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.

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.

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.

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.

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.

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.

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.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Diagnosing epileptic seizures in patients with Alzheimer's disease and deciding on the appropriate treatment plan.

INTRODUCTION: Alzheimer's disease (AD) is the predominant cause of dementia and a significant contributor to morbidity among the elderly. Patients diagnosed with AD face an increased risk of epileptic seizures. AREAS COVERED: Herein, the authors review the challenges in the diagnosis of seizures in patients with AD, the risks of seizures related to medications used in AD and the pharmacological treatment of seizures in AD. The authors also provide the reader with their expert opinion on the subject matter and future perspectives. EXPERT OPINION: Healthcare professionals should maintain a vigilant approach to suspecting seizures in AD patients. Acute symptomatic seizures triggered by metabolic disturbances, infections, toxins, or drug-related factors often have a low risk of recurrence. In such cases, addressing the underlying cause may suffice without initiating antiseizure medications (ASMs). However, unprovoked seizures in certain AD patients carry a higher risk of recurrence over time, warranting the use of ASMs. Although data is limited, both lamotrigine and levetiracetam appear to be reasonable choices for controlling seizures in elderly AD patients. Decisions should be informed by the best available evidence, the treating physician's clinical experience, and the patient's preferences.

Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

Psychiatric and behavioral concerns of perampanel with concomitant levetiracetam in children with epilepsy.

PURPOSE: Perampanel (PER) is expanding the therapeutic scope for pediatric epilepsy owing to its efficacy and favorable safety profile. However, concerns about psychiatric and behavioral adverse events (PBAEs) in combination therapy with levetiracetam (LEV) continue to contribute to hesitation in its prescription. We investigated the risk profiles for PBAEs when adding PER to pediatric epilepsy treatment and analyzed the differences according to the presence of concomitant LEV. METHODS: We retrospectively reviewed the medical records of children aged 4-18 years with epilepsy who were prescribed PER as adjunctive therapy from March 2016 to February 2023. We compared the occurrence and management of PBAEs between the PER without LEV and PER with LEV groups. The risk factors for PBAEs were also analyzed. RESULTS: Ninety-four patients (53 boys and 41 girls) were included in this study. The median age of total patients at the time of adding PER was 14.9 years (12.3-16.4 years), and 53 patients (56.4 %) had concomitant LEV. Forty-seven PBAEs occurred in 34 patients (36.2 %), with no significant differences depending on whether concomitant LEV is present or not. The most common PBAEs were aggression (14.9 %), irritability (9.6 %), affect lability (7.4 %), and acute psychosis (6.4 %). PBAEs occurred at a lower dosage (2-6 mg/day) in 70.6 % of the patients. In addition, 73.5 % of patients with PBAEs continued PER treatment by follow-up observation or by reducing the PER dosage. No risk factors, such as the presence of concomitant LEV or lamotrigine, any comorbid conditions, higher PER dosage (8-12 mg/day), two or more concomitant anti-seizure medications, and younger age (<13 years) at PER add-on, showed significant associations. CONCLUSION: When expanding the use of anti-seizure medications in pediatric patients, real-world evidence on safety issues is crucial for pediatric epileptologists. We confirmed that combination therapy with PER and LEV did not increase the risk profile of PBAEs.

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model.

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

Therapeutic drug monitoring in pregnancy: Levetiracetam.

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. METHODS: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. RESULTS: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (µg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. SIGNIFICANCE: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT-qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT-qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

How to handle a missed or delayed dose of lacosamide in pediatric patients with epilepsy? a mode-informed individual dosing.

This study aims to investigate the effects on the pharmacokinetic (PK) of lacosamide (LCM), and to guide the individual dosing regimens for children and ones with poor medication adherence. Population PK research was performed based on 164 plasma samples of 113 pediatric patients aged from 1.75 to 14.42 years old. The PK characteristic of LCM was developed by a one-compartment model with first-order elimination. The typical value of apparent clearance (CL) and apparent volume of distribution (Vd) was 1.91 L·h-1 and 56.53 L respectively. In the final model, the variability of CL was significantly associated with the body surface area (BSA) and elevated uric acid (UA) level. In contrast, the impact of some prevalent anti-seizure medicines, such as valproic acid, levetiracetam, oxcarbazepine, lamotrigine, and perampanel, and gene polymorphisms of Cytochrome P450 (CYP)2C19, ATP-binding cassette (ABC)B1, and ABCC2 had no clinical significance on the PK parameters of LCM. BSA-based dosing regimen of LCM was provided according to Monte Carlo simulation approach; while the dosage should reduce half in patients with an UA level of more than 400 µmol·L-1 comparing with an UA level of 100 µmol·L-1. Individualize remedial doses of about 0.5- to 1.5-fold of regular doses were recommended in six common scenarios of missed or delayed doses, that depended on the delayed time. In current study, the population PK model of LCM in children with epilepsy was developed successfully. The BSA-based dosing regimen and individualized remedial strategy were recommended to guarantee the precise administration of LCM.

A Multicenter Study of Self-Limited Epilepsy With Centrotemporal Spikes: Effectiveness of Antiseizure Medication With Respect to Spike-Wave Index.

BACKGROUND: There is no certain validated electroencephalographic (EEG) parameters for outcome prediction in children with self-limited epilepsy with centrotemporal spikes. To assess the effectiveness of antiseizure medication (ASM) for seizure outcome with respect to the spike-wave index (SWI) on serial EEG recordings. METHODS: In this multicenter study, the study cohort consisted of 604 children with self-limited epilepsy with centrotemporal spikes. A data set of epilepsy centers follow-up between 2010 and 2022. The cohort was divided into 4 groups as those receiving 3 different monotherapy (carbamazepine [CBZ]/valproic acid [VPA]/levetiracetam [LEV]) and dual therapy. SWI analysis was performed with the percent of spikes in the 2-minute epoch in the 5th 6th minutes of the nonrapid eye movement sleep EEG record. The study group were also categorized according to seizure burden with seizure frequency (I) >2 seizures and (II) >5 seizures. Seizure outcome was evaluated based on the reduction in seizure frequency over 6-month periods: (1) 50% reduction and (2) seizure-free (complete response). RESULTS: ASM monotherapy was achieved in 74.5% children with VPA, CBZ, and LEV with similar rates of 85.8%, 85.7%, and 77.9%. Dual therapy was need in the 25.5% of children with SeLECT. More dual therapy was administered in children aged below 5 years with a rate of 46.2%. Earlier seizure-free achievement time was seen in children with LEV monotherapy with more complete-response rate (86.7%) compared the VPA and CBZ. CONCLUSIONS: We also determined that the children on dual therapy had more SWI clearance in the subsequent EEG recordings. The ROC curve analyses were performed to predict initial drug selection with using the SWI% might be used for the prediction of ASM type and drug selection in children.