Median Seizure Frequency Research Articles

The effect of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes in drug-resistant epilepsy

ObjectiveThe impact of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes has not been extensively evaluated outside of the original clinical trials and post-approval studies. The goal of this study was to ascertain the potential real-world effects of RNS on cognitive, psychiatric, and quality of life (QOL) outcomes in relation to seizure outcomes by examining 50 patients undergoing RNS implantation for drug-resistant epilepsy (DRE). MethodsWe performed a retrospective review of all patients treated at our institution with RNS for DRE with at least 12 months of follow-up. In addition to baseline demographic and disease-related characteristics, we collected cognitive (Full-Scale Intelligence Quotient, Verbal Comprehension, and Perceptual Reasoning Index), psychiatric (Beck Depression and Anxiety Inventory Scores), and QOL (QOLIE-31) outcomes at 6 and 12 months after RNS implantation and correlated them with seizure outcomes. ResultsFifty patients (median age 39.5 years, 64% female) were treated with RNS for DRE in our institution from 2005 to 2020. Of the 37 of them who had well-documented pre and post-implantation seizure diaries, the 6-month median seizure frequency reduction was 88%, the response rate (50% or greater seizure frequency reduction) was 78%, and 32% of patients were free of disabling seizures in this timeframe. There was no statistically significant difference at a group level in any of the evaluated cognitive, psychiatric, and QOL outcomes at 6 and 12 months post-implantation compared to the pre-implantation baseline, irrespective of seizure outcomes, although a subset of patients experienced a decline in mood or cognitive variables. SignificanceResponsive neurostimulation does not appear to have a statistically significant negative or positive impact on neuropsychiatric and psychosocial status at the group level. We observed significant variability in outcome, with a minority of patients experiencing worse behavioral outcomes, which seemed related to RNS implantation. Careful outcome monitoring is required to identify the subset of patients experiencing a poor response and to make appropriate adjustments in care.

Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: A "real-world" retrospective study.

Recent clinical trials have shown that cenobamate substantially improves seizure control in focal-onset drug-resistant epilepsy (DRE). However, little is known about cenobamate's performance in highly active (≥20 seizures/month) and ultra-refractory focal epilepsy (≥6 failed epilepsy treatments, including antiseizure medications [ASMs], epilepsy surgery, and vagus nerve stimulation). Here, we studied cenobamate's efficacy and tolerability in a "real-world" severe DRE cohort. We conducted a single-center retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment-emergent adverse events, and adjustments to concomitant ASMs were analyzed. Fifty-seven patients received cenobamate for at least 3 months (median duration, 11 months). The median cenobamate dose was 250 mg/day (range 75-350 mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra-refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75%-99% reduction in seizures (42.1% of cohort), and 16 had a 50%-74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic-clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ≥250 mg/day. Three-fourths of patients reported at least one side-effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ≥250 mg/day. Side-effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine, and perampanel. Patients with highly active and ultra-refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250 mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.

Communication about sudden unexpected death in epilepsy: Understanding the caregiver perspective

AbstractObjectiveWe aimed to characterize (1) the caregiver experience of learning about sudden unexpected death in epilepsy (SUDEP), and (2) caregiver preferences for SUDEP risk disclosure.MethodsWe distributed a 24‐question survey to caregivers of children with epilepsy. Free text questions were analyzed using a rapid qualitative analysis approach.ResultsTwo hundred and twelve caregivers of people with epilepsy completed the survey, including 12 bereaved caregivers. Caregivers' children had a high seizure burden, with a median seizure frequency of 24 seizures per year (range: 1 to ≥100). Most participants were aware of SUDEP at the time of the survey (193/212; 91%) though only a minority had learned about SUDEP from a healthcare provider (91/193; 47.2%). Caregivers typically learned about SUDEP from a nonprofit or online source (91/161; 56.5%). Almost all caregivers wanted to discuss SUDEP with their child's healthcare provider (209/212; 98.6%), and preferred disclosure from epileptologists (193/212; 91%), neurologists (191/212; 90.1%), and/or primary care providers (98/212; 46.2%). In open‐ended responses, caregivers highlighted the value of learning about SUDEP from a healthcare provider, the importance of pairing SUDEP risk disclosure with a discussion of how to mitigate risk, and the need for educational resources and peer support.InterpretationCaregivers of people with epilepsy appreciate when healthcare providers disclose information about SUDEP, yet typically hear about SUDEP elsewhere. These findings underscore the importance of interventions to improve and support SUDEP risk disclosure. Future work should evaluate strategies to disclose SUDEP risk and the impact of early SUDEP risk disclosure.

Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range=0-74.5), and patients were taking a median of three (range=0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Centromedian thalamic deep brain stimulation for drug-resistant epilepsy: single-center experience.

Neuromodulation of the centromedian nucleus of the thalamus (CM) has unclear effectiveness in the treatment of drug-resistant epilepsy. Prior reports suggest that it may be more effective in the generalized epilepsies such as Lennox-Gastaut syndrome (LGS). The objective of this study was to determine the outcome of CM deep brain stimulation (DBS) at the authors' institution. Retrospective chart review was performed for all patients who underwent CM DBS at Emory University, which occurred between December 2018 and May 2021. CM DBS electrodes were implanted using three different surgical methods, including frame-based, robot-assisted, and direct MRI-guided. Seizure frequency, stimulation parameters, and adverse events were recorded from subsequent clinical follow-up visits. Fourteen patients underwent CM DBS: 9 had symptomatic generalized epilepsy (including 5 with LGS), 3 had primary or idiopathic generalized epilepsy, and 2 had bifrontal focal epilepsy. At last follow-up (mean [± SEM] 19 ± 5 months, range 4.1-33 months, ≥ 6 months in 11 patients), the median seizure frequency reduction was 91%. Twelve patients (86%) were considered responders (≥ 50% decrease in seizure frequency), including 10 of 12 with generalized epilepsy and both patients with bifrontal epilepsy. Surgical adverse events were rare and included 1 patient with hardware breakage, 1 with a postoperative aspiration event, and 1 with a nonclinically significant intracranial hemorrhage. CM DBS was an effective treatment for drug-resistant generalized and bifrontal epilepsies. Additional studies and analyses may investigate whether CM DBS is best suited for specific epilepsy types, and the relationship of lead location to outcome in different epilepsies.

Seizure Evolution and Outcome in Pediatric Autoimmune Encephalitis

BackgroundOur study aimed to characterize seizure incidence and seizure outcome of pediatric autoimmune encephalitis (AE) focusing on subgroup analysis based on antibody (Ab). MethodsAmong 110 pediatric patients with AE, we compared seizure characteristics and outcomes in 68 patients with seizure, who satisfied the proposed criteria of pediatric AE. Accordingly, patients were classified into three groups, anti-myelin oligodendrocyte glycoprotein (anti-MOG) AE, anti-N-methyl-D-aspartic acid receptor (anti-NMDAR) AE, and Ab-negative AE. Univariate and multivariate analyses were performed to evaluate the risk factors for postencephalitic seizures, defined as persisting seizures six months after onset. ResultsSeizure incidence in the anti-NMDAR (88.9%) and Ab-negative (71.1%) groups differed from anti-MOG group (37.8%). Median seizure frequency within six months was higher in the Ab-negative group (6.0, interquartile range [IQR] 3.0 to 13.0) than in the anti-NMDAR group (3.0, IQR 2.0 to 4.5) and anti-MOG group (2.0, IQR 1.0 to 5.0). Patients in the Ab-negative group tended to develop postencephalitic seizures more frequently and have a lower seizure freedom rate than those in the anti-NMDAR and anti-MOG groups. Ab-negative status, high seizure frequency within six months, and the presence of status epilepticus were associated with the development of postencephalitic seizures on univariate analysis. On multivariate analysis, Ab-negative status remained the only significant variable linked with postencephalitic seizure (odds ratio, 4.17; 95% confidence interval, 1.02 to 18.05). ConclusionsWe delineated the seizure incidence, evolution, and outcome of pediatric patients with Ab-positive and Ab-negative AE. Ab-negative status is predictive of higher seizure burden, more frequent development of postencephalitic seizures, and less favorable seizure outcome than anti-NMDAR and anti-MOG Ab-positive status.

Repeated long sessions of transcranial direct current stimulation reduces seizure frequency in patients with refractory focal epilepsy: An open-label extension study

ObjectiveAlthough clinical trials have demonstrated that cathodal transcranial direct current stimulation (tDCS) is effective for seizure reduction, its long-term efficacy is unknown. This study aimed to determine the long-term effects of repeated cathodal long tDCS sessions on seizure suppression in patients with refractory epilepsy. MethodsPatients were recruited to participate in an extended phase of a previous randomized, double-blind, sham-controlled, three-arm, parallel, multicenter study on tDCS. The patients were divided into an active tDCS group (20 min of tDCS per day) and an intensified tDCS group (2 × 20 min of tDCS per day). Each tDCS session lasted 2 weeks and the patients underwent repeated sessions at intervals of 2 to 6 months. The cathode was placed over the epileptogenic focus with the current intensity set as 2 mA. Seizure frequency reduction from baseline was analyzed using the Wilcoxon signed-rank test for two related samples. A generalized estimating equation model was used to estimate group, time, and interaction effects. ResultsAmong the 19 patients who participated in the extended phase, 11 were in the active tDCS group and underwent 2–16 active tDCS sessions, and eight were in the intensified tDCS group and underwent 3–11 intensified tDCS sessions. Seizure reduction was significant from the first to the seventh follow-up, with a median seizure frequency reduction of 41.7%–83.3% (p < 0.05). Compared to the regular tDCS protocol, each intensified tDCS session substantially decreased seizure frequency by 0.3680 (p < 0.05). One patient experienced an increase of 8.5%–232.8% in the total number of seizures during three treatment sessions and follow-ups. ConclusionRepeated long cathodal tDCS sessions yielded significant and progressive long-term seizure reductions in patients with refractory focal epilepsy.

Safety and efficacy of cathodal transcranial direct current stimulation in patients with Lennox Gastaut Syndrome: An open-label, prospective, single-center, single-blinded, pilot study

PurposeLennox-Gastaut Syndrome (SLG) is a severe form of childhood refractory epilepsy. Only one pilot study has been conducted using cathodal transcranial direct current stimulation (c-tDCs; 2mAx30minx5days) in LGS with promising results (-99% seizure reduction at 5 days). Our aim was to explore and replicate the efficacy and safety of 10 daily sessions of c-tDCs in SLG. MethodsWe conducted a one-blinded, single-center pilot clinical study of c-tDCs (2mAx 30 min x 10 days), applied over the highest amplitude or frequent epileptiform interictal discharges areas using scalp EEG recordings without changes in their treatments. The tDCS device used was Enobio EEG® (Neuroelectrics, Barcelona, Spain). The primary outcome was based on the seizure frequency using seizure diaries before, during 10 days of treatment, and then on a 4 and 8 weeks of follow-up. The rate of adverse events was recorded as a secondary outcome. Descriptive statistics and Wilcoxon signed-rank test were used ResultsTwenty-four patients were enrolled. The mean age was 10.1 ± 5.8 years old and 75% male. All the patients had severe mental retardation and abnormal neurological examinations. A significant median percentual seizure frequency reduction was found: 68.12% (p = 0.05) at 1 week, 68.12% (p = 0.002) in the second week. We found no significant reduction at 1 and 2 months; mainly tonic and atonic seizures were reduced significantly at all times. Only mild self-limited side effects were recorded mainly itching and erythema in the application zone ConclusionTen sessions of c-tDCs in combination with pharmacologic treatment in LGS is safe and appears to reduce significatively tonic and atonic seizure frequency at 2 months of follow-up.

Onset of efficacy and adverse events during Cenobamate titration period.

ObjectivesCenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment‐emergent adverse events (TEAEs) during cenobamate titration.Materials & MethodsAdult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double‐blind studies C013 and C017) or cenobamate (open‐label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]).ResultsOnset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved.ConclusionsReductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long‐term treatment with adjunctive cenobamate was generally safe and well‐tolerated.

Perampanel for the treatment of patients with myoclonic seizures in clinical practice: Evidence from the PERMIT study

PurposeTo investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study. MethodsPERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. Results156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0–10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months. ConclusionPER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. Marinus Pharmaceuticals.

Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: A single-center retrospective study

ObjectiveWe explored the efficacy and safety profile of cenobamate as an adjunctive therapy in patients with refractory focal-onset epilepsy in the pediatric population. MethodsThis was a retrospective, single-center study of cenobamate used as an adjunctive medication in pediatric patients with refractory focal-onset epilepsy . We measured seizure reduction, median reduction in seizure frequency, median dose, responder rate, and treatment-emergent adverse events. ResultsWe studied the efficacy and safety profile of cenobamate in 21 pediatric patients (mean age 15.9). Cenobamate was up titrated using the prescribed starter pack with final doses ranging from 100 mg to 400 mg daily. The mean and median dose of cenobamate was 209.8 mg (±98.87 mg) and 200 mg (175–275), respectively. For patients weighing less than 50 kg, mean and median dose was 4.0 mg/kg/day (3.20–4.63) and 4.32 mg/kg/day, respectively. Mean and median baseline seizure frequency per month in this cohort was 15.38 and 16, respectively, prior to the introduction of cenobamate. After the adjunctive use of cenobamate, mean and median seizure frequency per month reduced to 7.29 and 1, respectively; median reduction in seizure frequency was 93.7%. Seizure reduction of at least 50% (responder rate) was noted in 13 (62.5%) patients and a seizure reduction of at least 75% noted in 11 (52.4%) patients, similar to that seen in adults. Four patients (19%) achieved seizure freedom. Of the 21 pediatric patients, 9 (42.8%) patients had treatment-emergent adverse events (TEAE) with the most commonly reported symptom being ataxia (5, 23.8%) and sedation (2, 9.5%). Three (14.3%) patients discontinued early due to these side effects. No children developed drug rash with eosinophilia and systemic symptoms (DRESS). ConclusionCenobamate demonstrates similar efficacy rates and safety profile within the pediatric population when compared to the published adult data, making it an effective, safe, and tolerable adjunctive medication for children with refractory focal-onset epilepsy, even at the maximum daily dose.

Safety and efficacy of responsive neurostimulation in the pediatric population: Evidence from institutional review and patient-level meta-analysis

BackgroundResponsive neurostimulation (RNS) is a novel technology for drug-resistant epilepsy rising from bilateral hemispheres or eloquent cortex. Although recently approved for adults, its safety and efficacy for pediatric patients is under investigation. MethodsA comprehensive literature search (Pubmed/Medline, Scopus, Cochrane) was conducted for studies on RNS for pediatric epilepsy (<18 y/o) and supplemented by our institutional series (4 cases). Reduction in seizure frequency at last follow-up compared to preoperative baseline comprised the primary endpoint. ResultsA total of 8 studies (49 patients) were analyzed. Median age at implant was 15 years (interquartile range [IQR] 12–17) and 63% were males. A lesional MRI was noted in 64% (14/22). Prior invasive EEG recording was performed in the majority of patients (90%) and the most common modality was stereoelectroencephalography (57%). The most common implant location (total of 94 RNS leads) was the frontal lobe (27%), followed by mesial temporal structures (23%) and thalamus (17%). At a median follow-up of 22 months, median seizure frequency reduction was 75% (IQR: 50–88%) and 80% were responders (>50% seizure reduction). Responses ranged from 50% for temporal lobe epilepsy to 81–93% for frontal, parietal, and multilobar epilepsy. Four infections were observed (8%) and there were no hematomas or postoperative neurological deficits. ConclusionCurrent evidence, albeit limited by potential publication bias, supports the promising safety and efficacy profile of RNS for medically refractory pediatric epilepsy. Randomized controlled trial data are needed to further establish the role of this intervention in preoperative discussions with patients and their families.

Perampanel in real-world clinical care of adolescent and adult patients with epilepsy: Results from the retrospective Phase IV PROVE Study

PurposeReport final data from adolescent (12–<18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care. MethodsData were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians’ recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs). ResultsThe Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10–12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%]). ConclusionPerampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed. ClinicalTrials.gov identifierNCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660).

Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures.

Pregabalin (PGB) is an effective adjunctive treatment for focal epilepsy and acts by binding to the alpha2-delta subunit of voltage-gated calcium channels to reduce excitatory neurotransmitter release. Limited data exist on its use in the neurocritical care setting, including cyclic seizures-a pattern of recurrent seizures occurring at nearly regular intervals. Although the mechanism underpinning cyclic seizures remains elusive, spreading excitation linked to spreading depolarizations may play a role in seizure recurrence and periodicity. PGB has been shown to increase spreading depolarization threshold; hence,we hypothesized that the magnitude of antiseizure effect from PGB is more pronounced in patients with cyclic versus noncyclic seizures in a critically ill cohort with recurrent seizures. We conducted a retrospective case series of adults admitted to two academic neurointensive care units between January 2017 and March 2019 who received PGB for treatment of seizures. Data collected included demographics, etiology of brain injury, antiseizure medications, and outcome. Continuous electroencephalogram recordings 48hours before and after PGB administration were reviewed by electroencephalographers blinded to the administration of antiseizure medications to obtain granular data on electrographic seizure burden. Cyclic seizures were determined quantitatively (i.e., < 50% variation of interseizure intervals for at least 50% of consecutive seizures). Coprimary outcomes were decrease in hourly seizure burden in minutes and decrease in seizure frequency in the 48hours after PGB initiation. We used nonparametric tests for comparison of seizure frequency and burden and segmented linear regression to assess PGB effect. We included 16 patients; the median age was 69years, 11 (68.7%) were women, three (18.8%) had undergone a neurosurgical procedure, and five (31%) had underlying epilepsy. All seizures had focal onset; ten patients (62.5%) had cyclic seizures. The median hourly seizure burden over the 48hours prior to PGB initiation was 1.87min/hour (interquartile range 1.49-8.53), and the median seizure frequency was 1.96 seizures/hour (interquartile range 1.06-3.41). In the 48hours following PGB (median daily dose 300mg, range 75-300mg), the median number of seizures per hour was reduced by 0.80 seizures/hour (95% confidence interval 0.19-1.40), whereas the median hourly seizure burden decreased by 1.71min/hour (95% confidence interval 0.38-3.04). When we compared patients with cyclic versus noncyclic seizures, there was a relative decrease in hourly seizure frequency (- 86.7% versus - 2%, p = 0.04) and hourly seizure burden (- 89% versus - 7.8%, p = 0.03) at 48hours. PGB was associated with a relative reduction in seizure burden in neurocritically ill patients with recurrent seizures, especially those with cyclic seizures, and may be considered in the therapeutic arsenal for refractory seizures. Whether this effect is mediated via modulation of spreading depolarization requires further study.

Efficacy of Frameless Radiosurgical Entorhino-Amygdalohippocampectomy for Pharmacoresistant Medial Temporal Lobe Epilepsy

<h3>Purpose/Objective(s)</h3> Evaluate the efficacy and safety of Linac based surgery in the treatment of pharmaco-resistant epilepsies of mesial temporal lobe origin due to medial temporal sclerosis. <h3>Materials/Methods</h3> Retrospective single institution study comprised of 12 MTLE pts. (10 pts. with MT Sclerosis on Dominant side) who underwent SRS between August 2015 to Jan 2019. The epileptogenic substrate was localized using invasive video-EEG monitoring with foramen ovale electrodes, magnetic resonance imaging, metabolic (PET) imaging. All patients underwent detailed neuropsychological testing and the ESI-55 quality-of-life questionnaire. The radiosurgical target included Anterior part of parahippocampal region; entorhinal area adjacent to the collateral sulcus & rhinal sulcus; hippocampus - head & Anterior part and Amygdalofugal part of the amygdaloid complex. Non-coplanar Volumetrically modulated plans or non-isocentric CK plans using variable collimator were generated for prescribed mean dose of 22gy (range: 20-24 Gy), without any dose heterogeneity. Normal structures doses were within acceptable limits. Radiosurgical treatment was performed by using the C-Arm Linac with hexapod robotics (9 pts.) or frameless robotic radiosurgery system with skull tracking (3pts.). A minimum 2-year follow-up period included clinical, neuropsychological, ophthalmic (Visual field charting) & radiologic evaluations. <h3>Results</h3> Median age at diagnosis is 28 yrs (Range: 17-42yrs). At each 6-month follow-up evaluation, the frequency of seizures was significantly smaller than that at the previous visit. The median seizure frequency of 10.25 the month before treatment was reduced to 0.33 at 2 years after treatment. At 2 years, 67% of the patients (8 of 12) were seizure free - 4 Engel class 1A, 3 Engel class 1B, 1 Engel class 2A responses. The median latent interval from SRS to seizure cessation was 9.5 months (range 6–20 months). One patient was immediately seizure free. The median latency in aura cessation was 14 months (range 9–22 months). Morphological changes, edema, on magnetic resonance imaging were visible at 10 months (median) after SRS (range 7–22 months) in nearly all patients. During the onset period of these radiological changes, three patients experienced headache associated, in two cases, with nausea and vomiting. In these three patients the signs resolved immediately after short course of low doses of steroids. No cases of permanent neurological deficit (except three cases of monosymptomatic visual field deficit), or morbidity, or mortality were observed <h3>Conclusion</h3> Initial experience of Frameless SRS, as non-invasive technique, for MTLE provides benefits especially in young patients requiring high social skills with dominant lobe involvement in the traditional realms of safety with short- to middle-term efficacy & superior neuropsychological outcomes, similar to published series in GKS studies but with appreciated realms of patient acceptance, comfort and costs. Further long-term follow up is required.

The Efficacy, Safety, and Outcomes of Brain-responsive Neurostimulation (RNS® System) therapy in older adults.

ObjectivesThe gold standard for the management of drug‐resistant focal epilepsy (DRE) is resection of epileptogenic zone. However, some patients may not be candidates for resection. Responsive neurostimulation is approved in patients above 18 years of age for such patients. We aimed to investigate whether RNS outcomes and safety varied based on age.MethodsWe performed a single‐center retrospective cohort study of patients with DRE who were treated with RNS between May 2008 and February 2020. We included patients who had been implanted with RNS for >6 months (N = 55), dividing them into older (N = 11) and younger adults (N = 44) depending on implantation age (≥50 and <50 years, respectively).ResultsMean age at implantation in older adults was 54.9 ± 3.5 years. Seizure onset age, epilepsy duration, and comorbidities were significantly higher in older adults ( P < .01). Stimulation parameters, treatment duration, and median seizure frequency reduction (76% in older vs 50% in younger adults) were statistically comparable between the two cohorts. Posttreatment, antiseizure medication burden was significantly decreased in older compared with younger adults (P = .048). Postoperative and delayed adverse events among older adults were mild. Compared with three younger adults, none of the older adults required device explantation due to surgical site infection.ConclusionOur study suggests that older adults treated with the RNS System achieve seizure outcomes comparable to younger adults with the additional benefit of a significant postimplantation medication reduction. With efficacy and safety similar to younger adults, brain‐responsive neurostimulation was well‐tolerated in older adults.

How much can medical management alone improve the outcome of adult drug-resistant epilepsy? An exploratory study on possibilities and limitations of combining multiple therapeutic actions

PurposeFailure to control epileptic seizures with two medications, adequately chosen and dosed, indicates drug-resistant epilepsy (DRE). The chance of pharmacologically controlling seizures is low for patients with DRE and uncontrolled seizures who are not candidates for surgery, who have already undergone surgery, or who already had a vagus nerve stimulator (VNS) placed. Patients experiencing these conditions must instead rely on medical management of their seizures, and there is no breakthrough solution on the horizon.Medical care of DRE might be optimized by systematically considering factors that promote and inhibit breakthrough seizures. For example, seizure control could be enhanced through measures such as increasing the frequency of follow-up visits, tracking treatment plan compliance, treating sleep disorders, rational polypharmacy, adjusting drug administration to achieve higher levels when seizures are more likely and educating patients on seizure triggers. A systematic and simultaneous implementation of all of these measures is likely to yield a sizable, clinically relevant, improvement.This paper presents an exploratory study on the effects of implementing such an approach, specifically evaluating this method’s impact on seizure frequency. MethodsI performed a retrospective chart review of 659 consecutive adult patients with epilepsy followed up at the University of Utah and at the Salt Lake City VA Medical center using the multimodal approach described above. I identified 27 patients who had DRE and uncontrolled seizures and in whom a medical management optimization protocol was implemented. I measured these patients’ seizure frequency at the beginning and the end of the study period and compared the results with those of a matching control group of 48 patients. ResultsThe optimization protocol did not increase the number of seizure-free patients with DRE; however, it was effective in minimizing seizure frequency in patients whose seizures remained uncontrolled. Among these patients, the median seizure frequency dropped by 64% in the optimization group but did not change in the control group. ConclusionsDespite the high occurrence of DRE, there is no accepted protocol for the related medical management. This paper describes an effective approach that can be implemented in a clinically relevant and readily achievable manner.

The perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder

IntroductionCDKL5 Deficiency Disorder (CDD) is a severe treatment-resistant form of early-onset epilepsy. Current treatment options are often ineffective and associated with adverse effects, forcing families to seek alternative therapies for their children including products derived from cannabis. Reportsof miraculous cures and a public preferencefor ‘natural’ therapies have resulted in considerable public interest, and so this study aimed to characterize the use of cannabis in these individuals, as well as compare caregiver perceptions of efficacy and safety to objective evidence of seizure control and number of antiepileptic drugs used. MethodsFamilies from the International CDKL5 Disorder Database were invited to complete questionnaires which included data relating to their child’s current and past treatments, including use of any cannabis-derived preparations. Perceived effects on seizure control, as well as additional benefits and adverse effects were reported. Seizure frequency and number of antiepileptic drugs were compared between those actively using cannabis products and those who were not. Longitudinal analysis was performed on a subset of the study population to compare these same variables at pre-treatment and post-treatment time points. ResultsThree hundred and twelve caregivers answered questions regarding their child’s use of antiepileptic medications. Of these, 82 (26%) described use of cannabis preparations either at present, or in the past, with the most common being cannabidiol. Of 70 caregivers that described their perceived effect on seizure control, more than two thirds reported an improvement in seizure control, either temporary (16%) or lasting (54%). Additional benefits included improvements in attention, cognition, and sleep. The majority of responses (78%) described adverse effects as ‘none’, though some reported an increase in sedation and gastrointestinal upset. There was no reduction in the median seizure frequency nor the number of different antiepileptic drugs, for those who were actively using cannabis products compared to those who were not. Similarly, individuals who were not using cannabis products at an initial time point had no differences in seizure frequency nor number of antiepileptic drugs at a second timepoint when they had started using this treatment. ConclusionsAlthough this is an observational study, limited by potential participation bias and the unreliable nature of unblinded self-assessment, it suggests that caregivers perceive cannabis products, especially cannabidiol, to have a tolerable adverse effect profile and adequate efficacy. Despite this, cannabis was not associated with a reduction in seizure frequency nor number of antiepileptic drugs when compared to non-users or when compared to pre-treatment. Randomized controlled trials are urgently needed to more reliably assess this treatment’s safety and efficacy.

A phase 1b/2a study of soticlestat as adjunctive therapy in participants with developmental and/or epileptic encephalopathies

ObjectiveTo evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE). MethodsThe study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by evaluation of changes in seizure frequency from baseline. ResultsEighteen patients (median age, 28.5 years) were enrolled and randomized, and 14 (78 %) completed the study. In Part A, TEAEs occurred in 71.4 % of soticlestat-treated patients and 100 % of placebo-treated patients. In Part B, the overall incidence of TEAEs was 68.8 %. In Part A, TEAEs that occurred in more than one patient in the soticlestat group were dysarthria (n = 3, 21.4 %), lethargy (n = 2, 14.3 %), upper respiratory tract infection (n = 2, 14.3 %), fatigue (n = 2, 14.3 %), and headache (n = 2, 14.3 %). Four patients discontinued treatment because of TEAEs, of whom two reported drug-related seizure clusters as serious TEAEs. There were no deaths. Pharmacokinetic analysis showed dose-dependent increases in systemic exposure and peak plasma soticlestat concentrations. At the end of Part B, the overall mean percent change from baseline in plasma 24HC was −80.97 %. Changes from baseline in median seizure frequency were +16.71 % and +22.16 % in the soticlestat and placebo groups, respectively, in Part A, and −36.38 % in all participants in Part B. ConclusionSoticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox–Gastaut syndrome.