Percent Reduction In Seizure Frequency Research Articles

Efficacy and Safety of adjunctive Perampanel in a prospective, real-world, Phase IV study in Indian patients aged ≥12 years for Treatment of focal-onset Epilepsy: Study 508.

ESPRITE (Study 508; NCT03836924) evaluated the real-world safety, tolerability, and efficacy of adjunctive perampanel in patients aged ≥12 years with focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS), in India. ESPRITE was a prospective, multicenter, single-arm, observational, Phase IV study with a 6-month Treatment Period. Patients were aged ≥12 years and had been prescribed perampanel for adjunctive treatment of FOS, with or without FBTCS. Assessments included incidence of treatment-emergent adverse events (TEAEs; primary endpoint), median percent reduction in seizure frequency per 28 days from baseline, 50% responder rates, and seizure-freedom rates. Overall, 200 patients were enrolled (199 patients in the Safety Analysis Set and 174 patients who completed all visits in the main efficacy analyses). TEAEs (all mild or moderate in severity) were reported in 18.1% (n = 36/199) of patients (the most common were dizziness [3.0%] and irritability [2.0%]). TEAEs leading to discontinuation of perampanel were reported in 2.0% of patients; no deaths or serious TEAEs occurred. At 6 months, median percent reduction in seizure frequency was 100.0%, 50% responder rate was 83.3%, and seizure-freedom rate was 49.4%. Adjunctive perampanel (at a mean daily dose of 4 mg/day) was shown to be well tolerated and effective in patients aged ≥12 years with FOS, with or without FBTCS, from India. Many patients do not receive adequate treatment for epilepsy and need effective seizure control medications. In this 6-month clinical study, 199 patients from India, aged 12 years or older, added perampanel to the anti-seizure medications they were already taking. At 6 months, 49% of patients experienced no seizures since starting perampanel and seizure frequency was reduced by half in 83% of patients. Side effects occurred in 18% of patients (most commonly dizziness and irritability) and caused 2% to stop perampanel; no deaths were reported. Perampanel was an effective and generally safe added medication for patients with epilepsy from India.

Efficacy and Safety of Fenfluramine in Lennox-Gastaut Syndrome: A Systematic Review (P13-1.007)

<h3>Objective:</h3> This systematic review aims to explore the efficacy, safety, and tolerability of fenfluramine for seizure control in patients with Lennox-Gastaut syndrome (LGS). <h3>Background:</h3> Fenfluramine has been recently approved as an adjunctive medication for seizure control in patients with Lennox-Gastaut syndrome (LGS). Previously, it has been used in treatment of patients with Dravet syndrome. <h3>Design/Methods:</h3> We conducted a systematic literature search on MEDLINE, Cochrane, and EMBASE as per guidelines of Preferred Reporting Items for Systematic Reviews (PRISMA). Two clinical trials analysing the effects of different doses of fenfluramine were included in this review. <h3>Results:</h3> In a double-blind phase 3 randomised control trial (RCT), participants were randomised to receive fenfluramine (0.2 or 0.7mg/kg/d) or a placebo. In another open-label clinical trial (Lagae et al.), patients were administered fenfluramine with median dose being 0.4mg/kg/d. 50% or greater reduction in seizure frequency was assessed in both trials. The responder rate in the open-label trial was 62% at 20 weeks and 66.7% at 15 months, while responder rate in the RCT was also significant in both groups (28% in the 0.2mg/kg/day group and 25% in the 0.7mg/kg/day). The median percentage reduction in seizure frequency in the open-label trial was 53% in core and 58% in extension period, while 14.2% reduction in 0.2mg/kg/d and 26.5% reduction in 0.7mg/kg/d were reported in the RCT. Adverse effects were reported in 70% of patients in the open-label trial while the RCT reported ≥1 adverse effects in 78%, 90% and 75% of the participants from 0.2mg/kg/d, 0.7mg/kg/d and placebo groups, respectively. Adverse effects commonly seen were decreased appetite, somnolence, and fatigue. <h3>Conclusions:</h3> Adjunctive use of fenfluramine results in significant improvement in LGS patients refractory to standardised anti-seizure therapies. The side effects reported are usually mild. <b>Disclosure:</b> Mr. Qureshi has nothing to disclose. Ms. Kareem has nothing to disclose. Miss Mehdi has nothing to disclose. Miss Nadeem has nothing to disclose. Miss Majid has nothing to disclose. Dr. Hassan has nothing to disclose. Bakhtawar Ahmad has nothing to disclose. Mr. Aemaz Ur Rehman has nothing to disclose. Dr. Iftikhar has nothing to disclose. Dr. Khokhar has nothing to disclose.

ELEVATE Study 410: Assessment of Cognition (EpiTrack ® ) Following Perampanel (Monotherapy/First Adjunctive) in Patients with Epilepsy and a History of Psychiatric/Behavioral Events (P11-1.011)

<h3>Objective:</h3> To assess change from baseline in cognition (EpiTrack^®) scores, efficacy, and safety in a subgroup of patients with a history of psychiatric and behavioral events from the Phase IV ELEVATE Study (Study 410; NCT03288129). <h3>Background:</h3> ELEVATE assessed perampanel monotherapy/first adjunctive therapy in patients aged ≥4 years with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). <h3>Design/Methods:</h3> The study consisted of Screening, Titration (≤13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, patients received perampanel at 2 mg/day, which was up-titrated to 4 mg/day (further dose increases [of 2 mg] based on response and tolerability; maximum, 12 mg/day). The primary endpoint was retention rate at 3, 6, 9, and 12 months. Other endpoints included seizure freedom (Maintenance Period), median percent reduction in seizure frequency (Maintenance Period), cognition (assessed using EpiTrack^® [patients ≥6 years of age; baseline, and 3 and 12 months]), and safety. <h3>Results:</h3> In the Safety Analysis Set, 54 patients received perampanel monotherapy/first adjunctive therapy. Of those, 24 patients (FOS, n=17; FBTCS, n=2; GTCS, n=4) had a history of psychiatric and behavioral events and were included in this post hoc analysis. The mean (standard deviation) changes from baseline in EpiTrack^® total score at 12 months and end of treatment were −1.1 (3.14; n=11) and −0.5 (2.61; n=23), respectively (increase=improvement). Median percent reduction in seizure frequency/28 days during the entire Maintenance Period was 73.2% (n=22). The incidence of any treatment-emergent adverse events (TEAEs) in this subgroup was 95.8% (n=23/24). The most common TEAEs were dizziness (25.0%, n=6/24) and vomiting (20.8%, n=5/24). <h3>Conclusions:</h3> Perampanel as monotherapy/first adjunctive therapy was generally safe and efficacious in patients from ELEVATE with a history of psychiatric and behavioral events; EpiTrack^® score in these patients was consistent with that observed in the overall patient population. <b>Disclosure:</b> Dr. Punia has nothing to disclose. Dr. Samad has received personal compensation for serving as an employee of Eisai. Dr. Ngo has received personal compensation for serving as an employee of Eisai Inc.. Dinesh Kumar has received personal compensation for serving as an employee of Eisai. Dr. Malhotra has received personal compensation for serving as an employee of Eisai.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

ObjectiveIndividuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use.Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. MethodsThis is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5–18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF®) parent form, a questionnaire capturing parents’/caregivers’ perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF® were mapped to the current edition, the BRIEF®2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF®2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman’s rho correlation coefficients assessed associations between change in BRIEF®2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and ≥50% MCSF reduction. Changes in the distribution of BRIEF®2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as Reliable Change Index (RCI) values ≥95% certainty relative to a reference population of neurotypically developing healthy volunteers, were then assessed by cross-tabulations and Somers’ D tests (p ≤ 0.05). When there was a significant meaningful improvement in an index score, post-hoc analyses using the same statistical methods were conducted to evaluate the individual BRIEF®2 scales composing that index. Supplemental analyses examined the proportions of patients in MCSF reduction groups <25% and ≥75% who achieved clinically meaningful improvement or worsening in everyday EF using RCI values ≥95% certainty and ≥80% certainty, respectively, relative to the reference population. ResultsAt the time of analysis, 58 children and young adults (mean age: 11 ± 4 years) had reached OLE Year 1 of fenfluramine treatment with a 75% median percentage reduction in seizure frequency from pre-randomization baseline. Overall, there was a significant correlation between change in MCSF and change in BRIEF®2 T-scores for ERI (p = 0.008), but not for BRI, CRI, or GEC (p > 0.05). At OLE Year 1, 78% (n = 45) of total children/young adults had ≥50% MCSF reduction (50% [n = 29] achieved ≥75% MCSF reduction) and 22% (n = 13) of total children/young adults had <50% MCSF reduction (12% [n = 7] showed <25% MCSF reduction). The ≥50% MCSF reduction group was significantly more likely to achieve clinically meaningful improvement (RCI ≥ 95% certainty) in ERI (p = 0.002) and in CRI (p = 0.001) than the <50% MCSF reduction group. There were no significant differences in the proportions of children and young adults in the 2 MCSF reduction groups showing clinically meaningful worsening (RCI ≥ 80% certainty) on the BRIEF®2 indexes/composite. SignificanceIn children and young adults with DS, the magnitude of reduction in MCSF after long-term treatment with adjunctive fenfluramine was associated with clinically meaningful levels of improvement in everyday EF. Seventy-eight percent (78%) of children and young adults treated with adjunctive fenfluramine for 1 year in the OLE study achieved ≥50% reduction in MCSF, for a magnitude of efficacy associated with a significantly greater likelihood of experiencing clinically meaningful improvement in emotion regulation and cognitive regulation.

Long-term results of vagus nerve stimulation in children with Dravet syndrome: Time-dependent, delayed antiepileptic effect

ObjectiveThis study aimed to assess the long-term outcomes of vagus nerve stimulation (VNS) in children with pharmaco-resistant Dravet syndrome (DS). MethodsWe enrolled 22 patients with pharmaco-resistant DS who underwent VNS implantation at Severance Children’s Hospital from March 2005 to October 2020. Efficacy and tolerability were assessed at 3, 6, 12, 18, 24, 30, and 36 months after VNS implantation. Efficacy was measured as the percentage reduction in seizure frequency at each follow-up compared with the baseline (pre-implantation) values. ResultsMedian patient age at VNS implantation was 10.0 years (interquartile range 7.7–13.3). The median follow-up period was 4.3 years (interquartile range 3.0–6.5) after VNS implantation. All cases were followed up for ≥2 years after VNS implantation. Three (13.6 %) patients maintained seizure freedom for ≥1 year. Among them, one achieved seizure freedom after 30 months of VNS. More than 50 % reduction in seizure frequency was observed in 36.4 % (8/22), 54.5 % (12/22), and 63.2 % (12/19) of the patients at 12, 24, and 36 months, respectively. The median percent reduction in seizure frequency was 18.8 %, 50.6 %, and 60.0 % at 12, 24, and 36 months, respectively. Compared with the baseline value, the seizure frequency was significantly lower at 24, 30, and 36 months, as well as at the longest follow-up period (p < 0.05, Wilcoxon signed-rank test). The symptom that was mostly associated with adverse events was hoarseness (4/22, 18.2 %); however, they had temporary or minimal effects on activities of daily living. ConclusionsOur findings demonstrate that VNS therapy allows long-term, progressive, and time-dependent improvement in seizure control for pharmaco-resistant DS. Clinicians should be aware of the delayed VNS efficacy over the years and should encourage long-term VNS maintenance by patients.

What are the effects of intravenous immunoglobulins on seizures and quality of life of people with epilepsy? A Cochrane Review summary with commentary.

What are the effects of intravenous immunoglobulins on seizures and quality of life of people with epilepsy? A Cochrane Review summary with commentary.

An economic evaluation of vagus nerve stimulation as an adjunctive treatment to anti-seizure medications for the treatment of drug-resistant epilepsy in England

Introduction Anti-seizure medications (ASMs) are commonly used to prevent recurring epileptic seizures, but around a third of people with epilepsy fail to achieve an adequate response. Vagus nerve stimulation (VNS) is clinically recommended for people with drug-resistant epilepsy (DRE) who are not suitable for surgery, but the cost-effectiveness of the intervention has not recently been evaluated. The study objective is to estimate costs and quality-adjusted life-years (QALYs) associated with using VNS as an adjunct to ongoing ASM therapy, compared to the strategy of using only ASMs in the treatment of people with DRE, from an English National Health Service perspective. Methods A cohort state transition model was developed in Microsoft Excel to simulate costs and QALYs of the VNS + ASM and ASM only strategies. Patients could transition between five health states, using a 3-month cycle length. Health states were defined by an expected percentage reduction in seizure frequency, derived from randomized control trial data. Costs included the VNS device as well as its installation, setup, and removal; ASM therapy; adverse events associated with VNS (dyspnea, hoarseness, and cough); and health-state costs associated with epilepsy including hospitalizations, emergency department visits, neurologist visits, and primary care visits. A range of sensitivity analyses, including probabilistic sensitivity analysis, were run to assess the impact of parameter and structural uncertainty. Results In the base case, VNS + ASM had an estimated incremental cost-effectiveness ratio (ICER) of £17,771 per QALY gained compared to ASMs alone. The cost-effective ICER was driven by relative reductions in expected seizure frequency and the differences in health care resource use associated therewith. Sensitivity analyses found that the amount of resource use per epilepsy-related health state was a key driver of the cost component. Conclusions VNS is expected to be a cost-effective intervention in the treatment of DRE in the English National Health Service.

Effect of Ivermectin Treatment on the Frequency of Seizures in Persons with Epilepsy Infected with Onchocerca volvulus.

A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3–5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0–90.0) to 100% (50.0–100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

ObjectiveTo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.MethodsAdults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.ResultsOf 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2).ConclusionsAdjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.ClinicalTrials.gov identifierNCT00572195.Classification of evidenceThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

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.

Meta-analysis of drug efficacy in adult vs pediatric trials of patients with PGTC seizures.

ObjectiveA meta-analysis of published studies was performed to determine whether the efficacy of antiseizure drugs in adults with primary generalized tonic-clonic seizures (PGTCS) is comparable with that in the pediatric population (2–12 years of age).MethodsElectronic searches were conducted in EMBASE, Medline, and the Cochrane Central Register of Controlled Trials for clinical trials of PGTCS in adults and children 2–12 years of age. Neurologists used standardized search and study evaluations to select eligible trials. Median percent reduction in seizure frequency from baseline and ≥50% responder rates were used to compare drug efficacy in adults and children.ResultsAmong 7 adjunctive-therapy PGTCS trials in adults and children (2–12 years of age) that met evaluation criteria, effect sizes were consistent between adults and children for lamotrigine and topiramate. The baseline-subtracted median percent seizure reduction in seizure frequency ranged from 50.0% to 79.7% in children and 57.0% to 64.0% in adults. The ≥50% responder rate was similar between children and adults in a topiramate study (50% in children compared with 58% in adults).ConclusionsThis meta-analysis supports the use of drug response from antiseizure drug clinical trials for PGTCS in adults to predict comparable treatment response in children 2–12 years of age with PGTCS.

Efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of six randomized studies

ObjectiveThis post hoc analysis of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2–12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic–clonic (PGTC) seizures. MethodsAdolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs). ResultsThe Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients. ConclusionsAdjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy.

Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to &lt;12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

ObjectiveStudy 311 (NCT02849626) was a global, multicenter, open‐label, single‐arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once‐daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic‐clonic seizures [FBTCS]) or generalized tonic‐clonic seizures (GTCS).MethodsIn the 311 Core Study, a 4‐week Pre‐treatment Period (Screening/Baseline) preceded a 23‐week Treatment Period (11‐week Titration; 12‐week Maintenance) and 4‐week Follow‐up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure‐freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme‐inducing anti‐seizure drug (EIASD) use.ResultsOne hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment‐emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure‐freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use.SignificanceResults from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Economic and clinical evaluation of vagus nerve stimulation therapy.

The medical and social care of drug-resistant epilepsy (DRE) entails significant costs. Approximately 30 to 40 percent of patients with DRE who underwent vagus nerve stimulator (VNS) implantation achieve anabove 50percent reduction in seizure frequency. The study objective was to analyze the effect of VNS on clinical effects improvement and therapy cost reduction in patients with DRE over a 2-year follow-up period. The second purpose of the study was to compare average costs of VNS treatment of patients with DRE in selected countries, taking into account the purchasing power parity. The study included all the patients who had VNS implanted at our department between 2014 and 2018. Data on clinical events and medical costs were collected prospectively and obtained from medical documentation. We also reviewed relevant literature on costs of VNS therapy in patients with DRE from the last 18years. Resource utilization and epilepsy-related events were reduced during the follow-up period compared to the baseline. Average total cost was estimated at EUR7703.59 in year1 and at EUR7108.38 in year2 following VNS implantation. Average direct costs of VNS treatment of patients with DRE over the last 18years varied between the countries and ranged from EUR24790.43 in the United States to EUR64.84 in the United Kingdom. Vagus nerve stimulator is a cost-effective therapy yielding measurable clinical and therapeutic outcomes over the long term. Moreover, theanalysis contained in this review highlights the poor consensus of methodological approaches.

A randomized, open-label, multicenter comparative trial of levetiracetam and topiramate as adjunctive treatment for patients with focal epilepsy in Korea

ObjectiveThe objective of this trial was to compare the effectiveness of levetiracetam (LEV) and topiramate (TPM) as adjunctive treatment for patients with focal seizures in Korea. MethodsIn this Phase IV, open-label, multicenter trial (NCT01229735), adults were randomized to treatment with LEV (1000–3000 mg/day) or TPM (200–400 mg/day). Only patients achieving LEV ≥1000 mg/day or TPM ≥100 mg/day after a 4-week up-titration entered the 20-week dose-finding and subsequent 28-week maintenance periods. The primary outcome was the 52-week retention rate; others included safety and exploratory efficacy outcomes. ResultsOf 343 randomized patients (LEV 177; TPM 166), 211 (61.5%) completed the trial. In the full analysis set (FAS), retention rate was 59.1% with LEV vs 56.6% with TPM (p = 0.7007), while in the prespecified sensitivity analysis, based on data from patients who received drug doses in the recommended range (LEV 176; TPM 113), it was 59.1% with LEV vs 42.5% with TPM (p = 0.0086). In the FAS, median percent reduction in seizure frequency from baseline was 74.47% with LEV and 67.86% with TPM (p = 0.0665); ≥50% responder rate was 69.0% vs 64.8% (p = 0.4205), and the 6-month seizure-freedom rate was 35.8% vs 22.3% (p = 0.0061). In the sensitivity analysis, differences between groups were greater, favoring LEV. Incidences of treatment-emergent adverse events (TEAEs) were 70.6% with LEV vs 77.1% with TPM; most frequently somnolence (20.3%), dizziness (18.1%), and nasopharyngitis (13.6%) with LEV; and decreased appetite (15.7%), dizziness (14.5%), and headache (14.5%) with TPM. Discontinuations due to TEAEs were 7.9% with LEV and 12.7% with TPM. ConclusionsIn this open-label trial, the 52-week retention rate was not significantly different between LEV and TPM. However, LEV was associated with a substantially higher seizure freedom rate and a more favorable safety profile than TPM in this population of Korean patients with focal seizures.

Chronic subthreshold cortical stimulation and stimulation-related EEG biomarkers for focal epilepsy.

Brain stimulation offers an alternative to focal resection for the treatment of focal drug-resistant epilepsy. Chronic subthreshold cortical stimulation is an individualized biomarker-informed open-loop continuous electrical stimulation approach targeting the seizure onset zone and surrounding areas. Before permanent implantation, trial stimulation is performed during invasive monitoring to assess stimulation efficacy as well as to optimize stimulation location and parameters by modifying interictal EEG biomarkers. We present clinical and neurophysiological results from a retrospective analysis of 21 patients, showing a median percent reduction in seizure frequency of 100% and responder rate of 89% with a median follow-up of 27 months. About 40% of patients were free of disabling seizures for a 12-month period or longer. We find that stimulation-induced decreases in delta (1–4 Hz) power and increases in alpha and beta (8–20 Hz) power during trial stimulation correlate with improved long-term clinical outcomes. These results suggest chronic subthreshold cortical stimulation may be an effective alternative approach to treating focal drug-resistant epilepsy and that short-term stimulation-related changes in spectral power may be a useful interictal biomarker and relate to long-term clinical outcome.

Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial.

BackgroundEXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.MethodsAfter completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3–15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).ResultsOf 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2–36.1; N = 352) at week 18, 46.6% (95% CI, 40.9–52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7–65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5–36.1) at week 18, 46.7% (95% CI, 40.2–54) at 1 year, and 56.9% (95% CI, 50–68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5–35.2; N = 361) at week 18, 38.8% (95% CI, 33.7–44.1; N = 358) at 1 year, and 41% (95% CI, 34.6–47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).ConclusionsSustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.Classification of evidenceThis study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

Short-term and longer-term effects of brivaracetam on cognition and behavior in a naturalistic clinical setting—Preliminary data

PurposeTo assess short-term and longer-term effects of brivaracetam (BRV) on cognition and behavior in a naturalistic clinical setting. MethodsAnalyses were based on 43 patients with epilepsy who had undergone a neuropsychological screening before adjunctive treatment with BRV and a follow-up evaluation either after 5 days or 25 weeks. The standard assessment focused on reaction times (Neurocog FX), attention and executive functions (EpiTrack), and verbal memory (short version of the VLMT). Self-perceived cognition and behavior was evaluated by an extended version of the Adverse Events Profile. In addition, health-related quality of life (QOLIE-10) was reassessed at the longer-term interval. ResultsRepeated measures analysis of variance revealed a significant improvement under BRV with regard to attention and executive functions (p = .03) without an interaction with the length of the observation interval. A statistical trend in the same direction was also seen for the reaction times (p = .07), but not for the unchanged verbal memory performance. Subjective measures indicated improvements in concentration (p = .02) and especially in comprehension (p < .001), and health-related quality of life (p = .002). Mood and aggression scores were unchanged. At the longer-term follow-up, an at least 50 percent reduction in seizure frequency was observed in 53% of the patients, 21% were seizure free. ConclusionThese preliminary data point to a favorable cognitive profile of BRV similar to its precursor levetiracetam. Objective gains in attention and executive functions were accompanied by self-reported improvements in concentration and comprehension. Future studies with larger sample sizes and better control conditions are needed to confirm these findings.