Baseline Seizure Frequency Research Articles

Long-term efficacy and safety of adjunctive perampanel in pediatric patients aged 4–19 years with epilepsy: a real-world study

This study determined the 24-month outcomes of perampanel treatment in children and adolescents with epilepsy. The percentage of ≥ 50% responders was 47.3% (139/294) at 12 months and 49.0% (144/294) at 24 months. A 100% reduction in seizures for more than 12 months was observed in 12.2% (36/294). Discontinuation occurred in 39.8% (117/294). The most common reason for discontinuation was adverse events (29.1%, 34/117). Baseline seizure frequency was higher in children aged < 12 years than in patients aged ≥ 12 years; however, the percentage of seizure reduction and ≥ 50% responders did not significantly differ between the two groups. The rate of early discontinuation was higher (p < 0.001) and the duration of perampanel treatment was shorter in children aged < 12 years (p = 0.001). Most children aged < 12 years discontinued PER due to inadequate effectiveness, while adverse event was the most common reason in patients aged ≥ 12 years (p = 0.045). Only slow titration was significantly associated with ≥ 50% of responders. In conclusion, this study showed that perampanel can be utilized effectively and safely for a prolonged period in pediatric patients aged 4 to < 12 years, as well as in patients aged 12 years and older.

Everolimus precision therapy for the GATOR1-related epilepsies: a case series.

Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.

Clinical efficacy and safety of anterior thalamic deep brain stimulation for intractable drug resistant epilepsy

BackgroundDeep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) is a neuromodulation therapy for patients with refractory focal seizures evolving into bilateral tonic-clonic seizures when pharmacotherapy as well other neuromodulation techniques including vagus nerve stimulation or responsive neurostimulation have failed. ObjectiveWe performed a prospective single-center study investigating the clinical efficacy and exact ANT DBS lead location in patients with DRE. MethodsThe primary outcome measure was the proportion of patients with more than 50 % reduction in diary-recorded seizures when compared to three preoperative months (baseline seizure frequency). The close postoperative follow-up was performed every 3 months. The seizure frequency, stimulation settings and adverse events were closely monitored during follow-up visits. We also analyzed the seizure outcome with location of ANT DBS active contacts. ResultsBetween May 2020 and October 2022, 10 adult patients with a mean age of 38.5 years (range, 30–48 years) underwent bilateral ANT DBS surgery (mean duration of DRE 28.6 years, range 16–41 years). The median seizure count in three months period preceding surgery (baseline seizure count) was 43.2 (range, 4–150). Nine patients achieved more than 50 % seizure reduction at the last follow-up (mean range 3–33 13.6 months, months). ANT DBS caused seizure reduction 3 months after procedure as well as at last follow-up by 60.4 % and 73.3 %, respectively. Due to relatively small number of studying individuals we cannot precisely locate the area within ANT associated with good clinical outcome. Patients with temporal lobe epilepsy had a remarkable reduction of seizure frequency. No patient suffered transient or permanent neurological deficits. ConclusionsClinical efficacy of ANT DBS may support more widespread utilization of this neuromodulation technique especially for seizures originating from temporal lobes.

The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study

ObjectiveAssess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. MethodsThis multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at ‘personalized’ seizure outcome time points based on baseline seizure frequency. ResultsBaseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and ‘personalized’ outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). ConclusionsMeaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.

Difficulties in the implementation of the ketogenic diet in adult patients with refractory epilepsy

BackgroundKetogenic diet therapies (KDT) are appropriate therapeutic options for pediatric and adult patients with intractable epilepsy. The application of KDT among adult patients with refractory epilepsy is limited compared to children for several reasons, including poor compliance. We present the significant reasons for the lack of adherence to KDT in our adult patients with intractable epilepsy. MethodsThis study was conducted retrospectively in adult patients with drug-resistant epilepsy who wereofferedand accepted toimplementKDT between 2014 and 2021. Demographic and clinical data were collected via electronic health records. The eventual outcome of KDT results was obtained from the consultant dietitian. The prevalence and reasons for the failure to implement KDT were investigated. We also obtained detailed information about patients who successfully applied the KDT. ResultsA total of 33 patients (18F; median age 28) who wereoffered and accepted to implement KDT were included. Baseline seizure frequency was >4 per week in 49%, and more than half of the patients used >3 anti-seizure medications (ASM). Epilepsy types were temporal in 10 (30%), extratemporal in 10 (30%), generalized in 6 (18%), and unclassified in 7 (22%) patients.Only 3 patients (9%) were able to maintain KDT in the long term. One of them (33%) benefited from this therapy.In the remaining 30 patients, the reasons for failure were inability to contact the dietitian in 5, failure to apply KDT for a particular reason in 7, inappropriate blood test results or any medical/surgical comorbidities in 6, improvement in seizure burden due to change in ASM in 5, still insufficient knowledge of KDT in 3, unresponsiveness to diet due to incorrect implementation in 1 and unidentified reasons in 3 patients. ConclusionsA significant percentage of adult patients with refractory seizures failed to use KDTin our study(91%).Strategies to improve compliance and minimize the side effects might increase the number of drug-refractory epilepsy patients who could benefit from this therapy.

Retrospective chart review study of use of cannabidiol (CBD) independent of concomitant clobazam use in patients with Lennox-Gastaut syndrome or Dravet syndrome

PurposeThis retrospective chart review study (GWEP20052) evaluated plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution) use without clobazam as add-on therapy in patients aged ≥2 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) enrolled in a European Early Access Program. MethodsData were extracted from patient charts covering a period starting 3 months before CBD treatment and concluding after 12 months of CBD treatment, or sooner if a patient discontinued CBD or started clobazam. ResultsOf 114 enrolled patients, data were available for 107 (92 LGS, 15 DS) who received CBD without clobazam for ≥3 months. Mean age: 14.5 (LGS) and 10.5 (DS) years; female: 44% (LGS) and 67% (DS). Mean time-averaged CBD dose: 13.54 (LGS) and 11.56 (DS) mg/kg/day. Median change from baseline in seizure frequency per 28 days over 3-month intervals varied from −6.2% to −20.9% for LGS and 0% to −16.7% for DS. Achievement of ≥50% reduction in drop (LGS) or convulsive (DS) seizures at 3 and 12 months: LGS, 19% (n = 69) and 30% (n = 53); DS, 21% (n = 14) and 13% (n = 8). Retention on CBD without clobazam (enrolled set): 94%, 80%, 69%, and 63% at 3, 6, 9, and 12 months. Adverse event (AE) incidence was 31%, most commonly somnolence, seizure, diarrhea, and decreased appetite. Two patients discontinued CBD owing to AEs, and four patients with LGS experienced elevated liver enzymes. ConclusionResults support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice.

Pregnancy Seizure Outcomes for Epilepsy Patients with Catamenial Seizure Exacerbation (P8-1.011)

<h3>Objective:</h3> To assess the risk of increased seizure frequency during pregnancy/early postpartum for patients with a catamenial seizure exacerbation pattern (CSEP) <h3>Background:</h3> Prior studies demonstrated that seizure frequency is mostly stable during pregnancy/early postpartum when therapeutic drug monitoring is performed. Yet, clinical factors - seizure frequency in the 9 months preconception, epilepsy type, ASM regimen and, in one prior study, CSEP - may influence seizure outcomes. <h3>Design/Methods:</h3> Clinical data was collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women’s Hospital. Within each participant, baseline seizure frequency was calculated for the 9 months preconception, and it was determined if seizure frequency increased during pregnancy or the postpartum period. CSEP was determined retrospectively by chart review. Associations between categorical variables were evaluated using the Fisher-Exact test. <h3>Results:</h3> Ninety-nine patients contributing 114 pregnancies were included from 2013–2018. 24 patients contributing 24 pregnancies were determined to have a CSEP (probable n=17 and possible n=7), 29.2% with generalized and 70.8% with focal epilepsy. Only 50% of CSEP group had been seizure free in the 9 months preconception versus 71.7% in the entire cohort; yet, only 16.7% were on polytherapy. The rate of seizure worsening was not significantly different for CSEP group versus the entire cohort during pregnancy (20.8% vs 15.8%) and postpartum (5.3% vs 9.8%). As previously reported, frontal lobe epilepsy was a risk factor: 50.0% of CSEP patients with frontal lobe epilepsy experienced seizure worsening in pregnancy vs 52.9% of all frontal lobe epilepsy patients. <h3>Conclusions:</h3> CSEP patients have a similar risk of seizure worsening in pregnancy/early postpartum to all patients with epilepsy, despite the worse preconception seizure baseline and a lower rate of polytherapy than expected. CSEP does not mediate the high risk of seizure worsening during pregnancy for frontal lobe epilepsy. <b>Disclosure:</b> The institution of Dr. Voinescu has received research support from NIH. Dr. Voinescu has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Neurodiem. Dr. Voinescu has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Physicians’ Education Resouce. Dr. Voinescu has received personal compensation in the range of $500-$4,999 for serving as a Speaker with American Epilepsy Society. Dr. Voinescu has a non-compensated relationship as a Board Member and Chair with My Epilepsy Story that is relevant to AAN interests or activities. Dr. Voinescu has a non-compensated relationship as a Speaker with Epilepsy Foundation that is relevant to AAN interests or activities. Dr. Voinescu has a non-compensated relationship as a Grant Reviewer with Epilepsy Ireland that is relevant to AAN interests or activities. Dr. Voinescu has a non-compensated relationship as a Grant Reviewer with American Epilepsy Society that is relevant to AAN interests or activities. Dr. Voinescu has a non-compensated relationship as a Member of Scientific Advisory Committee with North American AED Pregnancy Registry that is relevant to AAN interests or activities. Dr. Lemus Esquivel has nothing to disclose. Dr. Liu has nothing to disclose. Mrs. Allien has nothing to disclose. Dr. Pennell has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for American Epilepsy Society. The institution of Dr. Pennell has received research support from NIH. The institution of an immediate family member of Dr. Pennell has received research support from Department of Defense. The institution of an immediate family member of Dr. Pennell has received research support from Environmental Protection Agency. The institution of an immediate family member of Dr. Pennell has received research support from NIH. The institution of an immediate family member of Dr. Pennell has received research support from Advanced Energy Consortium. Dr. Pennell has received publishing royalties from a publication relating to health care.

Predictors of Sustainability of Response With Cenobamate: Post-hoc Subset Analysis of a Phase 3, Open-Label, Study (P14-1.005)

Predictors of Sustainability of Response With Cenobamate: Post-hoc Subset Analysis of a Phase 3, Open-Label, Study (P14-1.005)

Concomitant Drug Load Reduction During Adjunctive Cenobamate Therapy: Post-hoc Analysis of a Phase 3, Open-Label Study (P11-1.006)

<h3>Objective:</h3> Changes in concomitant antiseizure medication (ASM) drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 safety study. <h3>Background:</h3> Many patients with epilepsy require adjunctive therapy, which can increase their ASM drug load. <h3>Design/Methods:</h3> Patients 18–70 years old with uncontrolled focal seizures taking stable doses of 1–3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient’s prescribed dose for each ASM by its defined daily dose, a World Health Organization standardized daily maintenance dose, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65–70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency &lt;3 vs ≥3 seizures/28 days. <h3>Results:</h3> Data from 240 patients were available (median exposure duration 30.2 months, mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, mean percent reductions in concomitant ASM drug load occurred at Month 12 (29.44%) and 24 (31.82%), and in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.24% at Month 24). All assessed patient subgroups exceeded 30% reduction in concomitant ASM drug load at Month 24. Patients with low (−0.25 to &lt;0), moderate (−0.59 to −0.25), or high (−3.3 to −0.59) change in concomitant ASM drug load vs no change, respectively, had similar maintenance of ≥50% (89.29%, 86.42%, 90.57% vs 85.99%) and 100% response rates (80.65%, 84.29%, 70.00% vs 82.00%). <h3>Conclusions:</h3> Adding cenobamate led to reduced mean concomitant ASM drug load during Year 1 and Year 2. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics. Reductions in ASM drug load did not impact maintenance of response rates. See also abstract by O’Dwyer et al. <b>Disclosure:</b> Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Louis Ferrari has received personal compensation for serving as an employee of SK Life science. Mr. Stern has received personal compensation for serving as an employee of SK Life Science. Mr. Wade has nothing to disclose. Dr. Weingarten has received personal compensation for serving as an employee of SK Life Science. The institution of Dr. Connor has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for SK Life Sciences. The institution of Dr. Connor has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Sciences. The institution of Dr. Rosenfeld has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for SK Life Science. Dr. Rosenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Science. The institution of Dr. Rosenfeld has received research support from SK Life Science. The institution of Dr. Rosenfeld has received research support from UCB Pharma.

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Treatment Outcomes During Brivaracetam Treatment by Seizure Freedom Status at Baseline: Post hoc Analysis of a Real-world, US Study (P14-1.001)

Treatment Outcomes During Brivaracetam Treatment by Seizure Freedom Status at Baseline: Post hoc Analysis of a Real-world, US Study (P14-1.001)

Second-line cannabis therapy in patients with epilepsy

Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (EpidiolexⓇ) was approved by the FDA in 2018 for the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also investigated the clinical impact that a second MBT has on side effect profile. We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2 different formulations of MBT, including a pharmacologic formulation of CBD (EpidiolexⓇ), artisanal marijuana, and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however, subjects' historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects. Seizure frequency, side effect profiles, and predictors of responder status were evaluated. Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p=.4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p=.03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p=.04). We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.

Termination of seizures by ictal transcranial focal cortex stimulation.

Whereas high-level evidence exists on chronic neuromodulatory effects of different brain stimulation approaches in reducing seizure frequency, evidence for acute antiseizure effects of electrical brain stimulation during seizures is sparse. As part of an ongoing trial, we implanted a patient with a novel focal cortex stimulation (FCS) device with a Laplacian electrode placed over a precentral focal cortical dysplasia. The baseline seizure frequency was 125 per month, consisting of (i) focal aware sensory seizures that invariably progressed to uni- or bilateral tonic contraction and clonic jerking, and (ii) primary motor seizures. Besides an overall reduction in seizure frequency, on-demand stimulation had an immediate effect on seizures with a sensory phase, whereby 63%-86% of these seizures were terminated by ictal stimulation. These observations provide the first evidence that ictal self-triggered transcranial focal cortex stimulation can significantly interfere with the progression of seizure semiology.

Tolerability of clobazam as add-on therapy in patients aged 50years and older with drug-resistant epilepsy.

To evaluate the tolerability of clobazam in patients with drug-resistant epilepsy aged 50years and older. We performed a single center, retrospective chart review of patients at least 50years of age with drug resistant epilepsy of any type who started clobazam as an add on therapy. Retention rate, safety, and tolerability at 6 and 12months and last follow-up, and the discontinuation rate due to side effects were analyzed. A total of 26 patients met inclusion criteria. Mean age was 62 ± 7.1years, and 69.2% of patients were female. The mean baseline seizure frequency before initiation of clobazam was 2 (range 1-30) seizures per month. The mean total daily dose of clobazam administered was 13 (range 5 to 30) mg/day. At the 12-month follow-up visit after clobazam initiation, 40% of patients were seizure-free and an additional 45% of patients had > 50% reduction in seizure frequency. The mean seizure frequency at 12-month follow-up was 1.5 (range 0-24) seizures per month. The mean total dose of clobazam at 12-month follow-up was 14.25 (range 5 to 25) mg/day. The mean duration of clobazam at last follow was 55.2 ± 27.02 (mean ± SD months) and 18 (69.2%) patients remained on clobazam. Twenty out of 26 (76.9%) patients reported at least one side effect and 6/26 (23%) discontinued the medication within a month of initiation. At last follow-up, 40% remained seizure free on stable dosing. Clobazam can be a safe and tolerable, add-on treatment older adults with drug-resistant epilepsy. Those who responded tolerated the medication well. Discontinuation due to side effects occurred soon after initiation of therapy.

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis.

Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome. Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73-11.54) and 4.71 (95% CI 0.57-39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33-5.02) and 0.50 (95% CI 0.031-7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89-3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93-14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment. Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

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

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

Yield and risk associated with prolonged presurgical video-EEG monitoring: a systematic review

Presurgical long-term video-EEG monitoring (LT-VEEG) is an important part of the presurgical evaluation in patients with focal epilepsy. Multiple seizures need to be recorded, often in limited time and with the need to taper anti-seizure medication (ASM). The aim of this study was to systematically study the yield – in terms of success – and risks associated with presurgical LT-VEEG, and to identify all previously reported contributing variables. A systematic review of the databases of PubMed Medline, Embase, Cochrane Central, and the Cochrane Database of Systematic Reviews were searched following the Preferred Reporting Items for Systematic Reviews (PRISMA) guideline. Publications about presurgical LT-VEEG reporting on variables contributing to yield and risk were included. Study characteristics of all included studies were extracted following a standardized template. Within these articles, studies presenting multivariable analyses of factors contributing to the risk of adverse events or the success of LT-VEEG were identified. We found 36 articles reporting on LT-VEEG, including 4,703 presurgical patients, both children and adults. Presurgical LT-VEEG monitoring led to an average yield of 85%. Adverse events occurred with an averaged total event rate of 17%, but the type of included events was variable among studies. Factors reported to independently contribute to successful LT-VEEG were: baseline seizure frequency, a shorter interval from the most recent seizure, extratemporal lobe epilepsy, and no requirement for ASM reduction. Factors independently contributing to the occurrence of adverse events were: ASM tapering, a history of status epilepticus, a history of focal to bilateral tonic-clonic seizures, psychiatric comorbidity, and ASM taper rate. This study reveals that the data on factors contributing to yield and risk of adverse events is significant and variable, and often reported with inadequate statistics. Future research is warranted to develop guidelines for ASM withdrawal during presurgical video-EEG monitoring, taking predefined factors for success and risks of adverse events into account.

Stiripentol for Drug-Resistant Epilepsy Treatment in Tuberous Sclerosis Complex

BackgroundDrug-resistant epilepsy (DRE) is common in tuberous sclerosis complex (TSC). The role of stiripentol (STP) in seizure treatment in this population is not well understood. This study evaluates the efficacy and tolerability of STP in patients with TSC with DRE. MethodsWe performed a retrospective review of patients with TSC with DRE. Seizure frequencies at 1 month before (baseline) and 1, 3, 6, and 12 months after STP initiation were collected. ResultsOf the 1492 patients, 13 received STP and the number of patients with ≥50% seizure reduction at 1, 3, 6, and 12 months was 6/13 (46.2%), 4/13 (30.8%), 8/13 (61.5%), and 6/13 (46.2%), respectively. Six patients (46.2%) had favorable outcomes with persistent seizure reduction through 12 months. Their mean (±S.D.) percentage of seizure reduction at 1, 3, 6, and 12 months was 68.1 (±22.0), 71.3 (±23.2), 75.7 (±23.5), and 75.7 (±23.5), respectively. One patient had worsening seizures throughout the STP course. Three patients did not have seizure reduction until after 6 months, and 2 had initial seizure reduction before worsening. Younger age (P value <0.001), early STP treatment (P value <0.001), higher doses (P value = 0.004), and higher baseline seizure frequency (P value = 0.01) were associated with favorable outcomes. Side effects were seen in 85% of our cohort. ConclusionsAbout 46% of the patients had favorable outcomes. Younger age, early STP treatment, higher doses, and higher baseline seizure frequency were significantly associated with favorable outcomes.

Retention, efficacy, tolerability, and quality of life during long-term adjunctive brivaracetam treatment by number of lifetime antiseizure medications: A post hoc analysis of phase 3 trials in adults with focal seizures

ObjectiveTo evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life (HRQOL) during adjunctive brivaracetam (BRV) treatment in adults with focal seizures by number of lifetime antiseizure medications (ASMs). MethodsPost hoc analyses of a randomized, double-blind, placebo-controlled trial (N01358; NCT01261325) and corresponding open-label extension (OLE) (N01379; NCT01339559) of adjunctive BRV in adults (16–80 years of age) with focal seizures. Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by number of lifetime ASMs (1–2, 3–4, 5–6, or ≥ 7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs at BRV initiation. ResultsSeven hundred and forty patients received adjunctive BRV (safety set [SS]; median modal dose: 200 mg/day [N = 737]; median treatment duration: 2.67 years), of whom 13.8 % had 1–2, 20.8 % had 3–4, 21.1 % had 5–6 and 44.3 % had ≥7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. Kaplan-Meier estimated retention on BRV at 12 (83.2–65.9 %) and 36 months (63.0–44.1 %) was highest in patients with 1–2 lifetime ASMs and decreased with the number of lifetime ASMs. The estimated proportions of patients who discontinued BRV due to lack of efficacy or treatment-emergent adverse events (TEAEs) increased with the number of lifetime ASMs. Efficacy analyses included seven hundred and thirty eight patients (intention-to-treat set [ITT]). Median percentage reductions from baseline in focal seizure frequency/28 days (76.3–39.6 %), 50 % responder rates (66.7–39.8 %), 75 % responder rates (51.0–19.6 %), and continuous seizure freedom for ≥12 months at any time during BRV treatment (35.3–6.1 %) were highest in patients with 1–2 lifetime ASMs and decreased by the number of lifetime ASMs. The overall incidence of TEAEs (SS) was generally similar in each lifetime ASM subgroup (84.4–90.5 %). Discontinuations due to TEAEs increased with the number of lifetime ASMs (7.8–20.1 %). The greatest improvements in QOLIE-31-P scores occurred in the Seizure Worry and Daily Activities/Social Function subscales, with no clear pattern by the number of lifetime ASMs at 12 months and with the highest improvement in patients with 1–2 lifetime ASMs at 24 months. At 24 months, the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale scores improved in patients (SS) with 1–2 and 3–4 lifetime ASMs. HADS Depression subscale scores were generally stable independent of the number of lifetime ASMs. ConclusionsThe balance between efficacy, tolerability, and HRQOL was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to ≥7 ASMs before BRV initiation also benefitted from long-term adjunctive BRV treatment.

Modified Atkins diet versus levetiracetam for non-surgical drug-resistant epilepsy in children: A randomized open-label study

BackgroundThis study was undertaken to compare the efficacy of modified Atkins diet (MAD) among children with non-surgical drug-resistant epilepsy (DRE) to levetiracetam, when added to on-going anti-seizure medications. MethodsAn open-label, randomized controlled trial among children aged 2–12 years with non-surgical DRE was conducted. Eligible children were randomized in a 1:1 ratio to receive add-on MAD or levetiracetam. Baseline and post-intervention seizure frequency at 12 weeks was determined from seizure logs maintained by parents. The primary outcome was the proportion of responders, i.e., patients who achieved > 50% seizure reduction from baseline. Adverse events were compared. Analysis was intention-to-treat. (NCT04172311) ResultsOne hundred and one children were enrolled (MAD-51, levetiracetam-50). The majority of the enrolled children had generalized seizures of mixed types secondary to structural brain lesions and Lennox-Gastaut syndrome was the most common electroclinical syndrome (46%). The proportion of children with >50% seizure reduction at 12 weeks was significantly higher in the MAD arm compared to the levetiracetam arm (27/51(52.9%) vs 11/50(22%); p < 0.001). At 12-weeks post-intervention, the change in mean seizure frequency compared to baseline was -47.33 ± 39.57% in the MAD arm and -31.15 ± 32.18% in the levetiracetam arm (p = 0.03). Constipation (41.1%) was the most frequent adverse effect with MAD. Sedation/lethargy (18%) and anxiety and irritability (14%) were the most frequent adverse effects in the levetiracetam group. ConclusionAddition of MAD was found to be superior to levetiracetam among children with non-surgical DRE with predominant generalized seizures in achieving seizure reduction at 12 weeks. Both treatments were well tolerated. Adverse effects, although higher with MAD, were expected side effects.