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PharmacoEconomics Jan 2023Fenfluramine, tradename Fintepla, was appraised within the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process as... (Meta-Analysis)
Meta-Analysis Review
Fenfluramine, tradename Fintepla, was appraised within the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process as Technology Appraisal 808. Within the STA process, the company (Zogenix International) provided NICE with a written submission and a mathematical health economic model, summarising the company's estimates of the clinical effectiveness and cost-effectiveness of fenfluramine for patients with Dravet syndrome (DS). This company submission (CS) was reviewed by an evidence review group (ERG) independent of NICE. The ERG, Kleijnen Systematic Reviews in collaboration with Maastricht University Medical Centre, produced an ERG report. This paper presents a summary of the ERG report and the development of the NICE guidance. The CS included a systematic review of the evidence for fenfluramine. From this review the company identified and presented evidence from two randomised trials (Study 1 and Study 1504), an open-label extension study (Study 1503) and 'real world evidence' from a prospective and retrospective study. Both randomised trials were conducted in patients up to 18 years of age with DS, whose seizures were incompletely controlled with previous anti-epileptic drugs. A Bayesian network meta-analysis was performed to compare fenfluramine with cannabidiol plus clobazam. There was no evidence of a difference between any doses of fenfluramine and cannabidiol in the mean convulsive seizure frequency (CSF) rate during treatment. However, fenfluramine increased the number of patients achieving ≥ 50% reduction in CSF frequency from baseline compared to cannabidiol. The company used an individual-patient state-transition model (R version 3.5.2) to model cost-effectiveness of fenfluramine. The CSF and convulsive seizure-free days were estimated using patient-level data from the placebo arm of the fenfluramine registration studies. Subsequently, a treatment effect of either fenfluramine or cannabidiol was applied. Utility values for the economic model were obtained by mapping Pediatric Quality of Life Inventory data from the registration studies to EuroQol-5D-3L Youth (EQ-5D-Y-3L). The company included caregiver utilities in their base-case, as the severe needs of patients with DS have a major impact on parents and caregivers. There were several key issues. First, the company included caregiver utilities in the model in a way that when patients in the economic model died, the corresponding caregiver utility was also set to zero. Second, the model was built in R statistical software, resulting in transparency issues. Third, the company assumed the same percentage reduction for convulsive seizure days as was estimated for CSF. Fourth, during the final appraisal committee meeting, influential changes were made to the model that were not in line with the ERG's preferences (but were accepted by the appraisal committee). The company's revised and final incremental cost effectiveness ratio (ICER) in line with committee preferences resulted in fenfluramine dominating cannabidiol. Fenfluramine was recommended as an add-on to other antiepileptic medicines for treating seizures associated with DS in people aged 2 years and older in the National Health Service (NHS).
Topics: Child; Humans; Adolescent; Cannabidiol; Bayes Theorem; Prospective Studies; Quality of Life; Retrospective Studies; State Medicine; Epilepsies, Myoclonic; Cost-Benefit Analysis; Technology Assessment, Biomedical; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic
PubMed: 36301414
DOI: 10.1007/s40273-022-01209-8 -
Seizure Feb 2021Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy syndrome with limited treatment options. We aimed to evaluate the efficacy and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy syndrome with limited treatment options. We aimed to evaluate the efficacy and tolerability of fenfluramine in patients with Dravet syndrome using meta-analytical techniques.
METHODS
We searched for relevant randomized controlled trials and non-randomized studies involving children with Dravet syndrome on fenfluramine therapy in MEDLINE, CENTRAL, EMBASE, Google Scholar and Web of Science database (31 July 2020). The primary outcome for the efficacy of fenfluramine was reduction in monthly convulsive seizure frequency. We carried out a random effect meta-analysis focusing on efficacy and safety variables. Only Randomized Controlled Trials (RCT) were included in the meta-analysis. The risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome.
RESULTS
Of 61 publications initially screened, 12 were reviewed as full-text. Seven articles including 2 RCTs, 4 uncontrolled studies (3 prospective and one retrospective study), and one case report described responses to fenfluramine in 144 DS patients (54 % male, mean age of 8.8 years, median dose of 0.4 mg/kg/day). Fenfluramine was found to be more efficacious than placebo, in terms of mean convulsive and total seizure frequency reduction (mean difference: -45.3 % (95 % CI: -48.1 %, -42.4 %, p < 0.00001) and -39.7 % (-46.7 %, -32.7 %, p < 0.00001)). A greater proportion of patients in the fenfluramine arm achieved >25 %, >50 %, >75 % and 100 % seizure reductions (odds ratios: 6.5 (3.7, 11.5, p < 0.00001), 10.6 (5.3, 21.3, p < 0.00001), 22.7(6.9, 75.3, p < 0.00001) and 9.3(1.7, 51.4, p = 0.01) respectively). The incidence of serious adverse events was not greater in the fenfluramine groups (OR: 1.02 (0.5, 2.19, p = 0.96)).
CONCLUSION
Fenfluramine appears to be a safe and efficacious antiseizure medication in patients with Dravet syndrome.
Topics: Child; Epilepsies, Myoclonic; Female; Fenfluramine; Humans; Infant; Male; Seizures; Spasms, Infantile; Treatment Outcome
PubMed: 33461030
DOI: 10.1016/j.seizure.2020.12.016 -
Epilepsia Jun 2020To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques.
METHODS
We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated.
RESULTS
Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001).
SIGNIFICANCE
CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.
Topics: Anticonvulsants; Cannabidiol; Clobazam; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome
PubMed: 32452532
DOI: 10.1111/epi.16546 -
Frontiers in Neurology 2021Progressive myoclonic epilepsies (PMEs) are a heterogenous group of genetic diseases presenting with epilepsy, cognitive impairment, and severe action myoclonus, which...
Progressive myoclonic epilepsies (PMEs) are a heterogenous group of genetic diseases presenting with epilepsy, cognitive impairment, and severe action myoclonus, which can severely affect daily life activities and independent walking ability. Perampanel is a recent commercially available antiseizure medication with high efficacy against generalized seizures. Some reports supported the role of perampanel in ameliorating action myoclonus in PMEs. Here, we aimed to describe a case series and provide a systematic literature review on perampanel effects on PMEs. We report the perampanel effectiveness on myoclonus, daily life activities, and seizures on an original Italian multicenter case series of 11 individuals with PMEs. Then, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we performed a systematic review on perampanel effect on myoclonus and disability in PMEs. We searched PubMed, Scopus, and Google Scholar articles on perampanel and PMEs up to June 2020. No prospective trials were found. We reviewed 11 case series manuscripts reporting 104 cases of different PMEs. Here, we are reporting the effectiveness of perampanel in five individuals affected by Unverricht-Lundborg disease, three by Lafora disease, two by sialidosis, and one by an undetermined PME. Nine out of 11 individuals improved their disability related to the action myoclonus (two with Lafora disease did not). Among the 104 persons with PMEs collected by the systematic review, we found that more than half of the patients receiving perampanel exhibited an amelioration of action myoclonus and, consequently, of their independence in daily life activities. The Unverricht-Lundborg disease seemed to show the best clinical response to perampanel, in comparison with the other more severe PMEs. A significant seizure reduction was achieved by almost all persons with active epilepsy. Only 11% of PME patients dropped out due to inefficacy. Perampanel demonstrated a beneficial effect with regard to action myoclonus, disability, and seizures and was well-tolerated in people with PMEs, independently from their genetic diagnosis. Given the limited scientific evidence, broader prospective trials should be encouraged.
PubMed: 33841303
DOI: 10.3389/fneur.2021.630366 -
International Journal of Molecular... Apr 2021Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and...
Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000-2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase ( pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.
Topics: Animals; Epilepsies, Myoclonic; Epilepsy; Humans; Infant, Newborn; Movement Disorders; Seizures; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 33919646
DOI: 10.3390/ijms22084202 -
Neurological Sciences : Official... Oct 2023Variants of the NUS1 gene have been associated with an extensive spectrum of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's... (Review)
Review
BACKGROUND
Variants of the NUS1 gene have been associated with an extensive spectrum of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorder of glycosylation. It is rarely reported in progressive myoclonus epilepsy (PME).
METHODS AND RESULTS
Herein, we report the case of PME caused by a novel de novo NUS1 missense variant (c.302T>A, p.Met101Lys). In addition, we reviewed the current literature of NUS1-associated PME. At present, five patients with NUS1 variants and PME have been reported in the literature. Due to limited cases reported, the relationship between NUS1 variants and PME is not well-established.
CONCLUSIONS
Our case provides further evidence of the role of NUS1 variants in PME. These findings expand the clinical phenotypes of NUS1 variants, which should be included in the PME genetic screening panel.
Topics: Humans; East Asian People; Mutation, Missense; Myoclonic Epilepsies, Progressive; Myoclonus; Receptors, Cell Surface
PubMed: 37249665
DOI: 10.1007/s10072-023-06851-4 -
Archives of Iranian Medicine Sep 2019The genetic generalized epilepsies (GGEs) are a set of disorders presenting with generalized seizures, in addition to general spike-wave activity. The present study aims...
The genetic generalized epilepsies (GGEs) are a set of disorders presenting with generalized seizures, in addition to general spike-wave activity. The present study aims to investigate the clinical manifestations and genetic origin of generalized tonicclonic seizures and the subgroups of GGEs, including childhood absence epilepsy (CAE), juvenile absence epilepsy, and juvenile myoclonic epilepsy (JME). Information compiled from genome-wide association studies (GWASs) in the EPICure project revealed associations with many genes. Besides, copy number variant (CNV) discoveries have been the most inspiring turning point of epilepsy genetic research. This phenomenon could give us an idea about microdeletions/microduplications as genetic variants throughout the whole genome. Nowadays, next-generation sequencing (NGS) approaches support neurogeneticists to unravel the predisposed putative variants in GGE to establish a better diagnosis. Consequently, previous experiments supply data for antiepileptic drugs (AEDs) to test susceptible variants, which influence the response to drugs. As a final point, all these data should provide the current GGE patients with better genetic counseling and follow-up services.
Topics: Adolescent; Adult; Anticonvulsants; Child; DNA Copy Number Variations; Epilepsy, Generalized; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; High-Throughput Nucleotide Sequencing; Humans; Precision Medicine
PubMed: 31679374
DOI: No ID Found -
Epilepsy & Behavior : E&B May 2020Patients with juvenile myoclonic epilepsy (JME) show evidence of cognitive impulsivity that may be linked to later adverse psychosocial outcomes. Here, we quantify the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with juvenile myoclonic epilepsy (JME) show evidence of cognitive impulsivity that may be linked to later adverse psychosocial outcomes. Here, we quantify the strength of association and estimate effect size (ES) of response inhibition by pooling available evidence in a meta-analysis.
METHODS
We conducted a systematic review of the literature using Ovid MEDLINE and Ovid EMBASE databases (covering 2001-2019) with a search strategy using combinations of the specific Medical Subject Headings (MeSH) terms 'juvenile myoclonic epilepsy, cognitive impulsivity, response inhibition, Stroop, cognition, personality, traits' using the 'explode' feature where possible. We also searched within references of retrieved articles. We included studies reporting ESs describing established measures of response inhibition in teenage and adult patients with JME.
RESULTS
Using the ESs pooled from 16 studies comprising 1047 patients and controls, we found ESs for response inhibition to be homogeneous with a significant moderate mean ES of d = 0.50 (95% confidence interval [CI]: 0.37-0.63).
CONCLUSIONS
We confirm that reduced response inhibition is a consistently observed homogeneous trait in patients with JME.
Topics: Adolescent; Adult; Cognition; Female; Humans; Impulsive Behavior; Inhibition, Psychological; Male; Myoclonic Epilepsy, Juvenile; Neuropsychological Tests; Personality; Reaction Time
PubMed: 32240946
DOI: 10.1016/j.yebeh.2020.107038 -
Epilepsy & Behavior : E&B Sep 2021Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, with predictable negative consequences for informal caregivers' mental health. This... (Review)
Review
BACKGROUND
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, with predictable negative consequences for informal caregivers' mental health. This systematic review aimed to evaluate the representativeness of depression, anxiety, and burden in these caregivers and assess their quality of life.
METHODS
The PRISMA recommendations were followed, and a comprehensive search was conducted on PubMed/MEDLINE, WoS and Scopus databases, without date or language limits. Only observational quantitative studies on adult informal caregivers of patients with DS were considered.
RESULTS
Of 876 records found, 21 full-text articles were assessed and only 6 met the inclusion criteria. The latter have mostly a cross-sectional design and include samples composed by 19 to 742 caregivers, mainly mothers/females. Most of the study participants had a Bachelor's degree/higher educational level and were married. An important incidence of depression and anxiety on DS caregivers was reported, with significantly higher levels compared with population norms and with carers of other patients with epilepsy. Depression/anxiety were shown to be significantly associated with caregivers' fatigue and compromised sleep quality. Other important aspects of burden have been identified; however, comparisons between studies were not possible as different scales were used. Caregivers' health-related quality of life is also affected, with mothers reporting a worse perception on this domain.
CONCLUSIONS
Mental health and quality of life of DS caregivers are compromised, with mothers bearing an apparently greater burden. Studies using validated instruments for this population to assess the previously considered outcomes are needed, in order to inform the development of preventive strategies and problem-oriented interventions.
Topics: Adult; Caregivers; Cross-Sectional Studies; Depression; Epilepsies, Myoclonic; Female; Humans; Mental Health; Quality of Life
PubMed: 34280725
DOI: 10.1016/j.yebeh.2021.108206 -
Neurology. Genetics Aug 2019Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients...
OBJECTIVE
Our goal was to perform a systematic review of the literature to demonstrate the prevalence of cardiac abnormalities identified using cardiac investigations in patients with mitochondrial myopathy (MM).
METHODS
This systematic review surveys the available evidence for cardiac investigations in MM from a total of 21 studies including 825 participants. Data were stratified by genetic mutation and clinical syndrome.
RESULTS
We identified echocardiogram and ECG as the principal screening modalities that identify cardiac structural (29%) and conduction abnormalities (39%) in various MM syndromes. ECG abnormalities were more prevalent in patients with m.3243A>G mutations than other gene defects, and patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) had a higher prevalence of ECG abnormalities than patients with other clinical syndromes. Echocardiogram abnormalities were significantly more prevalent in patients with m.3243A>G or m.8344A>G mutations compared with other genetic mutations. Similarly, MELAS and MERRF had a higher prevalence compared with other syndromes. We observed a descriptive finding of an increased prevalence of ECG abnormalities in pediatric patients compared with adults.
CONCLUSIONS
This analysis supports the presence of a more severe cardiac phenotype in MELAS and myoclonic epilepsy with ragged red fibres syndromes and with their commonly associated genetic mutations (m.3243A>G and m.8344A>G). This provides the first evidence basis on which to provide more intensive cardiac screening for patients with certain clinical syndromes and genetic mutations. However, the data are based on a small number of studies. We recommend further studies of natural history, therapeutic response, pediatric participants, and cardiac MRI as areas for future investigation.
PubMed: 31403078
DOI: 10.1212/NXG.0000000000000339