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Revista Da Associacao Medica Brasileira... 2022The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures.
METHODS
This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses.
RESULTS
Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%.
CONCLUSIONS
This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.
Topics: Adult; Child; Humans; Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Lennox Gastaut Syndrome; Seizures; Tuberous Sclerosis
PubMed: 36417631
DOI: 10.1590/1806-9282.2022D689 -
Neuropsychology Review Dec 2016Psychiatric disorders and associated poor psychosocial outcomes are recognised to be a common sequelae of epilepsy. The extent to which this is true of genetic... (Review)
Review
Psychiatric disorders and associated poor psychosocial outcomes are recognised to be a common sequelae of epilepsy. The extent to which this is true of genetic generalised epilepsies (GGE), particularly syndromes other than juvenile myoclonic epilepsy (JME) is unclear. This systematic review synthesises findings regarding psychiatric and associated comorbidities in adults and children with GGE. Systematic review yielded 34 peer-reviewed studies of psychiatric and psychosocial outcomes in adults and children with GGE. Clinically significant psychiatric comorbidity was reported in over half of all children and up to a third of all adults with GGE. There was no evidence to support the presence of personality traits specific to JME or other syndromes; rather rates mirrored community samples. A small number of studies report poor psychosocial outcomes in GGE, however the interpretation of these findings is limited by paucity of healthy comparison groups. Some evidence suggests that anti-epileptic drug polytherapy in children and seizure burden at all ages may constitute risk factors for psychopathology. Findings highlight the importance of early screening so as not to overlook early or developing symptoms of psychopathology.
Topics: Anticonvulsants; Comorbidity; Epilepsy, Generalized; Humans; Mental Disorders
PubMed: 27726043
DOI: 10.1007/s11065-016-9333-1 -
Epileptic Disorders : International... Apr 2018Idiopathic (genetic) generalized epilepsies (IGEs) are age-related epileptic syndromes with typical age onset in childhood or adolescence. We report a patient with de... (Review)
Review
Idiopathic (genetic) generalized epilepsies (IGEs) are age-related epileptic syndromes with typical age onset in childhood or adolescence. We report a patient with de novo late-onset absence status epilepticus (ASE) occurring at the age of 64 years, with clinical and EEG features suggestive of late-onset IGE. We also discuss the relationship between de novo late-onset ASE and late-onset IGE, and provide a comprehensive and critical review of the available literature on late-onset (i.e. onset ≥60 years) IGE. MEDLINE (1966-2016 [23 April]) was systematically searched in order to identify reports of patients with late-onset IGE. Grey literature was also comprehensively searched. We identified nine patients with electroclinical features suggestive of late-onset IGE. Median age at seizure onset was 71 years (range: 60-80), with a female prevalence (67%). A family history of epilepsy was reported in 67% of cases. All patients had generalized tonic-clonic seizures, and 44% also had myoclonic seizures. Treatment and outcome were reported for six patients; all of whom reached seizure freedom under monotherapy with valproic acid (83%) or lamotrigine (17%) (range of follow-up: 3 to 24 months). Late-onset IGE are entities with unknown prevalence and incidence, and should be differentiated on the basis of late-onset reactivation of previous IGE. Late-onset IGEs are probably unrecognized or misdiagnosed, based on a common misconception that all elderly individuals with first-ever seizures have focal symptomatic epilepsy. Late-onset IGE should be actively investigated by accurate history taking aimed at identifying seizures, which may have been unnoticed, and familial antecedents of epilepsy. In elderly patients presenting with de novo late-onset ASE, a diagnosis of late-onset IGE should be considered in the differential diagnosis, particularly in atypical cases (e.g. absence of triggering factors, coexistence of generalized tonic-clonic or myoclonic seizures, and interictal generalized epileptiform discharges).
Topics: Aged; Aged, 80 and over; Brain; Diagnosis, Differential; Electroencephalography; Epilepsy, Generalized; Female; Humans; Middle Aged; Status Epilepticus
PubMed: 29620008
DOI: 10.1684/epd.2018.0961 -
Epilepsia Apr 2021Dravet syndrome (DS) is a rare severe epilepsy syndrome associated with slowed psychomotor development and behavioral disorders from the second year onward in a... (Meta-Analysis)
Meta-Analysis
Dravet syndrome (DS) is a rare severe epilepsy syndrome associated with slowed psychomotor development and behavioral disorders from the second year onward in a previously seemingly normal child. Among cognitive impairments, visuospatial, sensorimotor integration, and expressive language deficits are consistently reported. There have been independent hypotheses to deconstruct the typical cognitive development in DS (dorsal stream vulnerability, cerebellar-like pattern, sensorimotor integration deficit), but an encompassing framework is still lacking. We performed a scoping review of existing evidence to map the current understanding of DS cognitive and behavioral developmental profiles and to summarize the evidence on suggested frameworks. We searched PubMed, Scopus, PsycInfo, and MEDLINE to identify reports focusing on cognitive deficits and/or behavioral abnormalities in DS published between 1978 and March 15, 2020. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Twenty-one reports were selected and tabulated by three independent reviewers based on predefined data extraction and eligibility forms. Eighteen reports provided assessments of global intelligence quotients with variable degrees of cognitive impairment. Eleven reports analyzed single subitems contribution to global cognitive scores: these reports showed consistently larger impairment in performance scales compared to verbal ones. Studies assessing specific cognitive functions demonstrated deterioration of early visual processing, fine and gross motor abilities, visuomotor and auditory-motor integration, spatial processing, visuo-attentive abilities, executive functions, and expressive language. Behavioral abnormalities, reported from 14 studies, highlighted autistic-like traits and attention and hyperactivity disorders, slightly improving with age. The cognitive profile in DS and some behavioral and motor abnormalities may be enclosed within a unified theoretical framework of the three main hypotheses advanced: a pervasive sensorimotor integration deficit, encompassing an occipito-parietofrontal circuit (dorsal stream) dysfunction and a coexistent cerebellar deficit.
Topics: Cognition; Epilepsies, Myoclonic; Executive Function; Humans; Mental Status and Dementia Tests; Neuropsychological Tests
PubMed: 33646591
DOI: 10.1111/epi.16844 -
Orphanet Journal of Rare Diseases Sep 2023Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype-phenotype correlations.
METHODS
We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy.
RESULTS
250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23-6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75-5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration.
CONCLUSIONS
This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.
Topics: Humans; Lafora Disease; Prognosis; Tandem Mass Spectrometry; Myoclonic Epilepsies, Progressive; Disease Progression; Ubiquitin-Protein Ligases
PubMed: 37658439
DOI: 10.1186/s13023-023-02880-6 -
Epilepsy Research May 2024Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to...
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to systematically explore genotypic and phenotypic features and prognostic factors of neonatal-onset PDE. A literature search covering PubMed, Elsevier, and Web of Science was conducted from January 2006 to August 2023. We identified 56 eligible studies involving 169 patients and 334 alleles. The c.1279 G>C variant was the most common variant of neonatal-onset PDE (25.7 %). All patients were treated with pyridoxine; forty patients received dietary intervention therapy. 63.9 % of the patients were completely seizure-free; however, 68.6 % of the patients had neurodevelopmental delays. Additionally, homozygous c.1279 G>C variants were significantly associated with ventriculomegaly, abnormal white matter signal, and cysts (P<0.05). In contrast, homozygous c.1364 T>C was associated with clonic seizure (P=0.031). Pyridoxine used immediately at seizure onset was an independent protective factor for developmental delay (P=0.035; odds ratio [OR]: 3.14). Besides, pyridoxine used early in the neonatal period was a protective factor for language delay (P=0.044; OR: 4.59). In contrast, neonatal respiratory distress (P=0.001; OR: 127.44) and abnormal brain magnetic resonance imaging (P=0.049; OR: 3.64) were risk factors. Prenatal movement abnormality (P=0.041; OR: 20.56) and abnormal white matter signal (P=0.012; OR: 24.30) were risk factors for motor delay. Myoclonic seizure (P=0.023; OR: 7.13) and status epilepticus (P=0.000; OR: 9.93) were risk factors for breakthrough seizures. In conclusion, our study indicated that pyridoxine should be started immediately when unexplained neonatal seizures occur and not later than the neonatal period to prevent poor neurodevelopmental outcomes.
Topics: Humans; Infant, Newborn; Aldehyde Dehydrogenase; Epilepsy; Genotype; Phenotype; Prognosis; Pyridoxine; Seizures
PubMed: 38636407
DOI: 10.1016/j.eplepsyres.2024.107363 -
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 -
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 -
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 -
The Cochrane Database of Systematic... Oct 2015This is an updated version of the original Cochrane review published in Issue 11, 2013.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 Issue 11, 2013.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
We searched the Cochrane Epilepsy Group Specialised Register (27 April 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 27 April 2015) and MEDLINE (1946 to 27 April 2015). We systematically searched the online trials registry ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform and 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
In the updated search, we identified no additional studies suitable for inclusion. We found no RCTs assessing drugs other than STP. The previous version of this review included 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 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). Investigators found no significant differences in proportions of dropouts from 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, noting that higher proportions of participants in the STP group experienced side effects than in 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. 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; Randomized Controlled Trials as Topic; Seizures
PubMed: 26482210
DOI: 10.1002/14651858.CD010483.pub3