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      Prophylactic drug management for febrile seizures in children

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          Abstract

          Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 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. To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; but also to evaluate any other drug intervention where there was a sound biological rationale for its use. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2016, Issue 7); MEDLINE (1966 to July 2016); Embase (1966 to July 2016); Database of Abstracts of Reviews of Effectiveness (DARE) (July 2016). We imposed no language restrictions. We also contacted researchers in the field to identify continuing or unpublished studies. Trials using randomised or quasi‐randomised participant allocation that compared the use of antiepileptic, antipyretic or other plausible agents with each other, placebo or no treatment. Two review authors (RN and MO) 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 author (MC) checked all original inclusions, data analyses, and updated the search. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36, and 48 months and at age 5 to 6 years in the intervention and non‐intervention groups, and adverse medication effects. We assessed the presence of publication bias using funnel plots. We included 40 articles describing 30 randomised trials with 4256 randomised participants. We analysed 13 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 phenobarbitone, phenytoin, valproate, pyridoxine, ibuprofen or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, acetaminophen or placebo; nor for continuous phenobarbitone 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, with a risk ratio (RR) of  0.64 (95% confidence interval (CI) 0.48 to 0.85 at six months), RR of 0.69 (95% CI 0.56 to 0.84) at 12 months, RR 0.37 (95% CI 0.23 to 0.60) at 18 months, RR 0.73 (95% CI 0.56 to 0.95) at 24 months, RR 0.58 (95% CI 0.40 to 0.85) at 36 months, RR 0.36 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 60 to 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow‐up (RR 0.59 (95% CI 0.42 to 0.83) at 6 months; RR 0.54 (95% CI 0.42 to 0.70) at 12 months; and RR 0.69 (95% CI 0.53 to 0.89) at 24 months). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64), an effect found against an extremely high (83.3%) recurrence rate in the controls, which is a result that needs replication. The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone‐treated children were found in two studies. In general, adverse effects were recorded in up to 30% of children in the phenobarbitone‐treated group and in up to 36% in benzodiazepine‐treated groups. We found evidence of publication bias in the meta‐analyses of comparisons for phenobarbitone versus placebo (eight studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months, with too few studies to identify publication bias for the other comparisons. Most of the reviewed antiepileptic drug trials are of a methodological quality graded as low or very low. Methods of randomisation and allocation concealment often do not meet current standards; and treatment versus no treatment is more commonly seen than treatment versus placebo, leading to obvious risks of bias. Trials of antipyretics and zinc were of higher quality. We found reduced recurrence rates for children with febrile seizures for intermittent diazepam and continuous phenobarbitone, with adverse effects in up to 30%. Apparent benefit for clobazam treatment in one trial needs to be replicated to be judged reliable. 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. Prophylactic drug management for febrile seizures in children Background Seizures occurring with a fever in children are common and affect about one in thirty under the age of six years. On average, one out of three children who have had a febrile seizure will have at least one more. We reviewed the evidence about the effect of drugs to prevent seizures (antiepileptics), drugs to lower temperature (antipyretics) and zinc on children with febrile seizures. Objective We wanted to know in how many children these drugs would prevent a recurrence or bring unwanted effects. Methods We included 30 studies with a total of 4256 children in the review. Children who had had at least one febrile seizure were put into groups who either had the study treatment or not. The studies recorded any further seizures at various time intervals between 6 months and up to 6 years of age in each group. Unwanted medication effects were also noted. Results The quality of study design and evidence provided by these studies was often low or very low for the antiepileptic drugs. Poor methods known to lead to obvious risks of bias were used. This was to do with the way children were put in each group and how random this allocation was. Other issues included whether the parents and/or doctors knew which group each child was in or perhaps if the study was of treatment compared to no treatment. The quality of trials of antipyretics or zinc was better, with the evidence graded moderate to high. Zinc therapy gave no benefit. Nor was there benefit in treating children just at the time of the fever with either antipyretic drugs or most antiepileptic drugs. At times a significant result was noted. In statistics this means there was a less than 1 in 20 chance of this happening by chance. For example, at times between 6 and 48 months follow‐up, intermittent diazepam (an antiepileptic drug) led to a reduction in the number of recurrent seizures by about a third. Continuous phenobarbitone resulted in significantly fewer recurrences at 6, 12 and 24 months, but not at 18 and 60 to 72 months However, as recurrent seizures are only seen in about a third of children anyway this means that up to 16 children would have to be treated over a year or two to save just one child a further seizure. As febrile seizures are not harmful we viewed these significant findings (in the statistical sense) to be unimportant. This is particularly so as adverse effects of the medications were common. Lower comprehension scores in phenobarbitone‐treated children were found in two studies. In general, adverse effects were recorded in up to about a third of children in both the phenobarbitone and benzodiazepine‐treated groups. The benefit found for treatment with clobazam in one study published in 2011 needs to be repeated to show that this finding is reliable. Author’s conclusions Neither continuous nor intermittent treatment with zinc, antiepileptic or antipyretic drugs can be recommended for children with febrile seizures. Febrile seizures can be frightening to witness. 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. The evidence is current to 21 July 2016.

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          Most cited references 59

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          Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

          Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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            The Prevalence and Incidence of Convulsive Disorders in Children

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              A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions.

              Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions. To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies. The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out. The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls. A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35). Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.
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                Author and article information

                Journal
                Cochrane Database of Systematic Reviews
                Wiley-Blackwell
                14651858
                February 22 2017
                :
                :
                Affiliations
                [1 ]Cochrane Epilepsy Group
                Article
                10.1002/14651858.CD003031.pub3
                © 2017
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