Percent Reduction In Seizure Frequency Research Articles

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.

Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan

BackgroundEpilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients. MethodsPrimary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms. ResultsOverall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus −6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores. ConclusionsAdjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.

Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial

Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported. Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. Novartis Pharmaceuticals Corporation.

Behavioral interventions as a treatment for epilepsy: A multicenter randomized controlled trial.

To evaluate the effect of a stress-reduction intervention in participants with medication-resistant epilepsy. Adults with medication-resistant focal epilepsy (n = 66) were recruited from 3 centers and randomized to 1 of 2 interventions: (1) progressive muscle relaxation (PMR) with diaphragmatic breathing, or (2) control focused-attention activity with extremity movements. Following an 8-week baseline period, participants began 12 weeks of double-blind treatment. Daily self-reported mood and stress ratings plus seizure counts were completed by participants using an electronic diary, and no medication adjustments were permitted. The primary outcome was percent reduction in seizure frequency per 28 days comparing baseline and treatment; secondary outcomes included stress reduction and stress-seizure interaction. In the 66 participants in the intention-to-treat analysis, seizure frequency was reduced from baseline in both treatment groups (PMR: 29%, p < 0.05; focused attention: 25%, p < 0.05). PMR and focused attention did not differ in seizure reduction (p = 0.38), although PMR was associated with stress reduction relative to focused attention (p < 0.05). Daily stress was not a predictor of seizures. Both PMR and the focused-attention groups showed reduced seizure frequency compared to baseline in participants with medication-resistant focal seizures, although the 2 treatments did not differ. PMR was more effective than focused attention in reducing self-reported stress. NCT01444183.

Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2mg every 2-4weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Magnitude and pattern of placebo response in clinical trials of antiepileptic medications: Data from the Food and Drug Administration 1996–2016

This study aimed to replicate and extend the findings of previous investigations looking at treatment responses in antiepileptic clinical trials over time and to examine the effects of subject age and duration of treatment.To address the potential biases of published literature, we examined the reported data from 14 investigational antiepileptic drugs (AEDs) (34 trials, 59 treatment arms, 10,783 patients) reviewed and approved by the US FDA (1996–2016). For each treatment arm, we recorded drug and placebo response (percent reduction in seizure frequency), calculated effect sizes, and examined these measures over time.Regression analysis showed that placebo response has increased significantly over time (R2=0.292, p=0.001) from 5% to 20% reduction in seizure frequency in 20years. Response to drug treatment appears to have increased in parallel but the trend was not statistically significant (p=0.143). Effect sizes have remained stable over time (p=0.084). Treatment duration was not related to treatment response or outcomes. Including younger patients in trials appeared to predict lower drug response (β=1.44, p=0.012) and effect size (β=0.014, p=0.047) but not placebo response (p=0.141).These FDA-reviewed and source-verified data support and extend prior findings from published literature that response to placebo treatment is noticeably increasing over time, nearly quadrupling in magnitude, while AED efficacy remains the same due to a parallel increase in drug response. The rise in placebo response appears to be an ongoing phenomenon rather than a mere historical artifact. Future design and interpretation of data from clinical trials of investigational antiepileptic drugs can be informed by these observations.

Felbamate as an add-on therapy for refractory partial epilepsy

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and 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. Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We 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 with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01713946. Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. Novartis Pharmaceuticals Corporation.

Efficacy of levetiracetam as first add-on therapy to carbamazepine and valproate sodium for children with epilepsy

We examined the effectiveness of levetiracetam (LEV) as add-on therapy after failed treatment with a first anti-epileptic drug in a prospective cohort of children with epilepsy. Eligible patients with epilepsy experienced uncontrolled seizures with the first anti-epileptic drug and were 1-15-year-old. Afte ra3m obaseline period, patients were administered LEV at an initial dose of 10 mg/kg/d, which, if needed, was incrementally increased by 5 mg/kg/d weekly up to a maximum dose of 60 mg/kg/d. Seizure frequency was defined as the mean seizure frequency per month. Clinical response to LEV over the following period of at least 6 mo was divided into five categories. A total of 37 patients were enrolled. The majority of patients (97.30%) had localization-related epilepsy. The responder rate (rate of patients with ≥50% reduction in seizure frequency) was 30/37 (81.08%). In addition, 20 of 37 (54.05%) patients showed complete seizure cessation. Mean percentage reduction in seizure frequency (all types of seizures) during the first 6 mo treatment period compared to baseline was 89.28% in responders, compared with 25.22% in non-responders. This proportion remained stable during the second 6 mo period (90.17%). Significant changes in seizure frequency were seen between before LEV administration and both the first 6 mo (P < 0.01) and second 6 mo (P < 0.01) in responders, but not in non-responders. Mean effective dose of LEV was 27.51 mg/kg/d. Somnolence was the only reported individual adverse event (5.41%), and was mild in all cases, so LEV discontinuation was not needed. LEV appears useful as a first add-on treatment in children with localization-related epilepsy.

Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel

To evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases. Patients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12 mg/day). Patients then entered a planned, open-label treatment period. Perampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40-52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12 mg group (DB-PER 12 mg), 78.4% reached the daily dose of 10 or 12 mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12 mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study. Patients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel.

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years

Long-term (up to 8years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100–800mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had >1, >3, or >5years of lacosamide exposure, respectively. Median lacosamide modal dose was 400mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in >2% of patients. Ranges for median percent reductions in seizure frequency were 47–65%, and those for ≥50% responder rates were 49–63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained.

Felbamate as an add-on therapy for refractory epilepsy.

This review is an update of a previously published review in The Cochrane Database of Systematic Reviews (Issue 1, 2011) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. We searched the Cochrane Epilepsy Group Specialized Register (24 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), and PubMed (24 July 2013). This search was run for the original review on 20 May 2010. There were no language and 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. Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We 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. Three randomised controlled trials with a total of 153 participants were included. The first was a parallel design, the second had a two-period crossover design, and the third had a three-period crossover design. One study was at unclear risk of bias for random sequence generation and allocation concealment. And in the same study, there was no description of how to blind outcome assessment, performance blinding was for participants, might not be for doctors. Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.Since the last version of this review no new studies have been found.

Update On the Use of Lacosamide in the Treatment of Partial-Onset Seizures

ABSTRAT: Lacosamide has a novel mechanism of action, namely selective enhancement of slow inactivation of voltage-gated sodium channels. Trial data and clinical experience indicate that it is effective in the treatment of partial-onset seizures, and that it is well tolerated. Pivotal early clinical trials demonstrated median percent reductions in seizure frequency ranging from 26 to 35.3% in the 200 mg/day, from 36.4 to 39% in the 400 mg/day, and from 37.8 to 40% in the 600 mg/day treatment groups. Dose-related adverse events were similar in the early clinical trials, and were mainly CNS complaints including dizziness, nausea, vomiting, fatigue, ataxia, abnormal vision, diplopia and nystagmus. Because of the dose-dependent adverse events and lack of additional efficacy at the 600 mg/day daily dose, lacosamide has been approved as an adjunctive treatment at recommended daily doses of 200–400 mg/day.

WITHDRAWN: Traditional Chinese medicine for epilepsy.

Seizures are poorly controlled in many people with epilepsy, despite current antiepileptic treatments. Some turn to alternative or complementary therapy to treat their condition and the use of traditional Chinese medicinal herbs (TCMH) is increasingly popular. However, it remains unclear whether the existing evidence is rigorous enough to support its use.To determine the effectiveness and safety of traditional Chinese medicine in people with epilepsy.Our search included the Cochrane Epilepsy Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1950 to 2007) and EMBASE (1974 to 2007).Randomised controlled trials evaluating traditional Chinese medicine in people of any age with any type of epilepsy, and comparing one formula of TCM with no intervention, placebo or single Western medicine (monotherapy).Two review authors independently extracted trial data and assessed quality. We assessed the following outcomes: (a) seizure freedom for at least one year; (b) 50% or greater reduction in seizure frequency; (c) percentage reduction in seizure frequency and duration; and (d) adverse events.Five short-term studies involving 1125 participants met the inclusion criteria. All the studies were of poor methodological quality and had a high probability of selection, detection and performance bias.Two studies assessed seizure freedom for one year. One found no difference between Xiaxingci granule and phenytoin for primary generalized tonic-clonic seizures (RR 1.00; 95% CI 0.07 to 14.90).The other study found no difference between Dianxianning pill and valproate (RR 13.00; 95% CI 0.74 to 227.72) for different types of epilepsy.Three studies assessed a 50% or greater reduction in seizure frequency. One found an advantage for Tianmadingxian capsule when compared to phenytoin (RR 1.37; 95% CI 1.23 to 1.53) in different types of epilepsy, the second an advantage for Zhixian I pill when compared to phenytoin (RR 1.31; 95% CI 1.16 to 1.48) in primary generalized tonic-clonic seizure, and the third an advantage for an 'Antiepilepsy capsule' when compared to phenobarbital (RR 1.21; 95% CI 1.02 to 1.43) for primary and secondary generalized tonic-clonic seizure. One study reported the incidence of adverse effects and the Peto odds ratio was 0.04 (99% CI 0.01 to 0.12, P < 0.00001) favouring TCMH compared to phenobarbital.The current evidence is insufficient to support the use of traditional Chinese medicine as a treatment for epilepsy. Much larger, high quality randomised clinical trials are needed to evaluate the effectiveness and safety of traditional Chinese medicinal herbs for treating epilepsy.

Zonisamide efficacy as adjunctive therapy in children with refractory epilepsy.

Approximately one third of epileptic children do not achieve complete seizure improvement. Zonisamide is a new antiepileptic drug which is effective as adjunctive therapy in treatment of intractable partial seizures. The purpose of the current study was to evaluate the effectiveness, safety, and tolerability of Zonisamide in epileptic children. From November 2011 until October 2012, 68 children who referred to Children's Medical Center and Mofid Children Hospital due to refractory epilepsy (failure of seizure control with the use of two or more anticonvulsant drugs) entered the study. The patients were treated with Zonisamide by dose of 2- 12 mg/kg daily in addition to the previous medication. We followed the children every three to four-weeks intervals based on daily frequency, severity and duration of seizures. During the follow-up equal and more than fifty percent reduction in seizure frequency or severity known as response to the drug. In this study 68 patients were examined that 61 children reached the last stage.35 (57.4%) were male and 26 (42.6%) patients were female. After first and six months of Zonisamide administration daily seizure frequency decreased to 2.95±3.54 and 3.73±3.5 respectively. There was significant difference between seizure frequency in first and six month after Zonisamide toward initial attacks. After six months ZNS therapy a little side effects were created in 10 patients (16.4%) including stuttering(4.9%), decreased appetite (4.9%), hallucination (1.6%), dizziness(1.6%), blurred vision(1.6%) and suspiring(1.6%) as all of them eliminated later dosage reduction. This study confirms the short term efficacy and safety of Zonisamide in children with refractory epilepsies.

Sodium valproate for epilepsy in rural China: An efficacy and safety assessment in primary care

Sodium valproate (VPA) is a broad-spectrum anti-epileptic drug usually well tolerated. We conducted a pilot study to assess the feasibility, efficacy and side-effects of VPA in the treatment of convulsive epilepsy in primary care settings in rural China as an alternative to phenobarbital. People with convulsive epilepsy were identified at primary health care level and provided with VPA monotherapy. Local trained physicians identified participants, managed treatment, and carried out the follow-up, whilst diagnoses were confirmed by a neurologist. Participants were followed for 12 months. Efficacy was assessed from the percentage reduction in seizure frequency and by retention of treatment. Tolerability was assessed by reports of treatment-emergent effects. Of 532 people enrolled, 512 completed the assessment. Most (431 people, 84%) had a decrease in seizure frequency of at least 50% and 218 became seizure-free. Treatment retention was 96% at one year. VPA was well tolerated and only 47 people reported adverse events which were mostly mild. Only two people discontinued VPA due to side-effects. In this 12-month assessment, VPA had favourable efficacy, few side effects and overall good acceptability. It was also relatively cheap. VPA is, therefore, a suitable alternative to phenobarbital as treatment of convulsive epilepsy in rural areas of China.

Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy

To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZG[RTG]) 1,200 mg/day as adjunctive treatment in adults with drug-resistant epilepsy with partial-onset seizures with or without secondary generalization. RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZG[RTG] 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase. In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZG[RTG], 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZG[RTG]) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo. This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.

Epilepsy Treatment Stimulus Package? Deep Brain Stimulation in Treatment-Resistant Focal Epilepsy

Electrical Stimulation of the Anterior Nucleus of Thalamus for Treatment of Refractory Epilepsy. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Epilepsia 2010;51(5):899–908. PURPOSE: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. METHODS: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. RESULTS: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model ( p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and “most severe” seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. DISCUSSION: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial

To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs). This multicenter, double-blind, placebo-controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8-week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force-titrated weekly (100 mg/day increments) to the target dose, and entered a 12-week maintenance period. A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention-to-treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic-clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose-related adverse events included dizziness, nausea, and vomiting. Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial-onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic-clonic seizures.

Cumulative effect of vagus nerve stimulators on intractable seizures observed over a period of 3 years

Objective The objective of the study was to evaluate the efficacy of vagus nerve stimulator (VNS) therapy and identify factors associated with reduction of seizures. The VNS is an accepted therapeutic option for patients with refractory partial epilepsy. There are, however, limited data regarding efficacy in any specific group of patients with epilepsy. Methods This is a retrospective review of patients with epilepsy on VNS therapy initiated between January 2000 and December 2007 at a university medical center. Information collected included demographics, epilepsy type and duration, antiepileptic drug usage, stimulation parameters, and seizure frequency at baseline, 3 months, 6 months, 1 year, 2 years, and 3 years after VNS therapy initiation. Seizure frequency at different follow-up intervals was compared with baseline frequency. Patients were stratified into three subsets based on VNS response. Relationships between VNS response and factors including demographics, location of seizure focus, type or duration of epilepsy, and VNS settings were examined as a whole as well as in subsets. Results Fifty-four patients were implanted with VNSs over a period of 7 years. Four patients were excluded. A total of 50 patients (31 men, 19 women) with mean age 39 years and on VNS therapy were included in this study. Average duration of VNS therapy was 4.5 years. Baseline average frequency was 10 seizures per month. Significant decreases in median seizure frequency were noted at 3 months ( P < 0.001), 6 months ( P < 0.001), 1 year ( P = 0.004), 2 years ( P < 0.001), and 3 years ( P < 0.0001). Seventy-two percent of the patients reported a decrease in seizure frequency within the first 3 months, which increased to 80% by the end of 3 years. Overall, the percentage reduction in seizure frequency was 64% at 3 months and increased to 86% at the end of 3 years. In the subset of patients who responded to VNSs, reduction in seizure frequency improved from 80 to 89% by the end of 3 years. There were no correlations between seizure frequency and specific VNS settings, epileptic focus, or duration or type of epilepsy, in the group as a whole or in its subsets. Data suggest a favorable VNS response in patients with higher baseline seizure frequency. Conclusions Significant reductions in seizure frequency were noted with VNS therapy over a 3-year follow-up period with a possible cumulative effect. Lateralization or localization of epileptic focus or epilepsy subtype did not correlate with response to VNSs.