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Addiction (Abingdon, England) Oct 2022There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of pharmacotherapies for AW.
METHODS
Six databases were searched for randomized clinical trials through November 2021. Trials were included after a blinded review by two independent reviewers. Outcomes included incident seizures, delirium tremens, AW severity scores, adverse events, dropouts, dropouts from adverse events, length of hospital stay, use of additional medications, total benzodiazepine requirements, and death. Effect sizes were pooled using frequentist random-effects network meta-analysis models to generate summary ORs and Cohen's d standardized mean differences (SMDs).
RESULTS
Across the 149 trials, there were 10 692 participants (76% male, median 43.5 years old). AW severity spanned mild (n = 32), moderate (n = 51), and severe (n = 66). Fixed-schedule chlormethiazole (OR, 0.16; 95% CI, 0.04-0.65), fixed-schedule diazepam (OR, 0.16; 95% CI, 0.04-0.59), fixed-schedule lorazepam (OR = 0.19; 95% CI, 0.08-0.45), fixed-schedule chlordiazepoxide (OR = 0.21; 95% CI, 0.08-0.53), and divalproex (OR = 0.22; 95% CI, 0.05-0.86) were superior to placebo at reducing incident AW seizures. However, only fixed-schedule diazepam (OR, 0.19; 95% CI, 0.05-0.76) reduced incident delirium tremens. Oxcarbazepine (d = -3.69; 95% CI, -6.21 to -1.17), carbamazepine (d = -2.76; 95% CI, -4.13 to -1.40), fixed-schedule oxazepam (d = -2.55; 95% CI, -4.26 to -0.83), and γ-hydroxybutyrate (d = -1.80; 95% CI, -3.35 to -0.26) improved endpoint Clinical Institute Withdrawal Assessment for Alcohol-Revised scores over placebo. Promazine and carbamazepine were the only agents significantly associated with greater dropouts because of adverse events. The quality of evidence was downgraded because of the substantial risk of bias, heterogeneity, inconsistency, and imprecision.
CONCLUSIONS
Although some pharmacotherapeutic modalities, particularly benzodiazepines, appear to be safe and efficacious for reducing some measures of alcohol withdrawal, methodological issues and a high risk of bias prevent a consistent estimate of their comparative performance.
Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Carbamazepine; Diazepam; Female; Humans; Male; Network Meta-Analysis; Seizures; Substance Withdrawal Syndrome
PubMed: 35194860
DOI: 10.1111/add.15853 -
JAMA Pediatrics Mar 2023Despite advances in the understanding of dietary therapies in children with drug-resistant epilepsy, no quantitative comparison exists between different dietary... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Despite advances in the understanding of dietary therapies in children with drug-resistant epilepsy, no quantitative comparison exists between different dietary interventions.
OBJECTIVE
To evaluate the comparative efficacy and safety of various dietary therapies in childhood drug-resistant epilepsy.
DATA SOURCES
Systematic review and network meta-analysis (frequentist) of studies in PubMed, Embase, Cochrane, and Ovid published from inception to April 2022 using the search terms ketogenic diet, medium chain triglyceride diet, modified Atkins diet, low glycemic index therapy, and refractory epilepsy.
STUDY SELECTION
Randomized clinical trials comparing different dietary therapies (ketogenic diet, modified Atkins diet, and low glycemic index therapy) with each other or care as usual in childhood drug-resistant epilepsy were included. Abstract, title, and full text were screened independently by 2 reviewers.
DATA EXTRACTION AND SYNTHESIS
Data extraction was conducted following Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Cochrane risk-of-bias tool was used to assess the study quality. Effect sizes were calculated as odds ratio with 95% CI using random-effects model. The hierarchy of competing interventions was defined using the surface under the cumulative ranking curve.
MAIN OUTCOMES AND MEASURES
Short-term (≤3 months) 50% or higher and 90% or higher reduction in seizure frequency and treatment withdrawal due to adverse events were the primary efficacy and safety outcomes.
RESULTS
Of 2158 citations, 12 randomized clinical trials (907 patients) qualified for inclusion. In the short term, all dietary interventions were more efficacious than care as usual for 50% or higher seizure reduction (low glycemic index therapy: odds ratio [OR], 24.7 [95% CI, 5.3-115.4]; modified Atkins diet: OR, 11.3 [95% CI, 5.1-25.1]; ketogenic diet: OR, 8.6 [95% CI, 3.7-20.0]), while ketogenic diet (OR, 6.5 [95% CI, 2.3-18.0]) and modified Atkins diet (OR, 5.1 [95% CI, 2.2-12.0]) were better than care as usual for seizure reduction of 90% or higher. However, adverse event-related discontinuation rates were significantly higher for ketogenic diet (OR, 8.6 [95% CI, 1.8-40.6]) and modified Atkins diet (OR, 6.5 [95% CI, 1.4-31.2]) compared with care as usual. Indirectly, there was no significant difference between dietary therapies in efficacy and safety outcomes.
CONCLUSIONS AND RELEVANCE
This study found that all dietary therapies are effective in the short term. However, modified Atkins diet had better tolerability, higher probability for 50% or higher seizure reduction, and comparable probability for 90% or higher seizure reduction and may be a sounder option than ketogenic diet. Direct head-to-head comparison studies are needed to confirm these findings.
Topics: Child; Humans; Drug Resistant Epilepsy; Network Meta-Analysis; Diet, Ketogenic; Seizures; Diet, High-Protein Low-Carbohydrate; Treatment Outcome
PubMed: 36716045
DOI: 10.1001/jamapediatrics.2022.5648 -
The Cochrane Database of Systematic... Jun 2021Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017.
OBJECTIVES
To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use.
SEARCH METHODS
For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots.
MAIN RESULTS
We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Confidence Intervals; Humans; Infant; Placebos; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Seizures, Febrile
PubMed: 34131913
DOI: 10.1002/14651858.CD003031.pub4 -
The Cochrane Database of Systematic... Jan 2018Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic-clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first-line drugs and phenobarbital, phenytoin and paraldehyde as second-line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008.
OBJECTIVES
To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic-clonic convulsion of any duration, including established convulsive (tonic-clonic) status epilepticus in children who present to a hospital or emergency medical department.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017).
SELECTION CRITERIA
Randomised and quasi-randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including convulsive status epilepticus in children.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information.
MAIN RESULTS
The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows:(1) This review provides only low- to very low-quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic-clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam.(2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high-quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate-quality evidence).(3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low-quality evidence).(4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low-quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate-quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate-quality evidence). In general, intravenously-administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access.(5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic-clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate-quality evidence).(6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate-quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93).Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non-intravenous routes of drug administration. Low- to very low-quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses.
AUTHORS' CONCLUSIONS
We have not identified any new high-quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic-clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first-line anticonvulsants for the treatment of an acute tonic-clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.
Topics: Administration, Inhalation; Administration, Oral; Administration, Rectal; Anticonvulsants; Child; Diazepam; Epilepsy, Tonic-Clonic; Humans; Injections, Intramuscular; Injections, Intravenous; Lorazepam; Midazolam; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 29320603
DOI: 10.1002/14651858.CD001905.pub3 -
CNS Drugs Mar 2021Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A...
BACKGROUND
Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.
OBJECTIVES
This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome.
METHODS
The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.
RESULTS
Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.
CONCLUSIONS
The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research.
Topics: Anticonvulsants; Cannabidiol; Case-Control Studies; Cross-Sectional Studies; Double-Blind Method; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Seizures
PubMed: 33754312
DOI: 10.1007/s40263-021-00807-y -
The Cochrane Database of Systematic... Jan 2023Epilepsy is clinically defined as two or more unprovoked epileptic seizures more than 24 hours apart. Given that, a diagnosis of epilepsy can be associated with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Epilepsy is clinically defined as two or more unprovoked epileptic seizures more than 24 hours apart. Given that, a diagnosis of epilepsy can be associated with significant morbidity and mortality, it is imperative that clinicians (and people with seizures and their relatives) have access to accurate and reliable prognostic estimates, to guide clinical practice on the risks of developing further unprovoked seizures (and by definition, a diagnosis of epilepsy) following single unprovoked epileptic seizure.
OBJECTIVES
1. To provide an accurate estimate of the proportion of individuals going on to have further unprovoked seizures at subsequent time points following a single unprovoked epileptic seizure (or cluster of epileptic seizures within a 24-hour period, or a first episode of status epilepticus), of any seizure type (overall prognosis). 2. To evaluate the mortality rate following a first unprovoked epileptic seizure.
SEARCH METHODS
We searched the following databases on 19 September 2019 and again on 30 March 2021, with no language restrictions. The Cochrane Register of Studies (CRS Web), MEDLINE Ovid (1946 to March 29, 2021), SCOPUS (1823 onwards), ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. In MEDLINE (Ovid) the coverage end date always lags a few days behind the search date.
SELECTION CRITERIA
We included studies, both retrospective and prospective, of all age groups (except those in the neonatal period (< 1 month of age)), of people with a single unprovoked seizure, followed up for a minimum of six months, with no upper limit of follow-up, with the study end point being seizure recurrence, death, or loss to follow-up. To be included, studies must have included at least 30 participants. We excluded studies that involved people with seizures that occur as a result of an acute precipitant or provoking factor, or in close temporal proximity to an acute neurological insult, since these are not considered epileptic in aetiology (acute symptomatic seizures). We also excluded people with situational seizures, such as febrile convulsions.
DATA COLLECTION AND ANALYSIS
Two review authors conducted the initial screening of titles and abstracts identified through the electronic searches, and removed non-relevant articles. We obtained the full-text articles of all remaining potentially relevant studies, or those whose relevance could not be determined from the abstract alone and two authors independently assessed for eligibility. All disagreements were resolved through discussion with no need to defer to a third review author. We extracted data from included studies using a data extraction form based on the checklist for critical appraisal and data extraction for systematicreviews of prediction modelling studies (CHARMS). Two review authors then appraised the included studies, using a standardised approach based on the quality in prognostic studies (QUIPS) tool, which was adapted for overall prognosis (seizure recurrence). We conducted a meta-analysis using Review Manager 2014, with a random-effects generic inverse variance meta-analysis model, which accounted for any between-study heterogeneity in the prognostic effect. We then summarised the meta-analysis by the pooled estimate (the average prognostic factor effect), its 95% confidence interval (CI), the estimates of I² and Tau² (heterogeneity), and a 95% prediction interval for the prognostic effect in a single population at three various time points, 6 months, 12 months and 24 months. Subgroup analysis was performed according to the ages of the cohorts included; studies involving all ages, studies that recruited adult only and those that were purely paediatric.
MAIN RESULTS
Fifty-eight studies (involving 54 cohorts), with a total of 12,160 participants (median 147, range 31 to 1443), met the inclusion criteria for the review. Of the 58 studies, 26 studies were paediatric studies, 16 were adult and the remaining 16 studies were a combination of paediatric and adult populations. Most included studies had a cohort study design with two case-control studies and one nested case-control study. Thirty-two studies (29 cohorts) reported a prospective longitudinal design whilst 15 studies had a retrospective design whilst the remaining studies were randomised controlled trials. Nine of the studies included presented mortality data following a first unprovoked seizure. For a mortality study to be included, a proportional mortality ratio (PMR) or a standardised mortality ratio (SMR) had to be given at a specific time point following a first unprovoked seizure. To be included in the meta-analysis a study had to present clear seizure recurrence data at 6 months, 12 months or 24 months. Forty-six studies were included in the meta-analysis, of which 23 were paediatric, 13 were adult, and 10 were a combination of paediatric and adult populations. A meta-analysis was performed at three time points; six months, one year and two years for all ages combined, paediatric and adult studies, respectively. We found an estimated overall seizure recurrence of all included studies at six months of 27% (95% CI 24% to 31%), 36% (95% CI 33% to 40%) at one year and 43% (95% CI 37% to 44%) at two years, with slightly lower estimates for adult subgroup analysis and slightly higher estimates for paediatric subgroup analysis. It was not possible to provide a summary estimate of the risk of seizure recurrence beyond these time points as most of the included studies were of short follow-up and too few studies presented recurrence rates at a single time point beyond two years. The evidence presented was found to be of moderate certainty.
AUTHORS' CONCLUSIONS
Despite the limitations of the data (moderate-certainty of evidence), mainly relating to clinical and methodological heterogeneity we have provided summary estimates for the likely risk of seizure recurrence at six months, one year and two years for both children and adults. This provides information that is likely to be useful for the clinician counselling patients (or their parents) on the probable risk of further seizures in the short-term whilst acknowledging the paucity of long-term recurrence data, particularly beyond 10 years.
Topics: Adult; Child; Humans; Anticonvulsants; Case-Control Studies; Cohort Studies; Epilepsies, Partial; Epilepsy; Prognosis; Prospective Studies; Retrospective Studies; Seizures
PubMed: 36688481
DOI: 10.1002/14651858.CD013847.pub2 -
The Cochrane Database of Systematic... Apr 2020Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012.
OBJECTIVES
To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019).
SELECTION CRITERIA
We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE.
MAIN RESULTS
We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections.
AUTHORS' CONCLUSIONS
Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.
Topics: Adolescent; Age Factors; Autistic Disorder; Chickenpox Vaccine; Child; Child, Preschool; Clinical Trials as Topic; Crohn Disease; Epidemiologic Studies; Humans; Infant; Measles; Measles-Mumps-Rubella Vaccine; Mumps; Purpura, Thrombocytopenic; Rubella; Seizures, Febrile; Vaccines, Attenuated
PubMed: 32309885
DOI: 10.1002/14651858.CD004407.pub4 -
European Journal of Neurology Feb 2022New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active... (Review)
Review
BACKGROUND AND PURPOSE
New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions.
METHODS
A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome.
RESULTS
Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called 'cryptogenic NORSE'. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described.
CONCLUSIONS
Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.
Topics: Adult; Child; Drug Resistant Epilepsy; Encephalitis; Epileptic Syndromes; Humans; Retrospective Studies; Status Epilepticus
PubMed: 34661330
DOI: 10.1111/ene.15149 -
Drugs Oct 2023Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs).
OBJECTIVE
The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA).
METHODS
Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.
CLINICALTRIALS
gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework.
RESULTS
Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07-0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57-76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04-5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06-0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59-1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS.
CONCLUSIONS
There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.
Topics: Humans; Anticonvulsants; Cannabidiol; Network Meta-Analysis; Randomized Controlled Trials as Topic; Seizures; Epilepsies, Myoclonic; Fenfluramine; Pharmaceutical Preparations
PubMed: 37695433
DOI: 10.1007/s40265-023-01936-y -
Health Technology Assessment... Mar 2022Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded...
BACKGROUND
Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting.
OBJECTIVES
To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting.
DATA SOURCES
We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020.
REVIEW METHODS
Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively.
RESULTS
Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness.
LIMITATIONS
The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data.
CONCLUSIONS
Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42020201953.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in ; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.
Topics: Adult; Anticonvulsants; Emergency Service, Hospital; Hospitals; Humans; Retrospective Studies; Status Epilepticus
PubMed: 35333156
DOI: 10.3310/RSVK2062