Cost Effectiveness of Adding Fenfluramine to Standard of Care for Patients with Dravet Syndrome in Sweden.

OBJECTIVE: This study evaluated, in a Swedish setting, the cost effectiveness of fenfluramine (FFA) as an add-on to standard of care (SoC) for reducing seizure frequency in Dravet syndrome, a severe developmental epileptic encephalopathy. METHODS: Cost effectiveness of FFA+SoC compared with SoC only was evaluated using a patient-level simulation model with a lifetime horizon. Patient characteristics and treatment effects, including convulsive seizures, seizure-free days and mortality, were derived from FFA clinical trials. Resource use and costs included cost of drug acquisition, routine care and monitoring, as well as ongoing and emergency resources. Quality of life (QoL) estimates for patients and their caregivers were derived from clinical trial data. Robustness was evaluated by one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analyses. RESULTS: Lifetime cost of FFA+SoC was ~3 million SEK per patient compared with ~1.5 million SEK for SoC only. FFA+SoC generated 15% more QALYs than SoC only (21.2 vs 18.5 over a lifetime), resulting in an incremental cost-effectiveness ratio (ICER) of ~540,000 SEK. Moreover, FFA+SoC had a higher probability of being cost effective than SoC only from a willingness-to-pay threshold of 710,000 SEK. Results remained generally consistent across scenario analyses, with only few exceptions (exclusions of carer utility or FFA effect on sudden unexpected death in epilepsy). CONCLUSION: Due to better seizure control, FFA is a clinically meaningful add-on therapy and was estimated to be a cost-effective addition to current SoC for patients with this rare disease in Sweden at a willingness-to-pay threshold of 1,000,000 SEK.

CBD in the Treatment of Epilepsy.

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.

Placebo response in patients with Dravet syndrome: Post-hoc analysis of two clinical trials.

OBJECTIVE: Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely, but factors influencing placebo response remain poorly understood. This study explored placebo response and its effects on safety, efficacy, and quality of life outcomes in patients with Dravet syndrome. METHODS: We performed exploratory post-hoc analyses of pooled data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials, comparing cannabidiol and matched placebo in 2-18 year old Dravet syndrome patients. All patients had ≥4 convulsive seizures during a baseline period of 4 weeks. RESULTS: 124 Dravet syndrome-treated patients were included in the analysis (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Convulsive seizures were experienced by all placebo group patients at all timepoints, with decreased median convulsive seizure frequency during the treatment period versus baseline; the number of convulsive seizure-free days was similar to baseline. Convulsive seizure frequency had a nominally significant positive correlation with age and a nominally significant negative correlation with body mass index. Most placebo-treated patients experienced a treatment-emergent adverse event; however, most resolved quickly, and serious adverse events were infrequent. Placebo treatment had very little effect on reported Caregiver Global Impression of Change outcomes versus baseline. INTERPRETATION: Placebo had little impact on convulsive seizure-free days and Caregiver Global Impression of Change versus baseline, suggesting that these metrics may help differentiate placebo and active treatment effects in future studies. However, future research should further assess placebo responses to confirm these results.

Enhancing the action of serotonin by three different mechanisms prevents spontaneous seizure-induced mortality in Dravet mice.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome. METHODS: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined. RESULTS: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex. SIGNIFICANCE: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.

Use of levetiracetam for the successful treatment of suspected myoclonic seizures: five dogs (2016-2022).

OBJECTIVES: Myoclonic seizures are considered a type of generalised seizure characterised by brief, jerking movements of the body. The aim of this study is to describe cases of suspected canine myoclonic seizure of idiopathic aetiology and to discuss the successful use of the anticonvulsant levetiracetam as treatment in each of these cases. MATERIALS AND METHODS: Dogs with epileptic myoclonus suspected to be idiopathic in aetiology were considered for inclusion. Medical records were reviewed for physical and neurologic examination findings, clinicopathologic results, and diagnostic imaging results. All included dogs were treated with levetiracetam, and their response was reported. RESULTS: Five dogs were included, all of which had suspected myoclonic seizures either observed in-person or on video recording by a board-certified veterinary neurologist. The duration of myoclonic seizures preceding treatment ranged from one day to one year. One dog also experienced a generalised tonic-clonic seizure. All dogs were treated with levetiracetam. Two dogs experienced long-term myoclonic seizure freedom (duration seizure-free of at least 1 year), and two dogs experienced marked decreased myoclonic seizure frequency. One dog experienced immediate abatement of myoclonic seizures, although levetiracetam was only utilised for 1 month following onset of myoclonic seizures in this patient. CLINICAL SIGNIFICANCE: Myoclonic seizures can be idiopathic in aetiology. Levetiracetam can be used effectively to rapidly stop myoclonic seizures and to decrease the frequency of myoclonic seizures.

Dravet syndrome seizure frequency and clustering: Placebo-treated patients in clinical trials.

OBJECTIVE: Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of these outcomes could improve trial designs. This analysis explored seizure types, seizure clusters, and factors affecting seizure cluster variability in Dravet syndrome patients. METHODS: Pooled post-hoc analyses were performed on data from placebo-treated patients in GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in Dravet syndrome patients aged 2-18 years. Multivariate stepwise analysis of covariance of log-transformed convulsive seizure cluster frequency was performed, body weight and body mass index z-scores were calculated, and incidence of adverse events was assessed. Data were summarized in three age groups. RESULTS: We analyzed 124 placebo-treated patients across both studies (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Generalized tonic-clonic seizures followed by myoclonic seizures were the most frequent seizure types. Mean and median convulsive seizure cluster frequency overall decreased between baseline and maintenance period but did not change significantly during the latter; variation in convulsive seizure cluster frequency was observed across age groups. Multivariate analysis suggested correlations between convulsive seizure cluster frequency and age (positive), and body mass index (BMI) (negative). INTERPRETATION: Post-hoc analyses suggested that potential relationships could exist between BMI, age and convulsive seizure cluster variation. Results suggested that seizure cluster frequency may be a valuable outcome in future trials. Further research is needed to confirm our findings.

Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

An Update on Stiripentol Mechanisms of Action: A Narrative Review.

Stiripentol (Diacomit®) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases.

The efficacy and safety of cannabidiol (CBD) in pediatric patients with Dravet Syndrome: a narrative review of clinical trials.

BACKGROUND: Dravet Syndrome (DS) is a rare and severe form of childhood epilepsy that is often refractory to conventional antiepileptic drugs. Emerging evidence suggests that Cannabidiol (CBD) offer therapeutic benefits for DS. This review aims to evaluate the efficacy and safety of CBD in pediatric patients with DS based on data from ten clinical trials. METHODS: A review was conducted to identify clinical trials assessing the efficacy and safety of CBD in pediatric patients diagnosed with DS. PubMed, MEDLINE, Scopus, Web of Science, and relevant grey literature were systematically searched for relevant articles up to October 2023, and clinical trials within the last 10 years were included. The search strategy incorporated controlled vocabulary terms and keywords related to "Cannabidiol," "Dravet Syndrome," and "pediatric patients." RESULTS: The analysis revealed promising efficacy outcomes. Notably, CBD demonstrated substantial reductions in seizure frequency, with some patients achieving seizure freedom. The findings emphasised the consistency of CBD's efficacy across different patient subgroups. The safety profile of CBD was generally acceptable, with adverse events often being manageable. CONCLUSION: This review consolidates evidence from multiple clinical trials, affirming the potential of CBD as a promising treatment option for pediatric patients with DS. While further research is needed to address existing knowledge gaps, CBD's efficacy and acceptable safety profile make it a valuable addition to the therapeutic tools for DS.

Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first-line add-on therapies for seizures in Dravet syndrome: A network meta-analysis.

OBJECTIVES: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS. METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs. RESULTS: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter. SIGNIFICANCE: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS. PLAIN LANGUAGE SUMMARY: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.

Efficacy of pharmacological treatments for Dravet syndrome: Systematic review and network meta-analysis.

BACKGROUND: Numerous anti-seizure medications (ASMs) have been developed to treat Dravet syndrome (DS). This network meta-analysis aimed to comprehensively analyse the efficacy of ASMs in DS patients, especially in non-seizure-free patients after treatment. METHODS: PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched. The treatment efficacy was assessed by the percentage reduction in monthly convulsive seizure frequency (MCSF) from baseline or individuals who achieved at least a 50 % or 75 % reduction from baseline in convulsive seizure frequency (CSF). RESULTS: Six randomised controlled trials with 633 participants and seven regimens based on four add-on ASMs-fenfluramine (FFA), stiripentol (STP), cannabidiol (CBD), and soticlestat-were included. All drug regimens were superior to the placebo at achieving at least 50 % and 75 % reductions in CSF, but only STP, 0.4 mg/kg/d FFA (FFA0.4), and 0.7 mg/kg/d FFA (FFA0.7) reduced MCSF. STP (50 mg/kg/d) had the highest correlation with reducing MCSF and achieving at least a 50 % reduction from baseline in CSF, followed by FFA0.4 and FFA0.7. Soticlestat and CBD may also be effective in reducing seizures in DS patients. CONCLUSION: STP can be recommended as the first choice among the included drug regimens for reducing seizures in DS patients, while FFA0.4 may be considered the second choice. Other drug regimens can be used as alternative treatments. STP, FFA0.4, and FFA0.7 may consistently present favourable efficacy in most DS patients, while other regimens may present prominent inter-individual variability. Appropriate dose selection and intense monitoring are necessary when treating DS using these drugs.

Efficacy of felbamate in a cohort of patients with epilepsy with myoclonic atonic seizures (EMAtS).

Epilepsy with myoclonic atonic seizures (EMAtS) is a rare childhood onset developmental and epileptic encephalopathy which is frequently refractory to medical therapy. The optimal antiseizure medication remains unknown. This study reports the efficacy of felbamate in children with EMAtS. Six large pediatric epilepsy centers performed a retrospective chart review on patients diagnosed with EMAtS at their institutions and collected data on felbamate usage and efficacy. Responders were classified as patients who had a 50% or greater reduction in seizures with a given therapy. Out of 259 patients, 37 (14%) were treated with felbamate. The efficacy of felbamate was 62%, which was greater than that of either levetiracetam or valproic acid (15%, p < 0.001% and 32%, p = 0.001 respectively) and similar to that of the ketogenic diet (69%, p = 0.8). Felbamate appears to be an effective treatment for EMAtS and should be strongly considered in the treatment course of this disease.

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

OBJECTIVE: To 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). METHODS: This 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. RESULTS: Seizure 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. SIGNIFICANCE: The 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.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Efficacy and safety of six new antiseizure medications for adjunctive treatment of focal epilepsy and epileptic syndrome: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of six new antiseizure medications (ASMs) for adjunctive treatment in adult patients with focal epilepsy and adolescents with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), or tuberous sclerosis complex (TSC). METHODS: A comprehensive literature search was performed using PubMed, Medline, Embase, and Cochrane library databases from inception to October 13, 2023. We included published studies for a systematic review and a network meta-analysis (NMA). The efficacy and safety were reported in terms of a 50% response rate and dropout rate along with serious adverse events (SAEs). The outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). RESULTS: Twenty eligible trials with 5516 patients and 21 interventions, including placebo, contributed to the analysis. Included ASMs were brivaracetam (BRV), cenobamate (CBM), cannabidiol (CBD), fenfluramine (FFM), everolimus (ELM), and soticlestat (SLT). The six new ASMs were compared in four different epilepsy subtypes. In focal epilepsy treatment, BRV seemed to be safe [vs placebo, risk ratio (RR) = 0.69, 95 % confidence interval (CI): 0.25-1.91] and effective (vs placebo, RR = 2.18, 95 % CI: 1.25-3.81). In treating focal epilepsy, CBM 300 mg was more effective at a 50 % response rate (SUCRA 91.8 %) compared with BRV and CBD. However, with the increase in dosage, more SAEs (SUCRA 85.6 %) appeared compared with other ASMs. CBD had good efficacy on LGS (SUCRA 88.4) and DS (SUCRA 66.2), but the effect on adult focal epilepsy was not better than that of placebo [vs placebo, RR = 0.83 (0.36-1.93)]. The NMA indicated that the likelihood of the most appropriate intervention (SUCRA 91.2 %) with minimum side effects（SUCRA 12.5 %）for the DS was FFM. Compared with CBD, high exposure to ELM demonstrated a more effective treatment of TSC (SUCRA 89.7 %). More high-quality SLT studies are needed to further evaluate the efficacy and safety. The comparison-adjusted funnel plots of annualized relapse rate and side effects in the included studies revealed no significant funnel plot asymmetry. CONCLUSIONS: This NMA indicated that the most effective treatment strategy for focal epilepsy, DS, Lennox-Gastaut syndrome, and TSC, respectively, included CBM 300 mg, FFM, CBD, and ELM. However, the aforementioned findings need further confirmation.

Impact of variant subtype on electro-clinical phenotype of Dravet syndrome- a South Indian cohort study.

OBJECTIVE: We aimed to compare the electroclinical correlates of truncating and missense variants of SCN1A variants in children with Dravet syndrome (DS) and to determine phenotypic features in relation to variants identified and seizure outcomes. METHODS: A single center prospective study was carried out on a South Indian cohort. Patients below 18 years of age who met the clinical criteria for DS who had undergone genetic testing and completed a minimum of one year follow up were included. We compared the differences in clinical profile, seizure outcome, developmental characteristics and anti-seizure medication (ASM) responsiveness profiles between patients with missense and truncating variants. RESULTS: Out of a total of 3967 children with drug-resistant epilepsy during the period 2015-2021, 49 patients who fulfilled the inclusion criteria were studied. Thirty-seven had positive genetic tests, out of which 29 were SCN1A variants and 9 were other novel variants. The proportion of missense (14; 48.3%) and truncating SCN1A variants (15; 51.7%) was similar. A significant trend for developing multiple seizure types was noted among children with truncating variants (p = 0.035) and seizure freedom was more likely among children with missense variants (p = 0.042). All patients with truncating variants had ASM resistant epilepsy (p = 0.020). Developmental outcomes did not differ between the variant subtypes. CONCLUSION: Our results show that children harbouring missense variants demonstrated a significantly lower propensity for multiple seizure subtypes and a higher proportion with seizure freedom. However developmental implications appear to be independent of variant subtype.

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

PURPOSE: Plant-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. METHODS: The 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. RESULTS: A 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. CONCLUSIONS: This 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.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Fenfluramine below the age of 2 years in Dravet syndrome: What about safety and efficacy?

Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. Infants with DS are especially vulnerable to the detrimental effects of prolonged and frequent seizures on development. Fenfluramine (FFA) is approved for the treatment of DS in patients aged 2 years and older. This study aims to evaluate the safety and efficacy of FFA in patients with DS younger than 2 years. We analyzed safety, tolerability, seizure, and neuropsychological outcome in a real-world setting. Developmental profile was investigated using Griffiths Mental Development Scales (GMDS). Five patients received FFA at a mean age of 14.9 months (9.6-18.6). Median follow-up was 13 months (interquartile range [IQR] = 12.9-24.4). All patients showed good tolerance to FFA. No significant variation of body mass index or echocardiographic issue was observed. Monthly median convulsive seizure frequency (MCSF) was 1.71 (IQR = 1.56-3.27) at the 6-month baseline period and .92 (IQR = .43-1.28) at last follow-up, with a median 54.43 (IQR = 40.91-60.83) percentage reduction in MCSF. Two of five patients had a performance improvement on GMDS subscales. Overall, the use of FFA below the age of 2 years in our small sample of patients was safe and represents a promising opportunity for seizure control and for protection of the neurodevelopmental outcome.

Progressive myoclonic epilepsy as an expanding phenotype of NGLY1-associated congenital deglycosylation disorder: A case report and review of the literature.

INTRODUCTION: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive. CASE PRESENTATION: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1. CONCLUSION: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.