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      Prophylactic drug management for febrile seizures in children

      , , ,

      Cochrane Epilepsy Group

      The Cochrane Database of Systematic Reviews

      John Wiley & Sons, Ltd

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          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.

          Search methods

          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 We also contacted researchers in the field to identify continuing or unpublished studies.

          Selection criteria

          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.

          Data collection and analysis

          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.

          Main results

          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.

          Authors' conclusions

          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.

          Plain language summary

          Prophylactic drug management for febrile seizures in children


          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.


          We wanted to know in how many children these drugs would prevent a recurrence or bring unwanted effects.


          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.


          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.

          Related collections

          Most cited references 59

          • Record: found
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          Is Open Access

          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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              Complex febrile seizures.

               Kelly Berg,  S Shinnar (1996)
              In the context of a prospective cohort study, we examined the associations between individual complex features of both first (n = 428) and recurrent (n = 240) febrile seizures and factors shown to predict outcome in children with febrile seizures. Thirty-five percent of first and 33% of recurrent febrile seizures had one or more complex features (focal onset, duration > or = 10 min, or multiple seizures during the illness episode). There were strong correlations between focality and prolonged duration for both first and recurrent febrile seizures. A low fever at the time of the seizure was marginally associated with prolonged duration. Most factors associated with either recurrent febrile seizures or subsequent unprovoked seizures were not associated with either the initial seizure being complex or the likelihood that a recurrence would be complex. However, the children with recurrent febrile seizures, complex features tended to repeat. This factor was statistically significant and particularly striking for prolonged duration. Genetic or other constitutional factors may explain why the prolonged feature recurs. Eleven (2.5%) children had three or four risk factors for recurrent febrile seizure that was prolonged. This very small group of children may be candidates for abortive therapy to be administered at the onset of a recurrent seizure.

                Author and article information

                martin.offringa@sickkids.ca , offringa@me.com
                Cochrane Database Syst Rev
                Cochrane Database Syst Rev
                The Cochrane Database of Systematic Reviews
                John Wiley & Sons, Ltd (Chichester, UK )
                22 February 2017
                February 2017
                21 February 2017
                : 2017
                : 2
                Hospital for Sick Children deptChild Health Evaluative Sciences 555 University Avenue Toronto ON Canada M5G 1X8
                Royal Manchester Children's Hospital deptDepartment of Paediatric Neurology Hospital Road Pendlebury Manchester UK M27 4HA
                Erasmus MC ‐ Sophia Children's Hospital deptPediatric Gastroenterology 's‐Gravendijkwal 230 3015 CE Rotterdam Netherlands 3000 CB
                University of Liverpool deptDepartment of Biostatistics Block F, Waterhouse Building 1‐5 Brownlow Hill Liverpool UK L69 3GL
                PMC6464693 PMC6464693 6464693 CD003031.pub3 CD003031
                Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
                Child health
                Treatment for acute symptomatic seizures


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