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PloS One 2024Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients.
MATERIAL AND METHODS
The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis.
RESULTS
A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity.
CONCLUSION
In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.
Topics: Adolescent; Humans; Child; Myoclonic Epilepsy, Juvenile; Epilepsy, Absence; Seizures; Drug Resistant Epilepsy; Risk Factors; Electroencephalography; Anticonvulsants
PubMed: 38593118
DOI: 10.1371/journal.pone.0300930 -
Seizure Mar 2021Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically... (Review)
Review
PURPOSE
Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome.
METHODS
A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified.
RESULTS
We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome.
CONCLUSION
Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.
Topics: Electroencephalography; Female; Humans; Male; Myoclonic Epilepsy, Juvenile; Prognosis; Seizures; Sex Characteristics
PubMed: 33524768
DOI: 10.1016/j.seizure.2021.01.005 -
Children (Basel, Switzerland) Mar 2023Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein... (Review)
Review
BACKGROUND
Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects).
PATIENTS AND METHODS
We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected.
RESULTS
497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed.
CONCLUSIONS
Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.
PubMed: 36980111
DOI: 10.3390/children10030553 -
PloS One 2017Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we... (Review)
Review
BACKGROUND
Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies.
METHODOLOGY
A systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms.
RESULTS
Fifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach.
CONCLUSIONS
Thus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors.
PROSPERO REGISTRATION NUMBER
CRD42016036063.
Topics: Connexins; Databases, Factual; Genetic Association Studies; Humans; Myoclonic Epilepsy, Juvenile; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Receptors, Metabotropic Glutamate; Transcription Factors; Gap Junction delta-2 Protein
PubMed: 28636645
DOI: 10.1371/journal.pone.0179629 -
The Cochrane Database of Systematic... Jan 2019Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate in people with JME. This is an update of a Cochrane Review first published in 2015, and last updated in 2017.
OBJECTIVES
To evaluate the efficacy and tolerability of topiramate in the treatment of JME.
SEARCH METHODS
For the latest update, on 10 July 2018 we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid 1946- ), and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) investigating topiramate versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders and proportion of participants experiencing adverse events (AEs).
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.
MAIN RESULTS
We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate and valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS, or becoming seizure-free. Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group.Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged all three studies to be at low to unclear bias for the remaining risk of bias domains (random sequence, allocation, blinding). We judged the quality of the evidence from the studies to be very low.
AUTHORS' CONCLUSIONS
We have found no new studies since the last version of this review was published in 2017. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.
Topics: Adolescent; Anticonvulsants; Child; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Young Adult
PubMed: 30687937
DOI: 10.1002/14651858.CD010008.pub4 -
Seizure Apr 2021Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on... (Review)
Review
Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood. Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality. Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP). Further studies in older adults are needed to understand the long-term outcomes of patients with DS.
Topics: Adult; Epilepsies, Myoclonic; Humans; Infant; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Quality of Life; Spasms, Infantile; Young Adult
PubMed: 33677403
DOI: 10.1016/j.seizure.2021.02.025 -
Scientific Reports Dec 2021Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and... (Meta-Analysis)
Meta-Analysis
Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical cannabinoids (tetrahydrocannabinol, cannabidiol and other cannabis derivatives) versus control in children, independently assessed by two reviewers. Eight studies were included, all of which are randomized controlled trials. Cannabidiol is associated with 50% reduction in seizures rate (Relative Risk (RR) = 1.69, 95% CI [1.20-2.36]) and caregiver global impression of change (Median Estimated difference = (- 1), 95%CI [- 1.39-(- 0.60)]) in Dravet syndrome, compared to placebo. While cannabidiol was associated with a reduction in reported seizure events (RR = 0.59, 95% CI [0.36-0.97]), no association was found in products contained also tetrahydrocannabinol (RR = 1.35, 95% CI [0.46-4.03]). Higher dose of cannabidiol was associated with decreased appetite (RR = 2.40, 95% CI [1.39-4.15]). A qualitative assessment suggests that medical cannabinoids might be associated with adverse mental events. In conclusion, cannabidiol is associated with clinical improvement in Dravet syndrome. However, cannabidiol is also associated with decreased appetite. Adverse mental events were reported as well, however, more research should be performed to assess well this outcome.
Topics: Animals; Cannabinoids; Child; Epilepsies, Myoclonic; Humans; Medical Marijuana
PubMed: 34873203
DOI: 10.1038/s41598-021-02770-6 -
Epilepsy & Behavior : E&B May 2022Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has... (Review)
Review
Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has changed considerably, and a comprehensive systematic review of the contemporary literature is lacking. Here we synthesized published evidence on the occurrence of clinical impacts by age, the economic and humanistic (health-related quality-of-life [HRQoL]) burden, and health state utility. We provide an evidence-based, contemporary visualization of the clinical manifestations, highlighting that DS is not limited to seizures; non-seizure manifestations appear early in life and increase over time, contributing significantly to the economic and humanistic burden of disease. The primary drivers of HRQoL in DS include seizure severity, cognition, and motor and behavioral problems; in turn, these directly affect caregivers through the extent of assistance required and consequent impact on activities of daily living. Unsurprisingly, costs are driven by seizure-related events, hospitalizations, and in-home medical care visits. This systematic review highlights a paucity of longitudinal data; most studies meeting inclusion criteria were cross-sectional or had short follow-up. Nonetheless, available data illustrate the substantial impact on individuals, their families, and healthcare systems and establish the need for novel therapies to address the complex spectrum of DS manifestations.
Topics: Activities of Daily Living; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Seizures; Spasms, Infantile
PubMed: 35334258
DOI: 10.1016/j.yebeh.2022.108661 -
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 -
Experimental and Therapeutic Medicine Aug 2021The co-occurrence of epilepsy and psychiatric disorders is long known. The scope of this systematic review was to describe the prevalence of specific interictal...
The co-occurrence of epilepsy and psychiatric disorders is long known. The scope of this systematic review was to describe the prevalence of specific interictal psychiatric disorders in patients with epilepsy and to assess possible associations between psychiatric disorders and other sociodemographic or clinical characteristics of epilepsy patients. MEDLINE and ScienceDirect were searched for original articles published between January 2015 and February 2021 describing studies that involved epilepsy patients with psychiatric comorbidities. We identified 13 studies with heterogenous methodology and reporting. Prevalence of any psychiatric disorder observed was up to 51% in idiopathic generalized epilepsy (IGE), up to 43.1% in temporal lobe epilepsy (TLE) and up to 43.3% in a general population of patients with epilepsy. The most frequent psychiatric comorbidities associated with epilepsy included mood/affective disorders (up to 40% for lifetime occurrence and up to 23% for current occurrence), anxiety disorders (up to 30.8% for lifetime occurrence and up to 15.6% for current occurrence), personality disorders [up to 11% in juvenile myoclonic epilepsy (JME)] and psychotic disorders (up to 4% of epilepsy patients). In focal epilepsy, depressive disorders might be associated with specific brain imaging findings and with cognitive impairment. Anxiety disorders are associated with a higher frequency of generalized tonico-clonic seizure (GTCS) and with worse social functioning. Psychotic disorders were found to be associated with longer duration of epilepsy. Childhood maltreatment experiences were found to be a powerful predictor for the occurrence of psychiatric comorbidities in epilepsy patients, while data regarding association of other epilepsy characteristics with the presence of psychiatric disorders is conflicting.
PubMed: 34249153
DOI: 10.3892/etm.2021.10341