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CNS Drugs Mar 2020Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients. Cannabidiol (CBD)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is the first in a new class of antiepileptic drugs with a distinctive chemical structure and mechanism of action.
OBJECTIVE
The aim of this systematic review was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with DS using meta-analytical techniques.
METHODS
We searched for randomized, placebo-controlled, single- or double-blinded trials. Main outcomes included ≥ 50% reduction in baseline convulsive seizure frequency and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (95% CIs) were estimated through the inverse variance method.
RESULTS
Three trials were included involving 359 participants, 228 for CBD and 131 for placebo groups. In all trials, the active treatment was a plant-derived pharmaceutical formulation of purified CBD oral solution. The pooled RR for 50% response during the treatment was 1.69 (95% CI 1.21-2.36; p = 0.002). Across the trials, treatment was discontinued in 20 (9.0%) and 3 (2.3%) cases in the add-on CBD and placebo groups, respectively; the RR for CBD withdrawal was 3.12 (95% CI 1.07-9.10; p = 0.037). The RR to develop any AE during add-on CBD treatment was 1.06 (95% CI 0.87-1.28; p = 0.561). AEs significantly associated with adjunctive CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.
CONCLUSIONS
Adjunctive CBD resulted in a greater reduction in convulsive seizure frequency than placebo and a higher rate of AEs in patients with DS presenting with seizures uncontrolled by concomitant antiepileptic therapy.
Topics: Cannabidiol; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Odds Ratio; Randomized Controlled Trials as Topic
PubMed: 32040850
DOI: 10.1007/s40263-020-00708-6 -
European Journal of Nuclear Medicine... Jun 2020To describe cerebral glucose metabolism pattern as assessed by F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of...
PURPOSE
To describe cerebral glucose metabolism pattern as assessed by F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1.
METHODS
We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment.
RESULTS
Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6 years from disease onset (range 1-12 years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17 months (range 7-36 months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases.
CONCLUSIONS
FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.
Topics: Brain; Fluorodeoxyglucose F18; Humans; Lafora Disease; Positron-Emission Tomography; Prospective Studies; Retrospective Studies; Ubiquitin-Protein Ligases
PubMed: 31858178
DOI: 10.1007/s00259-019-04647-3 -
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 -
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 -
European Journal of Paediatric... Jul 2019Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of...
Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy - A systematic review of the literature using lacosamide as an example.
Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.
Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Observational Studies as Topic
PubMed: 31171490
DOI: 10.1016/j.ejpn.2019.05.002 -
European Journal of Paediatric... May 2019Dravet Syndrome is a rare developmental and epileptic encephalopathy characterised by epileptic seizures, cognitive impairment and motor disorders. Gait is markedly...
BACKGROUND
Dravet Syndrome is a rare developmental and epileptic encephalopathy characterised by epileptic seizures, cognitive impairment and motor disorders. Gait is markedly impaired and could benefit from targeted intervention to improve quality of life for patient and caregivers.
OBJECTIVE
To establish the state of the art regarding gait deviations in patients with Dravet Syndrome.
METHODS
A systematic search was performed in Pubmed, Web of Science, Science Direct and Embase. Studies that assessed gait deviations in patients diagnosed with Dravet Syndrome using clinical observation, video gait analysis or three dimensional (3D) gait analysis and reported gait characteristics, spatiotemporal or kinematic outcomes were included. Screening, quality assessment and data extraction were performed by independent reviewers.
RESULTS
Out of a total of 478 citations, nine articles were included. The total study population had an age range from 2.5 to 47 years. Three studies used clinical observation, three studies video analysis and three studies 3D gait analysis. Crouch gait was observed in about half of the population next to a variety of other gait deviations such as parkinsonian and cerebellar gait. Other findings included abnormalities in spatiotemporal parameters and kinematics, passive knee extension deficits, skeletal malalignment and neurological signs.
CONCLUSIONS
A variety of gait characteristics was observed with crouch gait being the most reported gait pattern. Inconsistency in methods and findings from clinical and instrumented evaluation impede thorough understanding of the causal mechanism and evolution behind these deviations.
PROSPERO REGISTRATION NUMBER
CRD42017070370.
Topics: Adolescent; Adult; Child; Child, Preschool; Epilepsies, Myoclonic; Female; Gait Disorders, Neurologic; Humans; Male; Middle Aged; Young Adult
PubMed: 30940509
DOI: 10.1016/j.ejpn.2019.03.003 -
Epileptic Disorders : International... Feb 2019Rolandic (RE), childhood absence (CAE) and juvenile myoclonic (JME) epilepsy encompass centrotemporal sharp waves, 3-Hz spike waves and >3-Hz spike or polyspike waves,... (Meta-Analysis)
Meta-Analysis
Rolandic (RE), childhood absence (CAE) and juvenile myoclonic (JME) epilepsy encompass centrotemporal sharp waves, 3-Hz spike waves and >3-Hz spike or polyspike waves, respectively. Evidence abounds for genetic roles in all three syndromes, yet involved genes for the vast majority of patients remain unknown. It has long been proposed that while each disease is genetically complex, its specific EEG trait may represent a genetically simpler endophenotype. This meta-analysis of the literature focuses on the frequency of EEG traits in clinically unaffected first-degree relatives towards determining inheritance patterns of the EEG endophenotypes. We used the Preferred Reporting Items for Systematic Review and Meta-Analysis for protocols (PRISMA-P) and searched Medline, EMBASE, CINHAL and the Cochrane Central Register of Controlled Trials. Following extensive screening, 15 studies were included with a total of 3,858 asymptomatic relatives. The prevalence of 'abnormal' EEG waves was 21%, 42% and 33% for JME, CAE and RE, respectively, close to what would be expected based on Mendelian inheritance. However, breaking down the reported EEG abnormalities, most consisted not of the respective EEG signature traits -prevalences of which were as low as 5%- but of non-specific EEG 'abnormalities'/variants. Prevalence of non-specific EEG 'abnormalities'/variants in the general population ranges from 0.1 to 10%. Underlying this 100-fold-wide range is a spectrum of what is considered 'abnormal' or variant. The prevalences of 'abnormalities'/variants in asymptomatic siblings in RE, CAE and JME significantly exceed even the highest value in the general population and fall within Mendelian expectations. These results suggest that EEG 'abnormalities'/variants shared with the general population are enriched in the three syndromes and are endophenotypes inherited in a genetically simple near-Mendelian fashion. Future work with modern EEG variant definitions should uncover genetic variants contributing to neuronal hypersynchrony in epilepsy.
Topics: Electroencephalography; Endophenotypes; Epilepsy, Absence; Epilepsy, Rolandic; Humans; Myoclonic Epilepsy, Juvenile; Siblings
PubMed: 30767897
DOI: 10.1684/epd.2019.1024 -
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 -
Drugs Nov 2018Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.
OBJECTIVE
The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.
METHODS
Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).
RESULTS
Four trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1-31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8-28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07-2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55-8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28-7.41; p = 0.657) and 4.20 (95% CI 1.82-9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87-16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22-12.86; p = 0.626) and 6.89 (95% CI 2.28-20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11-1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.
CONCLUSIONS
Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome
PubMed: 30390221
DOI: 10.1007/s40265-018-0992-5 -
Brain Research Bulletin Jun 2018Transcranial magnetic stimulation (TMS) may represent a valuable tool for investigating important neurophysiological and pathophysiological aspects of myoclonus....
Transcranial magnetic stimulation (TMS) may represent a valuable tool for investigating important neurophysiological and pathophysiological aspects of myoclonus. Moreover, repetitive TMS (rTMS) can influence neural activity. In this review we performed a systematic search of all studies using TMS in order to explore cortical excitability/plasticity and rTMS for the treatment of myoclonus due to different aetiologies. We identified and reviewed 40 articles matching the inclusion criteria; 415 patients were included in these studies. The reviewed TMS studies have detected abnormalities in motor cortex excitability and sensorimotor plasticity. The most consistent finding is a decrease in intracortical inhibition. Short-interval intracortical inhibition (SICI) is reduced in myoclonic epilepsies. Unlike the juvenile and the benign myoclonus epilepsy, long-interval intracortical inhibition, interhemispheric inhibition and sensorimotor integration were altered in patients with progressive myoclonic epilepsies. In patients with myoclonus-dystonia the results are partly conflicting. Cortical membrane excitability was impaired while parameters assessing cortical synaptic activity were normal in DYT11 gene carriers. In other studies normal SICI suggests that the GABAergic cortical circuits are largely intact and that the mechanisms of myoclonus-dystonia are different from those for cortical myoclonus and other dystonic disorders. In conclusion, different TMS study protocols have provided new insights into sensorimotor plasticity and cortical excitability of the different forms of myoclonus, and have shed some light on the pathophysiology of this movement disorder. Well-defined motor cortical excitability patterns can be identified in the different disorders characterized by myoclonus, even if preliminary findings should be confirmed in future studies in larger cohorts of patients. Repetitive TMS might have therapeutic potential at least in some patients with myoclonus, similar to that reported in other neurological and psychiatric disorders.
Topics: Humans; Myoclonus; Transcranial Magnetic Stimulation
PubMed: 29803873
DOI: 10.1016/j.brainresbull.2018.05.016