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Background: Levetiracetam has a favorable pharmacology profile to be used subcutaneously. However, its subcutaneous use is still considered off-label as this is beyond its license. The evidence base for its safety, tolerability, and efficacy is limited to observational studies. Objectives: To report the safety and efficacy of subcutaneous levetiracetam in Latino patients on home care. Design: Observational retrospective case series study. Subjects: Consecutive sample of Latino adults with life-limiting illnesses. Methods: A case series framework with 4 domains (selection, ascertainment, causality, and reporting) to ensure reporting quality was used. Additionally, 8 relevant outcomes established in a previous comprehensive review, were collected and reported. Adverse reactions were documented using the Common Terminology Criteria for Adverse Events. Results: Fifteen Latino patients with oncological and non-oncological diagnoses received subcutaneous levetiracetam for a mean of 21 days on home care. Levetiracetam was most frequently initiated subcutaneously due to loss of the oral route. The average dosage of subcutaneous levetiracetam was 1200 mg. Only 1 patient required a dose adjustment, and only 2 patients experienced a total of 5 seizures during the therapy trial. No adverse reactions were reported. Conclusions: Subcutaneous levetiracetam appears to be effective and safe. This case series of Latino patients in home care expands the evidence of its use in the home care setting. The preliminary data reported by now on multiple case series warrants robust trials., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Currently, its use is restricted in women of childbearing potential owing to high teratogenicity. Recent evidence extended this risk to men's offspring, prompting recommendations to restrict use in everybody aged <55 years. This study will evaluate mortality and morbidity risks associated with valproate withdrawal by emulating a hypothetical randomised-controlled trial (called a "target trial") using retrospective observational data. The data will be drawn from ~250m mainly US patients in the TriNetX repository and ~60m UK patients in Clinical Practice Research Datalink (CPRD). These will be scanned for individuals aged 16-54 years with epilepsy and on valproate who either continued, switched to lamotrigine or levetiracetam, or discontinued valproate between 2014-2024, creating four groups. Randomisation to these groups will be emulated by baseline confounder adjustment using g-methods. Mortality and morbidity outcomes will be assessed and compared between groups over 1-10 years, employing time-to-first-event and recurrent events analyses. A causal prediction model will be developed from these data to aid in predicting the safest alternative antiseizure medications. Together, these findings will optimise informed decision-making about valproate withdrawal and alternative treatment selection, providing immediate and vital information for patients, clinicians and regulators., Competing Interests: A.G.M. declares i) a UCB Pharma grant paid to University of Liverpool for the National Audit of Seizure Management in Hospitals (NASH) study, which is unrelated to the submitted work; ii) an Angelini grant to be paid to University of Liverpool as co-applicant for A multi-method PRoject to maximise efficient and equitable pathways tO suPport from a rEgional epiLepsy centre (PROPEL), which is unrelated to the submitted work; iii) Honoraria paid to University of Liverpool for lectures unrelated to the submitted work given at educational events sponsored by Sanofi, Eiasi, and GSK; iii) Support from Angelini for attendance unrelated to the submitted work at the 2024 International League Against Epilepsy (ILAE) congress. G.K.M declares an Angelini grant to be paid to University of Liverpool as co-applicant on the PROPEL study, which is unrelated to the submitted work; ii) Honoraria to be paid to University of Liverpool for delivering a lecture at an educational event sponsored by Angelini which was unrelated to the submitted work. The remaining authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors confirm there are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Mbizvo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV., Methods: Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed., Results: 173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID., Conclusion: PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM., Competing Interests: Declaration of competing interest RS has received institutional and research support from LivaNova, UCB, Eisai, Veriton Pharma, Bial, Angelini, UnEEG and Jazz/GW pharma outside the submitted work. He holds grants from NIHR AI, SBRI and other funding bodies all outside this work. No other author has any declared conflict of interest to this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction. Levetiracetam (LEV) is an antiepileptic drug approved by the Chilean Institute of Public Health as concomitant therapy for epileptic seizures in children older than 4 years of age. However, it is widely prescribed from the neonatal period, which makes it necessary to evaluate its off-label use. Objective. To determine the prescription-indication profile of LEV in the treatment of epileptic seizures in children younger than 4 years in a tertiary care hospital in southern Chile. Population and method. Observational, descriptive, and retrospective study. The medical records of patients who started treatment with LEV between 2014 and 2019 were reviewed, and data on sociodemographic, pharmacological, and clinical variables were collected. The analysis was based on the description of the profile of patients, prescriptions, follow-up, and safety. Results. A total of 68 patients were included: 40 (58.8%) were males, 49 (72.1%) were born at a gestational age ≥ 37 weeks. The main etiology of epilepsy was structural (35.3%); LEV was mostly used in children diagnosed with central nervous system malformation (17.6%), and monotherapy was the prevailing dosage (55.9%). LEV was used for focal seizures in 50% of cases. Five children (7.3%) had psychiatric disorders, classified as probable adverse drug reactions. Conclusion. LEV was used in children with various diagnoses, with a low rate of adverse events. The profile of drug use varied in the different age groups. Future studies are needed to identify effectiveness, especially in newborn infants and patients with refractory epilepsy., (Sociedad Argentina de Pediatría.)

Due to the limited number of studies in children with focal epilepsy and the importance of choosing the most suitable drug to control seizures in children, the administration of the most effective medication with the most negligible adverse events is vital. This study aimed to evaluate the effectiveness and adverse events of carbamazepine vs. levetiracetam monotherapy in children with focal seizures. A monocentric, randomized, controlled, double-blind, parallel-group clinical trial was designed. This study was approved by the Iranian Registry of Clinical Trials (registration number: IRCT20170216032603N2) on June 19, 2020, and conducted at the neurology department of Imam Ali Hospital, Karaj, Iran, from February 2020 to March 2021. This study assessed 120 patients with recently diagnosed focal seizures aged 2 to 14. Patients were randomly divided into two groups, who received carbamazepine (CBZ) 15 to 20 mg/kg and levetiracetam (LEV) 20 to 40 mg/kg daily, respectively. Patients were evaluated for improvement and complications at weeks 4, 12, and 24. Out of 120 patients included in the study, six patients were excluded due to various complications of CBZ. The mean number of seizures at the end of the fourth, twelfth, and twenty-fourth weeks were 1.09 ± 0.75, 0.62 ± 0.27, and 0.39 ± 0.12 in the carbamazepine group and 1.11 ± 0.63, 0.52 ± 0.21, and 0.37 ± 0.11 in the LEV group, respectively (P > 0.05). Similarly, the number of seizure-free patients was 34, 44, and 48 in the CBZ group compared to 41, 50, and 54 in the LEV group, respectively (P > 0.05). On the other hand, the frequency of somnolence, dermatologic complications, and agitation was considerably higher in the CBZ group (P < 0.05). Although both medicines were equally effective in seizure control, CBZ was associated with considerably more adverse events and less patient compliance. Physicians should be aware of this difference to prevent unwanted consequences., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Although prescription of direct oral anticoagulants (DOACs) for epileptic patients on anti-seizure medications (ASMs) is on the increase, international guidelines pose strict restrictions because this may lead to pharmacologic interactions. However, current evidence on their clinical relevance remains scanty. This retrospective, case-control study assessed the frequency of ischemic/hemorrhagic events and epileptic seizures involving DOAC-ASM cotherapy in the real world, compared with DOAC and ASM monotherapy, in age- and gender-matched controls., Methods: Data on patients who had been prescribed a concomitant DOAC and ASM therapy for at least 6 months were extracted from the database of the Pharmaceutical Service of the Alessandria Province (Italy). After exclusions, the case group included 124 patients, 44 on valproic acid (VPA) and 80 on levetiracetam (LEV) concomitant with a DOAC, and it was compared with the DOAC-control and ASM-control groups. The clinical and laboratory data were extracted from the electronic archives of the hospitals in the same province., Findings: Two (1.6%) ischemic and 2 (1.6%) major hemorrhagic events were observed in the case group. Four (3.2%) ischemic and no hemorrhagic events occurred in the DOAC-control group. There were no statistically significant differences in the ischemic and hemorrhagic events between the case group (patients on concomitant LEV or VPA who were prescribed a DOAC) and the DOAC-control group, and there was no difference in the recurrence rate of epileptic seizures between the case group and the ASM-control group., Implications: Although this study has some limits, mainly the small sample size, our findings indicate that neither LEV nor VPA concomitant treatment significantly affects the effects of DOACs in a real-world setting., Competing Interests: Declaration of competing interest All the authors report that they have no conflicts of interest regarding the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy., Methods: The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always")., Results: A total of 225 adults initiated on levetiracetam (n = 132, 59%), lamotrigine (n = 55, 24%), carbamazepine (n = 19, 8.4%), or oxcarbazepine (n = 19, 8.4%) were included. There were no significant differences in AEP total scores between ASMs. Patients with depression (adjusted marginal score ratio [aMSR] 1.23, 95% CI 1.09-1.39, p = 0.001) and anxiety (aMSR 1.15, 95% CI 1.04-1.26, p = 0.007) had worse AEP total scores than those without. After adjusting for depression and anxiety, levetiracetam users were >3 times more likely to report feelings of aggression (adjusted odds ratio [aOR] 3.38, 95% CI 1.07-10.7, p = 0.038) and almost half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21-0.99, p = 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%)., Discussion: Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

Purpose: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy., Methods: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex., Results: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001)., Conclusions: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Breakthrough seizures and status epilepticus require urgent management. Administration of intravenous push (IVP) levetiracetam has been demonstrated to be safe as compared to intravenous piggyback (IVPB). This transition can potentially offer faster time to administration and reduced drug and material cost. The objective of this study was to observe safety of administration in patients receiving levetiracetam via IVP compared to IVPB in acute care settings. Methods: This is a multi-center, observational, retrospective cohort study of 1214 adult patients who received levetiracetam pre- and post-implementation of IVP over a 6 month timespan. Primary outcome was time from order verification to administration of urgent first-time doses. Secondary outcomes included time to administration of loading doses and cost. Safety outcome was infusion site related reactions. Results: Time from order verification to administration of urgent first-time doses pre- and post-implementation of IVP administration was reduced from 61 minutes to 47 minutes ( P =0.0002). Infusion site related reactions were observed in 6 out of 5432 doses in the IVPB arm and in 5 out of 4700 doses in the IVP arm ( P =1). Total estimated cost was $76,171.96 for the 5449 IVPB total doses and $11,484.33 for the 4721 IVP total doses. Conclusions: Transition from IVPB to IVP administration reduced time from order verification to administration of urgent first-time doses with both administrations having similar incidence of infusion site related reactions. Cost savings and improved workflow were observed. Levetiracetam administered via IVP may be considered as a safe alternative method of administration in the acute care setting., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Levetiracetam is widely used in the emergency setting. Safety and tolerability of undiluted levetiracetam is prevalent in adults but is limited in pediatrics. The purpose is to determine the safety and tolerability of rapid administration of undiluted levetiracetam in pediatric patients. Methods: A retrospective, single-center, observational study was conducted in pediatric patients who received undiluted levetiracetam intravenous push. The primary outcome was adverse reactions, extravasation, need for intravenous line replacement, and discontinuation due to adverse reactions. The secondary outcome was turnaround time between ordering and administering first doses. Results: One hundred fourteen patients were included. Injection site reactions occurred in 7 patients. Extravasation occurred in 4 patients. Two patients required intravenous line replacement. There were no adverse events leading to discontinuation of levetiracetam. No difference was seen in the time from order to administration. Conclusion: Rapid administration of undiluted levetiracetam in pediatric patients was safe and well tolerated., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Anticonvulsant drugs are one of the most common causes of delayed hypersensitivity reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). These reactions are more prevalent with aromatic anticonvulsant drugs such as phenytoin and carbamazepine. However, immediate hypersensitivity reactions such as urticaria, angioedema, and anaphylaxis with anticonvulsant drugs are rare. We describe a 51-year-old woman who developed spreading skin rashes on her wrists with urticaria and pruritus 24 h after receiving intravenous levetiracetam., Conclusion: Clinicians should be aware of immediate hypersensitivity reactions with intravenous levetiracetam., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea., Methods: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification., Results: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups., Conclusion: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest None, (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Introduction: Levetiracetam is a relatively new and widely utilized anti-seizure medication; however, limited information is available regarding its adverse effects. This study aims to thoroughly investigate, evaluate, and present evidence on the safety profile of Levetiracetam, relying on data from the FDA Adverse Event Reporting System (FAERS) database to facilitate informed clinical decision-making., Methods: We employed various statistical measures, including Reporting Odds Ratio (ROR), Proportionate Reporting Ratio (PRR), and analysis by the Medicines and Healthcare Products Regulatory Agency (MHRA), to identify signals of adverse reactions associated with Levetiracetam. Positive signals consistent with Designated Medical Event (DME) were singled out for focused comparison and discussion., Results: The analysis of 26,182 adverse events linked to Levetiracetam as the primary suspected drug revealed 692 positive signals spanning 22 System Organ Classes (SOCs). Nervous system disorders were the most frequently reported, followed by psychiatric disorders, and general disorders and administration site conditions. 11 positive signals consistent with Preferred Terms (PTs) in DME were identified, predominantly concentrated in 6 SOCs. Among these, rhabdomyolysis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) exhibited relatively large values of A, ROR, and Chi-squared. Additionally, PTs related to spontaneous abortion, drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect showed significant strength., Conclusions: The study indicates that Levetiracetam carries a potential risk of causing rhabdomyolysis, SJS, TEN, DRESS as well as spontaneous abortion. Signals related to drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect warrant heightened attention in clinical use., Competing Interests: Declaration of competing interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Levetiracetam is a readily available, safe anticonvulsive medication. It is frequently administered as IV piggyback with a pump, carrier fluid, and tubing. The Established Status Epilepticus Treatment Trial demonstrated levetiracetam being similarly effective to previously used treatments in doses up to 4500 mg administered over 10 minutes. Objective: We sought to compare usage, cost, and waste of IV piggyback with IV push administration of levetiractam following implementation of an IV push protocol in an academic emergency department. Methods: A three-month review of levetiracetam administration was done following protocol implementation using IV push for initial treatment of benzodiazepine-refractory status epilepticus. The review quantified the number of IV push vs IV piggyback doses for all indications and evaluated cost of supplies necessary for administration. Results: During the study period, 137 patients received 142 doses of IV levetiracetam. Fifty-one doses (36%) were given as IV push rather than IV piggyback. The majority of doses 116 (82%) were 1000-2000 mg and 11 doses (8%) 3500-4500 mg. Estimated three-month savings with complete transition of IV piggyback to IV push would exceed $6000 just in our ED. The amount of sterile solution carrier fluid was also reduced and IV pump time freed. Conclusion: Implementation of an emergency department IV push levetiracetam protocol resulted in cost savings. Opportunities remain to improve clinical implementation practices. Medication administration represents one crucial target area where healthcare systems can implement policies to reduce waste and commit to climate-smart health care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Brivaracetam is often used as an alternative to levetiracetam in patients with epilepsy (PWE) encountering efficacy issues or adverse events with levetiracetam. This study evaluated the psychological status of PWE who were switched from levetiracetam to brivaracetam due to psychiatric tolerability concerns in comparison to those who remained on levetiracetam., Methods: We used various psychological assessments including the Symptom Checklist SCL-90-R, the Beck Depression Inventory-II, and the adverse event profile. Eligible participants completed the questionnaires at baseline and again 8 days later. Psychological changes were assessed using standard statistical methods to show differences between a group that immediately switched from levetiracetam to brivaracetam and another group with unchanged levetiracetam., Results: Between May 2020 and May 2021, 63 patients participated in the study, of whom 34 switched from levetiracetam to brivaracetam. At baseline, participants who switched to brivaracetam had fewer antiseizure medications but experienced more monthly seizures. Baseline scores for anxiety (p = 0.020) and psychoticism (p = 0.046) on SCL-90-R in PWE switched to brivaracetam were higher than in the remaining group. In the subsequent assessment, all psychological scores were reduced and were no longer significantly different between both groups. Using multiple regression, initial treatment with a single antiseizure medication and male gender emerged as predictors of psychological improvement., Conclusion: Our study found no increased risk of adverse events or psychiatric symptoms after switching from levetiracetam to brivaracetam. Though statistically non-significant, a trend towards improved psychiatric outcomes in the switch group warrants further investigation in future trials with stronger designs for enhanced statistical power., Competing Interests: Declaration of competing interest Bernhard Steinhoff has received speaker's honoraria from Al Jazeera, Angelini, Desitin, Eisai, GW Pharmaceuticals, Hikma, Medscape, Tabuk, and UCB Pharma, and has served as a paid consultant for Angelini, B. Braun Melsungen, Eisai, GW Pharmaceuticals, and UCB Pharma. Other authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

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 8‑hydroxy‑2‑deoxyguanosine (8‑OHdG) 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 lithium‑pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8‑OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8‑OHdG 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.

We report the case of an early adolescent male on lamotrigine and levetiracetam therapy with a 1-month history of progressive, bilateral, painless visual loss which resolved on cessation of lamotrigine. To our knowledge, we present the first case of lamotrigine and levetiracetam dual therapy associated with toxic optic neuropathy, supported by electrophysiology and optical coherence tomography (OCT) changes. Electrophysiology findings were consistent with retinal ganglion cell dysfunction, with bilateral optic nerve involvement. Macula OCT showed mild retinal ganglion cell loss in all inner quadrants bilaterally. This case highlights the importance of asking patients with epilepsy treated with lamotrigine and levetiracetam about visual problems and considering early dose reduction or cessation of treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Drug-induced psychiatric symptoms are an important cause of treatment failure. Worldwide, levetiracetam has been widely used to treat epilepsy; however, associated psychobehavioral abnormalities have been observed . This study aimed to characterize levetiracetam-induced severe psychiatric symptoms and to propose preventive and therapeutic measures., Methods: In this retrospective cluster sampling study, psychiatric symptoms of patients who had taken levetiracetam for at least 1 month were analyzed., Results: 111(7.8%) of the 1,412 included patients exhibited severe psychiatric symptoms. Hallucinations, delusions, aggressive behavior, and agitation were the most common manifestations . Some patients also showed suicidal and self-harm behaviors. These symptoms were mainly controlled by reducing the dose of levetiracetam, stopping the drug, or adding antipsychotic drugs to the treatment regimen., Conclusion: The severe psychiatric symptoms caused by levetiracetam require special attention., (Copyright © 2022. Published by Elsevier Ltd.)

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first-line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population., (© 2024 International League Against Epilepsy.)

Study Objective: Recent studies suggest rapid administration of high-dose, undiluted levetiracetam is safe in adults; however, no information exists in pediatric patients. The purpose of this study was to evaluate the safety and tolerability of undiluted levetiracetam at a pediatric institution., Design: Retrospective, single-center, cohort study., Setting: Pediatric Academic Medical Center., Patients: All patients who received high-dose >60 mg/kg (-10%) up to 4500 mg undiluted or diluted intravenous levetiracetam were included., Intervention: Rapid intravenous administration of undiluted versus diluted levetiracetam., Measurements and Main Results: A total of 776 levetiracetam doses were included, 358 doses administered and 418 doses wasted. The doses administered (61 undiluted and 297 diluted) accounted for a total of 252 patients (39 received undiluted, and 213 received diluted levetiracetam) (median [minimum-maximum range] age, 2 years [1 day to 32.7 years]; mean (standard deviation [SD]) weight, 20.1 kg [22.1 kg]). The incidence of hemodynamic disturbances and infusion-related reactions was not statistically significant between undiluted (24.6%) and diluted (26.3%) groups (p = 0.87). The median (interquartile range [IQR]) time difference between first-line antiseizure medication and levetiracetam administration in patients with status epilepticus was 18 min (10.5-30.5) in the undiluted group versus 36.5 min (21.8-67.3) in the diluted group (p < 0.01). Additionally, there was a significant amount of drug waste from dispensed but not administered doses of the diluted bag compared to undiluted vials (57.6% diluted vs. 18.7% undiluted, p < 0.001)., Conclusion: Undiluted levetiracetam was not associated with an increased incidence of adverse effects compared to diluted levetiracetam in high-doses, up to 4500 mg given over 5 min in pediatric patients., (© 2023 Pharmacotherapy Publications, Inc.)

Purpose: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy)., Results: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy., Conclusion: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option., Competing Interests: Conflicts of Interest FJE Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T O’Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P Perucca is supported by the Australian National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation. He has also received speaker honoraria or consultancy fees given to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. JE Graham, AA Hitchcock, CM Lander, and MJ Eadie have no relevant conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Side effects of antiepileptic drugs vary depending on the drug itself, drug dose and duration of use. One of these side effects is related to vision., Methods: Patients who had been ordered visual evoked potential (VEP) measurements for various reasons between October 1 st , 2017 and October 1 st , 2019 at a pediatric neurology outpatient clinic and who were on levetiracetam monotherapy for at least six months for the treatment of focal/generalized epilepsy were included in the study and their files were scanned retrospectively (study group: SG). Patient files were evaluated for age, gender, dose and duration of levetiracetam use, presence of a family history of epilepsy, EEG result, cranial magnetic resonance imaging and VEP test results and the parameters were recorded. Twenty-four patients of similar age range without epilepsy were included in the study as the control group (CG)., Results: Eighteen patients 8 boys (44.4%), 10 girls (55.6%) and 24 healthy controls 9 boys (37.5%), 15 girls (62.5%) were included in the study and control groups, respectively. No statistically significant difference was found when the mean VEP latencies were compared between the patient and control groups for the right (P=0.451) and left (P=0.323) eyes. There was a statistically significant difference between the groups, respectively, when VEP amplitudes of the right and left eyes of the SG and CG were compared (P=0.001; P=0.001). There is no correlation between levetiracetam dose and duration of treatment and VEP parameters., Conclusions: The data obtained in this study showed that levetiracetam use affected VEP amplitude outcome but did not affect VEP latency outcome in pediatric patients.

Purpose: Levetiracetam is an antiepileptic drug known for its high tolerability, and severe adverse drug reactions are rare. We report the case of a severe cutaneous adverse drug reaction in a patient who was switched from brand-name to generic levetiracetam., Summary: A 29-year-old woman undergoing contrast-enhanced computed tomography developed lesions over her trunk starting 6 hours after imaging. Although initially diagnosed as an allergy to the radiocontrast agent, the condition progressively worsened into toxic epidermal necrolysis-drug reaction with eosinophilia and systemic symptoms overlap syndrome, despite adequate hydration and treatment. Investigation of the patient's medications revealed that she had been switched from brand-name to generic levetiracetam a week before the onset of symptoms. Levetiracetam was immediately discontinued, with the patient recovering after 2 weeks of intensive care. Adverse drug reaction analysis identified excipients in generic levetiracetam as the likely cause of the severe reaction., Conclusion: This is the first reported case of severe cutaneous drug allergy after a brand-to-generic switch for levetiracetam. Brand-to-generic switches of medications can potentially cause severe allergic reactions due to differences in excipients., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND Trimethoprim/sulfamethoxazole and levetiracetam are commonly prescribed medications in the treatment of infections and seizures, respectively. Despite their known efficacy, each has a reputation for triggering severe and sometimes life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Although the mechanism of such cutaneous adverse drug reactions cannot be fully explained, it is thought to be a type IV T cell and NK cells-mediated hypersensitivity reaction that leads to keratinocyte apoptosis and epidermal necrosis. It is also thought that cutaneous adverse drug reactions are also linked to a patient's genetic predispositions, especially the human leukocyte antigens profiles and the N-acetyl transferase 2 phenotypic variation. CASE REPORT We describe a case of Stevens-Johnson syndrome in a severely ill 51-year-old man who was treated in an outside health care facility simultaneously with Trimethoprim/sulfamethoxazole and levetiracetam. The patient presented to our Emergency Department with Stevens-Johnson syndrome believed to possibly be related to the combination of these 2 agents. CONCLUSIONS The concomitant use of Trimethoprim/sulfamethoxazole and levetiracetam might have been responsible for heightening the potential of these 2 medications to trigger an unfortunate adverse drug reaction, but no formal culprit was able to be identified and no in vivo study was performed, due to ethical considerations. Thus, through this case report we strive to increase awareness of the potential risk of simultaneously prescribing these 2 medications.

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., Competing Interests: There are no conflicts of interest., (© 2024 Feriha Hadzagic Catibusic, Sajra Uzicanin, Emina Vukas Salihbegovic, Zinka Huseinbegovic.)

Objective: Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment., Methods: This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately., Results: There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval [CI] = 1.43-6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48-4.47) compared to a nonexposed cohort., Significance: Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Levetiracetam is widely used in post-stroke epilepsy. However, it is suspected to possess P-glycoprotein (P-gp) induction properties, and therefore, a potentially significant interaction with direct oral anticoagulants (DOACs). We aimed to search for ischemic stroke signals with levetiracetam and the DOACs., Methods: In this retrospective pharmacovigilance study, we used the FAERS database to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the adjusted reporting odds ratio (adjROR) and the lower bound of the shrinkage 95% confidence interval. When shrinkage is positive, an increased risk of a specific adverse event occurrence is emphasized over the sum of the individual risks when these same drugs are used separately., Results: We identified 1841 (1.5%), 3731 (5.3%), 338 (4.9%), and 1723 (1.3%) ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. The adjROR of the interaction effect was 3.57 (95% CI 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. A significant signal in the classical enzyme inducer, carbamazepine, strengthened our results (adjROR; 8.47, 95% CI 5.37-13.36)., Conclusions: Our study shows a strong signal for the levetiracetam interaction with the DOACs. Our findings suggest implementation of a drug monitoring strategy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Kappa opioid receptor (KOR) agonists have anticonvulsant effect but their antiepileptogenic effect is unknown. U50488, a selective KOR agonist is used to determine its effect on status epilepticus (SE), spontaneous convulsive seizures (SS) and cognitive impairment in rat lithium-pilocarpine SE model. Effect of an antiepileptic drug levetiracetam is also studied., Method: Male Wistar rats with SE were divided into three groups namely, LiP, LiP + U50488 (10 mg/kg, i.p.) and LiP + levetiracetam (400 mg/kg, i.p.) group. SE was terminated after 90 min of its onset with diazepam (15 mg/kg, i.p.) and phenobarbitone (25 mg/kg, i.p.). Drug treatment was started after 15 min of onset of SE and repeated once after 4 h. Rats were video monitored 12 h daily (9 AM to 9 PM) to determine severity of SE using modified Racine scale and onset and frequency of SS from day 0 to day 21. Morris water maze (MWM) test was done at baseline i.e. day -1 (before lithium administration) and day 22, to assess cognitive impairment., Results: As compared to LiP, U50488 decreased the severity of SE (1.98 ± 0.13 vs 2.95 ± 0.12; p-value < 0.0001) but not levetiracetam (2.62 ± 0.09; p-value = 0.3112). Survival increased with both U50488 (90%, n = 10) and levetiracetam (81.8%, n = 11) as compared to NS (56.2%, n = 16). No effect on onset and frequency of SS was found in U50488/levetiracetam group. U50488 improved seizures-induced cognitive impairment. Levetiracetam group showed thigmotactic (wall hugging) behaviour in MWM in 8 out of 9 rats., Conclusion: Acute treatment with U50488, a kappa opioid receptor agonist has a beneficial effect on SE, SE-related mortality and memory impairment. The dual protective effect of U50488 on seizures and related cognitive impairment is advantageous over currently used antiseizure drugs which are known to cause cognitive impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Lacosamide and levetiracetam are antiseizure medications (ASMs) commonly utilized in the treatment and prevention of seizures. Historically, these agents have been administered as slow IV infusions after further dilution. Recent literature suggests that rapid administration via undiluted IV push may be safe and may increase efficiency of administration. Objective: This study aimed to evaluate the safety and tolerability of undiluted IV push lacosamide and levetiracetam over 5 min. Methods: This study was conducted as a single-centered, retrospective, observational cohort that analyzed the rapid administration of undiluted lacosamide and levetiracetam. Adult patients admitted from September 1st, 2019, to May 31st, 2020, receiving at least one administration of IV push lacosamide at any dose or levetiracetam at doses ≤ 1500 mg were evaluated. The primary safety outcomes were the incidence of hypotension and bradycardia. Results: A total of 86 subjects were evaluated; 36 patients were administered lacosamide, and 50 patients were administered levetiracetam. Hypotension or bradycardia occurred in 6 patients in the lacosamide group (16.6%) and 6 patients in the levetiracetam group (12.0%). There were no reported infusion site reactions. Among the subjects who received lacosamide and had a 12-lead electrocardiogram (EKG), there were no reported incidences of a prolonged PR interval. Conclusions: In this safety-analysis cohort, undiluted lacosamide and levetiracetam were not associated with significant adverse events when administered via IV push over 5 min. This seems to be a safe alternative method of administration to intermittent infusion. A larger, prospective cohort is needed to confirm these findings.

Background: Levetiracetam is a commonly used anti-seizure medication, with the development of neuropsychiatric symptoms being the most common side effect. Preliminary literature describes the improvement of these symptoms with pyridoxine, mostly within the pediatric population. However, randomized control trial data investigating this relationship is sparse., Objective: The objective of this study was to critically assess evidence regarding the role of pyridoxine in the treatment of neuropsychiatric symptoms from levetiracetam., Methods: The objective was addressed through the development of a structured, critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, medical librarians, clinical epidemiologists, and content experts in the field of epilepsy., Results: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared pyridoxine versus placebo for the treatment of neuropsychiatric symptoms from levetiracetam in a pediatric population and included 105 patients (46/105 received pyridoxine, 59/105 received placebo). It found that both groups had a significant reduction in behavioral symptoms at the 2-,4-and 6-week time points ( P <0.05). However, the authors noted that the pyridoxine group had almost double the relative reduction when compared with the placebo group at all time points: 1.9 at 2 weeks, 2.0 at 4 weeks, and 1.8 at 6 weeks ( P =0.001)., Conclusions: This study suggests that pyridoxine for the treatment of levetiracetam-induced behavioral side effects may result in modest improvement, although many limitations prevent conclusive results. There remains a need for a double-blinded, randomized control trial in both the adult and pediatric populations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To elucidate the incidence and risk factors for paradoxical effects (i.e., increased seizure frequency, increased seizure severity, or onset of new seizure types) of levetiracetam (LEV) in people with epilepsy (PWE) and identify the usefulness of electroencephalography (EEG) in predicting these effects., Methods: We examined data for consecutive PWE treated with LEV. All PWE underwent EEG and magnetic resonance imaging (MRI) before LEV administration. We also evaluated the incidence of paradoxical LEV effects and conducted multivariate logistic regression analyses to identify the associated factors., Results: In total, 210 (66.2%) of 317 PWEs treated in our department had a history of LEV use. The incidence of paradoxical LEV effects was 5.2% (n = 11) and was significantly associated with a high LEV dose (p = 0.029), high seizure frequency (p = 0.005), temporal lobe epilepsy (p = 0.004), focal awareness seizure (p = 0.004), focal impaired awareness seizure (p = 0.007), spike (p = 0.015), rhythmic epileptiform discharges (REDs; p = 0.003), and MRI-identified focal cortical dysplasia (FCD; p < 0.0001). Multivariate analyses revealed that REDs (odds ratio [OR] = 5.35, p = 0.048, 95% confidence interval [CI]: 1.01-28.21) were independently associated with paradoxical LEV effects., Conclusions: Paradoxical LEV effects occurred in PWE, particularly in those with drug-resistant focal epilepsy. Furthermore, the occurrence of REDs in EEG was an independent factor associated with the paradoxical effects of LEV in PWE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To identify pediatric patients who require therapeutic drug monitoring (TDM) of levetiracetam (LEV)., Methods: We retrospectively investigated 2413 routine therapeutic drug monitoring data on serum LEV concentration from 1398 pediatric patients (age, 0-15 years). Samples were grouped by age (infants, < 1 year; preschool children, 1-5 years; primary school children, 6-11 years; and adolescents, 12-15 years), and the LEV concentration-to-dose (CD) ratio was calculated., Results: The mean CD ratio was highest in adolescents (analysis of variance, p < 0.001); 22.5 % and 15.7 % higher in adolescents than in preschool children and school children, respectively (Scheffé test, p < 0.001); and higher in infants than in preschool children. Preschool children had the lowest ratio and tended to show an increase in the ratio from age 2 to 5 years. Use of enzyme-inducing antiseizure medication reduced the CD ratio by 6.1 % in infants, 12.2 % in preschool children, 5.9 % in primary school children, and 9.4 % in adolescents. The mean CD ratio was 2.7 %, 26.9 %, and 39.3 % higher in preschool children, primary school children, and adolescents with defined chronic kidney disease (CKD) than in the respective age group of patients without CKD. The therapeutic concentration range for a long-term LEV therapy was 11 to 32 μg/mL., Conclusions: LEV pharmacokinetics are significantly different between infant and preschool children, so TDM of LEV is clinically useful in these patients. In pediatric patients at higher risk for CKD, glomerular filtration rate and LEV levels should be carefully monitored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Patients with epilepsy often show treatment-related psychiatric symptoms. Among the novel antiseizure medications (ASM), Perampanel (PER), Levetiracetam (LEV), and Topiramate (TPM) have been reported to have a relatively high frequency of psychiatric adverse events. However, these psychiatric symptoms are not identical; PER and LEV show adverse events of irritability and aggression, while TPM shows typical symptoms of depression and schizophrenia. It is important to understand the characteristics of these psychiatric adverse events to design appropriate treatment regimens for epileptic patients. (Received August 1, 2022; Accepted December 24, 2022; Published April 1, 2023).

Granulomatous interstitial nephritis (GIN) is a type of tubulointerstitial nephritis characterised by tubulointerstitial infiltration of mononuclear cells and eosinophils. It accounts for about 6% of all tubulointerstitial nephritis and is detected in ∼0.5%-0.9% of all renal biopsies. GIN has been linked to several antibiotics, non steroidal anti-inflammatory drugs (NSAIDs), and granulomatous disorders like tuberculosis and sarcoidosis but is rarely reported with anti-epileptic medications like phenytoin and levetiracetam. We present a case report of a man in his early 20's with previously normal renal function who developed GIN following levetiracetam and phenytoin consumption for 7 years. After withdrawal of the causative drug and starting steroid therapy, his kidney function gradually improved. In cases of GIN, medication history is important in the evaluation of aetiology., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The management of epilepsy during pregnancy requires optimal seizure control, avoiding the potential teratogenic effects of antiepileptic drugs., Objectives: This study aims to describe the clinical characteristics and perinatal outcomes of pregnant patients with epilepsy; to analyse the factors associated with seizures during pregnancy; to describe the most commonly used antiseizure drugs in these patients; and to analyse changes in treatment regimens in 2 periods, 2000-2010 and 2011-2018., Methods: We conducted a prospective observational study of patients with epilepsy who reported their pregnancy between 2000 and 2018. Patients were evaluated in the first and second trimesters of pregnancy, after delivery, and at one year. Data were collected on demographic variables, epilepsy, and perinatal and obstetric variables., Results: A total of 101 pregnancies were included. Patients' mean age was 32.6 years; 55.4% had focal epilepsy, 38.6% had generalised epilepsy, and 5.9% had undetermined epilepsy. We recorded 90 live births, 9 miscarriages, and 5 cases of congenital malformations, 4 of which were born to women who received valproate monotherapy. Forty patients (39.6%) presented seizures, with 16 (40%) presenting generalised tonic-clonic seizures. The variables associated with seizures during pregnancy were poor seizure control in the year prior to pregnancy (66.7% vs 15.1%; P < .001), treatment with 2 or more antiseizure drugs (30% vs 14.8%; P < .001), and untreated epilepsy (25% vs 0%; P < .001). Antiseizure medications most widely used in monotherapy were lamotrigine (n = 19; 27.1%), valproate (n = 17; 24.2%), and levetiracetam (n = 12; 17.1%). In the most recent period (2011-2018), we observed a greater proportion of patients receiving monotherapy (81.5%, vs 55.3%), as well as a decrease in the use of carbamazepine (2.3%, vs 23.1%) and valproate (20.5%, vs 30.8%); and a marked increase in the use of levetiracetam (27.3%, vs 0%)., Conclusions: The factors associated with the presence of seizures during pregnancy were previous poor seizure control, treatment with 2 or more antiseizure drugs, and lack of treatment during pregnancy. The most commonly used drugs were lamotrigine, valproate, and levetiracetam, with an increase in levetiracetam use and a decrease in valproate use being observed in the later period (2011-2018)., (Copyright © 2020 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B 6 (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019., Methods: An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool., Results: Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed "significant" improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN., Conclusion: Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Study Objectives: The objective of this study was to identify the incidence of levetiracetam-associated BAEs in NCC patients., Design: Single-center retrospective cohort analysis., Data Source: Patient charts., Patients: 965 adult ICU patients with a neurological injury receiving levetiracetam that were admitted to an intensive care unit., Measurements and Main Results: There were 965 patients included; 52% males with a median GCS of 13. Injury types included TBI (43.1%), ICH (21.8%), SAH (20.5%), and CI (14.6%). BAEs were identified in 46% of patients. Of these, 60% had documentation of agitation/restlessness, delirium, or anxiety while receiving levetiracetam, only 25% had a positive CAM-ICU, 13% had restraints ordered, and 42% received antipsychotics. Patients with TBI had the highest incidence of BAEs (52.4%). The median time to initiation of levetiracetam after hospital admission was 6.4 hours and BAEs occurred after 1.3 days of levetiracetam initiation., Conclusions: In this study, we found that almost half of our NCC population experienced levetiracetam associated BAEs which were mostly hyperactive in nature. We believe that the incidence of BAEs in our specific patient population cannot solely be attributed to ICU delirium given the lower risk of developing hyperactive delirium in ICU patients as compared to other subtypes. Therefore, monitoring and determination of the benefit versus risk in those experiencing BAEs is highly encouraged., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Competing Interests: Competing interests: None declared.