Monitoring levetiracetam concentration in saliva during pregnancy is stable and feasible.

AIMS: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy. METHODS: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy. RESULTS: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 µg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 µg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007. CONCLUSION: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted.

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.

Clinical Experience With Lacosamide as an Adjunct Treatment for Neonatal Seizures: A Retrospective Single-Center Study.

BACKGROUND: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures. METHODS: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects. RESULTS: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted. CONCLUSIONS: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.

Efficacy of second-line anticonvulsant agents with adult status epilepticus: A systematic review and network meta-analysis.

BACKGROUND: Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs. OBJECTIVE: We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing multiple second-line AEDs for SE to investigate the efficacy of AEDs. METHODS: We searched MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal and included RCTs for patients aged ≥15 years with SE on December 31, 2023. We compared multiple second-line AEDs for SE including fosphenytoin (fPHT), lacosamide (LCM), levetiracetam (LEV), phenytoin (PHT), phenobarbital (PHB), and valproate (VPA). The primary and secondly outcomes were termination of seizures integrating the absence of seizure recurrence at 30 min and 60 min, and adverse events associated with AEDs, respectively, with expressing as relative risk (RR) with a 95% confidence interval (CI). We conducted a NMA using frequentist-based approach with multivariate random effects, and assessed the certainty based on the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: Seven RCTs (n = 780) were included, and statistically significant difference was detected between VPA vs. PHB (RR, 0.67; 95% CI, 0.53-0.85; very low certainty), fPHT vs. PHB (RR, 0.66; 95% CI, 0.48-0.90; very low certainty), LCM vs. PHB (RR, 0.62; 95% CI, 0.41-0.93; very low certainty), and LEV vs. PHB (RR, 0.69; 95% CI, 0.51-0.94; very low certainty). Moreover, PHB was the highest in the ranking for termination of seizures. For adverse events, no significant reduction was observed owing to the selection of AEDs, although the ranking of PHB was the lowest. CONCLUSIONS: PHB may have been the most effective for seizure termination as second-line AEDs in adult patients with SE. However, the certainty of almost all comparisons was "very low", and careful interpretation is essential.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

BACKGROUND: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. ANIMALS: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. METHODS: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. RESULTS: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 µg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. CONCLUSION AND CLINICAL IMPORTANCE: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

How many patients do you need? Investigating trial designs for anti-seizure treatment in acute brain injury patients.

BACKGROUND/OBJECTIVES: Epileptiform activity (EA), including seizures and periodic patterns, worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized control trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, and complex physiology of acute brain injury, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine the feasibility of RCTs evaluating EA treatment. METHODS: In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework, we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. RESULTS: Sample sizes ranged from 500 for levetiracetam 7 mg/kg versus placebo, to >4000 for levetiracetam 15 versus 7 mg/kg to achieve 80% power (5% type I error). For propofol 1 mg/kg/h versus placebo, 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. CONCLUSIONS: Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and propose use of this simulation-based RCT paradigm to assess the feasibility of future trials of anti-seizure treatment in acute brain injury.

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.

Serum perampanel levels in patients with seizures are not affected by hemodialysis.

Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. PLAIN LANGUAGE SUMMARY: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

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.

Levetiracetam Dosing Based on Glasgow Coma Scale Scores in Pediatric Traumatic Brain Injury Patients.

INTRODUCTION: Severe traumatic brain injury (TBI) increases the risk of early posttraumatic seizures (EPTS). Guidelines suggest the use of prophylactic antiseizure agents, including levetiracetam. This study aims to evaluate the feasibility of using levetiracetam dosing based on Glasgow Comas Scale (GCS) scores with higher doses used for more severe TBI. METHODS: Patients 6 months to 18 years old admitted to Penn State Hershey Children's Hospital (PSHCH) with a TBI who received levetiracetam for EPTS prophylaxis with at least one documented GCS score were included. Patients were divided into two cohorts: before and after implementation of the pediatric TBI Cerner PowerPlan at PSHCH which standardized levetiracetam dosing based on GCS scores. Primary outcome was appropriate dosing of levetiracetam based on GCS. Secondary outcomes included seizure occurrence and adverse effects. RESULTS: Eighty-five patients were included: 42 in the pre-PowerPlan group and 43 in the post-PowerPlan group. Overall, 46 (54%) patients received the appropriate levetiracetam dose based on GCS (pre-PowerPlan, n = 19 [45%] vs. post-PowerPlan n = 27 [63%], p = 0.104). Sixty-four percent of severe TBI patients received appropriate levetiracetam dosing after implantation of the PowerPlan compared with 28% prior to the PowerPlan (p = 0.039). Three patients in each group experienced a seizure while on levetiracetam. Two patients experienced agitation and somnolence attributed to levetiracetam. CONCLUSION: Levetiracetam dosing based on GCS scores in pediatric TBI patients is a novel approach, and dosing accuracy may be increased with use of a PowerPlan. Additional large-scale studies are needed to evaluate efficacy and safety of this approach prior to widespread implementation.

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.

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.

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.

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.

Second antiseizure medication monotherapy in patients with adult-onset epilepsy: A register-based analysis.

OBJECTIVE: Revision of therapy is fundamental in epilepsy care, since only half of patients achieve seizure freedom and tolerate the first antiseizure medication (ASM). We studied the selection and retention of second antiseizure medication monotherapy in adults who discontinued treatment with one of the three most frequently prescribed first ASMs, and the impact of age or brain comorbidities. METHODS: Using Swedish national registers, we conducted a population-based, retrospective cohort study from 2007 to 2019 on patients age ≥ 30 at the epilepsy diagnosis that had switched to a second monotherapy after the three most common initial monotherapies (n = 7369). Retention rates (RR) were estimated via Kaplan-Meier. Discontinuation of the second monotherapy was defined as 12-month prescription gap or initiation of a third ASM. Analyses were stratified by sex, age, and presence of stroke or dementia. RESULTS: The three most commonly prescribed second ASMs were carbamazepine, levetiracetam, and lamotrigine. The 1-year retention rate was 63-76% in all patients. For groups with stroke or dementia, the maximal 1-year RRs were 77% and 87%, respectively. After five years, retention rates ranged from 12% to 39%. There were no major differences between ASMs, apart from in patients discontinuing carbamazepine, where lamotrigine had a superior retention compared to levetiracetam as second monotherapy. SIGNIFICANCE: The three most often prescribed second ASMs seem to be suitable treatment options according to present guidelines. The second ASMs' retention rates were initially high in all studied patient groups but dropped to approximately the expected proportion of second monotherapy responders over the next five years. This suggests that therapy revision could be expedited.

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.