Concomitant Antiepileptic Drugs Research Articles

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.

We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis.

Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI). In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted. Cannabidiol use was associated with an increased probability of liver enzyme elevation (N=12 trials, n=1229; OR=5.85 95% CI=3.84-8.92, p<0.001) and DILI (N=12 trials, n=1229; OR=4.82 95% CI=2.46-9.45, p<0.001) compared to placebo controls. In participants taking cannabidiol (N=28 trials, n=1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000mg/day or ≥20mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300mg/day. No cases of severe DILI were reported. Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.

Treatment with Cenobamate in Adult Patients with Lennox–Gastaut Syndrome: A Case Series

Background. Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) in which drug resistance to antiepileptic drugs (AEDs) is common. Focal-onset seizures (FOS) are among the seizure types characterizing LGS. Cenobamate (CNB) is a new AED indicated for the treatment of FOS and it has shown promising results in terms of seizure frequency reduction in both clinical trials and real-world experience. To date, the use of CNB in patients with DEEs is limited to Dravet syndrome. Methods: This was a retrospective study aimed to determine the 12-month effectiveness and tolerability of CNB in patients with LGS following real-world practice. Results: Four patients with LGS receiving CNB treatment were identified. At 12 months from starting CNB, the reduction in baseline seizure frequency ranged from 25 to 74%, with two patients achieving ≥50% seizure reduction. CNB was generally well tolerated and adjustments in doses of concomitant AEDs were required. Conclusions: CNB may represent a promising therapeutic option in patients with drug-resistant epilepsy associated with LGS. Further research is needed to confirm this preliminary evidence.

Therapeutic Drug Monitoring for Rufinamide in Japanese Patients With Epilepsy: Focus on Drug Interactions, Tolerability, and Clinical Effectiveness.

The purposes of this study were to assess drug interactions between rufinamide and concomitant antiepileptic drugs (AEDs) and to identify the therapeutic window for rufinamide. Serum samples (n = 1531) were obtained from 178 patients (aged 2-57 years), and clinical records were retrospectively reviewed to evaluate the safety and efficacy of rufinamide (mean observation time, 1073 ± 846 days). Rufinamide exhibited linear pharmacokinetics at doses of up to 60 mg/kg (range, 50-3200 mg/d). Concomitant use of the enzyme-inducing AEDs such as phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. Clinical response was seen in 41 patients (23.0%), with a median therapeutic concentration (interquartile range) of 20.6 mcg/mL (13.3-27.0). There was no difference in the therapeutic concentrations between seizure types, but patients with tonic/atonic seizures tended to have higher rufinamide concentrations. During the study period, adverse events were reported in 64 patients (35.8%), including somnolence, gastrointestinal disorders, dizziness, and irritability/behavior disorders. Conditional logistic regression analysis showed that patients administered a concentration greater than 20 mcg/mL had an 8.6-fold higher incidence of adverse events. Therapeutic drug monitoring for rufinamide is clinically useful for predicting drug interactions between rufinamide and concomitant AEDs. When a patient has tonic/atonic seizures, careful titration is required for concentrations greater than 20 mcg/mL.

157  Efficacy of adjunctive cenobamate: post-hoc analysis in patients grouped by concomitant anti-epileptic drug type

PurposeThere has been little success with polytherapy for patients with drug-resistant epilepsy. The need for optimizing AED combinations is high. Cenobamate is a novel AED with a unique, dual, complementary mechanism of action (MoA) combining GABA-A positive allosteric modulation (via a binding site different from benzodiazepines) together with broad spectrum sodium channel blockage. Here we assessed the efficacy of cenobamate when combined with AEDs grouped by MoA.MethodsA post-hoc exploratory analysis of the study C017, in adult epilepsy patients with uncontrolled focal onset seizures who had ≥4 seizures/month despite treatment with stable doses of 1–3 AEDs.ResultsIn the maintenance phase, 183/397 (46%) patients were receiving at least one GABA modulator (felbamate, valproate, topiramate, tiagabine, vigabatrin) and 329/397 (82%) a sodium channel blockers (carbamazepine, oxcarbazepine, lamotrigine, lacosamide, eslicarbazepine). Added onto GABA modu- lators, cenobamate 100/200/400mg achieved seizure freedom rates (SFR) of 7.3%/15.6%/30.6% vs 2.1% for placebo; when added onto sodium channel blockers, cenobamate 100/200/400mg/day showed SFR of 2.3%/9.3%/17.5% vs 1.2% for placebo. Both results were statistically significant for 200 and 400mg. A consistent SFR with cenobamate for a subset of patients receiving background levetiracetam (11% 200mg and 25% 400 mg vs 2.5% placebo) as well as those with background benzodiazepines (20% 400 mg vs 0% placebo) occurred.ConclusionsAdjunctive cenobamate achieved significant dose-dependent SFR when combined with AEDs across multiple MoAs in patients with uncontrolled FOS.lee.finlan@arvelletx.com

Clinical impact of the dose and blood concentration of lacosamide in Japanese pediatric patients with epilepsy: A cohort study

PurposeThe relationship between treatment efficacy/tolerability and the dose/blood concentration of lacosamide (LCM) was investigated in a clinical cohort of Japanese pediatric patients with epilepsy. MethodsThis retrospective analysis reviewed the medical records of patients treated with LCM for >6 months at the Department of Pediatrics, Hiroshima University Hospital, from September 2017 to January 2021. The collected data included age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events leading to LCM discontinuation, dose at any evaluation point, serum concentration, and concomitant antiepileptic drugs (AEDs). ResultsThe study included 51 patients (31 male patients) between the ages of 2 and 19 years. All patients were Japanese. Epilepsy was classified as focal in 44 patients, generalized in six patients, and combined generalized and focal in one patient. The 50% responder rate for LCM treatment was 56.9%. Seven patients experienced complete seizure control (absence of seizures for 6 months before the follow-up visit). A relationship between dose and blood concentration was identified. Although the blood LCM concentration was higher in the responders than in the nonresponders (7.86 vs. 6.16 μg/mL; p = 0.028), there was no significant difference in dose between the two groups. Lacosamide showed efficacy at a dose >5 mg/kg/day in more than half of the 50% responders. The treatment-emergent adverse events (TEAEs) included seizure aggravation in five patients, irritability in two patients, and somnolence and drug eruption in one patient each. In six patients with TEAEs, the TEAEs developed within 1 month after treatment initiation and led to LCM discontinuation. ConclusionIn Japanese pediatric patients with epilepsy, LCM treatment is effective, particularly at higher doses. The blood concentration may be related more to efficacy than to dose. Lacosamide is generally well-tolerated by pediatric patients, and should be used at the maximum tolerable dose (needed to be gradually increased) in patients with otherwise insufficient seizure control. As TEAEs leading to discontinue treatment likely occur in early phase, it is needed to monitor patients carefully if TEAEs would happen in that phase.

GBAPerampanel Monotherapy- A Novel Treatment for Seizures: A Systematic Review

Perampanel (PER) has gained a current approval for monotherapy of treating focal-onset seizures with or without secondarily generalized seizures, and as an adjuvant therapy with concomitant antiepileptic drug (AED) for primary generalized seizures in patients aged older than 4 years. The recent studies on its monotherapy have become a breakthrough by recognizing its vast potential in clinical practices. This systematic review is aimed to correlate all the studies on monotherapy to validate the efficacy and safety profile of the drug.

The long-term efficacy of cannabidiol in the treatment of refractory epilepsy.

Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60months (median = 45.5months). We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1year after starting treatment and the most recent study visit. Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p=.12). Efficacy was also seen over a broad dose range, and up to 50mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions. This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.

Health-related quality of life in pediatric patients with partial onset seizures or primary generalized tonic-clonic seizures receiving adjunctive perampanel

RationaleStudy 311 (E2007-G000-311; NCT02849626) was a Phase 3, multicenter, open-label single-arm study of adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with partial-onset seizures (POS) (with/without secondarily generalized tonic-clonic seizures [SGTCS]) or primary generalized tonic-clonic seizures (PGTCS). Health-related quality of life (HRQoL) was an exploratory endpoint initially analyzed through simple descriptive summaries. The aim of this post hoc analysis was to provide a more thorough assessment of HRQoL. MethodsThis analysis focused on EQ-5D-Y data collected at Baseline, Week 23, and Week 52. Individual dimensions, visual analog scale (VAS) and summed misery index (MI) were evaluated at all visits and compared by seizure type (POS versus SGTCS versus PGTCS), age (4 to <7 versus 7 to <12), and use of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) (yes versus no). Paretian Classification of Health Change (PCHC) analysis summarized the proportion of patients who showed improvement or deterioration in HRQoL. Waterfall plots assessed changes in EQ-5D-Y scores by treatment-emergent adverse events (TEAEs) and by reduction in seizure frequency. Health state utility values associated with differing seizure frequency states were estimated using a linear mixed model. ResultsOne hundred and fifteen patients completed EQ-5D-Y at relevant study visits (Seizure type: POS n = 84 [of which 21 had SGTCS], PGTCS n = 31; Age: 4 to <7 years n = 30, 7 to <12 years n = 85; Concomitant EIAEDs: Yes n = 35, No n = 80). Completion rates out of those expected to complete EQ-5D-Y were high at both timepoints (84.4% at Week 23 and 97.2% at Week 52). Overall, VAS/MI remained stable over time (did not exceed minimal important difference); this was similar according to seizure type, age, and EIAED usage. In patients with ‘no problems’ on any EQ-5D-Y dimension at Baseline, nearly all retained their full health at Week 23 (94.7%), and all retained it at Week 52 (100.0%). PCHC analysis showed fewer patients with POS experienced deterioration in EQ-5D-Y than patients with PGTCS at Week 23 (24.1% versus 42.1%). Not experiencing a TEAE, or remaining seizure-free, was associated with improvements in VAS score at Week 23 compared to those experiencing TEAEs or seizures, respectively. Health state utility values (HSUVs) were estimated as follows: seizure free (LS Mean 0.914 [95% CIs 0.587, 1.240]), ≥1 seizure per year (0.620 [0.506, 0.734]), ≥1 seizure per month (0.596 [0.338, 0.855]), ≥1 seizure per week (0.284 [−0.014, 0.582]). ConclusionsAn in-depth analysis of EQ-5D-Y data allowed for a more nuanced exploration of HRQoL than previous descriptive summaries. Our findings provide evidence that perampanel as adjunctive therapy did not result in deterioration of patient HRQoL. The association between TEAEs or remaining seizure-free and HRQoL warrants further exploration. Increasing seizure frequency was associated with decreasing HSUVs; these can inform cost-effectiveness modeling of perampanel and other therapies aiming to reduce seizure frequency in pediatric patients.

Pharmacokinetics, tolerability, and clinical effectiveness of perampanel in Japanese patients with epilepsy

ObjectiveWe aimed to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum perampanel concentration and to correlate the concentration with clinical response and tolerability. MethodsA total of 4224 serum samples were obtained from 763 pediatric, adolescent, and adult patients for routine therapeutic drug monitoring. We compared the extent of enzyme induction between cytochrome P450 3A4 (CYP3A4) inducer regimens and built a statistical model to estimate the serum perampanel concentration that considered use of CYP3A4 inducers and inhibitors. To assess the tolerability and clinical effectiveness of perampanel therapy, we used the nested case-control approach. The case group was matched with the control group for age, sex, epilepsy type, and perampanel exposure periods. ResultsConcomitant use of the inducers phenytoin, carbamazepine, and phenobarbital dose-dependently reduced the perampanel concentration by 51 %, 67 %, and 37 %, respectively. The estimate model showed a good correlation between the predicted and measured concentrations (r2 = 0.62, p < 0.001). In 206 patients, the seizure reduction from baseline was > 50 % and the median perampanel concentration was 351 ng/mL (interquartile range, 191−603 ng/mL). Adverse events, such as somnolence, dizziness, and irritability, were experienced by 185 patients. The responder odds ratio was 5.1-fold higher in patients with a serum concentration > 600 ng/mL than in those with a serum concentration < 200 ng/mL; however, the former group had a 7.9-fold higher incidence of adverse events. ConclusionTherapeutic drug monitoring is clinically useful to assess drug interactions between perampanel and CYP3A4 inducers and inhibitors. We recommend that the target concentration of perampanel is initially set at 200–600 ng/mL. Serum concentrations > 600 ng/mL were associated with greater anti-seizure effects but had an increased risk of adverse events.

Pharmacokinetic variability of phenobarbital: a systematic review of population pharmacokinetic analysis.

Population pharmacokinetics with Bayesian forecasting provides for an effective approach when individualized drug dosing, while phenobarbital is a narrow therapeutic index drug that requires therapeutic drug monitoring. To date, several population pharmacokinetic models have been developed for phenobarbital, these showing a number of significant predictors of phenobarbital clearance and volume of distribution. We have therefore conducted a systematic review to summarize how these predictors affect phenobarbital pharmacokinetics as well as their relationships with pharmacokinetic parameters. A systematic search for studies of phenobarbital population pharmacokinetics that were carried out in humans and that employed a nonlinear mixed-effect approaches was made using the PubMed, Scopus, CINAHL Complete, and ScienceDirect databases. The search covered the period from these databases' inception to March 2020. Eighteen studies were included in this review, all of which used a one-compartment structure. The estimated phenobarbital clearance and volume of distribution ranged from 0.0034 to 0.0104L/h/kg and 0.37 to 1.21L/kg, respectively, with body weight, age, and concomitant antiepileptic drugs being the three most frequently identified predictors of clearance. Most models were validated through the use of an advanced internal approach. Phenobarbital clearance may be predicted from previously developed population pharmacokinetic models and their significant covariate-parameter relationships along with Bayesian forecasting. However, when applying these models in a target population, an external evaluation of these models using the target population is warranted, and it is recommended that future research be conducted to investigate the link between population pharmacokinetics and pharmacodynamics.

Does the accumulated antiepileptic drug load in chronic epilepsy reflect disease severity?

To ascertain factors that are related to the antiepileptic drug load in epilepsy. In this cross-sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n=1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n=91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic-clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%-10% of variance in drug load. Nearly the same variance (5%-8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long-lasting epilepsies.

Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial

ObjectiveTo evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic...

Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults.

The manufacturer of perampanel (PER) suggests an initial adult dose of 2-4 mg/day and an upward dose titration of 2 mg at no more frequently than 1- or 2-week intervals when used with enzyme-enhancing antiepileptic drugs (AEDs) or nonenzyme-enhancing AEDs, respectively. The general practice in our clinic is an initial dose of PER 2 mg/day and titrated by 2 mg/4 weeks to an initial target of 6 mg/day. Retrospective chart audit of patients starting PER in an adult epilepsy clinic between September 2013 and November 2016 with at least one 6-month follow-up visit was reviewed. Data collection included patient demographics, seizure characteristics, past and concurrent therapy, monthly seizure frequency before PER and at 6-month visit, and characteristics of PER discontinuation. Efficacy of treatment was assessed with the Engel classification and 50% responder rate. N = 102 patients; mean age = 40 years and 54% females. Focal onset seizures 85%, generalized 13%, and unknown 2%. Median prior AED exposure = 6 (range 3-20); median concomitant AED use = 2 (range 1-5). Follow-up range was 6-37 months. The median seizure frequency/month prePER treatment was 6 (range 0-30) for focal onset seizures and 1 (range 0-6) for generalized seizures. The retention rate amongst all patients at 6 months was 78.4%. At 6-month follow-up, 36% of all patients achieved Engel class I (seizure freedom) (30.7% of patients with focal onset seizures and 63.6% with generalized epilepsy). The 50% responder rate was 52% and 82% for focal and generalized epilepsy, respectively. PER has a good retention rate when titrated slowly and thus encouraging seizure freedom results in an otherwise medically refractory epilepsy population.

Eslicarbazepine acetate in post-stroke epilepsy: Clinical practice evidence from Euro-Esli.

ObjectivesTo assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients included in the Euro‐Esli study who had focal seizures associated with post‐stroke epilepsy (PSE).Materials and MethodsEuro‐Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments (evaluated after 3, 6 and 12 months of ESL treatment and at final follow‐up [“last visit”]) included rates of response (≥50% seizure frequency reduction), seizure freedom (no seizures since at least the prior visit) and retention. Safety/tolerability was assessed throughout ESL treatment by evaluating adverse events (AEs) and discontinuation due to AEs. A post hoc analysis was conducted of patients with PSE versus patients without PSE (“non‐PSE”).ResultsOf 1656 patients included in the analysis, 76 (4.6%) had PSE and 1580 (95.4%) had non‐PSE. Compared with non‐PSE patients, PSE patients were significantly older, had significantly shorter epilepsy duration, significantly lower total baseline seizure frequency, and were treated with significantly fewer prior and concomitant antiepileptic drugs (P < .001 for all). At the last visit, the responder rate was significantly higher in PSE versus non‐PSE patients (72.9% vs 60.6%; P = .040), as was the seizure freedom rate (48.6% vs 31.7%; P = .003). After 12 months, retention was significantly higher in PSE versus non‐PSE patients (87.8% vs 77.4%; P = .035). The incidence of AEs was similar for PSE versus non‐PSE patients (36.0% vs 35.8%; P = .966).ConclusionsThese findings suggest that ESL may be an effective and well‐tolerated treatment option for patients with focal seizures due to PSE.

Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study.

Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice.Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB−).Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10–12), 14 (10–20), and 15.5 mg/kg/day (10–20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was −41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB– patients.Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.

Antiepileptic combination therapy with Stevens-Johnson syndrome and toxic epidermal necrolysis: Analysis of a Japanese pharmacovigilance database.

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. 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). 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). 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.

Forced normalization: case series from a Spanish epilepsy unit

IntroductionForced normalization is a clinical situation of singular relationship betweenepilepsy and psychosis, in which a patient shows behavioural and psychiatric symptoms coinciding with a reduction or termination of seizures and a total or partial normalization ofelectroencephalogram. Behavioural symptoms (frequently psychosis) or mood disturbances may appear. More information about this phenomenon, risk factors and prognostic variables is needed. Materials and methodsWe conducted a systematic review of allthe patients followed at the specific Epilepsy Office in Virgen de la Victoria hospital, in order todetect and analyse the cases of forced normalization and to describe the clinical variables relatedto it. ResultsWe present a 10 patient case series, 6 women and 4 men with an average age of 51.5 years. Demographic data, neurological diagnosis, type of seizures, psychiatric comorbidity,related Antiepileptic Drugs (AEDs), pharmacoresistance, polytherapy, concomitant AEDs,therapeutic management and prognosis were analysed. ConclusionThis is a hospital-based studyabout the characteristics of forced normalization in patients with epilepsy. It is one of thelargest series reported in 30 years, to our knowledge. Psychiatric comorbidity and developmentaldelay seem to be strongly associated with forced normalization in our series, or this relationshipcould be biased by the special characteristics of an Epilepsy Office which proportionately assistsmore cases of refractory epilepsy, commonly associated with disabilities and comorbidity. Theprognosis is favourable. Our data could establish a starting point for the design of larger prospective and experimental studies.

Zonisamide add-on therapy for focal epilepsy.

The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop dug-resistant epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2018. To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid(September 2019). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field, to seek any ongoing or unpublished studies. Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the certainty of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and certainty of the evidence for each outcome in a 'Summary of findings' table. We did not find any new studies since the last version of this review. We included eight studies (1636 participants) from previous versions of this review. The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-certainty evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-certainty evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8). Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-certainty evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-certainty evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The following adverse effects were more likely to be associated with zonisamide than with placebo: ataxia (RR 3.85, 99% CI 1.36 to 10.93; 4 trials, 734 participants; low-certainty evidence); somnolence (RR 1.52, 99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-certainty evidence); agitation (RR 2.35, 99% CI 1.05 to 5.27; 4 trials, 598 participants; low-certainty evidence); and anorexia (RR 2.74, 99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-certainty evidence). Across the eight studies, we rated risk of bias domains at low or unclear risk of bias, apart from two studies, which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. When used as an add-on treatment in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs, moderate-certainty evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy, or to people with other seizure types or epilepsy syndromes.

Brivaracetam substituting other antiepileptic treatments: Results of a retrospective study in German epilepsy centers.

ObjectiveTo evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam.MethodsIn this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation.ResultsFive hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure‐free. In the SS, 34.6% of patients reported treatment‐emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug‐related. Incidences of behavioral AEs before (3‐month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs).SignificanceBrivaracetam was effective and well‐tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.