Trends in Antiseizure Medication Initiation, Switch, or Termination in Patients With Newly Diagnosed Epilepsy: A Nationwide Study.

BACKGROUND AND OBJECTIVES: Few studies evaluate physicians' choice of antiseizure medication (ASM) to treat patients with newly diagnosed epilepsy. The objective of this study was to analyze the choice of ASM and its use by age, sex, psychiatric comorbidities, and concurrent treatment with other drugs (antidepressant medications and contraceptives) in patients who initiated epilepsy treatment using monotherapy. METHODS: Included in this study were persons (any age) with an incident hospital diagnosis of epilepsy during 2010-2022 in the Swedish Patient Register (SPR), preceding a first dispensing of any ASM (as reported in the Swedish Prescribed Drug Register, SPDR) for the period 2010-2022. Incident patients were identified using retrospective information during 2000-2009 in the SPR. Primary outcome was first dispensed ASM by age, sex, comorbidity, and comedication with antidepressants or contraceptives (SPDR). Secondary outcomes were time to ASM switch or termination assessed by survival analyses. RESULTS: Of 67,984 patients included (mean age 46; 46% female), 66,441 initiated ASM treatment using monotherapy. Relative risk (RR) for initiating treatment using monotherapy did not differ between age groups, sex, or patients with concurrent treatment with antidepressants, contraceptives, or psychiatric illness (RR and 95% CI did include 1.0). The share initiating treatment using levetiracetam increased from 10% in 2010 to 55% in 2022; valproic acid: 10%-5%. The likelihood of initiating treatment using 1 of the 5 most frequent ASMs differed between all compared groups (0.3 < RR < 1; 95% CI < 1; 1 < RR < 15; 1 <95% CI). Seven percent of female patients of childbearing age initiated treatment with valproic acid, levetiracetam was the most frequent initial ASM in patients with psychiatric comorbidity (40.2%), and lamotrigine the most prescribed initial ASM to women on contraceptives (50.4%). Highest likelihoods of treatment termination were found among children (1.72 < RR < 3.07; 1 <95% CI) and among patients with psychiatric comorbidity (initiated on carbamazepine, RR 1.38; 1 <95% CI or lamotrigine, RR 1.31; 1 <95% CI). Thirty-one percent to 47% of patients switched from an initial monotherapy to a new monotherapy within 5 years. Twenty percent to 42% terminated ASM treatment within 5 years. DISCUSSION: Levetiracetam and lamotrigine were the most frequently dispensed initial ASMs, also among patients with comorbidities or comedications complicating the use of these ASMs, highlighting the need for improved education of prescribers concerning ASM selection in relation to individual patient characteristics. Use of ASMs in hospital is not captured in the SPDR.

Morphological and histopathological changes of maternal levetiracetam on the cerebellar cortex of the offspring of albino rat.

Levetiracetam (LEV) is being used by women with reproductive-age epilepsy at a significantly higher rate. The purpose of the study was to assess how levetiracetam treatment during pregnancy affected the offspring's weight and cerebellum. Forty pregnant rats were divided into two groups (I, II). Two smaller groups (A, B) were created from each group. The rats in group I were gavaged with approximately 1.5 mL/day of distilled water either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). The rats in group II were gavaged with about 1.5 mL/day of distilled water (containing 36 mg levetiracetam) either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). After the work was completed, the body weight of the pups in each group was recorded, and their cerebella were analyzed histologically and morphometrically. Following levetiracetam treatment, the offspring showed decreased body weight and their cerebella displayed delayed development and pathological alterations. These alterations manifested as, differences in the thicknesses of the layers of cerebellar cortex as compared to the control groups; additionally, their cells displayed cytoplasmic vacuolation, nuclear alterations, fragmented rough endoplasmic reticulum and lost mitochondrial cristae. Giving levetiracetam to pregnant and lactating female rats had a negative impact on the body weight and cerebella of the offspring. Levetiracetam should be given with caution during pregnancy and lactation.

Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population.

BACKGROUND: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. OBJECTIVE: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework. METHODS: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models. RESULTS: Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature. CONCLUSIONS: PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.

Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study.

BACKGROUND: Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM). MATERIALS AND METHODS: This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC). RESULTS: The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018). CONCLUSION: There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome.

Correlation of drug dose estimated from national prescription registers with mean blood level of antiseizure medication in pregnancy.

PURPOSE: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy. METHODS: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values. RESULTS: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate. CONCLUSIONS: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

OBJECTIVE: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics. METHODS: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines. RESULTS: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10-3, 95%CI = -16.08 to -8.58 × 10-3 (µg/mL)/(mg/day), p < 0.001, MD = -7.16 (µg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (µg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10-3 (µg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5. CONCLUSIONS: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Efficacy and safety of phenytoin and levetiracetam for acute symptomatic seizures in children with acute encephalitis syndrome: an open label, randomised controlled trial.

INTRODUCTION: Seizures represent a significant comorbidity in children with acute encephalitis syndrome (AES). Despite this, there is a notable absence of randomized controlled trials (RCTs) directly comparing antiseizure medications (ASMs) in children with AES. MATERIALS AND METHODS: This RCT aimed to assess the efficacy and safety of phenytoin and levetiracetam in controlling seizures among children with AES. Both ASMs were administered with a loading followed by maintenance dose. After a 12-week period, children exhibiting a normal electroencephalogram and no seizure recurrence underwent tapering and discontinuation of ASM. Clinical follow-up occurred daily for the first week, and subsequently at 4, 12, and 24 weeks, evaluating seizure recurrence, incidence of status epilepticus, cognition, behavior, functional status, ASM acquisition cost, and adverse effects. RESULTS: A total of 100 children (50 in each group) were enrolled. Within the first week, 5 and 3 children in the phenytoin and levetiracetam groups expired. Up to 1 week or death (whichever occurred earliest), 46 (92 %) and 44 (88 %) children remained seizure-free. Intention-to-treat analysis for both best and worst-case scenarios showed insignificant differences (p=0.52 and 1.0). No children experienced seizure recurrence after 1 week in either group. The number of patients with breakthrough status epilepticus, need for mechanical ventilation, duration of hospital stay, presence of epileptiform abnormalities in repeat electroencephalogram at 12 weeks, functional outcomes at 1, 12, and 24 weeks, as well as cognition and behavioral profiles at 24 weeks, were comparable in both groups (p>0.05 for all). However, the incidence of treatment-emergent adverse events (TEAEs) causally related to study medications was significantly higher in the phenytoin group (p=0.04). CONCLUSION: Levetiracetam and phenytoin are comparable in efficacy in terms of achieving clinical seizure control in children with acute encephalitis syndrome, although levetiracetam group demonstrated fewer adverse effects.

Effectiveness of Levetiracetam versus phenytoin in preventing seizure in traumatic brain injury patients: A systematic review and meta-analysis.

OBJECTIVE: Traumatic brain injury (TBI) and the subsequent Post-traumatic seizure (PTS) is a growing public health concern. Generally, anti-seizure drugs (ASDs) are recommended for PTS prophylaxis and treatment. This meta-analysis aimed to review the current state of knowledge and the evidence for the efficacy and safety of Levetiracetam (LEV) on the incidence of seizure in TBI patients compared to Phenytoin (PHT). METHODS: A search was carried out based on PubMed, MEDLINE, Europe PMC database, and Cochrane Library up to November 2023. A total of 16 studies (3 randomized clinical trials, 10 retrospective cohort studies, and 3 prospective cohort studies) including 5821 TBI patients included in our meta-analysis. We included studies comparing LEV and PHT after brain injury in both adults and children. Risk of bias assessment was done for randomized controlled trials (RCTs) with a risk-of-bias tool (RoB-2) and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies. Two RCTs in our meta-analysis had a high risk of bias, therefore we applied sensitivity analysis to evaluate the robustness of our results. RESULTS: The most commonly reported dosage for LEV was 500 mg twice daily and for PHT it was 5 mg/kg. There was no significant difference between LEV and PHT groups in reducing the early seizure incidence (OR = 0.85; 95% CI = [0.60, 1.21]; p = 0.375, fixed-effect, I2 = 21.75%). The result of sensitivity analysis for late seizure showed no significant difference between LEV and PHT in reducing the late seizure occurrence after TBI (OR = 0.87; 95% CI = [0.21, 3.67]; p = 0.853, fixed-effect, I2 = 0%). The mortality in TBI patients treated with LEV was not statistically significant compared to the PHT group (OR = 1.11; 95% CI = [0.92, 1.34], p = 0.266). The length of stay in the hospital was not significantly different between the LEV and PHT groups (MD = -1.33; 95% CI = [-4.55, 1.90]; p = 0.421). However, in comparison to PHT, LEV shortened the length of ICU stay (MD = -2.25; 95% CI = [-3.58, -0.91]; p =0.001). In terms of adverse effects, more patients in the PHT group have experienced adverse events compared to LEV but the difference was not significant (OR = 0.69; 95% CI = [0.44, 1.08]; p = 0. 11). CONCLUSION: The results of our meta-analysis showed LEV and PHT have similar effects on the occurrence of early and late seizures in TBI patients. Therefore, none of the drugs is superior to the other in reducing PTS. However, treating TBI patients with LEV did not shorten the length of hospital stay in comparison to PHT but reduced the length of ICU stay significantly. The analysis showed that patients in the LEV experienced fewer side effects than in the PHT group, while it was not sufficiently clear whether all reported side effects were related to the drug alone or other factors. The mortality was similar between the LEV and PHT groups. Finally, we recommend more high-quality randomized controlled trials to confirm the current findings before making any recommendations in practice.

Sudden Cardiac Death or Ventricular Arrythmia in Patients Taking Levetiracetam or Oxcarbazepine.

BACKGROUND AND OBJECTIVES: Levetiracetam is a widely used antiseizure medication. Recent concerns have been raised regarding the potential prolongation of the QT interval by levetiracetam and increased risk of sudden cardiac death. This could have profound implications for patient safety and for prescribing practice. This study assessed the potential association of levetiracetam with cardiac outcomes related to QT interval prolongation. We compared outcomes of patients taking levetiracetam with those taking oxcarbazepine as a comparator medication that has not been associated with prolongation of the QT interval. METHODS: The sample included patients who were newly prescribed levetiracetam or oxcarbazepine from January 31, 2010, to December 31, 2019, using administrative claims data from the OptumLabs Data Warehouse (OLDW). The analysis focused on a combined endpoint of sudden cardiac death or ventricular arrythmia, which are both linked to QT interval prolongation. We used a new user design and selected oxcarbazepine as an active comparator with levetiracetam to minimize bias. We used propensity score weighting to balance the levetiracetam and oxcarbazepine cohorts and then performed weighted Cox regressions to evaluate the association of levetiracetam with the combined endpoint. RESULTS: We identified 104,655 enrollees taking levetiracetam and 39,596 enrollees taking oxcarbazepine. At baseline, enrollees taking levetiracetam were older, more likely to have diagnosed epilepsy, and more likely to have diagnosed comorbidities including hypertension, cerebrovascular disease, and coronary artery disease. In the main analysis, we found no significant difference between levetiracetam and oxcarbazepine in the rate of the combined endpoint for the Cox proportional hazards model (hazard ratio [HR] 0.79, 95% CI 0.42-1.47) or Cox regression with time-varying characteristics (HR 0.78, 95% CI 0.41-1.50). DISCUSSION: When compared with oxcarbazepine, levetiracetam does not correlate with increased risk of ventricular arrythmia and sudden cardiac death. Our finding does not support the concern for cardiac risk to indicate restriction of levetiracetam use nor the requirement of cardiac monitoring when using it. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that sudden cardiac death and ventricular arrythmia are not more frequent in patients older than 17 years newly prescribed levetiracetam, compared with those prescribed oxcarbazepine.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study.

INTRODUCTION: There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome. MATERIAL AND METHODS: A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. RESULTS: There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862). CONCLUSIONS: Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.

Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.

BACKGROUND: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. METHODS: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. RESULTS: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). CONCLUSIONS: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. TRIAL REGISTRATION: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.

Efficacy and Safety of Levetiracetam for Childhood Epilepsies.

Background: Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED). Objective: The objective of the study was to investigate the efficacy and safety of levetiracetam for childhood epilepsies. Methods: This is single, tertiary centre observational, prospective study, that included paediatric patients who were treated with levetiracetam at Paediatric hospital University Clinical Centre Sarajevo, during the period of 15 years (2008-2022). Inclusion criteria were: paediatric patients age > 1 month, diagnosed with epilepsy according to International League Against Epilepsy. After the introduction of levetiracetam, each patient has been followed up at least 12 months. According to the outcome the patients were divided into 5 groups: seizure reduction >50%, seizure reduction <50%, complete seizure freedom, the same number of seizures and increased number of seizures. From these groups two intergroups have been formed: responders (seizure reduction >50% and complete seizure freedom) and non-responders (seizure reduction <50%, the same number of seizures and increased number of seizures). Results: The study enrolled 259 patients (141 female and 118 male), with mean age 7 years (3,0-12.0). Comorbidities were present at 129/259 (49.8%) patients. After 12 months of treatment, 25/259 (9.7%) patients had seizure reduction >50%, 30/259 (11.6%) patients had seizure reduction <50%, 154/259 (56.5%) patients had achieved seizure freedom, 31/259 (12%) patients had same number of seizures, while 19/259 (7.3%) patients had increased number of seizures. Seizure frequency between responders and non-responders, before treatment and after 12 months of treatment was statistically significant (p<0.001). Discussion: Non responders had the best outcome with ditherapy (30/79; 38%), while responders had the best outcome with monotherapy (161/180;89.4%). Conclusion: Levetiracetam is efficient antiepileptic drug for different types of epilepsies in childhood, used as mono, di or polytherapy.

Dose adjustment strategy of levetiracetam in pregnant patients with epilepsy: Case report and literature review.

RATIONALE: Pregnant patients with epilepsy are prone to preterm delivery, stillbirth, or cesarean section, and their mortality rate is almost 10 times higher than that of normal pregnant women. The potential negative influences of antiepileptic drugs (AEDs) on the fetus are weighed against the necessity for achieving optimal control of seizures. Treatment with AEDs during pregnancy is a major challenge for pregnant women and healthcare teams. PATIENT CONCERNS: This paper reports two cases of young women diagnosed with pregnancy and epilepsy. INTERVENTION: The dose of levetiracetam was adjusted under the guidance of therapeutic drug monitoring to reduce the effects of seizures on the fetus and the incidence of reproductive toxicity caused by adverse drug reactions. OUTCOMES: Epilepsy was well controlled in the two pregnant patients, and the newborns had no genetic disorders. LESSONS: It is recommended to regularly monitor the serum LEV level in pregnant patients with epilepsy. This practice serves as a foundation for adjusting the drug treatment plan and offering more precise guidance for medication management during pregnancy.

Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.