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Awake craniotomy is an established procedure for resecting brain tumors in eloquent lesions, and intraoperative seizure is one of the most important complications. Phenytoin is normally used to control intraoperative seizures. Recently, phenytoin was replaced with levetiracetam at our institution because the latter has fewer side effects. While the phenytoin dose is calibrated in accordance with the serum concentration, there is currently no consensus on a method of monitoring the serum concentration of levetiracetam or the effective concentration range needed to control intraoperative seizures during awake craniotomy. The present study therefore aimed to determine whether monitoring the serum levetiracetam concentration is useful for controlling intraoperative seizures during awake craniotomy. The intraoperative serum concentration of levetiracetam during awake craniotomy was measured in 34 patients and compared with that of phenytoin in 33 patients undergoing the same procedure. The levetiracetam concentration inversely correlated with body surface area (BSA) and estimated glomerular filtration rate (eGFR). Levetiracetam was superior to phenytoin in terms of the correlation between the serum concentration and the dose adjusted for BSA and eGFR (correlation coefficient, 0.49 vs 0.21). Furthermore, the serum levetiracetam concentration in patients with intraoperative seizures was below the 95% confidence interval (CI) of the regression line whereas the serum phenytoin concentration of two patients with seizures was within the 95% CI, indicating that evaluating the serum levetiracetam concentration against the BSA and eGFR-adjusted dosage may be useful in preventing intraoperative seizures during awake craniotomy by allowing prediction of the seizure risk and enabling more accurate dosage calibration., 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 © 2021 Elsevier Ltd. All rights reserved.)

Objective: Many nutrients essential to the fetus and for proper function of the placenta itself cannot freely diffuse across membrane barriers, and their transplacental transfer depends on transporters. Our previous studies provided evidence for altered expression of transporters for folic acid in trophoblasts exposed to antiseizure medications (ASMs). The goal of the current study was to explore the effects of older and newer ASMs on the expression and function of uptake transporters for choline, which interacts with folate at pathways for methyl group donation., Methods: BeWo cells were incubated for 2 or 5 days with valproate (42, 83, or 166 µg/ml), carbamazepine (6 or 12 µg/ml), levetiracetam (10 or 30 µg/ml), lamotrigine (3 or 12 µg/ml), lacosamide (5, 10, or 20 µg/ml), or their vehicles (n = 6/treatment group). Quantitative polymerase chain reaction (PCR) analysis was utilized to study the effects of ASMs on the transcript levels of the choline transporters SLC44A1 (CTL1) and SLC44A2 (CTL2). Transporter protein expression in valproate-treated cells was assessed by western blot analysis. Choline and acetylcholine were quantified in cell lysates by a choline/acetylcholine assay kit., Results: Compared with controls, valproate and levetiracetam at high therapeutic concentrations (83 and 30 µg/ml, respectively) lowered choline transporter transcript levels by up to 42% and 26%, and total choline levels by 20% and 21%, respectively (p < .05). At 83 μg/ml, valproate additionally reduced CTL1 and CTL2 protein expression, by 39 ± 21% and 61 ± 13% (mean ± SD), respectively (p < .01). Carbamazepine reduced SLC44A1 transcript levels, whereas lacosamide modestly decreased the expression of SLC44A2. Lamotrigine did not alter choline transporter expression., Significance: Antiseizure medications, particularly at high therapeutic concentrations, can interfere with the placental uptake of choline. In line with current knowledge from pregnancy registries and clinical studies, the present in vitro findings further support careful adjustment of maternal ASM doses during pregnancy., (© 2021 International League Against Epilepsy.)

Background: Levetiracetam is a relatively new-generation antiseizure drug approved for the treatment of focal and generalized seizures. Despite its favorable side effect profile and minimal drug-drug interactions, neuropsychiatric side effects are reported in up to 13% of children. A few case series have suggested that supplementation of pyridoxine may mitigate these side effects, but controlled trials are lacking. To address this issue, a randomized interventional study was carried out in a pediatric tertiary hospital to qualify and quantify the potential beneficial effect of pyridoxine in attenuating the neuropsychiatric side effects of levetiracetam in children., Methods: A total of 105 children with epilepsy who were taking levetiracetam (as a monotherapy or an adjunct) who showed behavioral symptoms coinciding with the start of levetiracetam, were included. Patients randomly and blindly received either a therapeutic (pyridoxine group, 46 of 105, 44%) or a homeopathic dose of pyridoxine (placebo, 59 of 105, 56%). A 30-item behavioral checklist was used to qualify and quantify the behavioral side effects at baseline and at different time points following initiation of treatment., Results: Both placebo and pyridoxine groups experienced a statistical reduction in behavioral scores when compared with baseline. Our study indicated that although there was a placebo effect, the improvement in neuropsychiatric symptoms was more prominent in children who received therapeutic doses of pyridoxine., Conclusions: These data provide clinicians with pertinent evidence-based information that suggests that a trial of pyridoxine in patients who experience behavioral side effects due to the use of levetiracetam may avoid unnecessary change of antiseizure medications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE., Methods: This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is "continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance." In both groups, diazepam is initially administered at 1-20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000-3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes., Discussion: The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application., Trial Registration: Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019.

Introduction: Visuospatial abilities are fundamental for good school achievements and good daily functioning. Previous studies showed an impairment of visuospatial skills in pediatric patients with epilepsy; pharmacological treatment, although indispensable for the seizure control, could further affect cognitive functions. The aim of our study was to evaluate the visuospatial skills in children and adolescents with different forms of epilepsy well-controlled by antiseizure monotherapy, both at baseline and after one year follow-up, through a standardized neuropsychological assessment., Methods: We recruited 207 children and adolescents (mean age = 10.35 ± 2.39 years) with epilepsy, well controlled by monotherapy with levetiracetam, valproic acid, ethosuximide, oxcarbazepine or carbamazepine and 45 age/sex-matched controls. All the participants performed the Rey-Osterrieth Complex Figure, a standardized test for visuospatial perception and visuospatial memory assessment, at baseline and after 12 month of drug therapy. Age, sex, executive functions, non-verbal intelligence, age at onset of epilepsy, epilepsy duration, epilepsy type, lobe and side of seizure onset were considered in our analysis. EEG, seizure frequency, and drug dose were also recorded., Results: At baseline, the epilepsy group performed significantly worse than controls in the Immediate Recall test but not the Direct Copy test, without differences between epilepsy subgroups. Immediate Recall scores were related to age of seizure onset and epilepsy duration and executive functions. The re-assessment after 1 year showed that the Immediate Recall mean scores were not significantly changed in the levetiracetam and oxcarbazepine group, while they significantly worsened in the valproic acid, ethosuximide and carbamazepine groups. The Immediate Recall scores were correlated to age, age at onset of epilepsy, epilepsy duration, and executive functions., Conclusions: Children with epilepsy may exhibit visuospatial memory impairment compared to their peer, that may be correlated to some features of the epilepsy itself and to the impairment of executive functions. Different antiseizure medications can affect visuospatial memory differently, so it is important monitoring this aspect in pediatric patients., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

We present a 75-year-old man who was admitted to our hospital due to 4 months of general deterioration, gait disturbance and cognition impairment which appeared very close to the start of levetiracetam (LEV) as a new antiepileptic drug. Brain CT shows central and less peripheral atrophy of brain, and diagnosis of normal pressure hydrocephalus was raised; however, removal of 30 cc of cerebrospinal fluid (CSF) by lumbar puncture in order to amend walking did not lead to gait improvement. After excluding metabolic, vascular, infection, inflammatory and other reasons explaining his status. Thinking that may be any correlation between LEV added in the last months and his clinical condition, we stopped LEV. Several days after that, there is marked improvement in his general sensation, alertness and cognitive status and there is marked improvement in walking balance to the point of being able to walk without the use of walker or cane or help from other person. Certain cognitive impairment and gait difficulties are not known as side effects of LEV treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We experienced 3 adult patients with intractable focal epilepsy treated by levetiracetam (LEV) as polytherapy, who showed paradoxical effect (PE). Starting dose of LEV was small (62.5, 250 mg/day) and we gradually increased by less than 250 mg/day, every more than 2 weeks. Within 6 months after LEV was added, LEV of 750 to 1,000 mg/day brought reduction of seizure frequency. Serum concentration of LEV was 13.3 and 14.0 μg/ml. In order to obtain better seizure control, LEV was increased up to 1,000-2,500 mg/day (19.3-35.0 μg/ml) within one year, and they developed PE. They all showed increased habitual seizures, occurring in cluster. Once dose of LEV deceased down to what produced the maximum seizure suppression, all of the patients regained the better seizure control. It is most likely that at least in some patients like present 3 cases, PE of LEV may express U curve association between dose and effect and that it was only delineated by slow titration.

Importance: Prolonged seizures are life-threatening emergencies associated with significant morbidity., Objective: To determine the efficacy and safety of levetiracetam in treating convulsive status epilepticus (CSE) in childhood., Data Sources and Study Selections: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature were searched from inception up to April 2020. Only randomised controlled trials (RCTs) that included children aged 1 month-18 years were assessed. Two reviewers performed data assessment and extraction., Data Extraction and Synthesis: Ten studies out of the 20 637 citations identified were included., Main Outcomes: Cessation of seizure activities, time to cessation of seizure activities, need for rapid sequence intubation (RSI), intensive care unit (ICU) admission, recurrence of seizures at 24 hours, adverse events and all-cause mortality., Results: We included 10 RCTs (n=1907). There was no significant difference in cessation of seizure activities when levetiracetam was compared with phenytoin (risk ratio (RR)=1.03, 95% CI 0.98 to 1.09), levetiracetam to fosphenytoin (RR=1.16, 95% CI 1.00 to 1.35) or levetiracetam to valproate (RR=1.10, 95% CI 0.94 to 1.27). No differences were found in relation to the timing of cessation of seizures for levetiracetam versus phenytoin (mean difference (MD)=-0.45, 95% CI -1.83 to 0.93), or levetiracetam versus fosphenytoin (MD=-0.70, 95% CI -4.26 to 2.86). There were no significant differences with regard to ICU admissions, adverse events, recurrence of seizure at 24 hours, RSI and all-cause mortality., Conclusion: Levetiracetam is comparable to phenytoin, fosphenytoin and valproate as a second line treatment of paediatric CSE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study aims to identify the determinants of cognitive dysfunction and compare the effect of CPZ and LTC on cognition in WWE., Methods: An observational study involving 87 consenting adult WWE aged between 16 and 40 years on LTC or CZP monotherapy. At enrollment, an interviewer-based questionnaire was used to obtain demographic and clinical information from participants. The diagnosis of epilepsy was mainly clinical and supported by electroencephalographic (EEG) features and classified based on recommendation by the 2017 International League Against Epilepsy (ILAE). Zung Self-Reporting Depression Scale (ZSRDS) was used to assess the mood of participants. The Community Screening Interview for Dementia (CSID) was used to assess various cognition domains. The National Hospital Seizure Severity Scale (NHS-3) was used to assess disease severity., Results: There were statistical differences between the CZP and LTC groups in all domains of cognition assessed except for orientation. The total CSID scores of the LTC group were 59.2 (4.9) as opposed to CZP group, 57.2 (5.0); p: .005. Those with focal onset seizures had lower median total CSID score (58; IQR: 54-62) when compared to those with generalized onset seizures (62; IQR: 58-62), p: .012. There was a significant correlation between ZSRD score and NHS-3 score; rho: 0.30, p: .007. Bivariate analysis shows statistically significant correlation between total CSID score and ZSRDS (rho: -0.65), BMI (rho: 0.22), and NHSS-3 score (rho: -0.36), respectively. However, the effect of AED on CSID scores was lost after multivariate quantile regression with only ZSRDS retaining significance., Conclusion: Depression, seizure severity, type and structural etiology were associated with cognitive impairment among WWE. However, on regression model, only depression was statistically significant. The presence of more risks for cognitive impairment in the CZP group limits possible conclusion of LTC superiority., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective: The study is aimed at comparing effects of older drugs like carbamazepine (CBZ) and newer agent like levetiracetam (LEV) on polycystic ovarian syndrome (PCOS) in women with epilepsy (WWE)., Methods: An interviewer-based questionnaire was used to obtain relevant clinical information from 50 WWE on CBZ and LEV monotherapy, respectively, and 50 age-matched controls. The diagnosis of epilepsy was clinical with electroencephalographic features taken into consideration and the seizures classified using the 2017 International League Against Epilepsy classification. The diagnosis of PCOS was based on the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine., Results: The frequency of PCOS and its subcomponent were higher among WWE compare to controls. PCOS was present in 22 (44%) of LEV group compare to 8 (16%) CBZ group. The frequency of its subcomponent was higher among those on LEV except for comparable effect with regard to oligomenorrhea. The levels of the sex steroid hormone were comparable in both groups of WWE except luteal phase luteinizing hormone, which was lower among the LEV group (P .001). The follicular phase estradiol level was lower (P .021), and follicle-stimulating hormone level was about 2-fold higher (P .03) among WWE compare to controls. The mean value testosterone was significantly lower among controls compared to WWE., Conclusions: The increased frequency of PCOS and its subcomponent and the unsatisfactory effect of LEV compared to CBZ on reproductive endocrine function underscore the need for routine reproductive endocrine evaluation to improve overall quality of life., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It is challenging to balance the fetal risks associated with the use of antiepileptic drugs (AEDs) against maternal and fetal risks of seizure worsening, and therefore it is very important to define and distinguish the possible risks entailed by different AEDs. This paper aims to undertake a comprehensive review regarding the possible risks of four classical (phenytoin, carbamazepine, phenobarbital, and valproate) and two newer (lamotrigine and levetiracetam) AEDs during pregnancy. The review focuses on major and organ-specific malformations, dose-dependent risks, mono vs polytherapy, and clinical pharmacokinetics. A discussion regarding the safety of AED use during breastfeeding is also provided., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Antiseizure medications (ASMs) can rarely result in severe, sometimes fatal, cutaneous adverse reactions. To date, few studies have reported on the incidence rates (IRs) of severe cutaneous adverse reactions (SCARs) due to ASM use. This study aimed to determine the IRs of SCAR resulting from the use of seven commonly prescribed ASMs, carbamazepine (CBZ), phenytoin (PHT), oxcarbazepine (OXC), lamotrigine (LMT), zonisamide (ZNS), levetiracetam (LVT), and topiramate (TPM), and to compare the associated risks among the drugs., Methods: Using a nationwide health claims database, we selected all the patients prescribed with one of the target ASMs. We defined a SCAR case as the first hospitalization with one of three specific codes provided by the International Classification of Diseases, 10th revision (L511, L512, and L27). We then calculated the IR of SCARs according to each target ASM., Results: The IR of SCARs for each ASM was as follows: 870/1 000 000 person-years (PYs) for CBZ, 5750/1 000 000 PYs for PHT, 1490/1 000 000 PYs for OXC, 3860/1 000 000 PYs for LMT, 1540/1 000 000 PYs for ZNS, 830/1 000 000 PYs for LVT, and 400/1 000 000 PYs for TPM. Concomitant use of antibiotics and nonsteroidal anti-inflammatory drugs significantly increased the risk of SCARs with OXC, LVT, or TPM use. Comorbid skin disease was associated with a significantly higher IR of SCARs from CBZ, PHT, OXC, LMT, or LVT use., Significance: This is the first study in Asia to determine the IRs of SCARs for various ASMs and compare the rates across drugs using a large dataset. The results from this study should help clinicians select safer ASMs in practice., (© 2020 International League Against Epilepsy.)

Background: Migraine is characterized by moderate to severe recurrent headache lasting for 4-72 h. Cortical hyperexcitability may play a crucial role in migraine onset. Therefore, antiepileptic drugs, such as levetiracetam, may be beneficial., Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective studies that evaluated the efficacy of levetiracetam in migraine prophylaxis. Electronic databases, including PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, were searched for articles on migraine prophylaxis and levetiracetam published before May 2020. The main outcomes were number of patients with >50% headache frequency reduction, frequency of headache, and headache severity., Results: We identified 4 RCTs involving 192 patients and 4 prospective studies involving 85 patients. The overall data on number of patients with >50% headache frequency reduction, headache frequency, and headache severity were subjected to meta-analysis, which revealed significant differences between the levetiracetam and the placebo groups (risk ratio [RR] of number of patients with >50% headache frequency reduction = 0.46, 95% confidence interval [CI] = 0.35 to 0.61; weighted mean difference [WMD] of headache frequency per month = -3.78, 95% CI = -5.52 to -2.03; standard mean difference [SMD] of headache severity = -2.42, 95% CI = -4.47 to -0.37)., Conclusion: Our study indicated that levetiracetam can significantly reduce headache frequency and severity in adults and children. Thus, oral levetiracetam can be a therapeutic option for migraine prophylaxis, especially concerning with the adverse effects or teratogenicity of other preventive treatments., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Levetiracetam and phenytoin are comparable for acute posttraumatic seizure(PTS) prophylaxis. Levetiracetam-induced hyponatremia has been reported in non-trauma patients. We studied hyponatremia in posttraumatic intracranial hemorrhage(ICH) patients receiving either drug., Methods: Retrospective review of patients with ICH receiving PTS prophylaxis was performed. Patients were categorized by degree of sodium nadir: normal, mild, moderate, or severe, and analyzed by levetiracetam versus phenytoin. Patients were matched 2:1 regarding age and injury severity score(ISS). Incidence and treatment for hyponatremia was examined., Results: 1735 ICH patients received PTS prophylaxis over an 8-year period. After exclusions and matching, there were 282 phenytoin and 564 levetiracetam patients. Age, ISS and initial sodium were comparable between the matched cohorts. There was no clinically significant difference in the rate or degree of hyponatremia. Treatment was more common in levetiracetam patients., Discussion: There was a small but clinically insignificant difference in the incidence of hyponatremia in traumatic ICH patients receiving levetiracetam vs. phenytoin for PTS prophylaxis. There was an increased rate of intervention for hyponatremia in the levetiracetam group, possibly due to a coincidental preventive paradigm shift., 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 © 2020 Elsevier Inc. All rights reserved.)

Background: Recent studies have shown conflicting results regarding the effectiveness of levetiracetam for treating benzodiazepine-refractory status epilepticus (SE) compared with phenytoin. Therefore, a meta-analysis was carried out to assess the value of levetiracetam versus phenytoin in the pharmacotherapy of benzodiazepine-refractory SE., Objective: The aim of this systematic review and meta-analysis was to compare the efficacy and safety of levetiracetam and phenytoin in the treatment of benzodiazepine-refractory SE., Methods: The MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that had been conducted to evaluate levetiracetam versus phenytoin for benzodiazepine-refractory SE, to April 2020. The data were assessed using Review Manager 5.3 software. The risk ratio (RR) was analyzed using dichotomous outcomes, and calculated using a random-effect model., Results: We pooled 1850 patients from 12 RCTs. Patients in the levetiracetam group had a significantly higher rate of clinical seizure cessation than in the phenytoin group (75.2% vs. 67.8%; RR 1.14, 95% confidence interval [CI] 1.05-1.25, p = 0.003). Moreover, less adverse events were observed in the levetiracetam group than in the phenytoin group (17.8% vs. 21.4%; RR 0.82, 95% CI 0.70-0.97, p = 0.02). In subgroup analysis, clinical seizure cessation was achieved more frequently with a higher dose of levetiracetam (> 30 mg/kg) [RR 1.15, 95% CI 1.00-1.32, p = 0.05]. Furthermore, in the subgroup of children, levetiracetam showed a higher rate of clinical seizure cessation than phenytoin (RR 1.13, 95% CI 1.02-1.25, p = 0.02)., Conclusion: Pharmacotherapy for BZD-refractory SE by LEV is superior to PHT in efficacy and safety outcomes.

Objective: To determine the pattern of treatment response in patients with idiopathic generalized epilepsy (IGE) and whether routinely assessed clinical and neurophysiological parameters allow predicting response to lamotrigine, levetiracetam, or valproic acid., Methods: In 328 adult patients with IGE, demographic data, imaging, EEG data, current and prior antiepileptic treatment, treatment outcome, and side effects were analyzed from the patients' medical files and patient interviews., Results: Seizure freedom with acceptable side effects at the first attempt was achieved in 61 (18.6%) patients. One hundred four (31.7%) patients tried ≥3 antiepileptic drugs before achieving seizure control at the last follow-up. Lamotrigine, levetiracetam, and valproic acid showed differential response rates (39.8% vs 47.5% vs 71.1%) that were most pronounced in patients with juvenile myoclonic epilepsy. The risk of having side effects was higher with valproic acid (23.7%) than with lamotrigine (10.4%) or levetiracetam (20.4%) treatment, contributing to the low retention rate of valproic acid (53.7%). Treatment resistance was associated with established risk factors. Multivariate analyses aiming at identifying clinical indicators for response to specific drugs did not reveal putative biomarkers when corrected for drug resistance., Conclusion: Despite a high rate of seizure control, the chance of achieving seizure control and acceptable side effects at first attempt was low due to an inverse association of effectiveness and side effects of the 3 most commonly used drugs. Routinely assessed clinical parameters were not indicative for response to specific drugs., Classification of Evidence: This study provides Class II evidence that for patients with IGE, various clinical factors do not predict a response to specific antiepileptic drugs., (© 2020 American Academy of Neurology.)

Background: To study the effect of levetiracetam in treating Sydenham chorea., Methods: We retrospectively collected the data of 140 patients diagnosed with Sydenham chorea in the pediatric neurology and pediatric cardiology outpatient clinics of Van Training and Research Hospital between January 2010 and December 2018., Results: There were 140 patients, 102 (70%) of whom were girls, with mean age of onset 11.8 ± 2.7 years. Symptomatic treatment was initiated in all patients at the time of diagnosis; this medication was changed during follow up in 15 patients. The most frequently prescribed drugs were haloperidol and sodium (Na) valproate, and the most frequently discontinued one was haloperidol, due to side effects. The second-choice drug was most often levetiracetam. Clinical response often began within the first 2 weeks, with Na valproate (P = 0.002), within 4 weeks with carbamazepine (P = 0.037) but 1-6 months with haloperidol (P = 0.018) and levetiracetam (P = 0.008). Time to full remission was similar with Na valproate, carbamazepine, haloperidol, and levetiracetam (P = 0.276). Our study indicated that levetiracetam was as effective as the other commonly used drugs in the symptomatic treatment of Sydenham chorea., Conclusion: Levetiracetam might be an option in the treatment of Sydenham chorea because of its acceptable effect and safety profile. This observation needs further support with evidence obtained through controlled and blinded trials., (© 2020 Japan Pediatric Society.)

Levetiracetam (LEV) has an improved pharmacological profile and is one of the most commonly used antiepileptic drugs (AEDs). However, associations between this pharmacological profile and behavioral side effects have been extensively reported in pediatric populations. We assessed behavioral changes after initiation of LEV, prescribed by the treating neurologist, in Chilean patients with epilepsy aged 4-15 years. A behavioral questionnaire was applied at baseline and at two, four, and twelve weeks of treatment. Thirty patients were enrolled: 16 males, 14 females, average age 8 years (range: 4-14). By week four, 23.3% of patients showed significant behavioral alterations that persisted throughout the observation period. No significant alterations emerged after four weeks in the remaining patients. Family history of psychiatric disease and prior behavioral difficulties were predisposing factors for adverse behavioral effects. Although previous studies associated adverse behavioral effects with LEV in pediatric patients with epilepsy, we believe that this is the first study to use a prospective methodology and standardized tools to quantify the symptomatology. Adverse behavioral effects may significantly affect quality of life for patients and families, diminishing the tolerability of treatment. To ensure successful therapy and improve medical decision-making, it is essential to consider predisposing factors for drug-related adverse effects and to regularly assess for behavioral alterations during treatment., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BACKGROUND Levetiracetam (LEV) is an anticonvulsant commonly used for treatment of generalized and partial seizure disorder. Some of the common side effects associated with levetiracetam include somnolence, dizziness, headaches, and mood changes. Rhabdomyolysis and increase in creatine kinase (CK) levels is one of the rarely reported effects of LEV. CASE REPORT We report a case of a 22-year-old man admitted for evaluation of new-onset generalized tonic-clonic seizures. The patient was started on levetiracetam 500 mg twice a day, after which his CK levels started to increase, with maximum level of 21 936 IU/L noted on day 5. No improvement in CK levels was observed even with aggressive intravenous hydration. In the absence of any other obvious cause, the persistent elevation in patient's CK levels was suspected to be due to LEV. Our suspicion was supported by significant decrease in CK levels (from 21 936 IU/L to 11 337 IU/L) after about 30 h of discontinuation of LEV. We reviewed cases of LEV-induced rhabdomyolysis reported in the literature over the last decade and found 13 cases with almost similar correlation between initiation of LEV and increase in CK levels. CONCLUSIONS Our case report stresses the importance of close monitoring of CK levels and kidney functions after initiation of LEV, and to consider changing the anticonvulsant medication if CK levels are noted to be significantly high to avoid kidney injury.

Objective Reversible splenial lesion syndrome (RESLES) is a clinical radiological syndrome characterized by a reversible lesion of the splenium of the corpus callosum with a decreased apparent diffusion coefficient (ADC) value. The clinical manifestations of RESLES are diverse. Methods Fifteen cases of adult RESLES patients (10 males and 5 females) were retrospectively selected from the radiology system using the key word "corpus callosum" at a university-affiliated tertiary care hospital between May 1, 2015 and December 31, 2019. The possible precipitating factors, clinicoradiological findings and modified Rankin Scale (mRS) on follow-up were then analyzed. Results The patient ages ranged from 22 to 53 years old. The mean age was 34 years old. The most common neurological symptoms included headache (3/15), dizziness (3/15), first onset of seizure (3/15), paroxysmal blurred vision (2/15), vertigo (2/15), amnesia (2/15), and confused consciousness without seizure (2/15), followed by drowsiness (1/15), paresthesia (1/15), dysmetria (1/15) and dysarthria (1/15). The precipitating factors included infection, seizure, anti-epileptic treatment with levetiracetam, carbamazepine, valproate, hyperglycemia, hypoglycemia, cerebral venous sinus thrombosis, and rabies vaccine injection prior to the onset of RESLES. All cases were carefully followed up and had excellent prognoses. Conclusion RESLES manifests as variety of symptoms with less specificity and precipitating factors. Paroxysmal blurred vision may be a relatively specific symptom of RESLES. Levetiracetam, carbamazepine or valproate could be the cause of RESLES, exposure to the rabies vaccine could be another predisposing factors for RESLES as well. RESLES type 1 was therefore found to be highly "reversible" with an excellent prognosis.

Introduction: Both levetiracetam (LEV) and brivaracetam (BRV) eliminate the electroencephalogram photoparoxysmal response (PPR) in the human phase IIa photosensitivity model of epilepsy. The physiochemical properties of BRV differ from those of LEV, having higher potency and lipophilicity plus 10- to 15-fold greater affinity for synaptic vesicle glycoprotein 2A., Objective: We compared the rapidity of the effects of both drugs in the central nervous system (CNS) of patients with photosensitive epilepsy using time to PPR elimination post-intravenous infusion as a pharmacodynamic endpoint., Methods: Using a randomized, double-blind, two-period, balanced, crossover design, we tested patients with photosensitive epilepsy with equipotent milligram doses of intravenous LEV 1500 mg versus BRV 100 mg post-15-min intravenous infusion (part 1) and post-5-min intravenous infusion (part 2, same doses). Eight patients per part were deemed sufficient with 80% power to determine a 70% reduction for intravenous BRV:LEV intrapatient time ratio to PPR elimination, with a 0.05 two-sided significance level. Plasma antiseizure medicine concentrations were measured using liquid chromatography/mass spectrometry., Results: Nine patients [six women; mean age 27.8 years (range 18-42)] completed the study; seven of these participated in both parts 1 and 2. In 31 of 32 instances, patients experienced PPR elimination. In mixed-effects model time analysis, BRV eliminated PPRs more quickly than did LEV (median 2 vs. 7.5 min, respectively). However, no statistically significant difference in BRV:LEV time ratio to PPR elimination was observed for two of our multiple primary outcomes: for the 15-min infusion alone (p = 0.22) or the 5-min infusion alone (p = 0.11). However, BRV was faster when we excluded an outlier patient in part 1 (p = 0.0016). For our remaining primary outcome, parts 1 and 2 data combined, the median intrapatient BRV:LEV time ratio was 0.39 [95% confidence interval (CI) 0.16-0.91], i.e., PPR elimination was 61% faster with BRV, p = 0.039. PPR was completely eliminated in ≤ 2 min in 11 patients with BRV and in four patients with LEV. No period or carryover effects were seen. No serious or severe adverse effects occurred. At PPR elimination (n = 16), median plasma [BRV] was 250 ng/mL (range 30-4100) and median plasma [LEV] was 28.35 μg/mL (range 1-86.7)., Conclusion: Outcome studies directly comparing LEV and BRV are needed to define the clinical utility of the response with BRV, which was several minutes faster than that with LEV., Clinical Trials: ClinTrials.gov Identifier = NCT03580707; registered 07-09-18.

Background: Prophylactic antiepileptic drugs (pAEDs) are often prescribed for seizure prophylaxis in patients undergoing surgical treatment of unruptured intracranial aneurysms (UIAs). We aimed to evaluate the benefit of pAEDs in patients undergoing surgical repair of UIAs., Methods: We randomly assigned eligible patients undergoing surgical repair of UIAs to receive levetiracetam for seven days post-operatively or standard care alone. The primary outcome was the evaluation of seizures in the perioperative period (within 4 weeks). We also evaluated seizure occurrence throughout follow-up and assessed functional outcomes using the modified Rankin scale score (mRS)., Results: 35 patients were randomized to the "no-levetiracetam" group and 41 patients were randomized to receive levetiracetam. The two study groups had similar overall baseline characteristics and the surgical complication rate was similar for both groups (p = 0.8). One patient in the "no-levetiracetam" group had a seizure in the perioperative period versus 2 patients in the group randomized to receive levetiracetam (2.9% vs 4.9%, respectively, p = 1.00). No patients in the "no-levetiracetam" group had any additional late seizures (mean follow-up of 20.4 months), but three patients in the levetiracetam group had late seizures during follow-up (mean follow-up of 19.1 months) (0% vs 7.3%, p = 0.2). mRS score of 0-2 at 90 days and at the latest follow-up were similar between the two groups (p = 1.00)., Conclusions: Perioperative seizure prophylaxis with levetiracetam does not reduce the rate of seizures as compared to controls in patients undergoing surgical repair of UIAs., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We performed observational cohort study to compare the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC), lamotrigine (LTG), and levetiracetam (LEV) monotherapy for newly diagnosed focal epilepsy patients., Methods: Three hundred and eighty eight newly diagnosed focal epilepsy patients aged 1-70 years were enrolled in this study between June 2009 and March 2016. Among the patients, 191 were treated with OXC, 98 were treated with LTG, and 99 were treated with LEV monotherapy. The study was performed in a real-world setting and the primary outcomes were the one-year and three-year seizure-free rates. The secondary outcomes were the one-year and three-year withdrawal rates, the time to treatment withdrawal, the time to the first seizure, and the time to achieve one-year remission., Results: The three-year seizure-free rates with LTG (39.8 %) and LEV (41.4 %) were significantly better than that with OXC (26.2 %) (both P < 0.05). However, no significant difference was observed among the three drugs for the one-year seizure-free rate. The three-year withdrawal rate was 50.8 %, 46.9 %, and 43.4 % for OXC, LTG, and LEV, respectively (all P > 0.05). The one-year withdrawal rate for OXC (31.7 %) was higher than those for LTG (30.6 %) and LEV (26.3 %) (all P > 0.05). LEV [Relative Risk (RR) = 0.69, 95 % CI: 0.49∼0.99] and LTG (RR = 0.63, 95 % CI: 0.44∼0.9) were significantly better than OXC in preventing first seizure. LEV appears to be the superior option with regard to the time to achieve one-year remission., Significance: The results of the study showed that LEV and LTG are significantly more effective than OXC for the treatment of newly diagnosed focal epilepsy. LEV has milder adverse events than OXC and LTG in clinical practice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Although phenytoin is one of the most commonly used antiepileptic drugs (AEDs), it has potential serious side effects and drug interactions. Levetiracetam is a relatively newer AED with favorable pharmacokinetics and could be an effective and safer option for the treatment of convulsive status epilepticus (CSE). We aimed to compare the efficacy and safety profile of intravenous levetiracetam and phenytoin as second-line treatment agents in children with CSE and acute repetitive seizures (ARS)., Method: Two hundred seventy-seven patients aged between 1 month and 18 years who received intravenous levetiracetam or phenytoin as a second-line AED with the diagnosis of CSE or ARS were retrospectively evaluated. Drug efficacy was defined as control of seizures without the need for any additional medication after completion of the infusion and no recurrence in the following 12 h. The primary outcome was drug efficacy. The secondary outcomes included application of an additional second-line AED, induction of anesthesia, and admission to the intensive care unit (ICU), and drug-related adverse reactions., Results: No differences were found between the two treatment groups with regard to patient characteristics and seizure type. The efficacy of levetiracetam was higher than that of phenytoin (77.6% vs 57.7%, P = 0.011) in children with CSE. There was no significant difference between the efficacy rates of levetiracetam and phenytoin for ARS (55.8% vs 58.8%, P = 0.791). Overall, drug efficacy was 70.9% for levetiracetam and 58.1% for phenytoin (P = 0.048). For CSE, the need for additional second-line treatment, anesthesia induction, and ICU admission was higher in the phenytoin group (P = 0.001, P = 0.038, P = 0.02, respectively). Drug-related adverse reactions were more frequent in the phenytoin group than the levetiracetam group (23.3% vs 1.4%; P < 0.001). The most common adverse reaction in the phenytoin group was hypotension. Phenytoin-related anaphylaxis was detected in one patient. No serious adverse effects related to levetiracetam were observed., Conclusions: Intravenous levetiracetam seems as effective as intravenous phenytoin in emergency treatment of children with ARS and more effective for CSE in stopping the seizure with less risk of recurrence. Levetiracetam has fewer cardiovascular side effects and has a safer profile than phenytoin. Intravenous levetiracetam is a favorable option as a first second-line AED for pediatric seizures., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods., Methods: A systematic review was conducted to identify RCTs that evaluated either one of perampanel or brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between perampanel and brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted., Results: Eight RCTs (four comparing perampanel to placebo, four comparing brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a significantly better responder rate compared to brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found., Conclusion: Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The study aimed to determine the frequency of metabolic syndrome (MetS) and obstructive sleep apnea syndrome (OSAS) in patients with epilepsy receiving monotherapy and the relationship between these syndromes and antiepileptic drugs (AEDs)., Methods: Two hundred and ninety-seven patients with epilepsy between the ages of 18-65 years receiving monotherapy for at least one year and 50 healthy participants were enrolled. Body mass indices and waist circumferences were measured. Serum fasting glucose levels, high-density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), triglyceride, and serum AED concentrations were noted. The frequency of MetS in patients with epilepsy was calculated. The snoring, tiredness, observed apnea, high blood pressure, body mass index, age, neck circumference, and male gender (STOP-Bang) questionnaire was used to determine the risk of OSAS. The relationship between these two syndromes and seizure type, disease duration, AED dosage, and treatment duration was analyzed., Results: Metabolic syndrome was more frequent in patients with epilepsy compared with healthy participants (32.6% vs. 12.0%), and it was diagnosed in 37.8% of patients receiving valproic acid (VPA), 36.1% of patients receiving carbamazepine (CBZ), 34.9% of patients receiving oxcarbazepine (OXC), and 30.5% of patients on levetiracetam (LEV). There was a positive correlation between VPA treatment duration and MetS existence (p < 0.05). However, MetS frequency did not change because of seizure type, disease duration, or AED dosages in patients with epilepsy receiving monotherapy. The risk for OSAS was higher in patients with epilepsy compared with healthy participants (24.6% vs. 12%), and it was calculated high in 27.7% of patients receiving CBZ, 32.2% of patients receiving LEV, and 30.2% of patients receiving OXC. The OSAS risk was higher in patients who have focal seizures than generalized seizures (p = 0.044). There was no relationship between OSAS risk and duration of epilepsy, duration of treatment, drug doses, and serum drug levels (p > 0.05)., Conclusion: Higher frequency of MetS and OSAS risk should be kept in mind on clinical follow-up of patients with epilepsy receiving monotherapy., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To examine central macular, RNFL (retinal nerve fibre layer), GCC (ganglion cell complex) thicknesses; and VEPs (visual evoked potential) in epileptic patients using levetiracetam for at least one year., Materials and Methods: Sixteen focal epileptic patients receiving levetiracetam monotherapy and 16 healthy subjects were included in the study. Central macular, RNFL and GCC thicknesses according to spectral domain OCT (optical coherence tomography); and VEPs parameters were compared between patients and healthy subjects., Results: The mean age of patient and control groups were 40 ± 16 and 38 ± 12 years respectively ( p  > 0.05). The patient group was on levetiracetam therapy for 64 ± 45 (12-168) months. Central macular thickness was thinner in the patient group ( p  = 0.008). There was no difference among groups regarding RNFL thicknesses. GCC thicknesses in all quadrants were similar among groups, except the superior quadrant; which was thinner in the patient group ( p  = 0.03). P100 amplitude in 30 min pattern was lower in the patient group ( p  = 0.04). N135 latency in 15 min ( p  = 0.03) and 7 min patterns ( p  = 0.01) was longer in the patient group., Conclusion: Central macular and GCC thicknesses; and VEP parameters in patients receiving levetiracetam treatment may differ from healthy subjects.

Objective: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated diseases characterized by an extensive loss of the epidermal skin layer, often resulting in death. SJS and TEN are often triggered by certain drugs, including antiepileptic drugs (AEDs). Epilepsy is very difficult to treat and often involves the combination of two or more AEDs. In this study, we quantified not only the risk of SJS or TEN associated with single-AED therapy but also the risk related to concomitant AED treatment using reporting-derived signals., Methods: An analysis of the Japanese Adverse Drug Event Report (JADER) database was performed from the first quarter of 2004 to the fourth quarter of 2018. The single-AED signals were evaluated using the proportional reporting ratio (PRR), and the combination therapy signals were evaluated using Ω shrinkage measure and combination risk ratio (CRR)., Results: SJS signals were associated with 11 AEDs, and TEN signals were related to 12 AEDs. Moreover, the following AED combinations were associated with SJS signals: carbamazepine-lorazepam (Ω 025 : 0.33, CRR: 2.18) and fosphenytoin-lorazepam (Ω 025 : 0.99, CRR: 39.20). The TEN signals were related to the following combinations: clobazam-gabapentin (Ω 025 : 0.35, CRR: 3.14), phenytoin-gabapentin (Ω 025 : 0.03, CRR: 2.18), valproic acid-gabapentin (Ω 025 : 0.15, CRR: 2.25), clobazam-clonazepam (Ω 025 : 0.03, CRR: 2.93), clobazam-valproic acid (Ω 025 : 0.29, CRR: 1.55), fosphenytoin-lamotrigine (Ω 025 : 0.05, CRR: 7.37), and lacosamide-levetiracetam (Ω 025 : 0.74, CRR: 1.85)., Significance: This study identified two AED combinations that increased the SJS signals and seven combinations that increased the TEN signals. Although AED monotherapies require attention for SJS and TEN, some AED combinations require extra caution., (© 2020 International League Against Epilepsy.)

Competing Interests: Declaration of Competing Interest None.

Objective: To identify clinical characteristics common among epileptic patients prescribed levetiracetam who report suicidal ideation or who exhibit suicidal behavior. A case is also provided that highlights the need for increased vigilance for neuropsychiatric sequelae in fragile epileptic patients prescribed levetiracetam, especially post dosage adjustment., Data Sources: PubMed was queried with no time limitation to December 2018 using a combination of controlled terms. Using the Boolean operators "AND" and "OR," the authors searched PubMed for case reports and case series on levetiracetam-related suicidal behavior. The search terms used were [levetiracetam] OR [Keppra] AND in combination with suicidal, suicide, suicidal ideation, suicide attempt, and suicidality., Study Selection: Relevant English-language human studies on levetiracetam and its effect on suicidal behavior were included. The search terms generated 78 results from the databases. After excluding all duplicates and applying the inclusion and exclusion criteria, a total of 14 clinical studies were retained for review., Data Extraction: Two reviewers independently extracted relevant data and assessed the methodological quality of each study., Results: The included studies reveal a number of risk factors for suicide ideation, suicide-related behavior, and suicide attempt among individuals taking levetiracetam. These risk factors include a prior psychiatric disorder, a history of traumatic brain injury, a history of substance use disorder, and a structural brain abnormality. Patients with these risk factors constitute a specific subgroup of patients with epilepsy who have an increased vulnerability to suicidal ideation or behavior if prescribed levetiracetam. These patients should, therefore, be monitored closely., Conclusions: Suicidal behavior in epileptic patients appears to be multifactorial in etiology. Psychiatric disorders are more prevalent in epileptic patients than in the general population and contribute to this risk. In spite of the high risk of suicidal behavior with the use of antiepileptic drugs, studies have shown that the benefits of anticonvulsant therapy often outweigh the risks. Nevertheless, timely consultation with a psychiatrist is invaluable in the care of these patients, particularly those with multiple risk factors, as in the index case. The risk of suicidality should be balanced with the risk of uncontrolled seizures. Specifically, in the case of levetiracetam, it is important to be aware of the subgroup of individuals with prior severe psychiatric illness, a history of traumatic brain injury, or a history of substance use disorder who might be at an increased risk of developing suicide-related behavior and suicidal ideations once levetiracetam is started., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Introduction: Dyskinesia of the ADCY5 mutation is a rare movement-onset disorder in childhood. It is characterized by isolated chorea movements or associated with myoclonus and dystonia affecting the limbs, neck and face. The low number of patients and families still does not allow an adequate genotype-phenotype relationship., Aims: The case of a child with movement disorders of early onset is presented in a family with three generations of affected members. An updated review of the casuistry and management of this rare disease is made., Case Report: A 6-year-old boy referred for language delay and hyperactivity. After six months of follow-up he begins to show chorea movements of predominantly facial and limb roots, especially when waking up. At one year of follow-up, generalized chorea at rest with orofacial involvement and awkward gait begins to show. His family history includes his mother, grandfather, maternal uncle and cousin, who were diagnosed with Meige's syndrome (oromandibular dystonia and periorbital muscles) with choreiform-like movement disorders without affiliation since childhood. The brain study by MRI showed no alterations. A clinical exome targeting movement disorders was performed that discovered the pathogenic mutation in the ADCY5 gene causing autosomal familial dyskinesia., Conclusion: The c.1126G>A p.A376T mutation shows a natural history with a non-progressive clinical phenotype in three generations of affected members, with childhood debut and response to guanfacine treatment.

Background: Anti-epileptic drug (AED) prophylaxis in the first-seven days post-traumatic brain injury (TBI) is known to reduce seizure frequency acutely. AED efficacy is equivalent; therefore, choice of AED may rest with their side-effects. We hypothesise that AEDs that impair balance will prolong recovery, shown by a longer hospital stay. We compared length of hospital stay (and reported dizziness) in TBI patients receiving the commonest AEDs used in our TBI patients, Phenytoin (which may cause imbalance), and Levetiracetam (which does not affect balance)., Method: A retrospective observational study was performed on TBI patients admitted to a Major Trauma Unit between October 2013 and June 2018. 100 of 278 patients treated with phenytoin or levetiracetam monotherapy for seizure prophylaxis were included. The inclusion criteria of admission Glasgow Coma Score of 14 or more and length of stay less than 3 weeks minimised confounding variables such as non-ambulant patients. Length of hospital stay and incidence of dizziness were assessed., Results: The length of hospital stay was longer for patients on Phenytoin versus Levetiracetam, i.e., 10.74 vs. 7.58 days (p = 0.015; unpaired, two-sided t test). Dizziness reported by patients on phenytoin was 24% and levetiracetam was 8% (p = 0.018; Chi-squared test)., Conclusion: In this cohort, using Phenytoin for acute TBI, seizure prophylaxis was associated with longer length of stay and more dizziness compared to Levetiracetam. Given their equivalent AED efficacy in acute TBI seizure prophylaxis, our data suggest that Levetiracetam is preferable to Phenytoin for early seizure prophylaxis in TBI. This requires evaluation in larger, prospective studies.

Objectives: The primary objective of the study was to analyze the efficacy of brivaracetam (BRV) in pediatric patients 12 months after starting treatment. The secondary objective was to establish safety 3, 6, and 12 months after starting treatment., Materials and Method: This was an observational and retrospective study. Data were collected from the electronic medical record. Inclusion criteria were as follows: patients under 18 years of age, diagnosis of focal or generalized epilepsy, treatment as an added therapy, initiation of treatment with BRV between June and September 2017, and at least one unprovoked seizure in the year prior to the start of treatment., Results: Forty-six patients were included. The response rate was 65%, including 30% seizure-free patients. The rate of adverse effects was 43.5%, resulting in withdrawal in 16 patients (34.7%). The most common adverse effects were drowsiness (17.3%) and irritability (17.3%)., Conclusions: Brivaracetam is effective in very diverse childhood epilepsies, including some that present with primarily generalized seizures. Given the characteristics of the population studied, we have not been able to confirm a better tolerability of BRV compared with levetiracetam (LEV)., Competing Interests: Declaration of competing interest All of the authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy., Methods: In a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the Wechsler Intelligence Scale for Children and the developmental neuropsychological assessment. Maternal IQ was measured using Wechsler Adult Intelligence Scale. Assessors were blinded to drug exposures., Results: One hundred and sixty-one children (one set of twins and 21 sibling pairs) of 139 mothers were included. As a group, children achieved average scores on neurocognitive outcomes. Children exposed to valproate (n = 22) performed lower on all six neurocognitive domains, especially language, than those exposed to carbamazepine (n = 32), lamotrigine (n = 82) or levetiracetam (n = 25). After controlling for maternal IQ and drug dose, the verbal IQ of valproate-exposed children was on average 9.1 points lower than those exposed to carbamazepine (95% confidence interval [CI] 1.3-17.0; p = 0.023), 10.3 lower than lamotrigine-exposed children (CI 3.4-17.3; p = 0.004) and 13.4 lower than levetiracetam-exposed children (CI 5.2-21.6; p = 0.002). No significant dose-effect was found. Virtually no significant differences were found between lamotrigine and levetiracetam or lamotrigine and carbamazepine exposed children., Conclusions: Consistent with previous research, valproate-exposed children experienced more problems compared to three other common antiepileptic drugs, while children exposed to lamotrigine, carbamazepine or levetiracetam revealed little to no problems. This illustrates the need for systematic follow-up of prenatally exposed children, to support pre-pregnancy counseling and treatment decisions in women of reproductive age.

Background: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups., Methods: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075., Findings: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group., Interpretation: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus., Funding: National Institute of Neurological Disorders and Stroke, National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Seizures are a morbid complication of intracerebral hemorrhage (ICH) and increase the risk for herniation, status epilepticus, and worse patient outcomes. Prophylactic levetiracetam is administered to approximately 40% of patients with ICH. It is unclear which patients are consciously selected for treatment by physicians. We sought to determine how patients are selected for treatment with prophylactic levetiracetam after ICH., Methods: We administered an adaptive conjoint analysis using decision making software to an NIH Stroke Trials Network Working Group. The adaptive conjoint analysis determines the most influential attributes for making a decision in an iterative, algorithm-driven process. We asked respondents which would most influence a decision to administer prophylactic levetiracetam. The attributes and their levels were taken from published phenotypes associated with prophylactic seizure medications and the likelihood of seizures after ICH: hematoma location (lobar or basal ganglia), hematoma volume (<=10 mL or >10 mL), level of consciousness (Glasgow Coma Scale 5-12 or Glasgow Coma Scale 13-15), age (<65 or ≥65 years), and race (White or Caucasian or Black/African American). The algorithm terminated when the attributes were ranked from most to least influential., Results: The study sample included 27 respondents who completed the adaptive conjoint analysis out of 42 who responded to the survey with a mean age of 43.4 ± 9.4 years. The attribute with the greatest weight was hematoma location (30%), followed by reduced level of consciousness (24%), hematoma volume (19%), race (14%), and age (13%). Ranks of attributes were different (P < .001)., Conclusions: The decision to administer prophylactic levetiracetam to patients with ICH is driven by lobar hematoma location and depressed level of consciousness. Future research on prophylactic seizure medication could focus on patients most likely to receive it., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Newer antiepileptic drugs (AEDs) are preferred over conventional AEDs with the perception of better safety profile and efficacy though there is a lack of confirmatory evidence. The present study assessed the adverse drug reactions' (ADRs) profile of AEDs prescribed in persons with epilepsy (PWE) as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern., Material and Methods: This prospective, cross-sectional, and observational study was conducted in PWE attending Neurology Outpatient-Department from February 2016 to April 2019 who were presented with any ADR. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale was used for the causality assessment of suspected ADRs., Results: Among the 1011 PWE on AEDs, male:female ratio was 622:389, adult:pediatric ratio 736:275, and conventional:newer AEDs ratio 624:387. Among monotherapy PWE (47.1%), commonly used AEDs were levetiracetam (34.4%), valproic acid (22.9%), carbamazepine (18.3%), phenytoin (11.9%), and other AEDs (12.5%). A total of 1990 ADRs (1.96 ADRs per PWE) were reported as per SOC; among them, newer vs. conventional AEDs did not reveal any significant difference; however, monotherapy vs. polytherapy showed differences in nervous system disorders (p = 0.01) and skin and subcutaneous tissue disorders (p = 0.005). Causality assessment revealed 0.3% certain, 27.3% probable, 61.3% possible, and 11.1% unlikely association of ADRs with AEDs. Depending on the ADRs, there was either withdrawal of AED (0.9%), reduction in dose (48.4%), or continuation in the same dose as before (50.7%)., Conclusion: The ADR analysis showed that newer AEDs were associated with a similar trend of ADRs as that of conventional AEDs. Thus, the choice among newer and conventional AEDs should preferably focus on the experience of better efficacy in addition to safety data., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background Antiseizure prophylaxis is recommended when high-dose of busulfan is given as part of the conditioning regimens in the allogenic hematopoietic stem cell transplant. Phenytoin has been widely used but its pharmacokinetics and pharmacodynamics profile makes its use complicated. Levetiracetam is a safe, effective and well tolerated antiseizure drug with good results in epileptic patients. Objective To describe our experience using oral (p.o) levetiracetam 1000 mg every 12 h (q12h) as an antiseizure prophylaxis, evaluating its preventive effects and adverse event rates after a high-dose of intravenous (i.v.) busulfan, as part of the conditioning regimen Methods Retrospective study of patients who underwent an allogenic hematopoietic stem cell transplant with a conditioning regimen based on high-dose of busulfan between January and November 2017. Results The study population comprised 36 patients, of whom 18 (50%) had acute myeloid leukemia as diagnosis. No seizures occurred in any patient. Levetiracetam was well tolerated and no serious adverse events were reported. Conclusions Our results suggest that giving levetiracetam at 1000 mg q12h p.o starting 12 h before the administration of i.v. busulfan until 48 h after the last dose, can be used as an alternative in the prevention of busulfan-induced seizures in adults.

Objective: Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital., Methods: We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications., Results: From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group., Significance: The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

Introduction To examine efficacy and tolerability of Levetiracetam monotherapy as a first line agent in a national cohort of children with epilepsy, naïve to anti-epileptic medication. Methods A retrospective analysis of children with epilepsy who attended 4 Irish tertiary Paediatric Neurology Clinics (2009-2015) started on Levetiracetam as a first line monotherapy. Results 182 children were identified aged one month to 16 years (mean 6.2 years (SD=5.1) Retention at 6 and 12 months was 88% (n=161) and 83% (n=145) respectively. 75% (n=104) achieved seizure freedom or > 50% improvement in seizure control at 12 months. 30% (n=55) experienced ≥1 adverse effect with aggression (12%; n=21) the most frequent. Treatment was discontinued in 16% (n=29) because of intolerance. Underlying conditions and epilepsy type were not found to influence efficacy or tolerability. Conclusion Levetiracetam monotherapy was observed as effective and safe for children with epilepsy although side effects limit tolerance in a sizeable minority., Competing Interests: All authors declare no conflict of interest.