Original Article
Phenobarbital for Febrile Seizures — Effects on Intelligence and on Seizure Recurrence
N Engl J Med 1990; 322:364-369February 8, 1990
- Abstract
- Abstract
Phenobarbital is widely used in the treatment of children with febrile seizures, although there is concern about possible behavioral and cognitive side effects. In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures, we compared the intelligence quotients (IQs) of a group randomly assigned to daily doses of phenobarbital (4 to 5 mg per kilogram of body weight per day) with the IQs of a group randomly assigned to placebo.
After two years, the mean IQ was 8.4 points lower in the group assigned to phenobarbital than in the placebo group (95 percent confidence interval, −13.3 to −3.5, P = 0.0057). Six months later, after the medication had been tapered and discontinued, the mean IQ was 5.2 points lower in the group assigned to phenobarbital (95 percent confidence interval, −10.5 to 0.04, P = 0.052). The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups.
We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage, which may outlast the administration of the drug by several months, is not offset by the benefit of seizure prevention. (N Engl J Med 1990; 322: 364–9.)
Media in This Article
Figure 1
Probability of Remaining Free of Seizures, from the Time of the Index Seizure to the Time of the Final Visit, According to Assigned Treatment (Kaplan–Meier Plots).Table 1
Clinical Characteristics of 217 Subjects with Febrile Seizures.Article Activity
- Article
PHENOBARBITAL is widely regarded as the drug of choice for the treatment of young children with febrile seizures,1 and it is also used to treat nonfebrile seizures in infants and young children.2 3 4 5 A number of authors have reported behavioral and cognitive side effects of this drug.6 7 8 Clinical concern about a special vulnerability of infants and children has been augmented by experimental studies that have shown deleterious effects of phenobarbital on developing neurons in vivo and in vitro.9 10 11 We undertook this study to examine cognition and behavior in children with febrile seizures for whom daily phenobarbital was prescribed, as compared with children with febrile seizures who received a placebo.
A Consensus Development Conference sponsored by the National Institutes of Health on the management of febrile seizures12 excluded from consideration for treatment children who had had a single brief febrile seizure and who had no specific risk factors for epilepsy. In accordance with this recommendation and local practice, patients who were very young, had had more than one febrile seizure, had a family history of epilepsy, or had lengthy, focal, or multiple seizures were assigned to receive either phenobarbital or placebo according to a randomized, double-blind study design. They were scheduled for testing at base line, periodically during two years of daily therapy, and six months after the withdrawal of medication was begun. We report the results of intelligence testing and the rates of subsequent seizures (febrile or nonfebrile) in the two treatment groups.
Methods
Children from the Seattle—Tacoma area who required medical care from their own physicians or at emergency rooms for the treatment of a febrile seizure from November 1982 through December 1985 were evaluated for eligibility for this study. Febrile seizures were defined as seizures associated with fever and unaccompanied by acute neurologic illness, occurring in children who had had no previous seizure of any other type. Children were considered eligible if they had had such a seizure within the previous three months, were not receiving daily anticonvulsant medication, and were between 8 and 36 months of age. In addition, eligible children were required to have one or more of the following characteristics: an age of less than 12 months; one or more previous febrile seizures; a seizure that lasted more than 15 minutes, was focal, or recurred within 24 hours; nonfebrile seizures in a parent or sibling; or abnormal neurologic status before the index seizure.
Eligible children whose families agreed to register them were randomly assigned to treatment. The adaptive-randomization methods of Pocock and Simon13 were used to achieve balance in the distribution of age (according to groups of 8 to 11, 12 to 18, 19 to 24, and 25 to 36 months), sex, and socioeconomic index (in three categories).14 Stratification was used to achieve balance in the distribution of scores on the Bayley Scales of Motor Development.
The children were assigned to receive either phenobarbital with 5 mg of riboflavin added per tablet or a placebo tablet identical in appearance and also containing riboflavin. The hospital pharmacy dispensed medication, keeping the patients and study personnel blinded about treatment assignment. The initial dose was 4 to 5 mg per kilogram of body weight once a day.15 Clinic visits were scheduled at 6 weeks and 6, 12, 18, 24, and 30 months after registration. Unscheduled visits were made if there were problems with medication or a recurrence. Medication was continued for 24 months, then tapered off over a period of approximately 2 months. Blood was drawn at each visit. For children taking placebo, factitious phenobarbital levels were reported to the blinded investigators. Urine was examined for fluorescence, indicating the presence of riboflavin. Blood was not drawn or urine collected if the parents reported having missed giving the children their doses for two or more days before the visit.
The investigators and parents were unaware of the treatment assignments. Changes in the dose of medication prescribed were based on reported or observed side effects, laboratory reports of blood levels (real in the case of children taking phenobarbital, spurious for those taking placebo), and recurrences of seizures. When there were side effects the parents considered intolerable, the dose was temporarily reduced. If that failed to resolve the problem, a switch to the other study medication (phenobarbital or placebo) was made without breaking the blinding, and if that failed, the medication was stopped altogether. If a child had had a single seizure before entry into the study, one recurrence was allowed while the child took the assigned medication during the study, but the blinding was broken and active treatment prescribed if more than one recurrence or a nonfebrile seizure occurred. If there had been two or more seizures before enrollment, the blinding was broken after a single recurrence.
The Bayley Scales of Infant Development were administered at the initial and six-week visits. For the 23 children with seizures who were 31 to 36 months old at study entry, the base-line Bayley scores were adjusted for age on the basis of an extrapolation derived from the control data. The Stanford–Binet Scales of Intelligence or the Bayley scales (as appropriate for age or level of function) were administered at the 12-month visit, and the Stanford–Binet at the 2-year and 2 1/2-year visits. A concurrent control group of children free of seizures but as similar as possible to the febrile-seizure group with respect to age and socioeconomic index underwent the same behavioral and cognitive testing but did not have medical examinations or blood tests. The phenobarbital load was estimated as the average daily blood level of the drug over each six-month interval, on the basis of medical records, including the parents' reports of compliance, changes in the prescription of medication, and blood levels determined during the scheduled and unscheduled visits.
Statistical Analysis
The reliability coefficient of the Bayley scales was estimated from the Bayley scores obtained for the controls at the base-line and six-week visits with use of the Pearson product correlation. The reliability coefficient of the Stanford–Binet test was estimated from the scores of the controls at two years and at the end of the study. The probability of remaining free of seizures was estimated separately for the two treatment groups by the Kaplan–Meier product-limit estimation method,16 and comparisons between treatment groups were made with the Gehan—Wilcoxon test.17 The Cox regression method was used to determine the effect of covariables.18
We determined base-line variables that were significantly related to IQ at two years among the controls with an analysis of covariance. Logistic regression was used to test whether the missing data on IQ at the 2-year and 2 1/2-year visits were random with respect to the variables affecting outcome.18 We generated an expected IQ score for each child with seizures on the basis of a regression equation using the socioeconomic index, the mental raw score, and the age of the controls at study entry. The patients with seizures were then cross-classified into a five-by-two table according to expected IQ level and assigned treatment. The means of the IQs within the two treatment groups and across the five IQ levels were calculated. The overall average for each treatment group was computed according to the weighted method of Horvitz and Thompson.19 We estimated the variance for each group by pooling the estimates for each IQ level within a treatment.
The primary outcomes — the Stanford–Binet score at 2 years and at 2 1/2 years — were assessed three times during the study, for safety monitoring. We used the O'Brien—Fleming method20 to determine the level of significance in the final analysis, taking into account the interim analyses. The method of Barlow et al. was used for the test of trend.21 Because the clinical implications of the results of testing at 2-year and 2 1/2-year visits were different, we did not adjust for the presence of two primary outcome variables. All the reported P values are two-sided.
Results
Approximately 1000 children were screened for eligibility; 638 qualified, and the parents of 421 of these declined to have their child studied. The most common reason for refusal to participate was parental reluctance to have the child take phenobarbital. The age and number of previous seizures of the 217 eligible children whose families chose to participate (Table 1Table 1
Clinical Characteristics of 217 Subjects with Febrile Seizures.) were not different from those of the children who did not participate. Concurrently, 150 age-matched children without seizures were recruited as controls.The distribution of base-line factors not stratified or balanced in the randomization process, including the characteristics of the index seizure, the presence of abnormalities on initial neurologic examination or neurodevelopmental history, and a family history of nonfebrile seizures, did not differ between treatment groups. At base line, the average Bayley mental indexes were 103.6 for the placebo group, 104.8 for the phenobarbital group, and 113.8 for the control group. The corresponding motor indexes were 104.1, 105.7, and 109.0, respectively.
Compliance with Protocol
Eighty-five percent of the control subjects, 86 percent of those assigned to placebo, and 77 percent of those assigned to phenobarbital, completed the final visit. Most subjects who left the study did so early, approximately two thirds of them within the first year. Seventy percent of the families of children in the phenobarbital group and 64 percent of those with children in the placebo group remained blind to treatment assignment through the 2 1/2-year visit. The psychometrists were not informed of the assignments, even if the blinding was broken for families or medical staff. Unblinding took place for several reasons: a recurrent febrile seizure that was at least the third such seizure for that child (in 54 cases), a nonfebrile seizure (6 cases), parental request (1 case), and accidental ingestions (2 cases: one patient and one feline neighbor).
Of the 94 children randomly assigned to placebo who finished the study, 42 continued to receive placebo, 24 were given phenobarbital, 5 were given prescriptions for mephobarbital, carbamazepine, or both, and 23 were taking no medication by the two-year visit. Of the 83 children assigned to phenobarbital who finished the study, 53 continued to receive phenobarbital, 2 switched to placebo without the blinding being broken, 3 were taking other anticonvulsant agents, and 25 were taking no medication by the two-year visit. According to calculations based on life table methods, by the one-year visit the probability that a subject would continue to receive the assigned medication was 0.82 in the phenobarbital group and 0.65 in the placebo group; at two years, the comparable figures were 0.66 and 0.46. From the six-month visit on, more than two thirds of the blood levels tested in the phenobarbital group were above 645.9 μmol per liter (15 μg per milliliter). Few exceeded 1291.8 μmol per liter (30 μg per milliliter).
At six weeks, when compliance was still relatively high, 56 percent of the parents whose children were taking their medication in the phenobarbital group and 35 percent of the parents of children in the placebo group thought the children had had definite or possible side effects. By two years, when the number of children still receiving the study medication was smaller, the parents of 15 percent of the phenobarbital group and 11 percent of the placebo group reported side effects.
Intelligence Tests
The primary study end point for cognitive function was the Stanford–Binet intelligence quotient. A substantial number of IQ data were missing (Tables 2Table 2
Average Stanford–Binet IQ Scores at the Two-Year Visit, According to Expected IQ Level and Treatment Group. and 3Table 3
Average Stanford–Binet IQ Scores at the Final Visit, According to Expected IQ Level and Treatment Group.), primarily because of missed visits. In addition, certain IQ data were considered invalid because of severe retardation (two cases), problems with language (six cases), or failure to complete the test (one case).Effect of Treatment on Adjusted IQ at 2 and 2 1/2 Years
Failure to complete the study was not randomly distributed among the subjects. The higher the socioeconomic status, the less likely it was that the subjects would miss the two-year visit. In a result less striking but still significant, the higher the Bayley mental score at base line, the less likely a child was to miss the two-year visit. Thus, the children who did not report for examination at two years were those expected to perform less well on testing. In addition, there were more missed visits in the phenobarbital group than in the placebo group at the 2-year visit (23 percent vs. 14 percent) and the 2 1/2-year visit (23 percent vs. 13 percent). The method of Horvitz and Thompson19 was used to take into account the potential bias created by missing data. The children who had had febrile seizures were grouped in strata according to base-line variables that affected the likelihood of missing a visit and also affected the IQ scores. This method assumes that within each stratum of each treatment group, data were randomly missing.
On the two-year Stanford–Binet test, the children assigned to phenobarbital had an average IQ score 8.4 points lower than that of the children assigned to placebo (P = 0.0057; 95 percent confidence interval, − 13.3 to − 3.5) (Table 2). The difference in average IQ between the phenobarbital and placebo groups was − 12.1 IQ points in the group with the lowest expected IQ and − 1.4 points in the group with the highest expected IQ, but there was no consistent pattern of decreasing difference across strata with increasing expected IQ (P = 0.092 by the monotone trend test). For 77 children assigned to phenobarbital, IQ scores were available at the two-year visit; of these, 46 had an estimated phenobarbital load for the 12 months before the visit of at least 430.6 μmol per liter (10 μg per milliliter). Blood phenobarbital levels measured on the day of testing did not correlate with the IQ scores.
At the 2 1/2-year visit, the phenobarbital group had an average IQ score 5.2 points lower than that of the placebo group (P = 0.052; 95 percent confidence interval, − 10.5 to 0.04) (Table 3), suggesting an effect that persisted several months after phenobarbital was discontinued.
Within-Subject Changes after Withdrawal of Treatment
Between the 2-year and the 2 1/2-year visits, the average IQ scores rose significantly in the phenobarbital group (5.5 points) and the controls (4.0 points), but not in the placebo group (2.1 points; Table 4Table 4
Changes in Stanford–Binet IQ Scores from the 2-Year Visit to the Final Visit at 2 1/2 Years.). Because of the rise in IQ also seen in the controls, we cannot assume that the gain in IQ in the treated group represents a recovery from the effect of the drug.Early Effects of Treatment
No clinically or statistically significant difference between treatment groups in scores on the Bayley scales was seen six weeks after treatment began. At the one-year visit, the children were given either the Bayley scales or the Stanford–Binet test, depending on age and developmental level. For the 65 children in the placebo group and the 48 children in the phenobarbital group who took the Stanford–Binet test, we compared the effect of treatment by calculating the average of the means within each of the five IQ levels. A difference of 5.2 IQ points was observed in favor of the placebo group. No significance test of this difference is reported because of potential bias in the selection of the test of cognitive ability at the one-year visit.
Recurrence of Seizures
The evaluation of the time from the index seizure to the next seizure, if any, took into account the variable lengths of follow-up. By the two-year visit, even after adjustment for age at the time of the index seizure and the number of previous febrile seizures (Cox regression method18), the seizure-free interval differed little between the phenobarbital and placebo groups (P = 0.20). Forty-six percent of the placebo group and 38 percent of the phenobarbital group had had another seizure, febrile or nonfebrile, within two years of the index seizure (Fig. 1Figure 1
Probability of Remaining Free of Seizures, from the Time of the Index Seizure to the Time of the Final Visit, According to Assigned Treatment (Kaplan–Meier Plots).). During the subsequent six months, an additional 1 percent of the subjects in both groups had a first recurrence after enrollment. According to a conservative method of determination,22 , 23 the power, which was sufficient to detect a 20 percent difference in the rates of recurrence, was 0.84. By two years after the index seizure, 4 percent of the phenobarbital group and 7 percent of the placebo group had had a nonfebrile seizure, as determined by the Kaplan–Meier16 life-table method. In two children originally assigned to the placebo group but switched to phenobarbital because of recurrences of febrile seizures, nonfebrile seizures occurred when phenobarbital was withdrawn abruptly without the knowledge of the study physicians.Blood phenobarbital levels at the time of a recurrence of seizure were unavailable in most cases. However, according to the report of the parents, approximately a third of the children with recurrences who had been assigned to phenobarbital were not receiving medication at the time of the first recurrence.
Discussion
An earlier small clinical trial of phenobarbital prescribed for the treatment of febrile seizures hinted at possible deleterious effects, as measured by the Bayley scales after one year of treatment.6 Another study24 did not find a lower IQ in children with febrile seizures who were treated with daily phenobarbital; its subjects were selected for IQ testing at the end of a prescribed course of the drug. They were tested before the drug was discontinued and again approximately three months later, but there was no IQ testing before they began treatment with phenobarbital. In a double-blind crossover study of valproate and phenobarbital in 21 children with epilepsy, phenobarbital was well tolerated clinically but associated with decreased performance on complex psychometric tasks.8 Normal adult volunteers and persons with epilepsy who were treated with phenobarbital showed decrements in performance on tests of concentration25 and in tasks requiring short-term memory.26 Adverse effects of phenobarbital on developing neurons in tissue culture,9 in animal models,27 and with prenatal exposure28 have been reported. A depression in the local cerebral rate of glucose metabolism in humans given phenobarbital has been seen with positron emission tomography.29
This study demonstrated lower measured intelligence in children assigned to long-term phenobarbital therapy. The children actually received the assigned medication for varying lengths of time, although most of the children tested at two years had received it for at least a year. Some children assigned to phenobarbital changed to placebo or to no treatment, and some who had been assigned to placebo changed to phenobarbital. A significant difference in IQ was found despite the dilution effect created by crossovers and noncompliance; it is possible that the results would have been more dramatic than was observed had all children actually maintained their assigned medication throughout the entire two-year period.
The analysis of the primary end points reported here was based on the intention to treat. It is tempting to consider an analysis with the patients grouped according to the treatment they were actually receiving at the time of testing. The reasons for not taking this approach are strong, however: some of the characteristics of the subjects and their families that are associated with noncompliance also have implications for intelligence and perhaps for the likelihood of recurrence of seizures. The advantage of a randomized study design is that it optimizes the chance that characteristics, known or unknown, that may influence the outcome will be distributed with similar frequency in the two arms of the study before treatment is begun; an analysis based on groups defined according to whether they took the prescribed medication destroys such a balance. Definitive analysis must be based on treatment assignment rather than on compliance.30
The parents of the children assigned to receive phenobarbital tended to report more behavioral problems early in the study, but after six weeks of medication there was no difference between groups in the results of cognitive testing. After two years, there was no difference in the frequency of parental reports of behavioral problems.
Blood levels measured at the time of IQ testing were unrelated to IQ scores. Unfortunately, the study design did not permit confident conclusions about the relation of IQ to the duration of exposure to phenobarbital.
Phenobarbital has been commonly accepted as effective in decreasing the rate of recurrence in studies of children with a first febrile seizure.31 32 33 34 Newton35 has questioned the methods used in many of the studies reporting phenobarbital to be effective in such treatment; a reanalysis of pooled data from British studies, published and unpublished, revealed no benefit. We observed no statistically significant or clinically important decrease in the rate of recurrence of seizures with prescription of phenobarbital among our selected population of children with febrile seizures, who were at a higher risk of further seizures than an unselected group. This lack of effect was apparent despite the efforts of the study staff to encourage compliance. Since the selection of subjects was based on factors that would lead many clinicians to consider treating these children, the results are applicable to practical clinical situations in which the assessment of the risks and benefits of phenobarbital treatment is particularly necessary.
The available alternatives to phenobarbital for the treatment of febrile seizures are few. Although sodium valproate may be effective,36 , 37 it can have rare but potentially serious medical complications.38 Carbamazepine39 , 40 and phenytoin41 are apparently ineffective. Intermittent treatment with other agents, such as diazepam given orally or rectally, can be considered.42 New approaches need to be evaluated with regard to both side effects and benefits.
Phenobarbital is a widely used drug in pediatric neurology and is administered to pregnant women, neonates, and children for the treatment of seizure disorders and a variety of other indications.2 3 4 5 , 43 This study found a depression of cognitive performance associated with phenobarbital, with indications of a disadvantage that outlasted the administration of the drug by several months and did not demonstrate a countervailing benefit.
Supported by contracts (NO1-NS-2–2395 and NO1-NS-5–2376) from the National Institute of Neurological Disorders and Stroke.
We are indebted to Martha Erickson, Mary Voeller, R.N., Lee Adelman, R.N., Kay Frey, R.N., Jerrold Milstein, M.D., and Jerry Sells, M.D., of the University of Washington; to Mary Livingston, Gail Carter, Jack Panossian, and Sylvia Edelstein of the National Institute of Neurological Disorders and Stroke; and to the members of the institute's Performance and Safety Monitoring Committee: Dr. Bennett Bertenthal, Dr. Sanford Cohen, Dr. John Freeman, Dr. Sally Shaywitz, and Dr. Janet Wittes.
Source Information
From the University of Washington School of Medicine, Seattle (J.R.F., S.I.S.), and the National Institute of Neurological Disorders and Stroke, Bethesda, Md. (Y.J.L., D.G.H., J.H.E., K.B.N.). Address reprint requests to Dr. Hirtz at the Developmental Neurology Branch, National Institute of Neurological Disorders and Stroke, Federal Bldg. Rm. 8C-02, Bethesda, MD 20892.
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