Febrile seizures recur frequently. Factors increasing the risk of febrile seizure recurrence include young age at onset, family history of febrile seizures, previous recurrent febrile seizures, time lapse since previous seizure <6 months, relative low temperature at the initial seizure, multiple type initial seizure, and frequent febrile illnesses. Prevention of seizure recurrences serves two useful purposes: meeting parental fear of recurrent febrile seizures in general and reducing the (small) risk of a long-lasting and eventually injurious recurrent seizure. In daily practice, children with febrile seizures often are treated with antipyretics during fever to prevent febrile seizure recurrences. Thus far, no randomized placebo-controlled trial has been performed to assess the efficacy of intermittent antipyretic treatment in the prevention of seizure recurrence.
We performed a randomized, double-blind, placebo-controlled trial. Children 1 to 4 years of age who had had at least one risk factor for febrile seizure recurrence were enrolled. They were randomly assigned to either ibuprofen syrup, 20 mg/mL, 0.25 mL (= 5 mg) per kilogram of body weight per dose, or matching placebo, to be administered every 6 hours during fever (temperature, ≥38.5°C). Parents were instructed to take the child's rectal temperature immediately when the child seemed ill or feverish and to promptly administer the study medication when the temperature was ≥38.5°C. Doses were to be administered every 6 hours until the child was afebrile for 24 hours. The parents were instructed not to administer any other antipyretic drug to the child. For measuring rectal temperature, a Philips HP5316 digital thermometer (Philips, Eindhoven, The Netherlands) was distributed. During subsequent treatment of the fever episode, parents had to call the investigator at least once each day to notify the investigator in case of febrile seizure recurrence. The investigator could be contacted by parents 24 hours per day.
The primary outcome was the first recurrence of a febrile seizure. Kaplan–Meier curves and Cox regression were used for the statistical analysis. The treatment effect on the course of the temperature was assessed using analysis of covariance, with temperature at fever onset as covariate. Two analyses were performed. In an intention-to-treat analysis, all first recurrences were considered regardless of study medication compliance. A per-protocol analysis was limited to those recurrences that occurred in the context of study medication compliance.
Between October 1, 1994, and April 1, 1996, 230 children were randomly assigned to ibuprofen syrup (111 children) or placebo (119 children). Median follow-up time was 1.04 years (25th–75th percentiles; 0.7–1.8 years) in the ibuprofen group and 0.98 years (0.7–1.6 years) in the placebo group. Of all children, 67 had a first febrile seizure recurrence, with 31 in the ibuprofen group and 36 in the placebo group. The 2-year recurrence probabilities were 32% and 39%, respectively. The recurrence risk in the ibuprofen group was 0.9 (95% confidence interval: 0.6–1.5) times the recurrence risk in the placebo group (intention to treat). Adjustment for baseline characteristics did not affect the risk-reduction estimate. Of the 67 recurrences, 30 occurred in the context of study medication compliance (13 ibuprofen, 17 placebo). The per-protocol analysis, which was limited to these events, showed similar results.
A significant reduction in temperature (0.7°C) after fever onset in the ibuprofen group compared with the placebo group was demonstrated if all 555 fever episodes were considered. In the fever episodes with a seizure recurrence, a similar temperature increase was shown in both groups, with no significant difference between the intention-to-treat and the per-protocol analysis.
The present study failed to demonstrate a preventive effect of intermittent antipyretic treatment during fever on the number of febrile seizure recurrences in children at increased risk. The possibility that antipyretics can reduce recurrence has been addressed before. None of these studies were placebo-controlled trials with a standardized antipyretic treatment schedule; hence, the results were inconclusive.
Although it had been described previously that ibuprofen reduces fever safely and adequately in children with febrile seizures, which is confirmed by the present study, we found that fever was not reduced in those fever episodes in which a recurrence occurred. Factors that may have influenced these results are discussed.
Preventive treatment alternatives include primarily intermittent treatment with diazepam. Only children with a high recurrence risk may benefit from it. In a meta-analysis, its efficacy could not be demonstrated. The most important issue in treating children with febrile seizures is reducing parental anxiety by providing information about the excellent prognosis.
We found no evidence that ibuprofen administration during fever prevents febrile seizure recurrence.