Seizures In Dravet Syndrome Research Articles

Novel antiseizure medications in the development pipeline: promising candidates and recent failures

AbstractIn the past decade, we have observed a paradigm shift in the discovery of novel antiseizure medications (ASMs), which is a consequence of significant progress in epilepsy genetics, the availability of novel disease models, drug-screening technologies, the discovery of new mechanisms of action, expanding existing drugs into new populations, or new routes of delivery. This resulted in a very rich pipeline of potential future treatments for epilepsy, including gene-modifying treatments for rare genetic epilepsies and mechanistically guided precision treatments. Hopes are high that this pipeline may bring therapeutic breakthroughs similar to those recently achieved with cenobamate for the common drug-resistant focal epilepsy and fenfluramine for seizures in Dravet syndrome. Furthermore, we stand at the beginning of a new era of epilepsy treatment expansion, from traditional seizure suppression to disease prevention and modification. This review discusses the most advanced and promising candidates in the clinical development pipeline but also describes recent failures in the development of novel ASMs.

Pharmacological management of prolonged seizures in Dravet syndrome including intravenous phenytoin.

Dravet syndrome (DS) is an infantile onset developmental and epileptic encephalopathy. Sodium channel blockers are known to exacerbate seizures in this syndrome. Due to its high incidence, the management of prolonged seizures is crucial for DS patients. There is still ambiguity regarding the use of intravenous phenytoin for prolonged seizure in DS patients mainly due to the lack of data, raising concern about the safety of it use. We conducted a retrospective study (from January 2009 to January 2020) aiming to assess the management of prolonged seizures in DS with a focus on the use of intravenous phenytoin. Data were collected for patients admitted to our hospital for seizures lasting >5 min. Among 52 identified patients in our database, 23 experienced 59 prolonged seizures managed in our hospital. Only four seizures ceased without rescue medication. Notably, the use of intravenous phenytoin was not associated with discernible adverse effects and was effective in stopping status epilepticus in 71% of cases. This study suggests the safety and efficacy of intravenous phenytoin for prolonged seizure in DS. There is a need for broader investigations of emergency treatments for evidence-based recommendations for the emergency plan of each patient.

The Therapeutic Role of Perampanel in Treating Pediatric Patients With Dravet Syndrome: A Scoping Review.

Sodium channelopathies are genetic disorders caused by mutations in genes, including sodium voltage-gated channel alpha subunit 1 (SCN1A),that lead to several epilepsy syndromes. Traditional treatments with sodium channel blockers often have limited effectiveness and side effects. Dravet syndrome (DS), a severe epilepsy starting in infancy, presents significant treatment challenges. Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, has shown promise for DS, reducing seizure frequency and improving quality of life (QoL). The limited availability of randomized controlled trials on PER among DS is challenging, but broader studies on refractory epilepsies offer insights. Real-world studies support PER's efficacy, underscoring its potential for managing refractory seizures in DS. Studies showed long-term effectiveness in reducing seizure frequency and enhancing QoL. While PER has minimal impact on cognitive development, it significantly improves seizure control. Numerous studies confirm the use of PER as an effective adjunctive treatment for DS; however, it is crucial to observe the safety profile, especially for pediatric sodium channelopathy patients. Common side effects include dizziness, drowsiness, and irritability, necessitating careful management. Long-term safety is generally favorable, but monitoring for behavioral and mood changes is essential. Additionally, the response to PER in DS varies widely, complicating its use. The limited clinical data and the need for careful dosage monitoring, especially in children, present significant challenges. Side effects, potential drug interactions, and high costs further complicate treatment. Despite increasing attention to its cost-effectiveness, accessibility remains limited in some regions, posing significant barriers for many families. In this paper, we review the role of PER in treating pediatric patients with DS, emphasizing clinical evidence and practical considerations.

Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers.

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

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. 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. 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. 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. 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.

Diagnosis, epilepsy treatment and supports for neurodevelopment in children with Dravet Syndrome: Caregiver reported experiences and needs

BackgroundDravet syndrome is a rare infantile onset epilepsy syndrome encompassing treatment resistant epilepsy and neurodevelopmental difficulties. There is limited data regarding caregiver experiences of diagnosis, treatment and supports for the associated neurodevelopmental problems. MethodSemi-structured interviews were conducted with caregivers of 36/48 children (75% of total population in Sweden) with Dravet syndrome. Data was analysed using thematic analysis. ResultsRegarding the diagnostic experience, themes were: Delays in diagnostic process, genetic testing not optimal, communication of Dravet syndrome diagnosis and support and information soon after diagnosis. Caregivers felt that delays in diagnosis and testing could have been avoided whilst experiences of communication of diagnosis and support after diagnosis varied. In terms of treatment for seizures, the themes were: Satisfied with treatment, emergency treatment, treatment with antiseizure medications, strategies to control seizures via temperature regulation/avoidance of infections and use of equipment and aids. Caregivers were in the main accepting that seizures in Dravet syndrome are very difficult to treat and that seizure freedom is often an unachievable goal. Many felt frustrated that they were expected to take responsibility with respect to choice of medication. They often employed strategies (e.g., avoidance of physical activity) to reduce seizures or their impact. In terms of supports for neurodevelopmental problems, the themes were: Struggled to access support, lack of integrated healthcare and satisfaction with school. Many caregivers felt that accessing necessary supports for their children and developmental and behavioural needs was a struggle and that the provision of support often lacked integration e.g., lack of collaboration between child’s disability service and school. Caregivers also expressed a desire that there would be better knowledge of Dravet syndrome in emergency departments and schools, that care would be better integrated and that there would be more supports for assessment and interventions regarding the associated neurodevelopmental problems. ConclusionThe responses of caregivers of children with Dravet syndrome highlight the need for supports from diagnosis for both epilepsy and neurodevelopmental problems. Good examples of provision were identified but parents often felt they lacked support and support often came from providers who lacked knowledge of the syndrome. Collaboration between medical, disability and school services was often lacking.

Clinical Characterization of [18F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy.

This series of studies characterized [18F]T-008, a PET radiotracer for imaging cholesterol 24-hydroxylase (CH24H), in healthy volunteers (ClinicalTrials.gov identifier NCT02497235). Assessments included radiation dosimetry, kinetic modeling, test-retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor. Soticlestat is currently in phase 3 development for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome. Methods: In the dosimetry study, 5 participants (3 men) underwent serial whole-body scans to estimate organ-absorbed doses and effective doses of [18F]T-008 using OLINDA/EXM 1.1. For the kinetic modeling and TRT study, 6 participants (all men) underwent two 210-min dynamic [18F]T-008 PET scans with arterial blood sampling. The regional total volume of distribution was estimated using a 1-tissue-compartment model, a 2-tissue-compartment model, and Logan graphic analysis. In the dose occupancy study, 11 participants (all men) underwent 120-min scans at baseline and 2 time points (peak and trough) after receiving single oral doses of soticlestat (50-600 mg). The relationship between effect-site soticlestat concentration and brain occupancy was evaluated with a specially developed pharmacokinetic model and a saturable maximal occupancy model. Results: The estimated mean whole-body effective dose was 0.0292 mSv/MBq (SD, 0.00147 mSv/MBq). [18F]T-008 entered the brain rapidly, with a distribution consistent with known CH24H distribution densities. The 2-tissue-compartment model and Logan graphic analysis best described the tracer kinetics. The mean TRT for estimating total volume of distribution was 7%-15%. Single doses of soticlestat in the range 50-600 mg resulted in occupancies of 64%-96% at 2 h and 11%-79% at 24 h. The estimated half-maximal effect-site concentration of soticlestat was 5.52 ng/mL. Conclusion: [18F]T-008 is a suitable PET radiotracer for quantitatively analyzing CH24H in the human brain. Using [18F]T-008 and PET, we demonstrated that soticlestat was brain-penetrant and established target engagement by displacing [18F]T-008 in a dose-dependent manner in the brain.

Depressed glutamate transporter 1 expression in a mouse model of Dravet syndrome.

Dravet syndrome (DS) is a monogenic, often refractory, epilepsy resultant from SCN1A haploinsufficiency in humans. A novel therapeutic target in DS that can be engaged in isolation or as adjunctive therapy is highly desirable. Here, we demonstrate reduced expression of the rodent glutamate transporter type 1 (GLT-1) in a DS mouse model, and in wild type mouse strains where Scn1a haploinsufficiency is most likely to cause epilepsy, indicating that GLT-1 depression may play a role in DS seizures. As GLT-1 can be upregulated by common and safe FDA-approved medications, this strategy may be an attractive, viable, and novel avenue for DS treatment.

Designing the 5HT2BR structure and its modulation as a therapeutic target for repurposing approach in drug-resistant epilepsy

The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (−53.44 kcal/mol) and Methylergonovine (−40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10−8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10–8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207–214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (−89.21 kcal/mol) than Methylergonovine (−63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy.

A systems medicine strategy to predict the efficacy of drugs for monogenic epilepsies.

Monogenic epilepsies are rare but often severe. Because of their rarity, they are neglected by traditional drug developers. Hence, many lack effective treatments. Treatments for a disease can be discovered more quickly and economically by computationally predicting drugs that can be repurposed for it. We aimed to create a computational method to predict the efficacy of drugs for monogenic epilepsies, and to use the method to predict drugs for Dravet syndrome, as (1) it is the archetypal monogenic catastrophic epilepsy; (2) few antiseizure medications are efficacious in Dravet syndrome; and (3) predicting the effect of drugs on Dravet syndrome is challenging, because Dravet syndrome is typically caused by an SCN1A mutation, but some antiseizure medications that are efficacious in Dravet syndrome do not affect SCN1A, and some antiseizure medications that affect SCN1A aggravate seizures in Dravet syndrome. We have devised a computational method to predict drugs that could be repurposed for a monogenic epilepsy, based on a combined measure of drugs' effects upon (1) the function of the disease's causal gene and other genes predicted to influence its phenotype, (2) the transcriptomic dysregulation induced by the casual gene mutation, and (3) clinical phenotypes. Our method correctly predicts drugs that are more effective, less effective, ineffective, and aggravating for seizures in people with Dravet syndrome. Our method correctly predicts the positive "hits" from large-scale screening of compounds in an animal model of Dravet syndrome. We predict the relative efficacy of 1462 drugs. At least 38 drugs are ranked higher than one or more of the antiseizure drugs currently used for Dravet syndrome and have existing evidence of antiseizure efficacy in animal models. Our predictions are a novel resource for identifying new treatments for seizures in Dravet syndrome, and our method can be adapted for other monogenic epilepsies.

Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis

Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs. Cannabidiol (CBD) has recently been approved as ASM for three refractory epilepsy syndrome indications in children and adults. In this study, we evaluated the overall clinical potential of an oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 16 weeks. A subgroup analysis by syndrome and CBD with or without concomitant clobazam was conducted. The key outcomes were reduction in seizure frequency, differences in 50% responder rates, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be more efficacious compared to placebo (OR = 2.45, 95% CI =1.81–3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38–3.70), LGS (OR = 2.98, 95% CI:1.83–4.85) and TSC (OR = 1.99, 95% CI = 1.06–3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33–2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63–5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD. In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessments, and therapeutic management guidelines are warranted.

Treatment-Refractory Dravet Syndrome: Considerations for Novel Medications.

Before 2018, there were no U.S. Food and Drug Administration-approved medications for managing seizures in Dravet syndrome (DS). Common agents used in the antiepileptic drug regimens of patients with DS included clobazam, valproic acid, topiramate, and levetiracetam, among others; however, these agents alone rarely provide adequate seizure control. Management of seizures in DS changed in recent years with the approval of cannabidiol and stiripentol in 2018 and fenfluramine in 2020. This continuing education article summarizes available efficacy and safety data involving cannabidiol, stiripentol, and fenfluramine and provides a practical review of dosing strategies, pharmacokinetics, and monitoring interventions relevant to their use.

161 Two-centre audit of cannabidiol use in adults with Dravet syndrome

BackgroundCannabidiol is a newly-available treatment option for seizures in Dravet syndrome (DS).MethodsAdults in a cannabidiol early access programme at two epilepsy centres were included. Can- nabidiol was titrated up to 20mg/kg, as tolerated. The primary outcome measure was &gt;30% reduction in convulsive seizures assessed at three months of treatment. Secondary outcome measures included later reduction in seizures and incidence of adverse drug reactions (ADRs).ResultsEighteen individuals (seven female; median age 27.5 years) with SCN1A mutation-positive DS took part. Median follow-up was 166 days; nine individuals continued on maintenance treatment. Median maximum dose was 18.6mg/kg/day. Four individuals (22.2%) had a &gt;30% reduction in convulsive seizures by three months; in two, this became evident after three months. ADRs occurred in 14 (77.8%). Commonest ADRs were somnolence and derangement of LFTs (all 18 took concomitant valproate), occurring in eight and seven individuals, respectively. ADRs led to discontinuation in three, including a seizure-free individual. Twelve people (66.7%) required dosage changes to other antiepileptic drugs.ConclusionCannabidiol was effective in a fifth of patients. Two additional patients showed later reduction in seizure frequency, suggesting longer follow-up is warranted. Treatment was complicated by ADRs. Dose adjustments of other antiepileptic drugs may be needed.k.silvennoinen@ucl.ac.uk

Serotonin receptors in epilepsy: Novel treatment targets?

Despite the availability of over 30 antiseizure medications (ASMs), there is no “one size fits it all,” so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each “5‐HT subtype” separately and its relation to “epilepsy or seizures.” Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe.

Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug‐resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up‐to‐date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany.

Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7mg/kg/day. Overall, 78 patients with DS (median age = 8.0 years, range = 2.1-46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5days (range = 31-572). Responder rates (a ≥50% reduction; n=78) and seizure-freedom rates at 3months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic-clonic seizures. Responder rates were consistent at 6 and 12months (n=66 and n=43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5-30) to 3.0 (range = 0-30) in the 3-month period before and after FFA treatment (p<.001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p=.005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an X‐linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5–12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2–26 years). Mean FFA treatment duration was 5.3 months (range: 2–9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic‐clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%–100%). Tonic seizure frequency was reduced by 50%–60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.

Data related to article "Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study"

Data related to article "Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study"

Cannabidiol in the Treatment of Epilepsy.

Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox–Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.

Fenfluramine as antiseizure medication for epilepsy.

Fenfluramine hydrochloride has classically been described as acting pharmacologically through a serotonergic mechanism. Therefore, it was initially used as an anorectic drug, given that impaired serotonin homeostasis may be associated with increased food intake. Although positive results were documented, cardiovascular concerns resulted in its temporary withdrawal. Nevertheless, a novel role in patients with epilepsy was later suggested by isolated clinical observations. The wide application of genetic testing allowed the classification (predominantly as Dravet syndrome) of patients in whom benefit was seen, while with the development of zebrafish models, its antiepileptic properties were confirmed at a molecular level. Data from randomized clinical trials have shown a beneficial effect of fenfluramine, as an adjunct therapy, on seizure control for children with Dravet syndrome, though there is still uncertainty about the impact on neurodevelopment in these patients. No signs of heart valve disease have been documented to date. Long-term and appropriately designed clinical studies will verify whether fenfluramine is a therapeutic agent of high importance, living up to the promise shown so far. What this paper adds Fenfluramine is a very promising repurposed therapy specifically for seizures in Dravet syndrome. The long-term effect of fenfluramine on neurodevelopmental prognosis requires further investigation.