Seizure Freedom Rates Research Articles

Multilobar Epilepsy Surgery in Childhood and Adolescence: Predictors of Long-Term Seizure Freedom.

Although multilobar resections correspond to one-fifth of pediatric epilepsy surgery, there are little data on long-term seizure control. To investigate the long-term seizure outcomes of children and adolescents undergoing multilobar epilepsy surgery and identify their predictors. In this retrospective study, we considered 69 consecutive patients that underwent multilobar epilepsy surgery at the age of 10.0± 5.0 yr (mean±SD). The magnetic resonance imaging revealed a lesion in all but 2 cases. Resections were temporo-parieto(-occipital) in 30%, temporo-occipital in 41%, parieto-occipital in 16%, and fronto-(temporo)-parietal in 13% cases. Etiologies were determined as focal cortical dysplasia in 67%, perinatal or postnatal ischemic lesions in 23%, and benign tumors in 10% of cases. At last follow-up of median 9 yr (range 2.8-14.8), 48% patients were seizure free; 33% were off antiepileptic drugs. 10% of patients, all with dysplastic etiology, required reoperations: 4 of 7 achieved seizure freedom. Seizure recurrence occurred mostly (80%) within the first 6 mo. Among presurgical variables, only an epileptogenic zone far from eloquent cortex independently correlated with significantly higher rates of seizure arrest in multivariate analysis. Among postsurgical variables, the absence of residual lesion and of acute postsurgical seizures was independently associated with significantly higher rates of seizure freedom. Our study demonstrates that multilobar epilepsy surgery is effective regarding long-term seizure freedom and antiepileptic drug withdrawal in selected pediatric candidates. Epileptogenic zones-and lesions-localized distant from eloquent cortex and, thus, fully resectable predispose for seizure control. Acute postsurgical seizures are critical markers of seizure recurrence that should lead to prompt reevaluation.

Vagus Nerve Stimulation in Intractable Epilepsy.

To investigate and compare the efficacy and safety of vagus nerve stimulation (VNS) therapy in different types of epilepsy. Patients, who were implanted with VNS between the years 2005 and 2020, were retrospectively included in the study. Age, gender, age at seizure onset, epilepsy types, VNS implantation year, replacement year, pre and post-VNS seizure frequency, number of responders, number of antiseizure medication and adverse events were recorded. In total, 41 patients were included in the study. The number of patients with focal epilepsy was 21 (51.2%). 10 patients (24.4%) had generalized epilepsy and 10 patients (24.4%) had ?combined generalized and focal epilepsy? (Lennox-Gastaut, Dravet syndrome). The Pre-VNS median seizure frequency was 1.5/day in the focal group, 0.6/day in the generalized group and 6/day in the combined group. Seizure frequencies dropped to 0.3/day in the focal group, 0.2/day in the generalized group and 3.0/day in the combined group at the 12th month after VNS (p < 0.001, p=0.004, p < 0.001). The response rate was found to be 68.3% at the 12th month after VNS. The number of antiseizure medications was decreased from 3.6/day to 3.1/day at the 12th months after VNS (p < 0.001). Two patients? (4.9%) VNS therapy was discontinued due to adverse events. The study indicates that VNS therapy is safe and effective in focal, generalized and combined epilepsy types. Despite having a low seizure freedom rate, VNS is a good alternative treatment option for patients who for any reason are not candidates for resective surgery.

Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht–Lundborg disease: An open-label, long-term follow-up trial

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht–Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures.Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595).Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht–Lundborg disease, with improvements in focal seizure frequency maintained over time.

NCMP-08. EFFICACY OF ANTIEPILEPTIC DRUGS IN GLIOMA PATIENTS WITH EPILEPSY: A SYSTEMATIC REVIEW

Abstract BACKGROUND Epilepsy is a common symptom in glioma patients, requiring antiepileptic drug (AED) treatment. However, comprehensive data on the efficacy and tolerability of AED treatment is currently lacking. In this systematic review we specifically assessed the efficacy of AEDs in patients with a grade II-IV glioma. METHODS Electronic databases PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane library were searched up to April 2020. Three different outcomes were extracted from all eligible articles: (I) seizure freedom; (II) ≥50% reduction in seizure frequency; and (III) treatment failure. To overcome variation with respect to sample sizes, weighted averages (WA) were calculated for outcomes at 6 and 12 months. RESULT A total of 64 studies were included. For monotherapy, the 6-months seizure freedom rate was highest for phenytoin (WA=72%), whereas the 12-months seizure freedom rate was highest for pregabalin (WA=75%). For achieving ≥ 50% seizure reduction, levetiracetam was the most effective AED at 6 and 12 months, with WA of 82 and 97% respectively. Considering the provided polytherapy combinations, levetiracetam combined with phenytoin was most effective followed by levetiracetam with valproic acid. Seizure freedom rates with polytherapy at 6 months and 12 months were highest for combinations with phenytoin and topiramate, respectively. For achieving a ≥ 50% seizure reduction, combinations with perampanel were found to be the most effective at 6 and 12 months. CONCLUSION Based on the current literature, phenytoin, levetiracetam and pregabalin are most effective as AED monotherapy in glioma patients with epilepsy. Well-controlled prospective studies are needed to help further guide clinician’s treatment choices.

Characteristics and treatment outcomes of newly diagnosed epilepsy in older people: A 30-year longitudinal cohort study.

To describe the clinical characteristics and evaluate the long-term treatment outcomes in older people with newly diagnosed epilepsy over the past 30years. We included patients newly diagnosed with epilepsy and commenced on antiseizure medications (ASMs) at age 65years or older between July 1982 and October 2012 at the Western infirmary in Glasgow, Scotland. They were followed up until April 2016 or death. Seizure freedom was defined as no seizure for at least 1year on unchanged medication at the last follow-up. A total of 201 patients (median age 73years, 59% male) were included. The median duration from initial seizure to starting treatment was 8 months (interquartile range: 3.0-24.0 months); 42.2% (85/201) patients had more than five seizures before commencing treatment. Brain imaging showed potentially epileptogenic lesions in 19.7% (38/193) of patients and other abnormalities in 56.5% (109/193); 78.6% patients (158/201) were seizure-free at the last follow-up, of whom 94.9% were taking monotherapy. Concomitant aspirin use (n=80) was associated with a lower probability of being seizure-free (relative risk 0.82, 95% confidence interval 0.70-0.97; P=.02). The use of second-generation ASMs as the initial monotherapy increased from 31.5% (23/73) before 2000 to 70.3% (90/128, P<.001) from 2000 onward. However, the seizure freedom rates (67.1% vs 55.5%; P=.35) and intolerable adverse-effect rates (16.4% vs 19.5%; P=.45) did not show any significant difference. There was often a long interval between seizure onset and the initiation of treatment in older people with new-onset epilepsy, although the majority responded well to ASM treatment. Brain imaging showed a high rate of abnormalities. Despite the increased use of second-generation ASMs, treatment outcomes in later-onset epilepsy have not improved over time. The possible effect of aspirin on treatment response warrants further investigation.

Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs

PurposeTo investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD). MethodsThis multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. ResultsOf the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. ConclusionPER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

The costs of epilepsy in Australia: A productivity-based analysis.

To determine the health economic burden of epilepsy for Australians of working age by using life table modeling and to model whether improved seizure control may result in substantial health economic benefits. Life table modeling was used for working age Australians aged 15-69 years with epilepsy and the cohort was followed until age 70 years. Published 2017 population and epilepsy-related data regarding epilepsy prevalence, mortality, and productivity were used. This model was then re-simulated, assuming the cohort no longer had epilepsy. Differences in outcomes between these cohorts were attributed to epilepsy. Scenarios were also simulated in which the proportion of seizure-free patients increased from baseline 70% up to 75% and 80%. In 2017, Australians of working age with epilepsy followed until age 70 years were predicted to experience over 14,000 excess deaths, more than 78,000 years of life lost, and over 146,000 productivity-adjusted life years lost due to epilepsy. This resulted in lost gross domestic product (GDP) of US $22.1 billion. Increasing seizure freedom by 5% and 10% would reduce health care costs, save years of life, and translate to US $2.6 billion and US $5.3 billion GDP retained for seizure freedom rates of 75% and 80%, respectively. Our study highlights the considerable societal and economic burden of epilepsy. Relatively modest improvements in overall seizure control could bring substantial economic benefits.

Cenobamate for the treatment of focal epilepsies

ABSTRACT Introduction Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients because the majority require anticonvulsant treatment for an extended period of time. Due to the fact that 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Cenobamate is the latest approved antiepileptic drug in focal epilepsy, and its mode of action is thought to be mediated by blocking voltage-gated sodium channels and interaction with the GABAergic system. Areas covered This article reviews animal studies, pharmacokinetics, pharmacodynamics, and the phase 1 to 3 trials and open-label extension data on cenobamate. Expert opinion Cenobamate has the potential to perform as an important ASD because trial data are indicative of remarkable responder and seizure freedom rates so far not seen with other ASDs. Cenobamate demonstrated significant efficacy at a dosage between 100 and 400 mg per day. The side-effect profile of this drug is comparable to other ASDs and is mainly CNS related; in particular, somnolence, dizziness, headache, diplopia, and nystagmus. However, slow titration is mandatory to decrease the risk of drug rash with eosinophilia and systemic symptoms (DRESS) that was observed in several patients with fast uptitration schemes.

Cross-national disparities contribute to heterogeneity in patient outcomes following invasive monitoring: A hierarchical mixed-effects analysis.

There is substantial variability in outcomes following invasive monitoring and surgical treatment of drug-resistant epilepsy (DRE). Patients with DRE are uniquely vulnerable to cross-national health care disparities, as their epilepsy is difficult to treat and requires extensive resources. In a large cross-national database of patients undergoing invasive monitoring for epilepsy surgery, we sought to evaluate the association between social, economic, and educational indicators of the country of treatment and patient outcomes following invasive monitoring. We performed a mixed-effects analysis of an individual patient database of 595 subjects enrolled in 33 studies encompassing 25 neurosurgical centers in 10 countries of invasive monitoring for epilepsy from 1996 to 2019. Upon preliminary univariate analysis, significant nation-level predictors of seizure outcome following either stereoelectroencephalography or subdural electrodes were hospital beds per 100,000 population, physician density, gross domestic product (GDP) growth, male and female educational attainment, and unemployment rate. On multivariate mixed-effects logistic regression, physician density (β=-0.5112, P<.00697) and GDP growth (β=0.53822, P<.00404) were the only nation-level covariates of significance associated with seizure outcome. A higher physician density was associated with lesser seizure freedom rates, whereas higher GDP growth was associated with greater seizure freedom rates. Although patient-specific variables were the primary determinant of seizure outcomes, cross-national disparities also contribute to heterogeneities. Our findings highlight the importance of a systems-level dialogue to improve surgical outcomes for DRE patients.

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.

The clinical utility of intraoperative electrocorticography in pediatric epilepsy surgical strategy and planning.

In this study, the authors aimed to determine 1) whether the use of intraoperative electrocorticography (ECoG) affects outcomes and complication rates of children undergoing resective epilepsy surgery; 2) which patient- and epilepsy-related variables might influence ECoG-based surgical strategy; and 3) what the predictors of epilepsy surgery outcomes are. Over a period of 12 years, data were collected on pediatric patients who underwent tailored brain resections in the Motol Epilepsy Center. In patients in whom an abnormal ECoG pattern (e.g., spiking, suppression burst, or recruiting rhythm) was not observed beyond presurgically planned resection margins, the authors did not modify the surgical plan (group A). In those with significant abnormal ECoG findings beyond resection margins, the authors either did (group B) or did not (group C) modify the surgical plan, depending on the proximity of the eloquent cortex or potential extent of resection. Using Fisher's exact test and the chi-square test, the 3 groups were compared in relation to epilepsy surgery outcomes and complication rate. Next, multivariate models were constructed to identify variables associated with each of the groups and with epilepsy surgery outcomes. Patients in group C achieved significantly lower rates of seizure freedom compared to groups A (OR 30.3, p < 0.001) and B (OR 35.2, p < 0.001); groups A and B did not significantly differ (p = 0.78). Patients in whom the surgical plan was modified suffered from more frequent complications (B vs A+C, OR 3.8, p = 0.01), but these were mostly minor (duration < 3 months; B vs A+C, p = 0.008). In all cases, tissue samples from extended resections were positive for the presence of the original pathology. Patients with intended modification of the surgical plan (groups B+C) suffered more often from daily seizures, had a higher age at first seizure, had intellectual disability, and were regarded as MR-negative (p < 0.001). Unfavorable surgical outcome (Engel class II-IV) was associated with focal cortical dysplasia, incomplete resection based on MRI and/or ECoG findings, negative MRI finding, and inability to modify the surgical plan when indicated. Intraoperative ECoG serves as a reliable tool to guide resection and may inform the prognosis for seizure freedom in pediatric patients undergoing epilepsy surgery. ECoG-based modification of the surgical plan is associated with a higher rate of minor complications. Children in whom ECoG-based modification of the surgical plan is indicated but not feasible achieve significantly worse surgical outcomes.

Eslicarbazepine Acetate: A Review in Focal-Onset Seizures

Eslicarbazepine acetate (Zebinix®), a voltage-gated sodium channel blocker, is a once-daily, orally administered anti-seizure medication available in the EU for use as monotherapy in adults with newly diagnosed focal-onset seizures and as adjunctive therapy in adults, adolescents and children aged > 6 years with focal-onset seizures. In adult patients, adjunctive eslicarbazepine acetate was generally associated with a significant decrease in seizure frequency and an increase in responder rate compared with placebo. The drug was also an effective monotherapy agent in adult patients, demonstrating noninferiority to controlled-release carbamazepine, in terms of seizure freedom rates. In paediatric patients, eslicarbazepine acetate provided seizure control when administered as adjunctive therapy, with the benefits appearing to be dependent on age and dose. The antiepileptic efficacy of eslicarbazepine acetate as adjunctive therapy or as monotherapy was maintained during longer-term extension studies, with each extension study period being up to 2 years. Oral eslicarbazepine acetate was generally well tolerated when administered as adjunctive therapy or monotherapy in adult patients and when administered as adjunctive therapy in paediatric patients, with most adverse events being of mild or moderate intensity. In conclusion, with the convenience of once-daily administration, eslicarbazepine acetate is an effective and generally well-tolerated treatment option for adults, adolescents and children aged > 6 years with focal-onset seizures.

The outcome of altering antiepileptic drug therapy before pregnancy

We investigated the outcome of altering antiepileptic drug (AED) therapy in the year before pregnancy on 2233 occasions in Australian women in the 20-year period of functioning of the Raoul Wallenberg Australian Pregnancy Register (APR).Therapy had been altered in 358 instances (16%) in the months prior to the pregnancy (median interval: 18 weeks). Antiepileptic drug doses had been changed in 141 pregnancies (39.4%), being decreased in 94; drugs changed in 151 (42.2%); drugs withdrawn without replacement in 66 (18.4%) but resumed in 40 before pregnancy ended. The main drugs involved were valproate (34%), phenytoin (16.5%), topiramate (12.6%), and carbamazepine (11.4%). Antiepileptic drug doses were increased significantly more often (16.9% vs. 6.4%) when epilepsy before pregnancy was not controlled, and AED treatment ceased significantly less often (13.6% vs. 24.0%). The alterations were more often made in women with generalized epilepsies and in those whose seizure disorders were not fully controlled in the prepregnancy year, suggesting that avoidance of teratogenicity and achieving improved seizure control often motivated the changes.Overall, the alterations did not result in improved rates of seizure freedom during pregnancy, as compared with pregnancies where therapy was unchanged; however, fetal malformation rates were lower 3.6% vs. 5.4%, but this difference did not attain statistical significance. The same trends regarding seizure control and malformations persisted after pregnancies involving valproate exposure were excluded.In conclusion, this analysis of the APR cohort did not demonstrate that altering AEDs before pregnancy produced a significant improvement in seizure control and the reduction in fetal malformation rate that occurred was not statistically significant.

Corrigendum

Epilepsia OpenVolume 5, Issue 3 p. 518-518 CORRIGENDUMOpen Access Corrigendum First published: 16 July 2020 https://doi.org/10.1002/epi4.12416AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the article by Yamamoto et al,1 the corresponding author’s contact information was published incorrectly. The correct email addresses are taka-yamamd@sis.seirei.or.jp and taka_mdms@icloud.com. Additionally, Table 2 included an error. The entry under “Exploratory endpoints, seizure-freedom rate in patients with:” should read “FIAS and/or FBTCS”. The corrected version of Table 2 follows. We apologize for these errors. TABLE 2. Efficacy analysis in the 26-week Maintenance Period of perampanel 4 mg/d or last evaluated dose (perampanel 4 or 8 mg/d) (mITT Analysis Set) N Perampanel 4 mg/d Perampanel 4 or 8 mg/d n (%) (95% CI) n (%) (95% CI) Primary endpoint Overall seizure-freedom ratea 73 46 (63.0) (50.9–74.0) 54 (74.0) (62.4–83.5) Secondary endpoints, cumulative probability of time to: First seizure onset 73 (30.8) (21.5–43.0) (18.2) (11.0–29.3) Withdrawal from the studyb 73 (23.7) (15.4–35.3) (23.3) (15.2–34.8) Exploratory endpoints, seizure-freedom rate in patients with: FBTCSa 48 31 (64.6) (49.5–77.8) 37 (77.1) (62.7–88.0) FIASa 41 24 (58.5) (42.1–73.7) 28 (68.3) (51.9–81.9) FIAS and/or FBTCSa 70 43 (61.4) (49.0–72.8) 51 (72.9) (60.9–82.8) Abbreviations: CI, confidence interval; FBTCS, focal to bilateral tonic-clonic seizures; FIAS, focal impaired awareness seizures; mITT, modified intent-to-treat. a CI was calculated using Clopper-Pearson's exact method. b Estimated by Kaplan−Meier method; at 26 weeks from the first date of the Maintenance Period. CI was calculated using Greenwood formula and log-log transformation. REFERENCE 1Yamamoto T, Lim SC, Ninomiya H, Kubota Y, Shin WC, Kim DW, et al. Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: the open-label Study 342 (FREEDOM Study). Epilepsia Open. 2020; 5: 274– 84. https://doi.org/10.1002/epi4.12398 Volume5, Issue3September 2020Pages 518-518 ReferencesRelatedInformation

The patterns of response of 11 regimens for infantile spasms

Infantile spasms (ISs) is a devastating form of an early infantile epileptic encephalopathy. The patterns of response of multiple regimens, and the difference in response rates for the cases who receive first-line therapies on time versus those who receive them after non-first-line therapies are unknown. We performed a study involving 314 ISs cases aiming to investigate the patterns of response of 11 regimens, and the difference in response rates for the cases received first-line therapies as first two regimens versus those who received other drugs prior to first-line options. As a result, the efficacy of each regimen was: the foremost two regimens; 36.99%, third; 10.27%, fourth; 6.16%, fifth; 5.48%, and from the sixth regimen onwards, each additional regimen added ≤ 2% probability of seizure freedom. There was a statistically significant difference in seizure freedom rates between cases received first-line therapies as first or second regimen versus those who received them later. Our study revealed for the first time that in ISs cases, seizure freedom is likely to be observed within the first five regimens, and an early administration of first-line therapies is superior to non-first-line options. These results will aid in management of ISs cases.

Cenobamate: A New Adjunctive Agent for Drug-Resistant Focal Onset Epilepsy.

To review the pharmacology, efficacy, and safety of oral cenobamate in the treatment of uncontrolled focal epilepsy. The PubMed database and ClinicalTrials.gov were searched using the following terms: cenobamate, Xcopri, and YKP3089. Articles published in English between January 2000 and April 2020 related to pharmacology, safety, and clinical trials were assessed. In a phase 2 trial, cenobamate reduced the median percentage change in seizure frequency from baseline by 56% compared with 22% for placebo (P < 0.0001). In another phase 2 trial of multiple cenobamate doses, cenobamate reduced seizure frequency by 36% (P = 0.0071) in the 100-mg group and 55% (P < 0.0001) in both the 200- and 400-mg groups, compared to 24% with placebo. Adverse effects of cenobamate appear to be similar to those of other antiseizure medications and primarily affect the neurological system. In patients taking antiseizure medications who continue to have focal seizures, cenobamate has efficacy at multiple doses and is generally well tolerated. Cenobamate may be distinguished from other antiseizure medications by high rates of seizure freedom not seen in previous placebo-controlled trials, which has the potential to significantly improve quality of life. However, despite this efficacy, Drug Reaction with Eosinophilia and Systemic Symptoms may remain a significant concern with cenobamate. As seen in clinical trials, cenobamate as an adjunctive, once-daily treatment represents an efficacious and generally well-tolerated therapy for patients with drug-resistant focal epilepsy.

Ketogenic diets for drug-resistant epilepsy.

Ketogenic diets for drug-resistant epilepsy.

Adjunctive perampanel and myoclonic and absence seizures: Post hoc analysis of data from study 332 in patients with idiopathic generalized epilepsy

PurposeThis post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332. MethodsPatients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs). ResultsDuring the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel. ConclusionIn this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open-label Study 342 (FREEDOM Study).

ObjectiveOur study assessed perampanel monotherapy in patients (aged ≥12 years) with focal‐onset seizures (FOS) with or without focal to bilateral tonic‐clonic seizures (FBTCS) in Japan and South Korea.MethodsStudy 342 (NCT03201900; FREEDOM) is a single‐arm, open‐label, Phase III study. Patients initially received perampanel in a 32‐week 4‐mg/d Treatment Phase (6‐week Titration; 26‐week Maintenance Periods). If they experienced a seizure during the 4‐mg/d Maintenance Period, they could be up‐titrated to 8 mg/d across an additional 30‐week Treatment Phase (4‐week Titration; 26‐week Maintenance Periods). Primary endpoint was the seizure‐freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment‐emergent adverse events (TEAEs) were monitored.ResultsAt data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4‐mg/d Titration Period, meaning 73 patients entered the 4‐mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure‐freedom rate in the 26‐week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9‐74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4‐83.5) at 4 or 8 mg/d. Cumulative probability of seizure‐onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5‐43.0) and 23.7% (95% CI: 15.4‐35.3) at 4 mg/d, and 18.2% (95% CI: 11.0‐29.3) and 23.3% (95% CI: 15.2‐34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness.SignificancePerampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.

To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS). This multicenter, retrospective, observational study was conducted in patients aged≥12years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12months and tolerability throughout the follow-up. A total of 98 patients (mean age = 49.6±21.7years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14months (range = 1-57) with a median dose of 4mg (range = 2-10). The retention rates at 3, 6, and 12months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3months, 78.1% at 6months, and 55.1% at 12months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P=.046). PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.