Reduction In Seizure Frequency Research Articles

The impact of ketogenic diet on drug-resistant epilepsy in children: A comprehensive review and meta-analysis.

The ketogenic diet (KD), characterized by high-fat and low-carbohydrate intake, is currently gaining widespread popularity as a treatment for drug-resistant epilepsy (DRE). In addition to the traditional ketogenic diet, several variants have been introduced to enhance compliance and flexibility, such as the modified Atkins diet (MAD) and the low glycemic index diet (LGID). These adaptations aim to provide patients with more manageable and sustainable options while harnessing the potential therapeutic benefits of DRE. The objective of this study is to evaluate the efficacy and safety of the KD in pediatric patients who exhibit DRE. In this study, we conducted a thorough review of existing literature by searching Cochrane, Embase, Medline, and PubMed. Our approach involved predefined criteria for data extraction and the assessment of study quality. Eleven RCTs with 788 participants were included in this study. The pooled effect estimates revealed a significant association between dietary interventions and seizure frequency reduction of > 50% (OR 6.68, 96% CI 3.52, 12.67) and > 90% (OR 4.37, 95% CI 2.04, 9.37). Dietary interventions also increased the odds of achieving seizure freedom (OR 4.13, 95% CI 1.61, 10.60). The common adverse effects included constipation (39.07%) and vomiting (10%). In conclusion, dietary interventions, notably the KD, hold promise for pediatric DRE, reducing seizures and achieving freedom. These non-pharmacological options improve the quality of life of non-responsive and non-surgical patients. The KD has emerged as a potential therapeutic approach. Further research is needed to address the limitations and investigate their long-term effects.

The dual effect of vagus nerve stimulation in pediatric patients with drug-resistant epilepsy: Is there more than seizure control?

This is a retrospective and comparative pilot study to investigate the role of vagus nerve stimulation (VNS) in improving cognitive functions in the pediatric age group with drug resistant epilepsy (DRE). It was conducted from January 2018 to February 2023. Children between the ages of 4 and 18 years were divided into two groups, the “VNS group” and the “best medical treatment (BMT) group”. Follow up period was 12 months. Demographic, clinical, etiological and investigational data were recorded. Cognitive assessment using the Modified Mini-Mental State Examination for children (MMSE) was recorded at baseline and 12 months later for each group. 76.4 % of patients were classified as epilepsy secondary to cerebral palsy. 75 % of patients showed ≥ 50 % seizure frequency reduction among the VNS group as compared to 12.5 % in the BMT group. None of both groups achieved seizure freedom. At 12 months, both BMT and VNS groups showed statistically significantly improved overall cognitive score from baseline records (p = 0.027) and (p = 0.012), respectively, with a significantly higher improvement in VNS group. Also, statistical sub-analysis of cognitive subscales in cerebral palsy patients in both groups was conducted and revealed a significant improvement (p = 0.02) in the VNS group. We concluded that there is a potential role of VNS in improving cognitive functions which was shown by using a cost-effective screening tool. A significant effect was observed specially in cerebral palsy patients. This is very beneficial in limited-resources countries since VNS has good safety profile, high seizure control, and added value to cognitive functions.

Effectiveness of Shugan Jieyu capsules for psychiatric symptoms of epilepsy: a systematic review and meta-analysis

BackgroundThe relationship between epilepsy and depression is bidirectional. One condition exacerbates the other. However, there are no current guidelines for treating depression in epilepsy patients. In some cases, seizures worsen when antidepressants (AD) are prescribed or when they are discontinued due to adverse events. The Shugan Jieyu capsule, composed of Acanthopanax senticosus and Hypericum perforatum, is a widely used herbal medicine for treating depression. This study aimed to explore the effectiveness and safety of Shugan Jieyu capsules (SJC) in relieving depression in patients with epilepsy.MethodsWe searched English, Korean, Japanese, and Chinese databases in October 2023 to collect all relevant randomized clinical trials (RCTs). The primary outcomes were the depression scale scores and seizure frequency. The secondary outcomes were quality of life (QoL) and adverse events.ResultsNine RCTs were included in this meta-analysis. Compared with AD, SJC showed significant differences in the improvement of depression (SMD: 3.82, 95% CI: 3.25, 4.39) and reduction in seizure frequency (MD: 0.39 times/month, 95% CI: 0.28, 0.50). SJC showed more beneficial results than antiepileptic drugs (AED) in terms of antidepressant effects (SMD: 1.10, 95% CI: 0.69, 1.51) and QoL (MD: 11.75, 95% CI: 10.55, 12.95). When patients were prescribed AED, the additional administration of SJC improved depression symptoms (SMD: 0.96, 95% CI: 0.28, 1.63). The SJC treatment group had a lower incidence of side effects than the control group. However, the difference was not statistically significant.ConclusionsOur results suggest that SJC may be effective in treating depression in patients with epilepsy. Additionally, SJC has the potential to help reduce seizure frequency in epilepsy patients with depression.

Long-term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life.

To investigate the effectiveness and tolerability of ketogenic diet therapy (KDT) in patients with developmental and epileptic encephalopathy (DEE) associated with genetic etiology which onset within the first 6 months of life, and to explore the association between response to KDT and genotype/clinical parameters. We retrospectively reviewed data from patients with genetic DEE who started KDT at Beijing Children's Hospital between January 1, 2016, and December 31, 2021. A total of 32 patients were included, involving 14 pathogenic or likely pathogenic single genes, and 16 (50.0%) patients had sodium/potassium channel gene variants. The median age at onset of epilepsy was 1.0 (IQR: 0.1, 3.0) months. The median age at initiation of KDT was 10.0 (IQR: 5.3, 13.8) months and the median duration of maintenance was 14.0 (IQR: 7.0, 26.5) months, with a mean blood β-hydroxybutyrate of 2.49 ± 0.62 mmol/L. During the maintenance period of KDT, 26 (81.3%) patients had a ≥50% reduction of seizure frequency, of which 12 (37.5%) patients achieved seizure freedom. Better responses were observed in patients with STXBP1 variants, with four out of five patients achieving seizure freedom. There were no statistically differences in the age of onset, duration of epilepsy before KDT, blood ketone values, or the presence of ion channel gene variants between the seizure-free patients and the others. The most common adverse effects were gastrointestinal side effects, which occurred in 21 patients (65.6%), but all were mild and easily corrected. Only one patient discontinued KDT due to nephrolithiasis. KDT is effective in treating early onset genetic DEE, and no statistically significant relationship has been found between genotype and effectiveness in this study. KDT is well tolerated in most young patients, with mild and reversible gastrointestinal side effects being the most common, but usually not the reason to discontinue KDT. This study evaluated the response and side effects of ketogenic diet therapy (KDT) in patients who had seizures within the first 6 months of life, and were diagnosed with genetic developmental and epileptic encephalopathy (DEE), a type of severe epilepsy with developmental delay caused by gene variants. Thirty-two patients involving 14 gene variants who started KDT at Beijing Children's Hospital between were included. KDT was effective in treating early onset genetic DEE in this cohort, and patients with STXBP1 variants responded better; however, no statistically significant relationship was found between gene variant and response. Most young patients tolerated KDT well, with mild and reversible gastrointestinal side effects being the most common.

Efficacy of vagus nerve stimulation for children with drug-resistant epilepsy: Retrospective study

IntroductionAccording to current investigations, there are controversy in our knowledge regarding the safety and efficacy of Vagus Nerve Stimulation (VNS) in children younger than 12 years old. Therefore, we performed this study and aimed to better evaluate the safety and efficacy of VNS in children younger than 12 years. MethodThe retrospective study comprised two groups. In the first group, patients (N = 19) underwent VNS implantation procedure and second group, (N = 21) received no VNS implantation. The main study parameters are as follows: (1) Primary outcome evaluated the proportion of cases with >50 % reduction of seizures at the last follow-up. (2) Changes in patients’ status in VNS group after procedure compared to before procedure. (3) Patient's complaints in VNS group compared to control group. ResultsOur results demonstrated that there was a significant reduction in the frequency of seizures (per month) in patients 6 months after VNS surgery compared to before VNS surgery (1044.3 ± 1526.7 VS 220.7 ± 421.6; P value = 0.028). 57.9 % of patients underwent VNS showed the response rate of 50 % reduction in seizure frequency. There was significant improvement in memory problem, work/ school limitation, social limitation, and tachycardia 6 months after VNS procedure compared to before VNS procedure in patients. The most common reported side effects were difficulty swallowing (31.5 %) and coughing (31.5 %) followed by stomach discomfort (15.8 %). ConclusionConsidering the significant reduction in the frequency of seizures and improvement of life aspects including in memory problem, work/ school limitation, social limitation, we recommend VNS as an effective treatment modality for drug-resistant epilepsy in children. However, the combination of VNS with other treatment modalities that could improve other aspects of quality such as energy levels, sleep pattern, and feeling management of life is recommended.

What have we learned from the real-world efficacy of FFA in DS and LGS? A post-marketing study in clinical practice

ObjectiveTo evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). MethodsThis was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. ResultsSeizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect.At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient’s death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SignificanceThe effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.

Long-Term Downregulation of the Sodium Channel Gene Scn8a Is Therapeutic in Mouse Models of SCN8A Epilepsy.

De novo mutations of the voltage-gated sodium channel gene SCN8A cause developmental and epileptic encephalopathy (DEE). Most pathogenic variants result in gain-of-function changes in activity of the sodium channel Nav1.6, poorly controlled seizures, and significant comorbidities. In previous work, an antisense oligonucleotide (ASO) reduced Scn8a transcripts and increased lifespan after neonatal administration to a mouse model. Here, we tested long-term ASO treatment initiated after seizure onset, as required for clinical application. ASO treatment was initiated after observation of a convulsive seizure and repeated at 4 to 6 week intervals for 1 year. We also tested the long-term efficacy of an AAV10-short hairpin RNA (shRNA) virus administered on P1. Repeated treatment with the Scn8a ASO initiated after seizure onset provided long-term survival and reduced seizure frequency during a 12 month observation period. A single treatment with viral shRNA was also protective during 12 months of observation. Downregulation of Scn8a expression that is initiated after the onset of seizures is effective for long-term treatment in a model of SCN8A-DEE. Repeated ASO administration or a single dose of viral shRNA prevented seizures and extended survival through 12 months of observation. ANN NEUROL 2024;95:754-759.

Efficacy and tolerability of rufinamide in the treatment of Lennox–Gastaut syndrome (experience of the Svt. Luka’s Association of Medical Institutions)

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

A prospective, observational, multicentre study to evaluate the efficacy of brivaracetam as adjuvant therapy for epilepsy: The Bravo study.

Epilepsy is a persistent tendency to experience epileptic seizures and can lead to various neurobiological disorders, with an elevated risk of premature mortality. This study evaluates the efficacy of brivaracetam adjuvant therapy in patients with epilepsy. A prospective observational multicentre study that was conducted in Pakistan from March to September 2022, by using a non-probability convenience sampling technique. The population consisted of 543 individuals with a diagnosis of epilepsy for whom adjunctive brivaracetam (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) was recommended by the treating physician. The research sample was drawn from various private neurology clinics of Karachi, Lahore, Rawalpindi, Islamabad and Peshawar. Data originating from routine patient visits, and assessments at three study time points, were recorded in the study case report form. Across 18 clinical sites, 543 individuals participated, with a mean age of 32.9 years. The most prescribed dosages were 50 mg BD, followed by 100 mg BD. Notably, brivaracetam combined with divalproex sodium was the most prevalent treatment, followed by brivaracetam with levetiracetam. At both the 14th and 90th day assessments, a significant reduction in seizure frequency was observed, with 63.1% of individuals showing a favourable response by day 90. Treatment-naive individuals exhibited higher rates of seizure freedom and response compared with treatment-resistant individuals. The study demonstrates the effectiveness of brivaracetam combination therapy in epilepsy management, with notable reductions in seizure frequency and favourable clinical responses observed, particularly in treatment-naive individuals.

Spectrum of NMDA Receptor Variants in Neurodevelopmental Disorders and Epilepsy.

N-methyl-D-aspartate receptors (NMDAR) are ligand-gated ion channels mediating excitatory neurotransmission and are important for normal brain development, cognitive abilities, and motor functions. Pathogenic variants in the Glutamate receptor Ionotropic N-methyl-D-aspartate (GRIN) genes (GRIN1, GRIN2A-D) encoding NMDAR subunits have been associated with a wide spectrum of neurodevelopmental disorders and epilepsies ranging from treatable focal epilepsies to devastating early-onset developmental and epileptic encephalopathies. Genetic variants in NMDA receptor genes can cause a range of complex alterations to receptor properties resulting in various degrees of loss-of-function, gain-of-function, or mixtures thereof. Understanding how genetic variants affect the function of the receptors, therefore, represents an important first step in the ongoing development towards targeted therapies. Currently, targeted treatment options for GRIN-related diseases are limited. However, treatment with memantine has been reported to significantly reduce seizure frequency in a few individuals with developmental and epileptic encephalopathies harboring de novo gain-of-function GRIN2A missense variants, and supplementary treatment with L-serine has been associated with improved motor and cognitive performance as well as reduced seizure frequency in patients with GRIN2B loss-of-function missense variants as well as GRIN2A and GRIN2B null variants.

Clinical phenotypes of developmental and epileptic encephalopathy-related recurrent KCNH5 missense variant p.R327H in Chinese children

KCNH5 gene encodes for the voltage-gated potassium channel protein Kv10.2. Here, we investigated the clinical features of developmental and epileptic encephalopathy (DEE) in five Chinese pediatric patients with a missense mutation (p.R327H) in KCNH5 gene. These patients had undergone video EEG to evaluate background features and epileptiform activity, as well as 3.0 T MRI scans for structural analysis and intelligence assessments using the Gesell Developmental Observation or Wechsler Intelligence Scale for Children. Seizure onset occurs between 4 and 10 months of age, with focal and generalized tonic-clonic seizures being common. Initial EEG findings showed multiple multifocal sharp waves, sharp slow waves or spike slow waves, and spike waves. Brain MRI revealed widened extracerebral space in only one patient. Mechanistically, the KCNH5 mutation disrupts the two hydrogen bonds between Arg327 and Asp304 residues, potentially altering the protein’s structural stability and function. Almost 80 % of patients receiving add-on valproic acid (VPA) therapy experienced a reduction in epileptic seizure frequency. Altogether, this study presents the first Chinese cohort of pediatric DEE patients with the KCNH5 p.R327H mutation, highlighting focal seizures as the predominant seizure type and incomplete mutation penetrance. Add-on VPA therapy was likely effective in the early stages of DEE pathogenesis.

A Prospective Post-Marketing Observational Study of Brivaracetam in People With Focal Epilepsy.

We evaluated the effectiveness and tolerability of brivaracetam (BRV), an adjunctive antiseizure medication, as a treatment for focal epilepsy in adults. In this prospective study, we enrolled 51 participants from 3 sites across Canada. At 6 months, 68% (26/38) of participants were still taking BRV, among whom 35% (8/23) attained seizure freedom and 48% (11/23) saw their seizure frequency reduced by over 50%. We did not measure any significant change in irritability, quality of life, depression, and anxiety while treated with BRV. Our findings suggest BRV is effective in reducing seizure frequency among adults with focal epilepsy.

Efficacy and safety of modified Atkins diet therapy for drug‐resistant epilepsy in children and adults: A systematic review and meta‐analysis

AbstractIntroductionDiet‐based treatments have been proposed for drug‐resistant epilepsy (DRE), and the Modified Atkins Diet (MAD) is an alternative. This study aimed to assess the efficacy and safety of MAD as an adjunctive therapy for reducing seizures in patients with drug‐resistant epilepsy.MethodsA literature search was done on six databases. Randomized controlled trial (RCT) studies were included, comparing DRE patients of all ages on standard antiseizure medications (ASD) who received MAD compared to no‐dietary or other dietary interventions. The outcomes are the seizure frequency reduction and the adverse events. Cochrane risk‐of‐bias tool and GRADE were used to assess study quality and the overall certainty of evidence. The effect size of the efficacy of MAD was computed as risk ratio (95% CI). Subgroup analysis based on each type of comparator was done.ResultsTen RCT studies (905 participants) were included, comparing MAD to no dietary intervention, ketogenic diet (KD), and low glycemic index treatment (LGIT). Overall, MAD is constantly and significantly more efficacious than no dietary intervention in reducing seizures ≥50% (RR 7.90, 95% CI 4.59–13.62), ≥90% (RR 4.61, 95% CI 2.05–10.36), and inducing complete seizure‐free (RR 7.79, 95% 2.61–23.22) with high certainty. Other dietary therapies and MAD did not differ significantly from one another in terms of efficacy. The risk of adverse events in MAD is insignificantly higher than in others (RR 1.19, 95% 0.92–1.55).ConclusionThe Modified Atkins Diet has better seizure reduction than no diet intervention but is comparable to other dietary interventions with a negligible increased risk of adverse events.

Identification of metabolic biomarkers of chronic vagus nerve stimulation (VNS) in subjects with drug-resistant epilepsy (DRE).

Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Efficacy and safety of a smartphone application-based treatment of ketogenic diet in pediatric refractory epilepsy.

We aimed to find predictors for smartphone application-based ketogenic diet (KD) treatment effectiveness and safety. The efficacy was evaluated according to the reduction in seizure frequency after the intervention of KD; safety was evaluated based on adverse effects. The ordinal logistic regression analysis was used to explore the influencing factors of efficacy. The study sample included 116 males and 65 females with a median age of 2.27 years. The baseline frequency of seizure was more than five times/day in 123 children, 50.83% of them received three or more antiepileptic drugs (AEDs). Seventy-two patients' KD initiation mode was outpatient, and 73 completed the 12-month follow-up. A total of 88 (48.62%) patients had reported a reduction in seizure ≥50%. Compared with 12 months, those who had received KD therapy for only 3 (P = 0.009) and 6 months (P = 0.005) were more likely to show negative outcomes. Outpatient initiation had better outcomes (P = 0.029) than inpatient initiation. For the number of AEDs applied, patients on two AEDs were more likely to achieve better outcomes (P = 0.001). Adverse events had been noted among 77 patients; BMI Z-score at KD initiation was associated with adverse effects (P = 0.003). Our study suggested that outpatient initiation and long-term treatment of KD should be encouraged. Our research shows that the KD is a helpful treatment for children with refractory epilepsy, reducing seizures by more than 50% in nearly half of the cases, with some experiencing complete seizure freedom. We used a smartphone app to improve communication between patients and their healthcare teams, resulting in a high retention, and app usage was linked to reduced adverse effects. We recommend early consideration of KD treatment for patients failing two AED, encourage outpatient initiation, and advocate for longer-term KD use.

Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs. Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100-400mg/day (65 measures). Results: we enrolled 54 patients with a median age of 27.9years. The mean follow-up was 10.7months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(μg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(μg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = -0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6months evaluation of 4.53 (p = 0.03). Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as "victim" and as "perpetrator" of drug-drug interactions.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey

PurposePlant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. MethodsThe BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. ResultsA total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1−73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51–80%). However, improvements in nonseizure outcomes (18–56%) were also reported in patients who either had no change or worsening of seizure frequency. ConclusionsThis survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling.

Despite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. We retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency ≥ 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values. A total of 389 epilepsy patients were reviewed having a mean dose of 178.4 ± 117.9 mg/day and the serum level, 3.9 ± 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 ± 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 ± 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L. This study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark

ObjectiveTo evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. MethodsA review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. ResultsThe median age of epilepsy onset was two years (interquartile range (IQR): 0.0–5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6–1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0–55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: −10.0–+4.0]). Callosotomy resulted in a seizure reduction of 86–99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0–30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). ConclusionHemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice

BackgroundThe randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC.ResultsThe study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0–106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3–4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment.ConclusionsSeizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.