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CNS Drugs Aug 2021The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary...
BACKGROUND
The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs).
OBJECTIVE
We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication.
METHODS
Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564).
RESULTS
Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type.
CONCLUSIONS
The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.
Topics: Anticonvulsants; Epilepsy, Generalized; Humans; Myoclonic Epilepsy, Juvenile; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34232492
DOI: 10.1007/s40263-021-00831-y -
Orphanet Journal of Rare Diseases Aug 2021Lafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.
METHODS
A search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan-Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.
RESULTS
Seventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89-96] at 5 years, 62% [95% CI 54-69] at 10 years and 57% [95% CI 49-65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36-55] at 5 years, 75% [95% CI 66-84] at 10 years, and 83% [95% CI 74-90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset < 18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability.
CONCLUSIONS
This study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.
Topics: Adolescent; Child; Humans; Lafora Disease; Prognosis
PubMed: 34399803
DOI: 10.1186/s13023-021-01989-w -
The Cochrane Database of Systematic... Jul 2020This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs.
OBJECTIVES
To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures.
SEARCH METHODS
For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine.
SELECTION CRITERIA
Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing.
MAIN RESULTS
We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74).
AUTHORS' CONCLUSIONS
This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.
Topics: Anticonvulsants; Chemotherapy, Adjuvant; Dizziness; Drug Eruptions; Drug Resistant Epilepsy; Epilepsy, Tonic-Clonic; Exanthema; Fatigue; Humans; Lamotrigine; Nausea; Patient Dropouts; Randomized Controlled Trials as Topic; Sleepiness
PubMed: 32609387
DOI: 10.1002/14651858.CD007783.pub3 -
Seizure Jan 2024Epilepsy is one of the most frequent neurological comorbidities in patients with Down Syndrome (DS). Young patients and adults are the most affected, the latter mostly... (Review)
Review
INTRODUCTION
Epilepsy is one of the most frequent neurological comorbidities in patients with Down Syndrome (DS). Young patients and adults are the most affected, the latter mostly showing a phenotype labeled as "Late-onset myoclonic epilepsy" (LOMEDS). Status epilepticus (SE) is a life-threatening complication in patients with epilepsy. In this study, we described a non-convulsive SE (NCSE) case in a patient diagnosed with LOMEDS. We also performed a systematic review of the literature on SE diagnosis and treatment in patients with Down Syndrome.
METHODS
Clinical and demographic characteristics of a DS patient diagnosed with NCSE were described. The systematic literature search dissected the diagnostic and therapeutic management of SE in patients with DS. The following databases were used: PubMed, EMBASE, and Google Scholar.
RESULTS
5 DS individuals (4 from the past literature + 1 novel case report) with SE have been identified. The median age at SE onset was 42 years (IQR: 21-60.5 years). The most common SE type was myoclonic SE (MSE), followed by NCSE. Two cases of acute symptomatic etiology were described, whereas a progressive symptomatic etiology was otherwise reported. Ictal EEG recording information was available in two patients who showed generalized spike waves and polyspike and wave discharges. In 3 cases, SE was treated with intravenous antiseizure medications that produced a complete resolution.
CONCLUSION
SE may represent a rare complication in patients with DS. Although no definitive conclusions may be achieved due to the lack of evidence, treatment with valproic acid seems effective, especially in MSE. NCSE management is more challenging. It requires low doses of anesthetics, which should be used cautiously due to the high rate of complications.
Topics: Adult; Humans; Middle Aged; Young Adult; Down Syndrome; Electroencephalography; Epilepsy; Status Epilepticus; Valproic Acid
PubMed: 38101201
DOI: 10.1016/j.seizure.2023.11.009 -
Seizure Oct 2021Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no systematic review has been conducted in LGS patients to provide an estimate of the efficacy and safety of rufinamide.
METHODS
Different electronic databases were searched for articles describing the use of rufinamide in patients with LGS. For determining primary efficacy outcomes as compared to placebo, we included only studies comparing the efficacy of rufinamide with placebo in LGS patients. We performed an additional analysis to include other uncontrolled studies with a minimum sample size of 20 to provide a more comprehensive estimate of efficacy.
RESULTS
A total of ten studies included 557 patients. Out of them, five studies were placebo-controlled, enrolling a total of 265 patients in the rufinamide group and 203 patients in the placebo group. The average percentage reduction in total seizure frequency per 28 days during the double-blind phase was 29.3% in the rufinamide group compared with 8.3% in the placebo group (difference between the two groups was 20.9%, 95%CI-14.4%-27.3%, p <0.00001). Even for individual seizure types like tonic-clonic seizures, atypical absence seizures, atonic seizures, focal seizures, and myoclonic seizures, rufinamide was more efficacious than placebo(p<0.00001). The number of patients with at least one treatment-emergent adverse effects was significantly higher in rufinamide treated patients (60.2%vs50.7%, p=0.02, RR-1.24(1.03,1.51).
CONCLUSION
Rufinamide is efficacious as adjunctive therapy in patients with LGS in terms of reduction in total seizure frequency and has mild adverse reaction.
Topics: Anticonvulsants; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; Triazoles
PubMed: 34273668
DOI: 10.1016/j.seizure.2021.07.004 -
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 -
PloS One 2017We aimed to identify the consistent regions of gray matter volume (GMV) abnormalities in idiopathic generalized epilepsy (IGE), and to study the difference of GMV... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We aimed to identify the consistent regions of gray matter volume (GMV) abnormalities in idiopathic generalized epilepsy (IGE), and to study the difference of GMV abnormalities among IGE subsyndromes by applying activation likelihood estimation (ALE) meta-analysis.
METHODS
A systematic review of VBM studies on GMV of patients with absence epilepsy (AE), juvenile myoclonic epilepsy (JME), IGE and controls indexed in PubMed and ScienceDirect from January 1999 to June 2016 was conducted. A total of 12 IGE studies, including 7 JME and 3 AE studies, were selected. Meta-analysis was performed on these studies by using the pooled and within-subtypes analysis (www.brainmap.org). Based on the above results, between-subtypes contrast analysis was carried out to detect the abnormal GMV regions common in and unique to each subtype as well.
RESULTS
IGE demonstrated significant GMV increase in right ventral lateral nucleus (VL) and right medial frontal gyrus, and significant GMV decrease in bilateral pulvinar. For JME, significant GMV increase was seen in right medial frontal gyrus, right anterior cingulate cortex (ACC), while significant GMV decrease was found in right pulvinar. In AE, the most significant GMV increase was found in right VL, and slight GMV reduction was seen in right medial dorsal nucleus, right subcallosal gyrus, left caudate and left precuneus. No overlapped and unique regions with significant GMV abnormalities were found between JME and AE.
SIGNIFICANCE
This meta-analysis demonstrated that thalamo-frontal network was a structure with significant GMV abnormality in IGE, and the IGE subsyndromes showed different GMV abnormal regions. These observations may provide instructions on the clinical diagnosis of IGE.
Topics: Epilepsy, Generalized; Female; Gray Matter; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Organ Size
PubMed: 28060866
DOI: 10.1371/journal.pone.0169076 -
Seizure Oct 2017Determine the impact of anti-epileptic drugs (AED) for drug resistant patients with idiopathic generalised epilepsy. (Meta-Analysis)
Meta-Analysis
PURPOSE
Determine the impact of anti-epileptic drugs (AED) for drug resistant patients with idiopathic generalised epilepsy.
METHODS
A systematic search of Medline, Cumulative Index to Nursing an Allied Health Literature (CINAHL), Cochrane Epilepsy Group Central Specialised Register, Cochrane Central Register of controlled Trials (CENTRAL), Embase and Lenus was performed. Nine randomised controlled trials were included. All trials compared antiepileptic drugs to placebo. Outcome measures assessed were 50% or greater reduction in seizure, seizure freedom and adverse events.
RESULTS
Seven trials report a 50% or greater reduction in seizure frequency. This was statistically significant (p=<0.00001) with a narrow confidence interval implying that the overall this meta-analysis has reasonable power to detect an effect. It demonstrated a significant statistical difference of seizure freedom occurring in the drug treatment group compared to placebo. Adverse events were identified with each drug and are reported. There were however methodological issues with the trials included. Quality appraisal was undertaken using the risk of bias assessment from Rev Man 5.3 tool for all randomised controlled trials retrieved.
CONCLUSION
This systematic review demonstrated efficacy of adjunctive anti-epileptic drugs with regard to 50% reduction and seizure freedom. Adverse events are identified in all of the studies in the drug treatment groups but are consistent with previous studies of these drugs. Additional adequately powered studies with long term follow up needs to be conducted to unequivocally establish the long term efficacy and tolerability of anti-epileptic drug's for patients with drug resistant idiopathic generalised epilepsy.
Topics: Anticonvulsants; Epilepsy, Generalized; Humans
PubMed: 28863398
DOI: 10.1016/j.seizure.2017.08.007