Fenfluramine for the Treatment of Dravet Syndrome and Lennox–Gastaut Syndrome

Balagura, Ganna; Cacciatore, Marta; Grasso, E; Striano, Pasquale; Verrotti, Alberto

doi:10.1007/s40263-020-00755-z

Cited by 33 publications

(27 citation statements)

References 30 publications

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“…The patients with SCN1A variants presented with early-onset seizures, drug-resistant epilepsy, developmental slowing and cognitive impairment, consistent with previous findings (35). Treatment strategies with some evidence of positive effects include VPA, clobazam, TPM, LEV, fenfluramine and bromides, or a KD (25,36). In our study, the seizures were controlled by VPA, CZP, and KD, and we were delighted to observe improved cognitive development.…”

Section: Discussionsupporting

confidence: 89%

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

et al. 2021

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Objective: The genetic aetiology of epileptic encephalopathy (EE) is growing rapidly based on next generation sequencing (NGS) results. In this single-centre study, we aimed to investigate a cohort of Chinese children with early infantile epileptic encephalopathy (EIEE).Methods: NGS was performed on 50 children with unexplained EIEE. The clinical profiles of children with pathogenic variants were characterised and analysed in detail. Conservation analysis and homology modelling were performed to predict the impact of STXBP1 variant on the protein structure.Results: Pathogenic variants were identified in 17 (34%) of 50 children. Sixteen variants including STXBP1 (n = 2), CDKL5 (n = 2), PAFAH1B1, SCN1A (n = 9), SCN2A, and KCNQ2 were de novo, and one (PIGN) was a compound heterozygous variant. The phenotypes of the identified genes were broadened. PIGN phenotypic spectrum may include EIEE. The STXBP1 variants were predicted to affect protein stability.Significance: NGS is a useful diagnostic tool for EIEE and contributes to expanding the EIEE-associated genotypes. Early diagnosis may lead to precise therapeutic interventions and can improve the developmental outcome.

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Section: Discussionsupporting

confidence: 89%

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

et al. 2021

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“…Fenfluramine (FFA) enhances serotonin release, positively modulates sigma‐1 receptors, 3 and has potent, durable efficacy in treating convulsive seizures in Dravet syndrome and drop seizures in Lennox‐Gastaut syndrome, 4,5 with approval for Dravet syndrome by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Long‐term open‐label extension studies and the Belgium experience demonstrated durable reduction in convulsive seizure frequency for up to 30 years in patients with Dravet syndrome, with no observations of pulmonary arterial hypertension or valvular heart disease in any patient at any time 6,7 …”

Section: Introductionmentioning

confidence: 99%

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder

et al. 2021

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CDKL5 deficiency disorder (CDD) is an X-linked disorder resulting from mutations in the CDKL5 gene, which encodes a kinase involved in synaptic plasticity, glutaminergic signaling, and dendrite formation. 1,2 Girls are ~4-fold more often affected, but boys are more severely affected. The incidence is ~1 per 50 000 births. 1 CDD typically presents in the first 3 months of life with treatment-resistant epilepsy (TRE) and hypotonia followed by global developmental delays and cortical visual impairment. 1,2 Infantile spasms and other generalized or mixed generalized/focal epilepsies may be the initial seizure type, with evolution to multiple seizure types that often straddle or fail to conform to standard classifications. Seizures often respond initially but recur, and most children have daily seizures despite multiple antiseizure medication (ASM) regimens. 1,2 Fenfluramine (FFA) enhances serotonin release, positively modulates sigma-1 receptors, 3 and has potent, durable efficacy in treating convulsive seizures in Dravet syndrome and

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“…The same results of efficacy, safety, and tolerability, even if less consistent in terms of the number of clinical trials performed, were achieved for the use of FFA in LGS at different dose regimens (from 0.1 to 0.8 mg/kg/day). Randomized controlled trials are still ongoing; thus in the next future, we will be able to confirm these results (102,107).…”

Section: Emerging Antiseizure Medications To Overcome Drug Resistant Epilepsymentioning

confidence: 80%

“…FFA is an amphetamine derivative and exerts its antiseizure effect by disrupting vesicle storage of serotonin, inhibiting its reuptake from the synapse, and by positive modulation on sigma 1 receptor. Furthermore, its metabolite norfenfluramine shows a high affinity for serotonin receptors in the brain (especially on 5HT2C and 1D, 5HT2A not clear) ( 102 ). Thus, FFA has been continued to use, as reported in many case series, in children with different types of epilepsy, among which pharmacoresistant patients ( 58 ).…”

Section: Pharmacological Therapy In Drug-resistant Epilepsymentioning

confidence: 99%

The Pharmacoresistant Epilepsy: An Overview on Existent and New Emerging Therapies

et al. 2021

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Epilepsy is one of the most common neurological chronic disorders, with an estimated prevalence of 0. 5 – 1%. Currently, treatment options for epilepsy are predominantly based on the administration of symptomatic therapy. Most patients are able to achieve seizure freedom by the first two appropriate drug trials. Thus, patients who cannot reach a satisfactory response after that are defined as pharmacoresistant. However, despite the availability of more than 20 antiseizure medications (ASMs), about one-third of epilepsies remain drug-resistant. The heterogeneity of seizures and epilepsies, the coexistence of comorbidities, and the broad spectrum of efficacy, safety, and tolerability related to the ASMs, make the management of these patients actually challenging. In this review, we analyze the most relevant clinical and pathogenetic issues related to drug-resistant epilepsy, and then we discuss the current evidence about the use of available ASMs and the alternative non-pharmacological approaches.

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Fenfluramine for the Treatment of Dravet Syndrome and Lennox–Gastaut Syndrome

Cited by 33 publications

References 30 publications

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder

The Pharmacoresistant Epilepsy: An Overview on Existent and New Emerging Therapies

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