First-line Antiepileptic Drug Research Articles

Clinical Feature and Outcome of Childhood Status Epilepticus in a Teaching Hospital, Odisha, India.

ObjectivesThe main aim is to find out the clinical feature and outcome of status epilepticus (SE) in children managed in a teaching hospital. The secondary aim is to identify the risk factors influencing the adverse outcomes.MethodsIn this prospective cohort, children aged 1 month to 14 years with SE as per the International League Against Epilepsy’s new guideline (2016) who presented to the emergency department during the period of November 2017 to October 2019 were enrolled. Clinical profile, treatment, and outcome of cases (n = 94) were noted.ResultsThe majority of children, 60 (63.82%), were less than five years of age. Prior history of seizures was present in 33 (35.1%) cases, whereas 61 (64.9%) cases presented with SE as the first episode of seizure. In 14 (42.4%) previous seizure cases, SE was due to drug default. No response to first-line antiepileptic drug (AED) was seen in 84 (89.37%) cases. Acute symptomatic etiology was the commonest etiology of SE in 64 (68%) cases, of which neuro-infections accounted for 44 (46.80%) cases. Longer duration (>60 minutes) of status (p < 0.01), ventilator support (p < 0.0001), and circulatory impairment (p < 0.0001) were attributable risk factors for mortality. A total of 28 children died (mortality rate, 29.8%), and 11 showed the persistence of their neuro-deficit.ConclusionsNeuro-infection is the most common etiology of SE in children. Longer duration of SE, more lag time for receiving the first AED, respiratory failure, and presence of shock are independent predictors for poor outcome. Hence, cessation of convulsion at the earliest leads to improved outcomes.

Levetiracetam as the First-line Antiepileptic in Neonatal Seizures

Background: The quest persists for an ideal newer antiepileptic drug (AED) with better efficacy and tolerability. Levetiracetam (LEV) is one of these AEDs with a novel mechanism of action, good pharmacokinetic profile, acceptable tolerability, and side-effect profile. The present study assessed the safety and efficacy of intravenous levetiracetam as a first-line AED in neonatal seizures.Methods: This prospective observational study was conducted on all term neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of a tertiary care center. Neonates with hypoglycemia, hypocalcemia, hypomagnesemia, inborn errors of metabolism, or those who received other AEDs prior to admission were excluded from the study. 20mg/kg Intravenous LEV was administered as first-line AED and graded up to 40mg/kg if seizures were not controlled in 2 h; thereafter, second-line AED was added.Results: Only 36.2% (21/58) of the cases responded to LEV as first-line AED. Hypoxic Ischaemic Encephalopathy(HIE) was the most common etiology of seizures (55.2%). Subtle seizures were most responsive to LEV (60%), while multifocal clonic seizures (22.3%) responded the least. No adverse effect of LEV was observed during the study period.Conclusion: Only 36.2% of the cases responded to LEV as first-line AED, and subtle seizures were the most responsive seizures. Therefore, the efficacy of LEV as first-line AED in neonatal seizures is yet to be proven by a larger study. There were no adverse effects of LEV during the study period indicating the relative safety of this drug.

Epilepsy Research in Mali: A Pilot Pharmacokinetics Study on First-Line Antiepileptic Drug Treatment.

Background and PurposeThe indication and benefit of plasma level of antiepileptic (AEDs) has been debating in the monitoring of people living with epilepsy and the epilepsy treatment gap has largely been documented in developed countries. This study was aimed to highlight the epilepsy treatment gap between rural and urban Mali.MethodsWe conducted a pilot study on AEDs treatment from September 2016 to May 2019. For 6 months, 120 children and young adults living with epilepsy (rural site, 90; urban site, 30) received phenobarbital, valproic acid and/or carbamazepine. At our rural study site, we determined the AED plasma levels, monitored the frequency, severity and the duration of seizure, and administered monthly the McGill quality of life questionnaire. At our urban study site, each patient underwent an electroencephalogram and brain computed tomography scan without close monitoring.ResultsAt the rural study site, patients were mostly on monotherapy; AED levels at 1 month (M1) (n=90) and at 3 months (M3) (n=27) after inclusion were normal in 50% at M1 versus 55.6% at M3, low in 42.2% at M1 versus 33.3% at M3 and high in 7.8% at M1 versus 11.1% at M3. AED levels at M1 and at M3 were significantly different p<0.0001. By M3, seizures (n=90) were <1/month in 26.7%, and lasted less than 1 minute in 16.7%. After a yearlong follow up, all 90 patients reported a good or excellent quality of life. At our urban study site, patients (n=30) were on carbamazepine and valproid acid in 66.67% and monotherapy (carbamazepine) in 33.33%. By November 2018, only six out 30 patients (on bi-therapy) were still taking their medications.ConclusionsEpilepsy diagnostic and treatment are a real concern in Mali. Our data showed appropriate AED treatment with close follow up resulted in a better quality of life of patients in rural Mali. We will promote the approach of personalized medicine in AED treatment in Mali.

Convulsive Status Epilepticus in Children: A Prospective Observational Study from India

AbstractConvulsive status epilepticus (CSE) is one of the commonest and life threatening pediatric neurological emergencies. Only few studies on pediatric status epilepticus (SE) are available from the Indian subcontinent. The aim was to study the etiology and immediate outcome of CSE in children getting admitted in pediatric emergency during the study period and to study association of various clinical presentations with immediate outcome. A prospective observational study was conducted in tertiary care institute of Northern India. Children aged between 1 month and 18 years with CSE were enrolled and followed up till discharge. Primary outcome was kept as hospital survival/mortality; those who survived were further graded on the basis of disability at discharge. A total of 81 patients with CSE were assessed for primary outcome. The mortality rate was found to be 15% (12/81); 83% deaths were due to acute central nervous system (CNS) infection. Ten percent of children (8/81) had disability at discharge, five had mild, and three had moderate disability. The neurocysticercosis was the most common etiology seen in 23% (19/81) of the children followed by febrile SE in 20% (13/81) of the study participants. CSE responded to first-line antiepileptic drugs (AED) in 15% children (12/81). Refractory status was seen in 13.5% (11/81) cases. Prehospital treatment was received only in 15% patients. Young age, low Glasgow coma scale score at admission, and requirement of critical care support were the factors found to be significantly associated with mortality. CSE has a high mortality especially in young children and acute CNS infections are the most common cause of it.

Efficacy of antiepileptic drugs in neonatal seizures: a systematic review protocol

IntroductionSeizures are one of the most common neurological disorders of neonates, which is also an emergency in the neonatal intensive care unit. For neonates, the recommended first-line antiepileptic drugs (AEDs)...

Altered spontaneous brain activity in patients with childhood absence epilepsy: associations with treatment effects.

The study aims to detect resting-state functional MRI (RS-fMRI) changes and their relationships with the clinical treatment effects of anti-epileptic drugs (AEDs) for patients with childhood absence epilepsy (CAE) using the fractional amplitude of low-frequency fluctuation (fALFF). RS-fMRI data from 30 CAE patients were collected and compared with findings from 30 healthy controls (HCs) with matched sex and age. Patients were treated with first-line AEDs for 46.2 months before undergoing a second RS-fMRI scan. fALFF data were processed using DPABI and SPM12 software. Compared with the HCs, CAE patients at baseline showed increased fALFF in anterior cingulate cortex, inferior parietal lobule, inferior frontal lobule, supplementary motor area and reduced fALFF in putamen and thalamus. At follow-up, the fALFF showed a clear rebound which indicated a normalization of spontaneous brain activities in these regions. In addition, the fALFF changes within thalamus showed significant positive correlation with the seizure frequency improvements. Our results suggest that specific cortical and subcortical regions are involved in seizure generation and the neurological impairments found in CAE children and might shed new light about the AEDs effects on CAE patients.

Electrical status epilepticus in sleep (ESES) — Treatment pattern and EEG outcome in children with very high spike–wave index

ObjectiveThe objective of the study was to determine electrical status epilepticus in sleep (ESES) outcome in children with very high spike–wave index (SWI; ≥85%), and assess treatment pattern. MethodsMedical records of children 1–17 years old with ESES were reviewed. In this study, ESES is defined as SWI in non-rapid eye movement (non-REM) sleep of ≥85%. Electrical status epilepticus in sleep resolution is defined as reduction of SWI to <50%. ResultsComplete data were available in 33 children. Age at ESES diagnosis ranged from 32 to 165 months, median 76 months. The median duration of follow-up was 33 months. Two-thirds of the children were on one or more antiepileptic drugs (AED) at ESES diagnosis. Antiepileptic drugs were used as first treatment for ESES in 24/33 (73%). Electrical status epilepticus in sleep initially resolved in 76%, but 56% had subsequent relapse. The relapse rate was higher for steroids (89%) and benzodiazepines (60%) as compared with nonbenzodiazepine AEDs (29%).At last follow-up, ESES resolved in 21 children (64%). Electrical status epilepticus in sleep resolution was associated with seizure freedom (Fisher's exact, p < 0.05). SignificanceUsing electroencephalogram (EEG) criteria, ESES resolved in 64%. We found high failure rate of first-line AEDs in preventing ESES, and high relapse rate. Standardization of ESES management is urgently needed.

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.

Observational study on the utilization pattern of adjuvant anti-epileptics and their adverse effects

Background: Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures. Pharmacological therapy is the cornerstone of treatment of epilepsy. In more than 50% patients seizure not controlled with first-line anti-epileptic drugs so added with adjuvant drugs. Therefore adjuvant anti-epileptic drugs play an important role in preventing seizure remission in known epilepsy patients. Observational study was to evaluate the utilisation pattern of adjuvant anti-epileptic drugs and to assess their clinical correlation and observe the adverse effects of the adjuvant anti-epileptics.Methods: Eligible 100 patients who attended the neurology outpatient department where enrolled in the study. Demographic data, type of epilepsy, presence or absence of seizure episode (4 months), adjuvant anti-epileptic prescribed along with the first-line drugs and adverse effects were noted. Clinical correlation and rationale for the usage of adjuvant anti-epileptics were assessed. Descriptive statistics used for statistical analysis.Results: The most common types of seizures were generalised tonic clonic seizures (41%) and complex partial seizures (37%). Most commonly used 1st line drug was phenytoin tablet. Most common adjuvant anti-epileptics used were clonazepam (30), clobazam (24) tablets. Most common adverse effect noted was dizziness (31%).Conclusions: Tablet clonazepam is effective adjunct for tonic clonic seizures. Clobazam table is recommended as add-on drug for focal and generalised seizures. Adjuvant anti-epileptic drugs decrease seizure remission with fewer tolerable adverse effects.

Treatment patterns in patients with a new diagnosis of epilepsy and psychiatric comorbidities

ObjectiveThe objective of this study was to describe antiepileptic drug (AED) treatment patterns in patients with epilepsy, with and without psychiatric comorbidities. MethodsThis was a retrospective claims-based cohort study using Truven Health MarketScan databases (Commercial and supplemental Medicare, calendar years 2012–2017; Medicaid, 2012–2016). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (<1 year for persons of 1 to <2 years of age; none for persons <1 year), and continuous medical and pharmacy enrolment without epilepsy/seizure diagnosis or AED prescription during baseline. Based on presence/absence of psychiatric diagnosis codes in the baseline period, persons were classified into two cohorts: with or without psychiatric comorbidities. Outcomes included percentage of treated persons (AED prescription), type, duration, and outcome of first-line AED treatment. ResultsThere were 18,062 persons in each cohort with and without psychiatric comorbidities, matched by age, sex, and insurance type, who met selection (or inclusion) criteria. More patients with psychiatric comorbidities were prescribed an AED after diagnosis (57.6% vs. 52.8%), and had at least two AEDs prescribed during follow-up (16.7% vs. 11.4%) than patients without psychiatric comorbidities. Most patients with and without psychiatric comorbidities prescribed AED monotherapy as first-line treatment (73.0% vs. 78.7%). Levetiracetam was the most common AED prescribed less frequently in patients with than without psychiatric comorbidities (40.8% vs. 56.7%). More patients with psychiatric comorbidities changed first-line AED treatment than patients without psychiatric comorbidities. ConclusionThe presence of psychiatric comorbidities may impact treatment decisions in newly diagnosed persons with epilepsy to optimize patient outcomes.

Efficacy and safety of levetiracetam in Japanese epilepsy patients: A retrospective cohort study

Levetiracetam is an antiepileptic drug with good tolerability that is used for focal and generalized epilepsy as well as acute treatment of status epilepticus; it is also a first-line antiepileptic drug for patients with concomitant medical conditions. The effect of blood levetiracetam concentration on its efficacy and safety in Japanese patients with epilepsy is unknown. This retrospective cohort study compared the efficacy and safety of levetiracetam alone and in combination with other antiepileptic drugs in 255 outpatients with epilepsy treated with levetiracetam. Electronic medical records were accessed to analyse clinical parameters including blood concentrations of levetiracetam and concomitant antiepileptic drugs, clinical laboratory values and adverse reactions. Combination of levetiracetam with antiepileptic drugs, even those that alter cytochrome P450 activity, did not affect blood levetiracetam concentrations. Similarly, levetiracetam use did not significantly affect blood concentrations of concomitantly used antiepileptic drugs. Although blood levetiracetam concentration was significantly increased in older patients and those with renal dysfunction, the rates of adverse reactions were not increased. Levetiracetam may be used effectively and safely without dose adjustment using blood concentration monitoring even when administered in combination with other antiepileptics for Japanese patients with epilepsy.

Levetiracetam versus Phenobarbitone in Neonatal Seizures — A Randomized Controlled Trial

To compare the efficacy and safety of intravenous Levetiracetam and Phenobarbitone in the treatment of neonatal seizures. Open labelled, Randomized controlled trial. Level III Neonatal Intensive Care Unit (NICU). 100 neonates (0-28 days) with clinical seizures. If seizures persisted even after correction of hypoglycemia and hypocalcemia, participants were randomized to receive either Levetiracetam (20 mg/kg) or Phenobarbitone (20 mg/kg) intravenously. The dose of same drug was repeated if seizures persisted (20 mg/kg of Levetiracetam or 10 mg/kg of Phenobarbitone) and changeover to other drug occurred if the seizures persisted even after second dose of same drug. Cessation of seizures with one or two doses of the first drug, and remaining seizure-free for the next 24 hours. Seizures stoped in 43 (86%) and 31 (62%) neonates in Levetiracetam and Phenobarbitone group, respectively (RR 0.37; 95%CI 0.17, 0.80, P<0.01). 10 neonates had adverse reactions in the phenobarbitone group (hypotension in 5, bradycardia in 3 and requirement of mechanical ventilation in 2 neonates) while none had any adverse reaction in Levetiracatam group. Levetiracetam achieves better control than Phenobarbitone for neonatal seizures when used as first-line antiepileptic drug, and is not associated with adverse drug reactions.

Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.

Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.

Levetiracetam and Adverse Psychiatric Events: Who Is at Risk?

Levetiracetam, a commonly used first-line antiepileptic drug (AED), has been associated with adverse effects such as depression and anxiety. To predict

Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience.

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial

IntroductionTherapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED)....

Association between SCN1A polymorphism rs3812718 and valproic acid resistance in epilepsy children: a case-control study and meta-analysis.

Resistance to valproic acid (VPA), a first-line antiepileptic drug (AED), is occurring at an alarming rate, particularly in children. Signal nucleotide polymorphisms are considered crucial in this process. Therefore, we investigated whether the SCN1A polymorphism rs3812718 could be associated with VPA resistance. A total of 231 children with epilepsy who were solely administered VPA were enrolled. DNA was extracted from the peripheral blood samples and was genotyped by the Mass Array method. Furthermore, a meta-analysis was conducted between the drug responsive and resistant patients who were exposed to voltage-gated sodium channels. Results revealed that the TT genotype was associated with a higher risk of developing drug resistance (OR = 2.636, 95% CI 1.08–6.433, P = 0.033). After adjusting for the risk factors, a significant difference was still observed between the responsive and resistant groups (OR = 2.861, 95% CI 1.141–7.174, P = 0.025). Moreover, the recessive model was associated with a decreased drug resistance (OR = 0.402, 95% CI 0.167–0.968, P = 0.042) after correcting the risk factors. Meta-analysis of nine studies revealed similar results. In conclusion, our results proved that the rs3812718 TT genotype was associated with a high risk of developing drug resistance, and the recessive model could decrease the risk of VPA resistance.

Safety evidence on the administration of Fucus vesiculosus L. (bladderwrack) extract and lamotrigine: data from pharmacokinetic studies in the rat

Fucus vesiculosus is often incorporated in weight loss dietary supplements to improve weight loss in overweight adults. Obesity is a common condition in epilepsy patients and is indeed increasing in refractory epilepsy and in patients under polytherapy. Since lamotrigine (LTG) is a first-line antiepileptic drug, used in monotherapy or adjunctive therapy, the main objective of this work was to investigate the potential pharmacokinetic-based interactions between F. vesiculosus and LTG in rats. In a first pharmacokinetic study, a single oral dose of F. vesiculosus extract (575 mg/kg, p.o.) was co-administered with a single-dose of LTG (10 mg/kg, p.o.). In a second study, rats were orally pretreated with F. vesiculosus extract (575 mg/kg/day, p.o.) for 14 days and received LTG (10 mg/kg, p.o.) on the 15th day. In the control groups, rats received water instead of the extract. After LTG administration, blood samples were taken until 96 h post-dose, and LTG concentrations measured in plasma were submitted to a non-compartmental pharmacokinetic analysis. The co-administration of F. vesiculosus extract and LTG caused no significant changes in the drug kinetics. However, the repeated pretreatment with F. vesiculosus extract significantly reduced the peak concentrations of LTG and caused a slightly decrease in the extent of systemic drug exposure. Overall, based on these results, no significant clinical impact is expected from the administration of F. vesiculosus dietary supplements and LTG.

The first-line antiepileptic drug carbamazepine: Reaction with biologically relevant free radicals

Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs by both adults and children. Despite its widespread use, CBZ is associated with central nervous system toxicity and severe hypersensitivity reactions, which raise concerns about its chronic use. While the precise mechanisms of CBZ-induced adverse events are still unclear, metabolic activation to the epoxide (CBZ-EP) has been thought to play a significant role.This work reports first-hand evidence that CBZ reacts readily with biologically relevant thiyl radicals with no need for bioactivation. Using liquid chromatography coupled with high resolution mass spectrometry, multiple products from direct reaction of CBZ with glutathione (GSH) and N-acetyl-L-cysteine (NAC) were unequivocally identified, including the same product obtained upon ring-opening of CBZ-EP. The product profile is complex and consistent with radical-mediated mechanisms. Importantly, side products and adducts compatible with this non-enzymatic pathway were identified in liver extracts from CBZ-treated Wistar rats.The reaction of CBZ with GSH and NAC is more extensive in the presence of oxygen. Taking into consideration that GSH conjugation is, in general, a detoxification pathway, these results suggest that under hyperoxia/oxidative stress conditions the bioavailability of the parent drug may be compromised. Additionally, this non-enzymatic process can be anticipated to play, at least in part, a role in the onset of CBZ-induced adverse reactions due to the concomitant generation of reactive oxygen species. Therefore, the search for causal relationships between the formation of non-enzymatically-driven CBZ products and the occurrence of CBZ-induced adverse events in human patients merits further research, aiming the translation of basic mechanistic findings into a clinical context that may ultimately lead to a safer CBZ prescription.

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors

Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach.For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.