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Objective: In the present study, we describe a novel class of small‐molecule synthetic compounds that ameliorate seizure‐like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism. Methods: Our electroshock assay examines seizure duration in C. elegans and can be used as a drug‐screening platform for the identification of novel anti‐seizure agents. The use of C. elegans allows for a rapid and efficient method of drug screening that may take years in other higher‐order model organisms. A novel wash method, paired with our electroshock assay, allows us to discern differences in biological activity when the C. elegans are incubated in different drug solutions, to establish whether these compounds can be "washed" off. Results: One of the RVMs (RVM‐3), reported here for the first time, was found to be potent at picomolar concentrations. Insights also provided information on the potential mechanisms of action of this compound. Covalent binding is thought to provide a strong irreversible bond because of a change in structure between two of the novel RVMs described in this work. This was also discerned through the novel wash method paired with our electroshock assay. Significance: RVM‐3 was evaluated using our assay and found to possess anti‐seizure activity at picomolar concentrations. These insights also provide information on the potential mechanisms of action of these compounds, which may include covalent binding. This was also discerned through a novel wash method paired with our electroshock assay. [ABSTRACT FROM AUTHOR]

Objective: Historically, approximately half of those with newly diagnosed epilepsy have responded to and tolerated the first antiseizure medication (ASM), but there are few contemporary real‐world data. Third‐generation ASMs have improved tolerability and are increasingly used according to prescription data. We aimed to describe current ASM selection and retention in adult onset focal epilepsy in western Sweden. Methods: A multicenter retrospective cohort study was performed at five public neurology care providers in western Sweden (nearly complete coverage in the area). We reviewed 2607 medical charts and included patients diagnosed with nongeneralized epilepsy after January 1, 2020 who had a seizure onset after age 25 years (presumed focal onset) and were started on ASM monotherapy. Results: A total of 542 patients (median age at seizure onset = 68 years, interquartile range = 52–77) were included. Most patients received levetiracetam (62%) or lamotrigine (35%), with levetiracetam being more common among men and those with structural causes or short epilepsy duration. During follow‐up (median = 471.5 days), 463 patients (85%) remained on the first ASM. Fifty‐nine (18%) patients discontinued levetiracetam, and 18 (10%) ended treatment with lamotrigine (p =.010), most commonly because of side effects. In a multivariable Cox regression model, the discontinuation risk was higher for levetiracetam than lamotrigine (adjusted hazard ratio = 2.01, 95% confidence interval = 1.16–3.51). Significance: Levetiracetam and lamotrigine were the dominating first ASMs for adult onset focal epilepsy in our region, indicating good awareness of problems with enzyme induction or teratogenicity of older drugs. The most striking finding is the high retention rates, perhaps reflecting a shift toward an older epilepsy population, higher tolerability of newer ASMs, or suboptimal follow‐up. The finding that treatment retention differed among patients receiving levetiracetam and lamotrigine aligns with the recent SANAD II results. It suggests lamotrigine may be underutilized in our region and that education efforts are needed to ensure it is considered the first choice more often. [ABSTRACT FROM AUTHOR]

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged. [ABSTRACT FROM AUTHOR]

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one‐third of epilepsy patients experience seizures despite therapy. Drug‐resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3–13.4 times higher mortality rate than in seizure‐free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic–clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long‐term, open‐label studies, 10%–36% of patients were seizure‐free for a median duration of ~30–45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open‐label extension studies. Mortality was reduced 5‐fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post‐launch information about the efficacy and safety of these ASMs. [ABSTRACT FROM AUTHOR]

Selection criteria for clinical trials for medication‐resistant epilepsy are used to limit variability and to ensure safety. However, it has become more challenging to recruit subjects for trials. This study investigated the impact of each inclusion and exclusion criterion on medication‐resistant epilepsy clinical trial recruitment at a large academic epilepsy center. We retrospectively identified all patients with medication‐resistant focal or generalized onset epilepsy who attended an outpatient clinic over a consecutive 3‐month period. We assessed each patient's eligibility for trials with commonly required inclusion and exclusion criteria to evaluate the proportion of eligible patients and the most common reasons for exclusion. Among 212 patients with medication‐resistant epilepsy, 144 and 28 patients met the criteria for focal or generalized onset epilepsy, respectively. Overall, 9.4% (n = 20) patients were eligible for trials (19 focal onset and one generalized onset). Most patients were excluded from the study due to insufficient seizure frequency (58% of focal onset, 55% of generalized onset). A small proportion of patients with medication‐resistant epilepsy were eligible for trials based on common selection criteria. These eligible patients may not be representative of the general population of patients with medication‐resistant epilepsy. Insufficient seizure frequency was the most common reason for exclusion. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to directly compare the effectiveness of first‐line monotherapy levetiracetam (LEV) versus enzyme‐inducing antiseizure medications (EIASMs) in glioma patients. Methods: In this nationwide retrospective observational cohort study, Grade 2–4 glioma patients were included, with a maximum duration of follow‐up of 36 months. Primary outcome was antiseizure medication (ASM) treatment failure for any reason, and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariate cause‐specific cox proportional hazard models were estimated, adjusting for potential confounders. Results: In the original cohort, a total of 808 brain tumor patients with epilepsy were included, of whom 109 glioma patients were prescribed first‐line LEV and 183 glioma patients first‐line EIASMs. The EIASM group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR] = 1.82, 95% confidence interval [CI] = 1.20–2.75, p =.005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR = 1.32, 95% CI =.78–2.25, p =.300), but treatment failure due to adverse effects differed significantly (aHR = 4.87, 95% CI = 1.89–12.55, p =.001). Significance: In this study, it was demonstrated that LEV had a significantly better effectiveness (i.e., less ASM treatment failure for any reason or due to adverse effects) compared to EIASMs, supporting the current neuro‐oncology guideline recommendations to avoid EIASMs in glioma patients. [ABSTRACT FROM AUTHOR]

Objective: Decades of genetic studies on people with many different epilepsies, and on many nonhuman species, using many different technologies, have generated a huge body of literature about the genes associated with seizures/epilepsy. Collating these data can help uncover epilepsy genes, pathways, and treatments that would otherwise be overlooked. We aimed to collate and structure these data into a database, and use the database to identify novel epilepsy genes and pathways, and to prioritize promising treatments. Methods: We collated all the genes associated with all types of seizures/epilepsy in all species, and quantified the supporting evidence for each gene, by manually screening ~10 000 publications, and by extracting data from existing databases. Results: The largest published dataset of epilepsy genes includes only 977 genes, whereas our database (www.sagas.ac) includes 2876 genes, which demonstrates that the number of genes that can potentially contribute to seizures/epilepsy is much higher than previously envisaged. We use our database to identify 12 hitherto unreported polygenic epilepsy genes, 479 high‐confidence monogenic epilepsy genes, and 394 more biological pathways than identified using the previously largest epilepsy gene dataset. We use a unique feature of Seizure‐Associated Genes Across Species—the number of citations for each gene—to demonstrate that a drug is more likely to affect seizures if there is more evidence that the genes it affects are associated with seizures, and we use these data to identify promising candidate antiseizure drugs. Significance: This database offers insights into the causes of epilepsy and its treatments, and can accelerate future epilepsy research. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate safety/tolerability and efficacy of adjunctive brivaracetam (BRV) in patients on one or two concomitant antiseizure medications (ASMs) and in patients on one specific concomitant ASM. Methods: Post hoc analysis was made of double‐blind trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in adults with focal seizures randomized to BRV (50–200 mg/day; approved therapeutic dose range for adults) or placebo with concomitant ASM regimen unchanged throughout a 12‐week evaluation period. Outcomes were analyzed in patients on one or two concomitant ASMs, and those on concomitant carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), or valproate (VPA) only. Results: Patients randomized to BRV with one or two concomitant ASMs, respectively (n = 181/557), reported similar incidences of treatment‐emergent adverse events (TEAEs; 68.0%/66.4%), drug‐related TEAEs (41.4%/41.5%), and TEAEs leading to discontinuation (6.6%/5.4%). Respective values for patients randomized to placebo with one or two concomitant ASMs (n = 95/331) were 60.0%/60.7% (TEAEs), 32.6%/30.2% (drug‐related TEAEs), and 2.1%/4.5% (TEAEs leading to discontinuation). The incidences of TEAEs, drug‐related TEAEs, and TEAEs leading to discontinuation by specific concomitant ASM (CBZ, LTG, OXC, VPA) were similar to the overall incidences in patients taking one concomitant ASM. In patients on one or two concomitant ASMs, respectively, 50% responder rates were numerically higher on BRV (42.3%/36.8% [n = 175/511]) versus placebo (18.3%/19.5% [n = 93/298]). Patients with one or two ASMs on BRV (n = 175/509) versus placebo (n = 92/298) also had numerically higher 100% responder rates (BRV, 9.1%/4.5%; placebo, 1.1%/.3%) and seizure freedom (6.9%/3.7%; 1.1%/0). For patients taking concomitant CBZ, LTG, OXC, or VPA, efficacy was numerically higher with BRV (n = 54/30/27/27) versus placebo (n = 34/13/10/14–15; 50% responder rates: BRV, 31.5%/30.0%/40.7%/70.4%; placebo, 17.6%/7.7%/20.0%/33.3%; 100% responder rates: BRV, 5.6%/10.0%/11.1%/11.1%; placebo, 0 for all; seizure freedom: BRV, 3.7%/6.7%/7.4%/11.1%; placebo, 0 for all). Significance: Therapeutic doses of BRV were efficacious and well tolerated regardless of the number of concomitant ASMs (one or two) or specific concomitant ASM (CBZ, LTG, OXC, VPA). [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to elicit patients' preferences for attributes characterizing antiseizure medication (ASM) monotherapy options before treatment consultation, and to explore the trade‐offs patients consider between treatment efficacy and risks of side effects. Further objectives were to explore how treatment consultation may affect patient preferences, to elicit physicians' preferences in selecting treatment, and to compare patient and physician preferences for treatment. Methods: This prospective, observational study (EP0076; VOTE) included adults with focal seizures requiring a change in their ASM monotherapy. Patients completed a discrete choice experiment (DCE) survey before and after treatment consultation. Physicians completed a similar survey after the consultation. The DCE comprised 12 choices between two hypothetical treatments defined by seven attributes. The conditional relative importance of each attribute was calculated. Results: Three hundred ten patients (mean [SD] age = 46.8 [18.3] years, 52.3% female) were enrolled from eight European countries, of whom 305 completed the survey before consultation and 273 completed the survey before and after consultation. Overall, this preference study in patients who intended to receive a new ASM monotherapy suggests that patient preferences were ordered as expected, with better outcomes being preferred to worse outcomes; patients preferred a higher chance of seizure freedom, lower risk of developing clinical depression, and fewer severe adverse events; avoiding moderate‐to‐severe "trouble thinking clearly" was more important than avoiding any other side effect. There were qualitative differences in what patients and physicians considered to be the most important aspects of treatment for patients; compared with patients, physicians had a qualitatively stronger preference for greater chance of seizure freedom and avoiding personality changes. Patients' preference weights were qualitatively similar before and after treatment consultation. Significance: For patients, seizure freedom and avoiding trouble thinking clearly were the most important treatment attributes. Physicians and patients may differ in the emphasis they place on specific attributes. [ABSTRACT FROM AUTHOR]

Objective: We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). Methods: Patients received either plant‐derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14‐day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. Results: Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2–18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0–26) and were currently taking a median of three (range = 1–5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p =.02) and Day 13 for CBD10 (p =.03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD‐treated patients (56.3%–72.9%). Significance: The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week study period. [ABSTRACT FROM AUTHOR]

Objective: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo‐controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox–Gastaut syndrome. Methods: Patients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. Results: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6–48.0). Patients had previously discontinued a median (range) of six (0–28) antiepileptic drugs (AEDs) and were currently taking a median of three (0–5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p =.008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. Significance: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week period. [ABSTRACT FROM AUTHOR]

Objective: This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first‐line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy. Methods: In this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow‐up was 36 months. Results: In total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%–38%] vs 50% [95% CI 45%–55%]; P <.001). When looking at specific reasons of treatment failure, treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95% CI 12%–19%] vs 28% [95% CI 23%–32%]; P < 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95% CI 11%–18%] vs 15% [95% CI 11%–18%]; P =.636). Significance: Our results suggest that levetiracetam may have favorable efficacy compared to valproic acid, whereas level of toxicity seems similar. Therefore, levetiracetam seems to be the preferred choice for first‐line AED treatment in patients with glioma. [ABSTRACT FROM AUTHOR]

Summary: Objective: This is an audit of the use of valproate (VPA) during pregnancy in women with epilepsy (WWE). Methods: We identified all pregnancies exposed to VPA in the Kerala Registry of Epilepsy and Pregnancy between January 2010 and December 2019. Subjects' past usage of antiepileptic drugs (AEDs), seizure count before and during pregnancy, fetal outcome, and major congenital malformations (MCMs) were abstracted from the registry records. The presumed reason for usage of VPA was deducted from the clinical records. Results: There were 221 pregnancies (17.75%) exposed to VPA (monotherapy, n = 149) during the audit period. The MCM rate for the completed pregnancies exposed to VPA was higher (n = 20, 10.36%) than that of VPA‐unexposed pregnancies (n = 39, 4.96%). The relative risk for MCM with VPA exposure was 2.1 (95% confidence interval = 1.24–3.48, number needed to treat with VPA to result in MCM = 19). Reasons for using VPA during pregnancy (some women had more than one reason) were (1) VPA was the first AED prescribed and was effective (68, 29.06%), (2) other AEDs were ineffective (128, 54.70%), and (3) other AEDs were discontinued due to adverse effects (17, 7.28%). Other reasons (21, 8.97%) were (1) VPA was selected after the epilepsy classification was revised (3, 1.28%), (2) other AEDs were expensive (2,.85%), and (3) patient switched to VPA from other AEDs for unspecified reason (16, 6.83%). VPA was discontinued during pregnancy for 6 (2.71%) persons. Less than 10% of women were tried on lamotrigine or levetiracetam before switching to VPA. Significance: Nine MCMs per thousand pregnancies can be avoided if VPA is not used in WWE. Safe and effective AEDs as alternatives to VPA are the need of the hour. Professional bodies and regulatory authorities need to implement updated guidelines on AED usage in girls and women. [ABSTRACT FROM AUTHOR]

Objective: The effects of anticonvulsants on lipids are the subject of considerable concern and investigation, but there are almost no data on this issue from randomized trials. We evaluated serum lipid profiles in adults with newly diagnosed epilepsy, following randomization to lacosamide (LCM) or carbamazepine (CBZ) monotherapy. Methods: We analyzed data from a Phase 3, international, randomized, double‐blind trial of LCM vs CBZ for the initial treatment of focal epilepsy. Serum lipid profiles in patients not taking lipid‐lowering agents and providing blood samples under fasting conditions before treatment, and following 3 or 12 months of treatment with LCM or CBZ at various doses were analyzed. Results: At 12 months, 271 patients satisfied the inclusion criteria for the analysis. No change was observed in LCM‐treated patients for total cholesterol, cholesterol fractions, or triglycerides. CBZ‐treated patients showed an increase of 21.1 mg/dL in total cholesterol, 12.6 mg/dL in low‐density lipoprotein (LDL) cholesterol, 12.5 mg/dL in non–high density lipoprotein (non‐HDL) cholesterol, and 8.5 mg/dL in HDL cholesterol; triglycerides remained unchanged. The proportion of patients with elevated total cholesterol levels (above the upper limit of the reference range) did not change in the LCM treatment group (37.0% at Baseline; 34.8% at 12 months), but increased from 30.8% (at Baseline) to 49.6% (at 12 months) in the CBZ treatment group. Significance: This study provides Class II evidence that CBZ elevates serum lipids, whereas LCM has no effect on lipids. It supports LCM as an appropriate choice for new‐onset focal epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Exposure to certain intrauterine antiepileptic drugs (AEDs) can negatively influence the language skills and intelligence of young children. It remains unanswered whether these deficits are transient or persist as children grow up. This study aims to evaluate the language function of children of women with epilepsy (CWE) aged 9‐13 years in comparison with their peers, and its relationship with intrauterine AED exposure. Methods: We included 191 CWE in our study from the Kerala Registry of Epilepsy and Pregnancy. Children in the same age group (n = 144) and without maternal epilepsy or antenatal AED exposure served as controls. We used Clinical Examination for Language Function version IV to assess language in both groups. Relevant data related to maternal epilepsy and AED use were obtained from the registry records. Results: The average Core Language Scaled Score (CLSS) was significantly lower in CWE as compared to controls (83.19 vs 90.18, P =.001). Similarly, the mean scaled scores in other language parameters were also significantly lower in CWE. In the multivariate analysis, compared to control children, the average CLSS in CWE was 4.5 units lower (95% confidence interval [CI] = −8.8 to −0.2, P =.04) with AED monotherapy exposure and 7.3 units lower with exposure to AED polytherapy (95% CI = −13.8 to −0.8, P =.03). Intrauterine exposure to phenobarbitone (n = 61) and valproate (n = 55) as either monotherapy or polytherapy showed a negative effect on CLSS in CWE as compared to control children. However, carbamazepine (n = 75) and phenytoin (n = 37) use was not associated with significant variation of CLSS. In head‐to‐head comparisons between AED monotherapies in CWE, phenobarbitone showed a negative effect on CLSS (−14.7, 95% CI = −23.1 to −6.4, P =.001) as compared to carbamazepine. Significance: Intrauterine exposure to phenobarbitone and valproate impairs language development in CWE, with effects persisting into the second decade. [ABSTRACT FROM AUTHOR]

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 (Ω025: 0.33, CRR: 2.18) and fosphenytoin‐lorazepam (Ω025: 0.99, CRR: 39.20). The TEN signals were related to the following combinations: clobazam‐gabapentin (Ω025: 0.35, CRR: 3.14), phenytoin‐gabapentin (Ω025: 0.03, CRR: 2.18), valproic acid–gabapentin (Ω025: 0.15, CRR: 2.25), clobazam‐clonazepam (Ω025: 0.03, CRR: 2.93), clobazam–valproic acid (Ω025: 0.29, CRR: 1.55), fosphenytoin‐lamotrigine (Ω025: 0.05, CRR: 7.37), and lacosamide‐levetiracetam (Ω025: 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. [ABSTRACT FROM AUTHOR]

Objective: We compared women with drug‐resistant focal epilepsy who had undergone surgery (WWE‐S) with those who were managed medically (WWE‐M) for maternal and fetal outcomes of their pregnancies. Methods: We classified all WWE‐S who were enrolled in a prospective registry of epilepsy and pregnancy (1998‐2015) as those who underwent the surgery before pregnancy (WWE‐SF) or after pregnancy (WWE‐PF). The comparator group (WWE‐M) was twice that number of age‐matched women with focal epilepsy in this registry. Their clinical profile, anti‐epileptic drug (AED) use, and pregnancy outcomes were extracted from the records of the registry. Results: The number of completed pregnancies with known outcome was 74 for WWE‐S (67 WWE‐SF and 7 WWE‐PF) and 134 for WWE‐M. Seizures increased during pregnancy for fewer WWE‐SF than for WWE‐M (14.9% vs 39.6%, P =.001). Compared to WWE‐M, fewer WWE‐SF had dose escalation during pregnancy (28.4% vs 14.9%, P =.025). Preterm deliveries were more frequent in WWE‐SF than WWE‐M (24.6% vs 12.2%, P =.029). The differences between the WWE‐SF and WWE‐M regarding the rates of fetal loss (10.4% vs 6.7%, P =.255), major congenital malformations (8.5% vs. 11.1%, P =.395), and development quotient at 1 year of age <85 (42.5% vs 42.3%, P =.569) were not statistically significant. Compared to WWE‐PF, fewer WWE‐SF had AED dose escalation (14.9% vs 85.7%, P =.001) or increase in seizures (14.9% vs 100%, P =.001) during pregnancy. WWE‐SF had fewer infants with development quotient <85 (41.0% vs 100%, P =.005). Significance: WWE‐SF can expect better control of seizures and decreased AED burden during pregnancy than WWE with focal epilepsies managed with medicines only. WWE who undergo surgery for epilepsy before their pregnancies can expect fewer seizures and lower AED burden during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate long‐term safety/tolerability of brivaracetam at individualized doses ≤200 mg/d (primary) and maintenance of efficacy over time (secondary) in adults with focal seizures or primary generalized seizures (PGS) enrolled in phase 3, open‐label, long‐term follow‐up trial N01199 (NCT00150800). Methods: Patients ≥16 years of age who had completed double‐blind, placebo‐controlled adjunctive brivaracetam trials NCT00175825, NCT00490035, NCT00464269, or NCT00504881 were eligible. Outcomes included safety, efficacy, and quality of life. Results: The safety set included 667 patients (focal seizures, 97.8%; PGS, 2.2%); the efficacy set included 648 patients with focal seizures and 15 patients with PGS. Overall, 49.2% of patients had ≥48 months of exposure. Treatment‐emergent adverse events (TEAEs) occurred in 91.2% of all patients (91.3% of focal seizures group), brivaracetam discontinuation due to TEAEs in 14.8%, drug‐related TEAEs in 56.7%, and serious TEAEs in 22.8%. The most common TEAEs in the focal seizures group (≥15%) were headache (25.3%) and dizziness (21.9%). Mean changes from baseline in Hospital Anxiety and Depression Scale scores at last value during 2‐year evaluation were −0.7 (standard deviation [SD] = 4.3) and −0.2 (SD = 4.4) overall. In the focal seizures group, median reduction from baseline in focal seizure frequency/28 days was 57.3%, 50% responder rate was 55.6%, and 6‐month and 12‐month seizure freedom rates were 30.3% and 20.3%, respectively. Efficacy outcomes improved by exposure duration cohort and then stabilized through the 108‐month cohort. Mean improvement from baseline in Patient‐Weighted Quality of Life in Epilepsy Inventory total score (efficacy set) was 5.7 (SD = 16.1, Cohen's d = 0.35) at month 12 and 6.5 (SD = 18.0, Cohen's d = 0.36) at month 24. Significance: Adjunctive brivaracetam was well tolerated, with a good safety profile in long‐term use in adults with epilepsy at individualized doses. Approximately half of the patients remained in the trial at 4 years. Brivaracetam reduced focal seizure frequency versus baseline. Efficacy improved with increasing exposure duration and remained stable through the 9‐year cohort. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and tolerability of lacosamide added to one or two antiepileptic drugs (AEDs) in the treatment of patients with brain tumor–related epilepsy (BTRE), and to evaluate patients' global impression of change and quality of life (QoL). Methods: This was a prospective, multicenter, single‐arm, noninterventional study with a 6‐month observation period (EP0045; NCT02276053). Eligible patients (≥16 years old) had active BTRE secondary to low‐grade glioma (World Health Organization grade 1 and 2) and were receiving treatment with one or two AEDs at baseline. Lacosamide was initiated by the treating physician in the course of routine clinical practice. Primary outcomes were 50% responders (≥50% reduction in focal seizure frequency from baseline) and Patient's Global Impression of Change (PGIC) at month 6. Secondary outcomes included seizure‐free status and Clinical Global Impression of Change (CGIC) at month 6, change in QoL (5‐Level EuroQol‐5 Dimension Quality of Life Assessment) and symptom outcomes (MD Anderson Symptom Inventory–Brain Tumor) from baseline to month 6, and Kaplan‐Meier estimated 6‐month retention on lacosamide. Safety variables included adverse drug reactions (ADRs). Results: Patients were recruited from 24 sites in Europe. Ninety‐three patients received lacosamide (mean [standard deviation] age = 44.5 [14.7] years; 50 [53.8%] male; median baseline focal seizure frequency = five seizures/28 days [range = 1‐280]), of whom 79 (84.9%) completed the study. At 6 months, 66 of 86 (76.7%) patients were 50% responders and 30 of 86 (34.9%) were seizure‐free. Improvements on PGIC were reported by 49 of 76 (64.5%) patients. Based on CGIC, 52 of 81 (64.2%) patients improved. QoL and symptoms outcome measures remained stable. Kaplan‐Meier estimated 6‐month retention rate was 86.0% (N = 93). Fifteen (16.1%) patients reported ADRs; four (4.3%) had ADRs leading to discontinuation (N = 93). Significance: Results of this prospective, noninterventional study suggest that add‐on lacosamide is effective and generally well tolerated in patients with BTRE. [ABSTRACT FROM AUTHOR]

Objective: A large‐scale, double‐blind trial (SP0993; NCT01243177) demonstrated that lacosamide was noninferior to controlled‐release carbamazepine (carbamazepine‐CR) in terms of efficacy, and well tolerated as first‐line monotherapy in patients (≥16 years of age) with newly diagnosed epilepsy. We report primary safety outcomes from the double‐blind extension of the noninferiority trial (SP0994; NCT01465997) and post hoc analyses of pooled long‐term safety and efficacy data from both trials. Methods: Patients were randomized 1:1 to lacosamide or carbamazepine‐CR. Doses were escalated (lacosamide: 200/400/600 mg/d; carbamazepine‐CR: 400/800/1200 mg/d) based on seizure control. Eligible patients continued randomized treatment in the extension. Primary outcomes of the extension were treatment‐emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Post hoc analyses of data from combined trials included 12‐ and 24‐month seizure freedom and TEAEs by number of comorbid conditions. Results: A total of 886 patients were treated in the initial trial and 548 in the extension; 211 of 279 patients (75.6%) on lacosamide and 180/269 (66.9%) on carbamazepine‐CR completed the extension. In the extension, 181 patients (64.9%) on lacosamide and 182 (67.7%) on carbamazepine‐CR reported TEAEs; in both groups, nasopharyngitis, headache, and dizziness were most common. Serious TEAEs were reported by 32 patients (11.5%) on lacosamide and 22 (8.2%) on carbamazepine‐CR; 12 (4.3%) and 21 (7.8%) discontinued due to TEAEs. In the combined trials (median exposure: lacosamide 630 days; carbamazepine‐CR 589 days), Kaplan‐Meier estimated proportions of patients with 12‐ and 24‐month seizure freedom from first dose were 50.8% (95% confidence interval 46.2%‐55.4%) and 47.0% (42.2%‐51.7%) on lacosamide, and 54.9% (50.3%‐59.6%) and 50.9% (46.0%‐55.7%) on carbamazepine‐CR. Incidences of drug‐related TEAEs and discontinuations due to TEAEs increased by number of comorbid conditions and were lower in patients on lacosamide. Significance: Long‐term (median ~2 years) lacosamide monotherapy was efficacious and generally well tolerated in adults with newly diagnosed epilepsy. Seizure freedom rates were similar with lacosamide and carbamazepine‐CR. [ABSTRACT FROM AUTHOR]

Objective: Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE). Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation. Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment‐emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty‐four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n = 24). Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE. [ABSTRACT FROM AUTHOR]

Summary: Ketamine is currently being used as an anesthetic/antiepileptic drug in refractory status epilepticus. To validate its use, 2 clinical trials are recruiting patients. However, preclinical studies of its use in chemically induced status epilepticus in rodents have shown that it is remarkably neuroprotective, through N‐methyl‐d‐aspartate–receptor blockade, even when given after the onset of status epilepticus. Human studies have shown that status epilepticus–induced brain damage can be caused by a glutamate analogue and that it occurs in the same brain regions as in the animal studies. We therefore propose that ketamine be started early in the course of human status epilepticus as a neuroprotectant and that it be continued until epileptic discharges are eliminated. Using it as an anesthetic/antiepileptic drug late in the course of refractory status epilepticus only ensures that it is given after widespread brain damage has occurred. [ABSTRACT FROM AUTHOR]

Summary: Objective: Patients with Lennox‐Gastaut syndrome (LGS) who completed 1 of 2 randomized, double‐blind, placebo‐controlled trials of add‐on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open‐label extension (OLE) study evaluating the long‐term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient‐reported outcomes from this trial. Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty‐five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12‐week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12‐week periods through week 48. Eighty‐eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. Significance: In this study, long‐term add‐on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures. [ABSTRACT FROM AUTHOR]

Summary: In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic‐ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM. [ABSTRACT FROM AUTHOR]

Summary: Attention‐deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large‐population prospective studies. [ABSTRACT FROM AUTHOR]

Summary: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. BRV differs from LEV in preclinical studies in that it exhibits a more potent and complete seizure protection across animal models. We reported previously that an allosteric modulator of the SV2A protein had differential effects on BRV compared with LEV, suggesting that they act at different sites or with different conformations of the SV2A protein. If this is the case, then we hypothesized that mutations of specific amino acids in the SV2A protein may have differential effects on BRV and LEV binding by the modulator. Mutation of some amino acids identified previously in the binding site of racetams to the SV2A protein had marked effects on binding of both [3H]BRV and [3H]LEV (eg, W300F, F277A, G303A, F658A, Y462A, W666A, I663A, D670A, and V661A). However, 3 amino acids were identified (K694, I273, and S294) in which mutation lost the effect of the modulator on [3H]LEV binding with no effect on the modulation of [3H]BRV binding. These results confirm that BRV and LEV bind to the human synaptic vesicle 2A protein at closely related sites but interact with these sites in a different way. [ABSTRACT FROM AUTHOR]

Summary: Objective: To pool observational data on the routine use of perampanel to obtain information on real‐world outcomes and data in populations typically underrepresented in clinical trials. Methods: Individual‐level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1‐year retention rate, 1‐year seizure freedom rate (duration ≥6 months), and incidence of treatment‐emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses. Results: The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27 years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One‐year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46‐50%), and 1‐year seizure‐free rate (≥6‐month duration) was 9.2% (74/803; 95% CI 7‐11%). Median treatment duration was 11.3 months (1832 patient‐years); median dose was 8 mg. In 388 individuals with available data at 3, 6, and 12 months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66‐70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure‐free rate, and higher number of prior AEDs with lower seizure‐free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65 years, 1‐year retention rate was 48% and seizure‐free rate was 28%. Significance: Across a large, treatment‐resistant population, add‐on perampanel was retained for ≥1 year by 48% of individuals, and 9% were seizure‐free for ≥6 months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel. [ABSTRACT FROM AUTHOR]

Abstract: Childhood absence epilepsy (CAE) is one of the most frequent epilepsies in infancy. The first‐line recommended therapy for CAE is based on the prescription of the narrow‐spectrum ethosuximide and the broad‐spectrum valproic acid, which have similar efficacy in the first 12 months. Nevertheless, some antiepileptic drugs (AEDs) may worsen seizure duration and type in this syndrome. In line with this, we have encountered a case of identical twins with CAE and early exposure to different antiseizure drugs leading to divergent outcomes. From this, we hypothesized that the first AED to treat CAE may determine the long‐term prognosis, especially in the developing brain, and that some situations leading to drug resistance may be explained by use of an inappropriate first AED. Therefore, we investigated this hypothesis by using a genetic mouse model of absence epilepsy (BS/Orl). Mice received a first appropriate or inappropriate AED followed by the same appropriate AED. Our data demonstrate that an inappropriate first AED has a negative impact on the long‐term efficacy of a second appropriate AED. This work supports the necessity to effectively diagnose epileptic syndromes prior to medication use, particularly in children, in order to prevent the deleterious effects of an inappropriate initial AED. [ABSTRACT FROM AUTHOR]

Objective To investigate what proportion of a regional cohort of cooled infants with neonatal encephalopathy develop epilepsy (determined by the International League Against Epilepsy [ILAE] definition and the number of antiepileptic drugs [AEDs]) up to 8 years of age. Methods From 2006-2013, 151 infants with perinatal asphyxia underwent 72 h cooling. Clinical and amplitude-integrated electroencepalography (aEEG) with single-channel EEG-verified neonatal seizures were treated with AEDs. Brain magnetic resonance imaging (MRI) was assessed using a 0-11 severity score. Postneonatal seizures, epilepsy rates, and AED treatments were documented. One hundred thirty-four survivors were assessed at 18-24 months; adverse outcome was defined as death or Bayley III composite Cognition/Language or Motor scores <85 and/or severe cerebral palsy or severely reduced vision/hearing. Epilepsy rates in 103 children age 4-8 years were also documented. Results aEEG confirmed seizures occurred precooling in 77 (57%) 151 of neonates; 48% had seizures during and/or after cooling and received AEDs. Only one infant was discharged on AEDs. At 18-24 months, one third of infants had an adverse outcome including 11% mortality. At 2 years, 8 (6%) infants had an epilepsy diagnosis ( ILAE definition), of whom 3 (2%) received AEDs. Of the 103 4- to 8-year-olds, 14 (13%) had developed epilepsy, with 7 (7%) receiving AEDs. Infants/children on AEDs had higher MRI scores than those not on AEDs (median [ interquartile range] 9 [8-11] vs. 2 [0-4]) and poorer outcomes. Nine (64%) of 14 children with epilepsy had cerebral palsy compared to 13 (11%) of 120 without epilepsy, and 10 (71%) of 14 children with epilepsy had adverse outcomes versus 23 (19%) of 120 survivors without epilepsy. The number of different AEDs given to control neonatal seizures, aEEG severity precooling, and MRI scores predicted childhood epilepsy. Significance We report, in a regional cohort of infants cooled for perinatal asphyxia, 6% with epilepsy at 2 years (2% on AEDs) increasing to 13% (7% on AEDs) at early school age. These AED rates are much lower than those reported in the cooling trials, even with adjusting for our cohort′s milder asphyxia. Long-term follow-up is needed to document final epilepsy rates. [ABSTRACT FROM AUTHOR]

Objective To evaluate acute and long-term effects of intravenous brivaracetam ( BRV) and BRV + diazepam ( DZP) combination treatment in a rat model of self-sustaining status epilepticus ( SSSE). Methods Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation ( PPS) as early treatment; or BRV (10-300 mg/kg), DZP (1 mg/kg), or BRV (0.3-10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE). Seizure activity was recorded electrographically for 24 h posttreatment (acute effects), and for 1 week at 6-8 weeks or 12 months' posttreatment (long-term effects). All treatments were compared with control rats using one-way analysis of variance (ANOVA) and Bonferroni's test, or Kruskal--Wallis and Dunn's multiple comparison tests, when appropriate. Results Treatment of established SSSE with BRV (10-300 mg/kg) resulted in dose-dependent reduction in SSSE duration and cumulative seizure time, achieving statistical significance at doses ≥100 mg/kg. Lower doses of BRV (0.3-10 mg/kg) + low-dose DZP (1 mg/kg) significantly reduced SSSE duration and number of seizures. All control rats developed spontaneous recurrent seizures ( SRS) 6-8 weeks after SSSE, whereas seizure freedom was noted in 2/10, 5/10, and 6/10 rats treated with BRV 200 mg/kg, 300 mg/kg, and BRV 10 mg/kg + DZP, respectively. BRV (10-300 mg/kg) showed a dose-dependent trend toward reduction of SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at 300 mg/kg. Combination of BRV (10 mg/kg) + DZP significantly reduced SRS frequency, cumulative seizure time, and spike frequency. In the 12-month follow-up study, BRV (0.3-10 mg/kg) + low-dose DZP markedly reduced SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at some doses. Early treatment of SSSE with BRV 10 mg/kg significantly reduced long-term SRS frequency. Significance These findings support clinical evaluation of BRV for treatment of status epilepticus or acute repetitive seizures. [ABSTRACT FROM AUTHOR]

Objective To assess heart-rate variability ( HRV) measures of interictal electrocardiography ( ECG) for drug-resistant epilepsy and to relate the findings to the outcome of vagus nerve stimulation ( VNS) treatment. Methods Time-domain, frequency-domain, and nonlinear analyses were used to analyze preoperative HRV measures in 32 patients with drug-resistant epilepsy who had received VNS implants at the same hospital and 32 healthy age- and sex-matched control subjects. HRV measurements based on ambulatory 24 h ECG recordings were analyzed to identify seizure reduction 1 year after VNS treatment. Responders were defined as having at least 50% seizure reduction 1 year after treatment. Results Patients with drug-resistant epilepsy had significantly lower time domain ( SDNN, RMSSD, pNN50), frequency domain ( VLF, LF, HF, TP), and nonlinear ( SD1, SD2) HRV measurements than matched healthy controls. None of the analyzed HRV measures of the responders differed significantly from their controls, whereas those of the nonresponders had significantly lower RMSSD, pNN50, HF, and SD1 than the responders. Significance The preoperative HRV indices demonstrate that nonresponders have more pronounced impairment of their cardiac autonomic function than the responders. Presurgical HRV measurements representing parasympathetic cardiac control or vagal tone were significantly associated with the responsiveness to VNS. Thus the measurements show promise for predicting the reduction of seizure frequency after VNS treatment. [ABSTRACT FROM AUTHOR]

Objective Brivaracetam ( BRV) and levetiracetam ( LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A ( SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. Methods Radioligand binding studies were carried out using [3H] BRV and [3H] LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue. Results The modulator increased the binding of both radioligands but by different mechanisms. For [3H] BRV, the increase was driven mainly by an increase in affinity, whereas for [3H] LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect. Significance These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein. [ABSTRACT FROM AUTHOR]

Objective Antiepileptic drug ( AED) treatment failures may occur because there is insufficient drug in the brain or because of a lack of relevant therapeutic response. Until now it has not been possible to measure these factors. It has been recently shown that the combination of transcranial magnetic stimulation and electroencephalography ( TMS- EEG) can measure the effects of drugs in healthy volunteers. TMS-evoked EEG potentials ( TEPs) comprise a series of positive and negative deflections that can be specifically modulated by drugs with a well-known mode of action targeting inhibitory neurotransmission. Therefore, we hypothesized that TMS- EEG can detect effects of two widely used AEDs, lamotrigine and levetiracetam, in healthy volunteers. Methods Fifteen healthy subjects participated in a pseudo-randomized, placebo-controlled, double-blind, crossover design, using a single oral dose of lamotrigine (300 mg) and levetiracetam (3,000 mg). TEPs were recorded before and 120 min after drug intake, and the effects of drugs on the amplitudes of TEP components were statistically evaluated. Results A nonparametric cluster-based permutation analysis of TEP amplitudes showed that AEDs both increased the amplitude of the negative potential at 45 msec after stimulation (N45) and suppressed the positive peak at 180 msec (P180). This is the first demonstration of AED-induced modulation of TMS- EEG measures. Significance Despite the different mechanism of action that lamotrigine and levetiracetam exert at the molecular level, both AEDs impact the TMS- EEG response in a similar way. These TMS- EEG fingerprints observed in healthy subjects are candidate predictive markers of treatment response in patients on monotherapy with lamotrigine and levetiracetam. [ABSTRACT FROM AUTHOR]

Pathologic increases in excitability levels of cortical tissue commonly underlie the initiation and spread of seizure activity in patients with epilepsy. By reducing the excitability levels in neural tissue, antiepileptic drug ( AED) pharmacotherapy aims to reduce seizure severity and frequency. However, AEDs may also bring about adverse effects, which have been reported to increase with higher AED load. Measures that monitor the dose-dependent effects of AEDs on cortical tissue and quantify its excitability level are therefore of prime importance for efficient clinical care and treatment but have been difficult to identify. Here, we systematically analyze continuous multiday electrocorticography ( ECoG) data from 10 patients under different levels of AED load and derive the recently proposed intrinsic excitability measures ( IEMs) from different brain regions and across different frequency bands. We find that IEMs are significantly negatively correlated with AED load (prescribed daily dose/defined daily dose). Furthermore, we demonstrate that IEMs derived from different brain regions can robustly capture global changes in the degree of excitability. These results provide a step toward the ultimate goal of developing a reliable quantitative measure of central physiologic effects of AEDs in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Objective To assess long-term use and safety of lacosamide ( LCM) ≤800 mg/day monotherapy in patients with partial-onset seizures ( POS) enrolled previously in a historical-controlled, conversion-to-monotherapy study ( SP902; NCT00520741). Methods Patients completing or exiting SP902 with LCM as monotherapy or as adjunctive therapy were eligible to enter this 2-year open-label extension ( OLE) trial ( SP904; NCT00530855) at a starting dose ±100 mg/day of their final SP902 dose. Investigators could adjust the LCM dose to 100-800 mg/day and add up to two antiepileptic drugs to optimize tolerability and seizure reduction. Results Three hundred twenty-two patients received LCM: 210 patients (65.2%) completed and 112 (34.8%) discontinued, most commonly owing to withdrawal of consent (9.3%). Two hundred fifty-eight patients (80.1%) had ≥1 year of and 216 (67.1%) had ≥2 years of LCM exposure, of whom 179/258 (69.4%) achieved LCM monotherapy lasting for any 12-month period, and 126/216 (58.3%) patients exposed for ≥24 months achieved LCM monotherapy for any 24-month period. Total exposure = 525.5 patient-years. The median modal dose was 500 mg/day. Two hundred ninety-two patients (90.7%) achieved LCM monotherapy at some point during the study. Sixty-five of 87 patients who exited and 193/235 who completed SP902 were exposed for ≥12 months, and 43.1% and 78.2%, respectively, achieved LCM monotherapy for ≥12 months. Median LCM monotherapy duration was 587.0 days (2-791 days); 91.0% of patients reported treatment-emergent adverse events, of which the most common were dizziness (27.3%), headache (17.1%), and nausea (14.3%). Compared with the SP902 study baseline, 74.2% of patients had a ≥50% seizure reduction and 5.6% were seizure-free at 24 months. Significance The majority of patients were receiving LCM monotherapy at 0, 12, and 24 months in this OLE. Lacosamide monotherapy (median dose of 500 mg/day) had a safety profile similar to that of adjunctive therapy studies. These results support the use of lacosamide as long-term monotherapy treatment for adults with POS. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effectiveness of lacosamide ( LCM) in pediatric patients, using time to treatment failure as the outcome measure, and to assess the impact of concomitant sodium channel blocker ( SCB) use on LCM retention. Methods This is a retrospective cohort study of patients <21 years old receiving LCM from 2010 to 2015. Kaplan-Meier survival curves were generated for time to LCM failure, defined as discontinuation of LCM or addition of another antiepileptic therapy. The impact of concomitant use of traditional SCB agents (phenytoin, carbamazepine, oxcarbazepine, and/or lamotrigine) and other factors including age, seizure types, fast drug titration, and prior antiepileptic drug history were evaluated using Cox regression. Results The analysis cohort included 223 patients, of whom 116 were taking one or more SCBs, with median follow-up of 7.4 months (1-53 months). For all patients, the probability of remaining on LCM without addition of another therapy was 44.7% at 12 months and 25.6% at 24 months. Concomitant SCB use was an independent predictor of time to LCM failure (hazard ratio [ HR] 1.91, 95% confidence interval [ CI] 1.38-2.65, p < 0.001).Although treatment emergent adverse effects were reported more often in patients taking SCB (65% vs. 39%, p < 0.001), intolerability was rarely the sole reason cited for LCM discontinuation, and SCB use was strongly associated with LCM failure, even when controlling for presence of treatment emergent adverse effects (adjusted HR 1.99, 95% CI 1.36-2.90, p < 0.001). Significance This study provides observational evidence for treatment persistence of LCM in children, in a large cohort with long-term follow-up, using time to treatment failure as the outcome measure. Concomitant SCB use was a key factor increasing risk of LCM failure, but not due to treatment-emergent adverse effects alone. [ABSTRACT FROM AUTHOR]

Objective Long-term use of antiepileptic drugs ( AEDs) is a significant risk factor for vitamin D deficiency in children with epilepsy. The aims of our study were to evaluate the prevalence and risk factors for vitamin D deficiency among Malaysian children with epilepsy. Methods Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in three tertiary hospitals in Malaysia from April 2014 to April 2015. Detailed assessment of pubertal status, skin pigmentation, sunshine exposure behavior, physical activity, dietary vitamin D and calcium intake, anthropometric measurements and bone health blood tests (vitamin D, alkaline phosphatase, calcium, phosphate, and parathyroid hormone levels) were obtained on all patients. Vitamin D deficiency was defined as 25-hydroxy vitamin D [25( OH)D] levels ≤35 nmol/L and insufficiency as 25( OH)D levels of 36-50 nmol/L. Results A total of 244 children (146 male) participated in the study. Ages ranged between 3.7 and 18.8 years (mean 12.3 years). 25( OH)D levels ranged between 7.5 and 140.9 nmol/L (mean 53.9 nmol/L). Vitamin D deficiency was identified in 55 patients (22.5%), and a further 48 (19.7%) had vitamin D insufficiency. Multivariate logistic regression analysis identified polytherapy >1 AED (odds ratio [ OR] 2.16, 95% confidence interval [ CI] 1.07-4.36), age >12 years ( OR 4.16, 95% CI 1.13-15.30), Indian ethnicity ( OR 6.97, 95% CI 2.48-19.55), sun exposure time 30-60 min/day ( OR 2.44, 95% CI 1.05-5.67), sun exposure time <30 min/day ( OR 3.83, 95% CI 1.61-9.09), and female ( OR 2.61, 95% CI 1.31-5.20) as statistically significant (p < 0.05) risk factors for vitamin D deficiency. Significance Despite living in the tropics, a high proportion of Malaysian children with epilepsy are at risk of vitamin D deficiency. Targeted strategies including vitamin D supplementation and lifestyle advice of healthy sunlight exposure behavior should be implemented among children with epilepsy, particularly for those at high risk of having vitamin D deficiency. [ABSTRACT FROM AUTHOR]

Objective During critical periods of brain development, both seizures and anticonvulsant medications can affect neurodevelopmental outcomes. In rodent models, many anticonvulsants trigger neuronal apoptosis. However, white matter apoptosis ( WMA) has not been examined after anticonvulsant drug treatment. Herein, we sought to determine if anticonvulsant drugs induced apoptosis in the developing white matter ( WM) in a rodent model. Methods Postnatal day (P)7 rats were treated with phenobarbital ( PB-75), MK-801 (dizocilpine, 0.5), lamotrigine ( LTG-20), carbamazepine ( CBZ-100), phenytoin ( PHT-50), levetiracetam ( LEV-250), or saline; all doses are mg/kg. Brain tissue collected 24 h after treatment was stained using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. The number of degenerating cells within WM, that is, anterior commissure ( AC), corpus callosum, cingulum, and hippocampus-associated WM tracts, was quantified. Results Saline-treated rats showed low baseline level of apoptosis in developing WM on P8 in all the areas examined. PB, PHT, and MK-801 significantly increased apoptosis in all four brain areas examined. Exposure to CBZ, LTG, or LEV failed to increase apoptosis in all regions. Significance Commonly used anticonvulsants ( PB, PHT) cause apoptosis in the developing WM in a rat model; the N-methyl- d-aspartate ( NMDA) receptor antagonist MK-801 has a similar effect. These results are consistent with reports of anesthesia-induced WMA during brain development. Consistent with the lack of neuronal apoptosis caused by LTG, LEV, and CBZ, these drugs did not cause WMA. Many infants treated with anticonvulsant drugs have underlying neurologic injury, including WM damage (e.g., following intraventricular hemorrhage [ IVH] or hypoxic-ischemic encephalopathy [ HIE]). The degree to which anticonvulsant drug treatment will alter outcomes in the presence of underlying injury remains to be examined, but avoiding drugs (when possible) that induce WMA may be beneficial. [ABSTRACT FROM AUTHOR]

Objective Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices. Methods The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis. Results When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism. Significance The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison. [ABSTRACT FROM AUTHOR]

Objective Evidence for the efficacy and safety of adjunctive lacosamide in the treatment of partial-onset seizures ( POS) was gained during placebo-controlled clinical trials in patients with treatment-resistant seizures who were taking one to three concomitant antiepileptic drugs ( AEDs). The VITOBA study (NCT01098162) evaluated the effectiveness and tolerability of adjunctive lacosamide added to one baseline AED in real-world clinical practice. Methods We conducted a 6-month observational study at 112 sites across Germany. Adult patients (≥16 years) with POS received lacosamide adjunctive to only one baseline AED. Seizure frequency reduction at the end of the observation period was compared with a 3-month retrospective baseline period. Results Five hundred seventy-one patients received lacosamide at least once (Safety Set [ SS]); 520 provided evaluable seizure records (Full Analysis Set [ FAS]); and 499 took in-label dosages of lacosamide (up to 400 mg) and were evaluated for effectiveness (modified FAS). Median baseline seizure frequency was 2.0 per 28 days: 47.1% of patients (235/499, mFAS) took a concomitant sodium channel-blocking (SCB) AED; 38.1% (190/499) had only one lifetime AED; and 18.4% (92/499) were aged ≥65 years ( mFAS). At the final visit, 72.5% (358/494) of patients showed a ≥50% reduction in seizure frequency from baseline, 63.8% (315/494) showed a ≥75% reduction, and 45.5% (225/494) were seizure-free. Seizure freedom rates were higher in patients aged ≥65 years (56.7%) compared with patients aged <65 years (43.1%), in patients with ≤5 years epilepsy duration (52.5%) versus >5 years duration (41.0%), and when added to first monotherapy (60.5%) rather than as a later therapy option. Treatment-emergent adverse events (TEAEs) were reported by 48.5% (277/571) of patients ( SS), with a profile similar to that observed in pivotal trials; 466 of patients (81.6%, SS) continued lacosamide therapy after the trial. Significance These results suggest that lacosamide use, added to one concomitant AED, was effective at improving seizure control and was well tolerated in patients treated in routine clinical practice. [ABSTRACT FROM AUTHOR]

The antiepileptic drug ( AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored. [ABSTRACT FROM AUTHOR]

Objective Evaluate the pharmacokinetics ( PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range. Methods Two single-dose, phase I studies in healthy adults were used to evaluate the PK profile and maximum tolerated dose ( MTD) of USL255 from 25-1,400 mg. Standard PK parameters assessed included area under the plasma concentration-time curve ( AUC) and maximum plasma concentration (Cmax). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [% CV]) of AUC and Cmax were evaluated. Investigator-reported adverse events ( AEs) were obtained throughout the studies. Results After the initial increase in plasma concentration levels immediately following administration of USL255 25-1,400 mg, plasma topiramate concentration-time profiles were flat up to 24 h after dosing. AUC was dose proportional from 25-1,400 mg, and Cmax was dose proportional from 50-1,400 mg; both AUC and Cmax were linear across the entire dose range. Low intersubject and intrasubject % CV values were observed for AUC0−t, AUC0−∞, and Cmax (intersubject % CV: 20.2, 19.6, and 22.4%, respectively; intrasubject % CV of dose-normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was generally safe and well tolerated with MTD established at 1,200 mg. Significance These results demonstrate that USL255 provides consistent plasma topiramate exposure across an extended-dosing interval and predictable plasma topiramate concentrations over a wide dosing range. Overall, the favorable safety profile and consistency of exposure suggest once-daily USL255 can be a useful treatment option for patients with epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures ( POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study ( PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life ( QOLIE-31-P) and clinical global impression of change ( CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects. [ABSTRACT FROM AUTHOR]

Objective To determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox- Gastaut syndrome ( LGS). Methods Eligible patients from two randomized controlled trials (Phase II OV-1002 and Phase III OV-1012) were able to enroll in open-label extension ( OLE) study OV-1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2 years for patients outside the United States) or until study completion in March 2012. Patients in the United States could have received clobazam for 6 years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (≥50%, ≥75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug ( AED) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting. Results Of 267 patients who enrolled in the OLE, 188 (70%) completed the trial. Two hundred seven patients were from the United States, which was the only country in which patients could be treated with clobazam for >2 years. Forty-four patients were treated with clobazam for 5 years, and 11 for 6 years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ≥50% decrease in median drop-seizure frequency from baseline to Month 3, 86% still had that degree of drop-seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop-seizure-free. Most patients who had achieved drop-seizure freedom in the original controlled trials remained drop-seizure-free in the OLE. Based on parents' and physicians' ratings of global evaluations, 80% of patients were 'very much improved' or 'much improved' after 3 years. Of the 43 patients with concomitant AED data who were treated for 5 years, 30% increased, 19% decreased, and 51% had no change in numbers of AEDs versus their Week 4 regimens. The mean modal clobazam dosage was 0.90 mg/kg/day at Year 1 and 0.97 mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for LGS patients over a 5-year span, and no new safety concerns developed over time. Significance In this largest and longest-running trial in LGS, adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3 years of therapy in this difficult- to-treat patient population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Purpose To evaluate the safety and tolerability of adjunctive brivaracetam ( BRV), a high-affinity synaptic vesicle protein 2 A ( SV2 A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. Methods This was a phase III, randomized, double-blind, placebo ( PBO)-controlled flexible dose trial ( N01254/ NCT00504881) in adults (16-70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). Key Findings A total of 480 patients were randomized ( BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients ( BRV 66.0%, PBO 65.3%) reported adverse events ( AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding ( BRV 56.0%, PBO 55.4%) to the maintenance ( BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache ( BRV 14.2% vs. PBO 19.8%), somnolence ( BRV 11.1% vs. PBO 4.1%), and dizziness ( BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO ( BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. Significance Adjunctive BRV given at individualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to evaluate the effect of the antiepileptic drug lacosamide on the pharmacokinetics and pharmacodynamics of the anticoagulant warfarin. Methods In this open-label, two-treatment crossover study, 16 healthy adult male volunteers were randomized to receive a single 25-mg dose of warfarin alone in one period and lacosamide 200 mg twice daily on days 1-9 with a single 25 mg dose of warfarin coadministered on day 3 in the other period. There was a 2-week washout between treatments. Pharmacokinetic end points were area under the plasma concentration-time curve ( AUC(0,last) and AUC(0,∞)) and maximum plasma concentration ( Cmax) for S- and R-warfarin. Pharmacodynamic end points were area under the international normalized ratio ( INR)-time curve ( AUCINR), maximum INR ( INRmax), maximum prothrombin time ( PTmax) and area under the PT-time curve ( AUCPT). Key Findings Following warfarin and lacosamide coadministration, Cmax and AUC of S- and R-warfarin, as well as peak value and AUC of PT and INR, were equivalent to those after warfarin alone. In particular, the AUC(0,∞) ratio (90% confidence interval) for coadministration of warfarin and lacosamide versus warfarin alone was 0.97 (0.94-1.00) for S-warfarin and 1.05 (1.02-1.09) for R-warfarin, and the AUCINR ratio was 1.04 (1.01-1.06). All participants completed the study. Significance Coadministration of lacosamide 400 mg/day did not alter the pharmacokinetics of warfarin 25 mg or the anticoagulation level. These results suggest that there is no need for dose adjustment of warfarin when coadministered with lacosamide. [ABSTRACT FROM AUTHOR]

Purpose The antiepileptic drug, lacosamide, exerts its therapeutic activity by enhancing slow inactivation of voltage-gated sodium channels. Because putative preventive or disease-modifying effects of drugs may affect epileptogenesis, intrinsic severity, and comorbidities, it is of particular interest to assess the effect of lacosamide on the development of epilepsy and associated cellular alterations. Methods The effect of lacosamide was evaluated in an electrical rat status epilepticus ( SE) model with a 24-day treatment phase following induction of SE. The impact of lacosamide on the development of spontaneous seizures based on continuous video-electroencephalography ( EEG) monitoring, as well as the impact on neuronal cell loss and alterations in hippocampal neurogenesis, was assessed. Key Findings Neither low-dose nor high-dose lacosamide affected the development of spontaneous seizures. A dose-dependent neuroprotective effect of lacosamide with significant reduction of neuronal cell loss was observed in the hippocampal CA1 region, as well as in the piriform cortex. In addition, lacosamide attenuated the impact of SE on the rate of hippocampal cell neurogenesis. Moreover, lacosamide prevented a significant rise in the number of persistent basal dendrites. Significance Our data do not support an antiepileptogenic effect of lacosamide. However, because lacosamide reduced SE-associated cellular alterations, it would be of interest to determine whether these effects indicate a putative disease-modifying effect of lacosamide in future studies. [ABSTRACT FROM AUTHOR]

Purpose Although oral topiramate ( TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration ( FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation. Methods This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with Win Nonlin 5.2. Key Findings All subjects completed the study. The mean (±standard deviation) absolute oral bioavailability was 109% (±10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (±0.29) and 0.94 L/kg (±0.24). Clearances were 1.33 L/h (±0.26) and 1.22 L/h (±0.26). The half-life values were 42.3 h (±6.2) and 41.2 h (±7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion. Significance In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted. [ABSTRACT FROM AUTHOR]

Purpose Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol® (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Methods Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies ( ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Key Findings Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [ SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume, half-life, and clearance were significantly altered by enzyme-inducing drugs. Significance A single 25-mg dose of intravenous topiramate caused minimal infusion site or systemic adverse effects in patients taking oral topiramate. Pharmacokinetic results show that oral topiramate is completely absorbed and that its steady-state elimination half-life is longer than previously assumed, which permits once or twice daily dosing even in the presence of enzyme-inducing drugs. The information from this study can inform the design of subsequent studies in adults, older children, and newborns, including controlled clinical trials intended to determine the efficacy and safety of intravenous topiramate for neonatal seizures. [ABSTRACT FROM AUTHOR]

Dogs with spontaneous diseases can exhibit a striking similarity in etiology, clinical manifestation, and disease course when compared to human patients. Therefore, dogs are intensely discussed as a translational model of human disease. In particular, genetic studies in selected dog breeds serve as an excellent tool to identify epilepsy disease genes. In addition, canine epilepsy is discussed as a translational platform for drug testing. On one hand, epileptic dogs might serve as an interesting model by allowing the evaluation of drug efficacy and potency under clinical conditions with a focus on chronic seizures resistant to standard medication, preventive strategies, or status epilepticus. On the other hand, several limitations need to be considered including owner-based seizure monitoring, species differences in pharmacokinetics and drug interactions, as well as cost-intensiveness. The review gives an overview on the current state of knowledge regarding the etiology, clinical manifestation, pathology, and drug response of canine epilepsy, also pointing out the urgent need for further research on specific aspects. Moreover, the putative advantages, the disadvantages, and limitations of antiepileptic drug testing in canine epilepsy are critically discussed. [ABSTRACT FROM AUTHOR]