug reactions; 61.3% (19) were using aromatic AEDs, and the leading suspected AED was carbamazepine (45.2%). Comparison of patients who did and did not develop AED hypersensitivity showed that hypersensitivity was more frequent among patients who were younger than 12 years, who used aromatic AEDs, or who used multiple AEDs. In addition, according to regression analysis results, aromatic AED use significantly increased the risk of AED hypersensitivity (P < .001).Conclusions:Although allergic reactions to AEDs are rare, they are of significance because they can cause life-threatening severe cutaneous drug reactions. Therefore, patients receiving AEDs, especially aromatic AEDs, must be monitored closely. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis With Antiepileptic Drugs: An Analysis of the US Food and Drug Administration Adverse Event Reporting System Borrelli EP, Lee EY, Descoteaux AM, Kogut SJ, Caffrey AR. Epilepsia. 2018;59(12):2318-2324.Objective:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially fatal adverse skin reactions that are most commonly triggered by certain medications. One class of medications that has been highly associated with SJS/TEN reactions is antiepileptic drugs (AEDs). We sought to quantify the risk of SJS/TEN associated with AEDs as a class, as well as individual AEDs, in the United States.Methods:An analysis was performed of the US Food and Drug Administration Adverse Event Reporting System from July 2014 through December 2017. Rates of SJS/TEN were calculated for each AED compared with all other non-AEDs. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), and 95% confidence intervals (CIs) were calculated using OpenEpi.Results:With 198 reports, AEDs had more reports of SJS/TEN than any other medication class. The AEDs as a class had an ROR of 8.7 (95% CI, 7.5-10.2) and a PRR of 8.7 (95% CI, 7.5-10.2) compared with all other non-AEDs. The AEDs with the highest risk estimates were zonisamide (ROR, 70.2; 95% CI, 33.1-148.7; PRR, 68.7; 95% CI, 32.9-143.5), rufinamide (ROR, 60.0; 95% CI, 8.3-433.5; PRR, 58.9; 95% CI, 8.4-411.5), clorazepate (ROR, 56.0; 95% CI, 7.8-404.1; PRR, 55.1; 95% CI, 7.8-385.0), lamotrigine (ROR, 53.0; 95% CI, 43.2-64.9; PRR, 52.2; 95% CI, 42.7-63.7), phenytoin (ROR, 26.3; 95% CI, 15.5-44.7; PRR, 26.1; 95% CI, 15.4-44.2), and carbamazepine (ROR, 24.5; 95% CI, 16.0-37.5; PRR, 24.3; 95% CI, 16.0-37.1).Significance:Although AEDs as a class were associated with 9 times the risk of SJS/TEN compared with non-AEDs, there were 6 AEDs with risk estimates greater than 20. Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS/TEN signs/symptoms, may help mitigate the number and severity of these adverse events.

Adverse Cutaneous Drug Reactions Associated with Old- and New- Generation Antiepileptic Drugs Using the Japanese Pharmacovigilance Database.

Adverse cutaneous drug reactions associated with antiepileptic drugs (AEDs) are a serious problem in the clinical setting. New-generation AEDs have been reported to be better tolerated than old-generation forms; however, information about the risks of adverse cutaneous drug reactions to new-generation AEDs is limited. The purpose of this study was to clarify the association of AEDs with adverse cutaneous drug reactions using a spontaneous reporting database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analyzed. Based on reports of all adverse events, we obtained 4805 reports of adverse cutaneous drug reactions associated with AEDs, and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for drug rash, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Individual AEDs had variable signals for drug rash, SJS, and TEN. The strongest signals were detected for drug rash caused by lamotrigine (ROR 9.18, 95% CI 8.65-9.74), SJS caused by zonisamide (ROR 9.85, 95% CI 8.23-11.78), and TEN caused by phenobarbital (ROR 14.08, 95% CI 11.28-17.57). There are clear differences in the risk of cutaneous reactions among AEDs, and further studies are needed to confirm these findings.