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Movement Disorders : Official Journal... Aug 2009Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder regarded as found almost exclusively among the Japanese. We have performed as... (Review)
Review
Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder regarded as found almost exclusively among the Japanese. We have performed as systematic review of published literature to investigate the clinical and genetic characteristics of non-Asian DRPLA. We identified 183 non-Asian patients in 27 families reported with DRPLA with a variable level of clinical information. Mean age at onset was 31 (range 1-67) with epilepsy, ataxia, and chorea common presenting features. A highly significant relationship was identified between repeat length and age at onset with repeat length accounting for 62% of the observed variation in age at onset (P < 0.0001). In addition, a highly significant relationship between repeat length and main presenting complaint was identified (P < 0.001). There was evidence of marked anticipation with a median intergenerational reduction in age at onset of 19 years with a corresponding increase of five repeats per generation. DRPLA is not exclusively found among the Japanese but has been reported worldwide. As such, DRPLA should be considered in the differential diagnosis of a wide spectrum of neurological disease, particularly if there is a dominant family history. Non-Asian DRPLA clinico-genetic phenomenology are similar to Asian series and our study confirms marked genetic anticipation together with a clear association between repeat length and clinical phenotype and disease severity.
Topics: Adolescent; Adult; Black or African American; Age of Onset; Aged; Anticipation, Genetic; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Infant; Male; Middle Aged; Myoclonic Epilepsies, Progressive; Nerve Tissue Proteins; Phenotype; Trinucleotide Repeats; White People; Young Adult
PubMed: 19514013
DOI: 10.1002/mds.22642 -
The Cochrane Database of Systematic... Nov 2013Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been recently licensed for add-on use.
OBJECTIVES
To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) as therapy for patients with SMEI.
SEARCH METHODS
We searched the Cochrane Epilepsy Group Specialised Register (15 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, The Cochrane Library, April 2013), MEDLINE (1946 to May 2013) and SCOPUS (1823 to May 2013). The online trials registries ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were systematically searched. The bibliographies of any identified study were searched for further references. We handsearched selected journals and conference proceedings. No language restrictions were imposed.
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment.
DATA COLLECTION AND ANALYSIS
Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. The following outcomes were assessed: at least 50% seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. Outcomes were assessed using a Mantel-Haenszel meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (95% CIs).
MAIN RESULTS
No RCTs assessing drugs other than STP were found. Two RCTs evaluating the use of STP (total of 64 children) were included. Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). No significant difference in the proportion of dropouts was found in the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects; higher proportions of participants were reported to experience side effects in the STP group compared with the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67).
AUTHORS' CONCLUSIONS
Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Further adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of SMEI.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dioxolanes; Epilepsies, Myoclonic; Female; Humans; Male; Randomized Controlled Trials as Topic; Seizures
PubMed: 24254932
DOI: 10.1002/14651858.CD010483.pub2 -
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 -
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 -
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 -
Epilepsy Research Oct 2013The findings of structural neuroimaging studies on gray matter volume (GMV) of juvenile myoclonic epilepsy (JME) with voxel-based morphometry (VBM) were inconsistent. We... (Meta-Analysis)
Meta-Analysis Review
The findings of structural neuroimaging studies on gray matter volume (GMV) of juvenile myoclonic epilepsy (JME) with voxel-based morphometry (VBM) were inconsistent. We aim to evaluate consistent gray matter changes in JME quantitatively. A systematic review of VBM studies on GMV of patients with JME and healthy control (HC) subjects indexed in PubMed and EMBASE from January 1990 to June 2012 was conducted. Coordinates were extracted from clusters of significant GMV difference between patients with JME and HC subjects. Meta-analysis was performed using Effect Size Signed Differential Mapping (ES-SDM). Seven studies with a total of 211 JME patients and 241 HC subjects were included in the meta-analysis. Increased GMV were observed in the bilateral medial frontal gyrus and anterior cingulate, whereas decreased GMV in the bilateral thalamus. The findings remain largely unchanged in the jackknife sensitivity analyses. The meta-analysis not only identified consistent changes in some regions of gray matter in patients with JME, but also supports the notion of thalamocortical circuitry involved in the pathogenesis of JME.
Topics: Adolescent; Adult; Brain; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Myoclonic Epilepsy, Juvenile; Reproducibility of Results; Young Adult
PubMed: 23962795
DOI: 10.1016/j.eplepsyres.2013.07.003 -
The Cochrane Database of Systematic... May 2017This is an updated version of the original Cochrane review published in 2015, Issue 10.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane review published in 2015, Issue 10.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for which stiripentol (STP) has been recently licensed as add-on therapy.
OBJECTIVES
To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) for patients with SMEI.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group Specialized Register (20 December 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 20 December 2016), MEDLINE (Ovid, 1946 to 20 December 2016) and ClinicalTrials.gov (20 December 2016). Previously we searched the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP, but this was not usable at the time of this update. We also searched the bibliographies of identified studies for additional references. We handsearched selected journals and conference proceedings and imposed no language restrictions.
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment.
DATA COLLECTION AND ANALYSIS
Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. We assessed the following outcomes: 50% or greater seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. We assessed outcomes by using a Mantel-Haenszel meta-analysis to calculate risk ratios (RRs) with 95% confidence intervals (95% CIs).
MAIN RESULTS
Since the last version of this review no new studies have been found. Specifically, we found no RCTs assessing drugs other than STP. The review includes two RCTs evaluating use of STP (total of 64 children). Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 versus 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 versus 1/31; RR 7.93, 95% CI 1.52 to 41.21). Investigators found no significant differences in proportions of dropouts from the STP group compared with the placebo group (2/33 versus 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects, noting that higher proportions of participants in the STP group experienced side effects than in the placebo group (100% versus 25%; RR 3.73, 95% CI 1.81 to 7.67). We rated the quality of the evidence as low to moderate according to GRADE criteria, as most information is from studies judged to be at an unclear risk of bias.
AUTHORS' CONCLUSIONS
Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Additional adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of patients with SMEI.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dioxolanes; Epilepsies, Myoclonic; Female; Humans; Male; Patient Dropouts; Randomized Controlled Trials as Topic; Seizures
PubMed: 28521067
DOI: 10.1002/14651858.CD010483.pub4 -
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 -
Epilepsia Open Apr 2024Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing... (Meta-Analysis)
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.
Topics: Humans; Cannabidiol; Anticonvulsants; Fenfluramine; Network Meta-Analysis; Seizures; Epilepsies, Myoclonic; Randomized Controlled Trials as Topic; Dioxolanes
PubMed: 38427284
DOI: 10.1002/epi4.12923