One-year seizure freedom and quality of life in patients with drug-resistant epilepsy receiving adjunctive vagus nerve stimulation in Japan.

OBJECTIVE: Amount of seizure-free days is a critical determinant of quality of life (QoL) in patients with drug-resistant epilepsy (DRE). The fractions of patients experiencing prolonged periods of seizure freedom with adjunctive vagus nerve stimulation (VNS) have yet to be assessed on a large scale. METHODS: Retrospective analysis of patients in the Japanese VNS prospective observational registry who experienced at least 1 year of seizure freedom from all seizures, focal seizures, or tonic-clonic seizures (TCS), as well as patient-reported change in QoL in these groups. RESULTS: The study included 362 patients with DRE, 147 were female (40.6%), and the median age at VNS implant was 23.0 years (range: 1.0-73.0). A total of 225 patients reported focal seizures and 184 patients reported TCS. After 36 months of adjunctive VNS, the cumulative proportion of patients experiencing at least 1 year of complete seizure freedom was 11% (38/356) with an average duration of seizure freedom of 19.4 months. In patients with focal seizures, 25% (n = 57/225) experienced at least 1 year of freedom from focal seizures with an average duration of 24.8 months. Higher cumulative rates of freedom from TCS were observed: 55% (n = 101/184) experienced at least 1 year without TCS with an average duration of TCS-free periods of 28.9 months. 82.1% of patients with 12-month complete seizure freedom reported markedly improved or improved QoL compared with 51.9% of patients who were not seizure-free. QoL changes in patients with 12-month seizure freedom from TCS and focal seizures were similar: 61.8% and 63% of respective patients reported either markedly improved or improved QoL at 36 months. SIGNIFICANCE: Complete seizure freedom is rare in patients treated with VNS; however, this analysis found approximately half of patients who experienced TCS prior to VNS experienced prolonged periods of freedom from TCS with adjunctive VNS. PLAIN LANGUAGE SUMMARY: We studied patients in Japan with epilepsy that is difficult to treat. To understand if adding vagus nerve stimulation (VNS) helps such patients, we looked at which patients stopped having all seizures or stopped having a specific seizure type (such as tonic-clonic seizures or focal seizures), and how long these periods lasted. With VNS treatment, about 2 out of 4 patients with tonic-clonic seizures and 1 out of 4 patients with focal seizures had more time without these seizure types. Without seizures, patients felt better about their daily lives. Even patients who still had seizures felt better about their daily lives after 3 years of VNS treatment. TRIAL REGISTRATION: The clinical trial registry number is UMIN000014728.

Role of Responsive Neurostimulation in Managing Drug-Resistant Epilepsy: A Systematic Review of Clinical Outcomes.

Drug-resistant epilepsy remains a substantial challenge in neurology, affecting patients who do not respond to conventional antiepileptic drugs. Responsive neurostimulation (RNS) has emerged as a promising therapeutic approach, yet comprehensive reviews synthesizing its clinical outcomes are sparse. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and involved a comprehensive database search through PubMed, Medline, Embase, the Cochrane Library, and Scopus, covering literature up to April 2024. The review targeted peer-reviewed articles evaluating the efficacy, safety, and quality of life impacts of RNS in patients with drug-resistant epilepsy. Key inclusion criteria encompassed clinical trials, cohort studies, and meta-analyses, while exclusion criteria included non-peer-reviewed and irrelevant studies. We identified five studies meeting our inclusion criteria. These studies collectively demonstrated that RNS significantly reduces seizure frequency and improves quality of life, while maintaining a favorable safety profile. Despite small sample sizes and potential selection biases, the benefits of RNS appeared consistent across diverse patient demographics. RNS represents a viable and effective treatment option for drug-resistant epilepsy, offering significant improvements in seizure control and patient quality of life. Future research should focus on long-term outcomes and refining patient selection to optimize the therapeutic benefits of RNS. The integration of RNS into standard epilepsy management protocols is recommended based on current evidence.

Vagus nerve stimulation in lesional and Non-Lesional Drug-Resistant focal onset epilepsies.

PURPOSE: Drug-resistant epilepsy (DRE) affects one-third of patients with focal epilepsy. A large portion of patients are not candidates for epilepsy surgery, thus alternative options, such as vagus nerve stimulation (VNS), are proposed. Our objective is to study the effect of vagus nerve stimulation on lesional versus non-lesional epilepsies. METHODS: This is a retrospective cohort study in a single center in London, Ontario, which includes patients with DRE implanted with VNS, implanted between 1997-2018 and the date of analysis is December 2023. PARTICIPANTS: Patients implanted with VNS were classified by lesional (VNS-L) and non-lesional (VNS-NL) based on their MRI head findings. We further subdivided the VNS groups into patients with VNS alone versus those who also had additional epilepsy surgeries. RESULTS: A total of 29 patients were enrolled in the VNS-L, compared to 29 in the VNS-NL. The median age of the patients in the study was 31.8 years, 29.31 % were men (N = 17). 41.4 % (n = 12) of the patients were VNS responders (≥50 % seizure reduction) in the VNS-L group compared to 62.0 % (n = 18) in the VNS-NL group (p = 0.03). When other epilepsy surgeries were combined with VNS in the VNS-L group, the median rate of seizure reduction was greater (72.4 (IQR 97.17-45.88) than the VNS-NL group 53.9 (IQR 92.22-27.92); p = 0.27). CONCLUSIONS: VNS is a therapeutic option for patients with lesional epilepsy, with slightly inferior results compared to patients with non-lesional epilepsy. Patients implanted with VNS showed higher seizure reduction rates if they had previous epilepsy surgeries. This study demonstrates that VNS in lesional epilepsies can be an effective treatment.

Efficacy and tolerability of classical and polyunsaturated fatty acids ketogenic diet in controlling paediatric refractory epilepsy - A randomized study.

OBJECTIVES: To measure and compare the efficacy and tolerability of a classical ketogenic diet (CKD) and a polyunsaturated fatty acids ketogenic diet (PUFAKD) in managing childhood refractory epilepsy. Efficacy was assessed by measuring the change in seizure frequency at 3, 6, 9, and 12 months within and between groups. The percentage reduction in seizures at <50 %, 50-90 %, >90 %, and 100 % was also measured. Tolerability was assessed and compared by recording adverse events - vomiting, nausea, lethargy, and constipation. METHODS: 52 children, aged 2-10 years, were randomized, 25 in the CKD group and 27 in the PUFAKD group. Fat: carbohydrate + protein ratio of 2.2:1-4:1 was maintained in both diets; the PUFAKD group only used unsaturated fats with an omega 3: omega 6 ratio of 1:2.8. Ketone levels were measured using keto-dipsticks, with 4+ and 4++ (80-160 mg/dL) being the most optimal values. RESULTS: A significant decrease (p=0.001) in seizures was observed (n=52), with no significant difference (p=0.537) between the two groups. The mean seizure reduction was 71.1 %, with no significant difference (p=0.488) in both groups. The mean compliance rate was 78.3 % (n=52). A statistically significant linear trend existed between a higher compliance rate and a greater reduction in seizures (p = 0.042, Z=4.039) among all children (n=52). Nausea (p=0.033) and vomiting (p=0.014) occurred more in PUFAKD than in CKD. CONCLUSION: No significant difference was seen in seizure reduction between the two groups. Compliance correlates with a greater seizure reduction. Despite similar seizure reduction rates, the novel PUFAKD exhibited poorer compliance and more pronounced adverse effects compared to CKD. CKD remained a superior choice over the novel PUFAKD in the management of paediatric refractory epilepsy. More controlled trials with varying PUFA compositions are recommended for long-term evaluations.

Focal cooling: An alternative treatment for drug-resistant epilepsy in a mesial temporal lobe epilepsy primate model-A preliminary study.

OBJECTIVE: Focal cooling is emerging as a relevant therapy for drug-resistant epilepsy (DRE). However, we lack data on its effectiveness in controlling seizures that originate in deep-seated areas like the hippocampus. We present a thermoelectric solution for focal brain cooling that specifically targets these brain structures. METHODS: A prototype implantable device was developed, including temperature sensors and a cannula for penicillin injection to create an epileptogenic zone (EZ) near the cooling tip in a non-human primate model of epilepsy. The mesial temporal lobe was targeted with repeated penicillin injections into the hippocampus. Signals were recorded from an sEEG (Stereoelectroencephalography) lead placed 2 mm from the EZ. Once the number of seizures had stabilized, focal cooling was applied, and temperature and electroclinical events were monitored using a customized detection algorithm. Tests were performed on two Macaca fascicularis monkeys at three temperatures. RESULTS: Hippocampal seizures were observed 40-120 min post-injection, their duration and frequency stabilized at around 120 min. Compared to the control condition, a reduction in the number of hippocampal seizures was observed with cooling to 21°C (Control: 4.34 seizures, SD 1.704 per 20 min vs Cooling to 21°C: 1.38 seizures, SD 1.004 per 20 min). The effect was more pronounced with cooling to 17°C, resulting in an almost 80% reduction in seizure frequency. Seizure duration and number of interictal discharges were unchanged following focal cooling. After several months of repeated penicillin injections, hippocampal sclerosis was observed, similar to that recorded in humans. In addition, seizures were identified by detecting temperature variations of 0.3°C in the EZ correlated with the start of the seizures. SIGNIFICANCE: In epilepsy therapy, the ultimate aim is total seizure control with minimal side effects. Focal cooling of the EZ could offer an alternative to surgery and to existing neuromodulation devices.

Efficacy of vagus nerve stimulation in managing drug-resistant absence epilepsy syndromes.

PURPOSE: Around 11% of patients with absence epilepsy develop drug-resistant absence epilepsy (DRAE), and are at increased risk for developing psychiatric and neurologic comorbidities. Current therapeutic options for DRAE are limited. The purpose of this study was to assess the efficacy of vagus nerve stimulation (VNS) in treating DRAE. METHODS: Our institution maintains a database of patients who received VNS between 2010 and 2022. We identified DRAE patients who were <18 years of age at seizure onset, were electro-clinically diagnosed with an absence epilepsy syndrome (childhood absence, juvenile absence, or Jeavons Syndrome) by an epileptologist, and had normal brain imaging. The primary outcome measure was post-VNS absence seizure frequency. RESULTS: Twenty-six patients (M/F:14/12) were identified. Median age at seizure onset was 7 years (IQR 4-10) and patients experienced seizures for 6 years (IQR 4.3-7.6) before VNS. After VNS, the median absence seizure frequency reduced to 1.5 days (IQR 0.1-3.5) per week from 7 days (IQR 7-7), a 66% reduction seizure frequency. VNS responder rate was 80%, and seven patients achieved seizure freedom. There was no significant effect on VNS efficacy between the time from DRAE diagnosis to VNS placement (p = 0.067) nor the time from first seizure onset to VNS implant (p = 0.80). The median follow-up duration was 4.1 years (IQR 2.4-6.7), without any significant association between follow-up duration and VNS efficacy (r2=0.023) CONCLUSIONS: VNS is effective in managing DRAE. The responder rate was 80%; seizure improvement was independent of age at both seizure onset and latency to VNS after meeting DRAE criteria.

Efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate in patients with focal to bilateral tonic-clonic seizures.

OBJECTIVE: To report the efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate (ESL) treatment in reducing focal to bilateral tonic-clonic seizures (FBTCS). METHODS: Data were pooled from 3 randomized clinical trials (RCTs) of adjunctive ESL in patients with focal seizures. Patients treated with 800 or 1200 mg/day ESL and who experienced ≥ 1 FBTCS during baseline were included. Efficacy was measured using FBTCS standardized seizure frequency (SSF), responder rates (≥50%, ≥75%, and 100%), and time to first FBTCS. Adverse events (AEs) were tabulated for each subgroup. RESULTS: Of the original 1447 patients, 438 patients in the safety population were included with ≥ 1 FBTCS at baseline (efficacy population, n = 429). Patients with ≥ 2 FBTCS (safety, n = 354; efficacy, n = 346) and ≥ 3 FBTCS (safety, n = 294; efficacy, n = 288) at baseline were also analyzed. The 1200 mg/day ESL group experienced lower least squares mean SSF vs placebo in patients with ≥ 1 baseline FBTCS (P = 0.0395) and ≥ 3 baseline FBTCS (P = 0.0091). The 50% responder rates improved for 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.005; ≥2 FBTCS, P = 0.0063; ≥3 FBTCS, P = 0.0016). The 75% responder rates improved with 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.0315; ≥2 FBTCS, P = 0.0215; ≥3 FBTCS, P = 0.0099), and with 800 mg/day ESL for ≥ 2 FBTCS at baseline (P = 0.0486). The 100% responder rate was higher in patients treated with 1200 mg/day ESL (not significant). Time to first FBTCS was longer with both 800 (P = 0.0008) and 1200 mg/day (P = 0.0020) ESL vs placebo for the ≥ 1 FBTCS subgroup, and with 1200 mg/day ESL for ≥ 2 FBTCS (P = 0.0060) and ≥ 3 FBTCS (P = 0.0152) subgroups. Overall, AEs occurred at similar rates across subgroups, and were lower than the original RCTs. CONCLUSION: Adjunctive ESL produced a robust response in patients with FBTCS, a seizure type associated with SUDEP and high injury rates. Adjunctive ESL was well tolerated in patients who experienced FBTCS.

Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study.

BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.

Efficacy of Levetiracetam as Add-On Therapy in the Treatment of Seizures in Neonates.

INTRODUCTION: There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving >80% seizure reduction after phenobarbital (PB) treatment. METHODS: Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated. RESULTS: A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36-44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n = 11), hemorrhagic or ischemic stroke (n = 16), central nervous system infection (n = 8), genetic (n = 8), metabolic disorders (n = 3), and unknown (n = 1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration. DISCUSSION: Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.

Ketogenic Diet and Multiple Health Outcomes: An Umbrella Review of Meta-Analysis.

Numerous studies have examined the effects of ketogenic diets (KD) on health-related outcomes through meta-analyses. However, the presence of biases may compromise the reliability of conclusions. Therefore, we conducted an umbrella review to collate and appraise the strength of evidence on the efficacy of KD interventions. We conducted a comprehensive search on PubMed, EMBASE, and the Cochrane Database until April 2023 to identify meta-analyses that investigated the treatment effects of KD for multiple health conditions, which yielded 23 meta-analyses for quantitative analyses. The evidence suggests that KD could increase the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), the respiratory exchange rate (RER), and could decrease total testosterone and testosterone levels (all p-random effects: <0.05). The combination of KD and physical activity can significantly reduce body weight and increase the levels of LDL-C and cortisol. In addition, KD was associated with seizure reduction in children, which can be explained by the ketosis state as induced by the diet. Furthermore, KD demonstrated a better alleviation effect in refractory childhood epilepsy, in terms of median effective rates for seizure reduction of ≥50%, ≥90%, and seizure freedom. However, the strength of evidence supporting the aforementioned associations was generally weak, thereby challenging their credibility. Consequently, future studies should prioritize stringent research protocols to ascertain whether KD interventions with longer intervention periods hold promise as a viable treatment option for various diseases.

Ketogenic diet in childhood epilepsy: clinical algorithm in a tertiary care center.

Background: Dietary therapies play a crucial role in managing patients, especially those who have specific types of epilepsy, display adverse effects, or are not responding to pharmacological treatments. The ketogenic diet (KD) is a high-fat, restricted carbohydrate, and adequate protein regimen. The KD has proven to be an effective nonpharmacological treatment for drug-resistant epilepsy (DRE) by generating ketones that act as an alternative fuel source for the brain, thereby reducing the occurrence of seizures. The advantages of KD have been attributed to its universal availability, numerous administration techniques, and affordability. Objective: This article presents the KD algorithm developed by a multidisciplinary team of experts at the Children's Hospital, Ain Shams University, Egypt. The algorithm serves as a guide for implementing the KD in the treatment of DRE in children. The algorithm has been previously validated through a study. Methods: The algorithm consists of seven essential stages: (1) referral of patients to the Complex Epilepsy Committee, (2) pre-diet assessment of patients, (3) referral of patients to the Clinical Nutrition (CN) team, (4) diet selection and initiation, (5) seizure follow-up and diet fine-tuning, (6) diet reassessment after 3 months, and (7) evaluation of the KD journey after 24 months. Results: The KD algorithm was systematically developed and proved highly influential in facilitating the implementation of the KD. The algorithm yielded significant health benefits in pediatric patients. Conclusion: The KD algorithm provides a systematic approach to implementing the ketogenic diet and has demonstrated positive health outcomes in pediatric patients.

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

OBJECTIVE: Although 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. METHODS: Patients 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. RESULTS: Among 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. CONCLUSION: Repeated long cathodal tDCS sessions yielded significant and progressive long-term seizure reductions in patients with refractory focal epilepsy.

Electroencephalographic changes in purified pharmaceutical cannabidiol therapy.

OBJECTIVE: Evaluate electroencephalographic changes in patients receiving purified pharmaceutical cannabidiol (CBD). METHODS: A total of 104 EEG studies from 52 patients with pediatric-onset refractory epilepsy, who were enrolled in the FDA-approved expanded access investigational new drug program, were retrospectively analyzed for electroencephalographic changes in the background, interictal epileptiform discharges (IEDs), ictal findings, and sleep architecture after CBD treatment. RESULTS: Patients were between 18 months and 52 years of age. After CBD treatment, 88.4% (46/52) of patients had EEG changes. Eighty-nine percent of these patients had changes in their background, 74% in IEDs, 46% in ictal findings, and 17% in sleep architecture. Seven out of 52 patients had modified hypsarrhythmia on their pre-treatment EEG. The pattern resolved in 2/7 patients (29%), diminished in prevalence in 4/7 (57%) subjects, and remained unchanged in 1/7 (14%) cases. Electrographic improvement was seen in 70% (32/46) of the patients, and worsening in 7% (3/46) of the cases. At the post-CBD EEG, 83% had a reduction in the frequency of the most predominant seizure type, and 25% reported subjective cognitive improvement. Of these patients, 88% (p = 0.09) and 92% (p = 0.45) had corresponding EEG changes, respectively. CONCLUSION: Our results revealed electrographic changes in association with the CBD treatment. Despite these changes, a substantial association between specific electrographic findings and clinical outcomes was not established.

Protective effects of medium chain triglyceride diet in a mouse model of Dravet syndrome.

OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS. METHODS: Scn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia-induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate. RESULTS: Dietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia-induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status. SIGNIFICANCE: The results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.

Daily listening to Mozart reduces seizures in individuals with epilepsy: A randomized control study.

OBJECTIVE: Epilepsy is one of the most common neurological disorders . Many individuals continue to have seizures despite medical and surgical treatments, suggesting adjunctive management strategies are required. Promising effects of daily listening to Mozart on reducing seizure frequency in individuals with epilepsy have been demonstrated over the last 20 years, but not in a rigorously controlled manner. In this study, we compared the effect on seizure frequency of daily listening to either Mozart K.448 or a spectrally similar, yet non-rhythmic control piece. We hypothesized that there would be no difference in seizure counts when participants listened to Mozart K.448 vs when they listened to the control piece. METHODS: We employed a randomized crossover design, in which each participant was exposed to both three months of daily listening to the first six minutes of Sonata for two pianos in D major by Mozart (Mozart K.448; treatment period) and three months of daily listening to phase-scrambled version (control period). There was a three-month baseline and a three-month follow-up period before and after the six-month listening period, respectively. Change in seizure counts obtained from the seizure diaries was considered as the main study outcome. RESULTS: Using three methodologies to investigate the existence of the treatment effect (paired t test, estimation statistics and plots, and Cohen's d), our results revealed a reduction in seizure counts during the treatment period, which was not observed for the control period (P-value < .001). SIGNIFICANCE: Using a spectrally similar control piece, our study advances previous reports that were limited by a "no music" control condition. Daily listening to Mozart K.448 was associated with reducing seizure frequency in adult individuals with epilepsy. These results suggest that daily Mozart listening may be considered as an adjunctive therapeutic option to reduce seizure burden in individuals with epilepsy.

Time course of 75%-100% efficacy response of adjunctive brivaracetam.

BACKGROUND: Time to sustained seizure frequency reduction can provide clinically meaningful epilepsy outcomes. AIMS OF THE STUDY: To examine the time course of brivaracetam (BRV) efficacy in adults with focal seizures and focal to bilateral tonic-clonic seizures (FBTCS). METHODS: Post hoc analysis of data pooled from three randomized controlled trials of oral adjunctive BRV in adults with epilepsy. Patients with focal epilepsy and a subpopulation with FBTCS receiving BRV 50, 100, or 200 mg/d (initiated without up-titration) or placebo for 12 weeks were analyzed for time to sustained ≥75%, ≥90%, and 100% seizure reduction without interruption from first day until trial ends. RESULTS: Evaluation included 1160 patients with focal seizures, including 352 patients with FBTCS. Sustained ≥75%, ≥90%, and 100% response in focal seizures was higher from day 1 for BRV 100 and 200 mg/d vs placebo (P < .01). Sustained ≥75% and 100% FBTCS reduction from day 1 was higher for BRV 100 and 200-mg/d groups vs placebo (P < .01). CONCLUSIONS: The majority of patients achieving 75%-100% sustained seizure frequency reduction (all focal seizure types and the subpopulation with FBTCS) with oral BRV (100 or 200 mg/d) achieved this response on the first-treatment day.

Transcutaneous vagus nerve stimulation for the treatment of drug-resistant epilepsy: a meta-analysis and systematic review.

BACKGROUND: The transcutaneous vagus nerve stimulation (tVNS) is a newly developed non-invasive technique in the treatment of drug-resistant epilepsy and results in positive effects for patients who cannot tolerate invasive vagus nerve stimulation. In this study, we aim to define the relationship between tVNS and seizure control, quality of life (QOL) and some other factors. METHODS: We found articles by searching through PubMed and Web of Science, and a total of three articles with 280 patients overall were included. These eligible studies include two randomized double-blinded trials and one randomized single-blinded trial. Meta-analysis and systematic review were performed, analysing the association between tVNS and seizure frequency using the available data. The responder rate, QOL and adverse effects were also analysed. RESULTS: The results showed a significant difference in seizure frequency between treatment group and control group (Z = 2.14, P = 0.03, 95% confidence interval (CI) -6.31 to -0.27; I2 = 10%). However, only two studies provided the data of responders, and the result failed to figure out a significant difference (Z = 0.75, P = 0.45, 95% CI (odds ratio) 1.47 (0.54-4.02); I2 = 61%). It is difficult to define whether tVNS improved QOL between treatment and control groups using the available data. The adverse effects seem to be very few, with the most common being headache. CONCLUSION: tVNS is an effective procedure to control the frequency of seizures according to the available data, especially for those patients who do not want to tolerate a surgical procedure.

(Re)Defining success in epilepsy surgery: The importance of relative seizure reduction in patient-reported quality of life.

OBJECTIVE: Previous work has suggested that seizure outcome is the most important predictor of quality of life (QoL) after epilepsy surgery, but it is unknown which specific seizure outcome measure should be used in judging surgical success. We assess three different seizure outcome measures (relative seizure reduction, absolute seizure reduction, and seizure freedom [yes/no]) to investigate which measure best predicts postoperative QoL. METHODS: We prospectively surveyed patients at outpatient visits before and after epilepsy surgery (n = 550). The QoL measure was the Quality of Life in Epilepsy (QOLIE-10) score at the patient's most recent office visit. We created multivariate regression models to predict postoperative QOLIE-10, with a different seizure outcome measure in each model. We compared models using adjusted R2 values and Akaike information criteria (AIC). RESULTS: Our cohort had a high level of disease severity and complexity (17% repeat surgery, 39% extratemporal, and 18% nonlesional). For the cohort as a whole, mean absolute seizure frequency decreased from 1 per day to 0.1 per day (P < .001), and mean reduction was 73% (95% confidence interval [CI] 66%-81%). Average improvement in QoL score was 5.3 (95% CI 4.1-6.5) points. Of patients who reported an improvement in QoL, 27% had persistent seizures. Comparison of regression models to predict QoL showed that the worst model was provided when using "absolute seizure reduction," but that models using "relative seizure reduction" and "seizure freedom (yes/no)" were equally strong. SIGNIFICANCE: In our high severity and complexity cohort, a substantial subset of patients (27%) reported improved QoL despite persistent seizures. Relative seizure reduction was at least as good a predictor of QoL as seizure freedom. A yes/no seizure freedom variable may be a suboptimal measure of surgical success, especially in high complexity cohorts.

Outpatient initiation of the ketogenic diet in children with pharmacoresistant epilepsy: An effectiveness, safety and economic perspective.

BACKGROUND: Children with pharmacoresistant epilepsy usually receive ketogenic diet (KD) as an inpatient, which makes it an expensive treatment. OBJECTIVE: To compare the effectiveness, safety, and costs of outpatient versus inpatient initiated KD. DESIGN: Retrospective observational non-inferiority study. PATIENTS/SETTING: Patients (1-18 years of age) who started KD either inpatient or outpatient. MAIN OUTCOME MEASURES: Effectiveness was defined as ≥50% seizure reduction. Safety was measured by the numbers of emergency visits and complications. Economic impact was analyzed by calculating total costs of treatment. STATISTICAL ANALYSES: Non-inferiority of outpatient initiation was tested using 95% confidence intervals of the differences in effectiveness and safety endpoints between groups with non-inferiority margins of 10%. Nonparametric bootstrap techniques were used to derive a 95% confidence interval for the mean difference in total costs between the groups. RESULTS: Hundred and five patients started KD in the period 2001 to 2017: 43 inpatient and 62 outpatient. At three months, the KD was effective in 61% of outpatients versus 63% of inpatients. The KD was considered safe in 36% of the outpatients, as compared to 29% in the inpatients. Outpatient initiation was shown to be non-inferior to inpatient initiation in terms of safety. Total health care costs of outpatient initiation were € 2901, as compared to € 8195 of inpatient initiation per patient (mean difference € 5294, 95% CI; -€ 7653 to -€ 2935). CONCLUSIONS: Our study suggests that outpatient KD initiation is no worse than inpatient initiation in terms of effectiveness and safety, while carrying lower health care costs.

Neurostimulation Devices Used in Treatment of Epilepsy.

OPINION STATEMENT: Epilepsy is a chronic neurological disorder frequently requiring lifelong treatment. In 70% of epilepsy patients, seizures are well controlled by antiepileptic medications. About 30% of epilepsy patients remain refractory to medical treatments and may need surgical interventions for better seizure control. Unfortunately and not infrequently, surgical intervention is not feasible due to various reasons such as multiple seizure foci, not resectable focus because of eloquent cortex location, or inability to tolerate surgery due to ongoing concomitant medical conditions. Neurostimulation devices have provided possible seizure control for refractory epilepsy patients who are not candidates for surgical intervention. Among them, vagal nerve stimulation (VNS) has been the oldest, in use since 1997. VNS was followed by responsive nerve stimulation (RNS) after obtaining FDA approval in 2013. Deep brain stimulation (DBS) has not yet met approval in the USA, but has been in clinical practice in Europe since 2010. Neurostimulation devices vary in how they are inserted and their mechanisms of action. VNS has been easily accepted by patients since it is placed extracranially. By contrast, DBS and RNS require invasive procedures for intracranial implantation. As use of these devices will continue to increase in the foreseeable future, we aimed to contribute to the foundation for new research to expand on current knowledge and practice by reviewing the current status of the literature.