Review Article

Treatment of Children With Simple Febrile Seizures: The AAP Practice Parameter
Robert J. Baumann, MD* and Patricia K. Duffner, MD
Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children. Despite their frequency, there has been little unanimity of opinion regarding the need for long-term antiepileptic therapy. As such, the American Academy of Pediatrics formulated a subcommittee to study the subject. A Practice Parameter was developed that addressed the issue of whether continuous or intermittent antiepileptic therapy is necessary for children with simple febrile seizures. The committee determined that with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. The risk of developing epilepsy is extremely low and, even in those patients who do, there is no evidence that recurrent simple febrile seizures produce structural central nervous system damage. Also, there is no evidence that recurrent simple febrile seizures cause either learning problems or premature death. The committee concluded that although there is the evidence that continuous antiepileptic therapy with phenobarbital or valproic acid and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the potential toxicities associated with antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. As such, longterm treatment is not recommended. 2000 by Elsevier Science Inc. All rights reserved. Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: The AAP practice parameter. Pediatr Neurol 2000;23:11-17. frequency, there has been little unanimity of opinion regarding the appropriate approach to either the neurodiagnostic evaluation or the potential long-term treatment of these children [2]. In 1980 the National Institutes of Health Consensus Statement, based in large part on work by Nelson and the National Collaborative Perinatal Project, concluded that febrile seizures are benign events and, in general, treatment is not recommended [3]. For those children at higher risk of epilepsy (i.e., those with abnormal neurologic development, complex febrile seizures, or a family history of afebrile seizures), treatment with phenobarbital might be considered. It also may be considered for those children whose first febrile seizure was before 12 months of age and who had multiple febrile seizures. Despite these recommendations, controversy has persisted regarding the appropriate approach for these children. As a result, the American Academy of Pediatrics (AAP) and its Committee on Quality Improvement, in collaboration with experts from the Section on Neurology, general pediatricians, consultants in the fields of child neurology and epilepsy, and research methodologists, developed practice parameters to address these issues. The first practice parameter, The Neurodiagnostic Evaluation of the Child With a Simple Febrile Seizure, was published in 1996 [4]. The second, The Long-Term Treatment of the Child With Simple Febrile Seizures, was published in 1999 [5]. The purpose of the present report is to expand on the rationale for the AAP recommendations for the long-term treatment of children with simple febrile seizures. Tables 1-4 provide details of some of the studies on which these recommendations were based and are modified from those prepared for the American Academy of Pediatrics.

Introduction Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children [1]. Despite their

Patient Population Both the first and second Practice Parameters provide recommendations solely for children who are neurologi-

From the *Departments of Neurology and Pediatrics; University of Kentucky; and Department of Neurology; Kentucky Clinic; Lexington, Kentucky; and Departments of Neurology and Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.

Communications should be addressed to: Dr. Duffner; Department of Neurology; Childrens Hospital of Buffalo; 219 Bryant Street; Buffalo, NY 14222. Received November 12, 1999; accepted February 28, 2000.

2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00148-X 0887-8994/00/$20.00

Baumann and Duffner: Treatment of Simple Febrile Seizures 11

Table 1.

Phenobarbital trials Design RC, SB 1. 2. Phenytoin 3. Placebo RC, DB 1. , antipyretics 2. Placebo, antipyretics Comparison 1. Cont. 2. No Rx Cohort study given 1. Within 30 days of SZ 2. 1 mo to 2 yr after SZ 3. No Rx RC, NB 1. Cont, 2. Int. 3. No Rx Children (n) SFS 48 47 43 First SFS 39 40 First SFS 49 73 First SFS 62 98 97 106 140 109 FS (SFS or CFS not specified) SZ type CFS Outcome Sig. 2 rec. in children 14 mo at first SZ Phenytoin ineffective more effective than antipyretics not sig. better than placebo Early (Gp 1) Sig. 2 risk Rec. Comments and phenytoin levels therapeutic in 45% and 44% of younger subjects

Investigators Bacon et al. [20], 1981

Camfield et al. [10], 1980

Compliance assessed

Heckmatt et al. [13], 1976

Rec. at 6-mo follow-up: 19% no Rx vs 8% cont. Compliance not monitored; often given int.

Van den Berg and Yerushalmy [32], 1971

Wolf et al. [11], 1977

No difference Int. vs no ; Sig. 2 rec. with cont.

Abbreviations: CFS Complex febrile seizure Cont. Continuous DB Double-blind FS Febrile seizure GP Group Int. Intermittent NB No blinding Phenobarbital

RC Rec. Rx SB SFS Sig. Spec. SZ

Randomized controlled Recurrence Therapy Single blind Simple febrile seizure Significantly Specified Seizure

cally healthy, between 6 months and 5 years of age, and who have had one or more simple febrile seizures. A simple febrile seizure was defined as a brief (less than 15 minutes) generalized seizure that occurred only once in a 24-hour period in a febrile child who did not have either central nervous system infection or a severe metabolic disturbance. The Practice Parameters were not intended for patients who have had complex febrile seizures (prolonged [i.e., greater than 15 minutes], focal, or recurrent within a 24-hour period, or any combination), nor do they pertain to those children with previous neurologic insults, known central nervous system abnormalities, or a history of afebrile seizures. Theoretical Risks of Simple Febrile Seizures The decision of whether to treat children with simple febrile seizures is determined by an assessment of the potential risks associated with having one or more simple febrile seizures. Of most concern is the risk of developing epilepsy. Nelson and Ellenberg [6] reported that neurologically normal children with simple febrile seizures and no family history of epilepsy had a 0.9% chance of developing epilepsy by 7 years of age. When Annegers et al. [7] extended the risk analysis up to 25 years of age, those children with multiple simple febrile seizures and a family history of epilepsy had a 2.4% risk of developing a

generalized seizure disorder, twice the incidence of the general population. However, no data are available to suggest that this small increase in the risk of epilepsy can be reduced by prophylactic antiepileptic treatment of children with simple febrile seizures. The higher incidence of epilepsy is likely the result of genetic predisposition, rather than structural damage caused by recurrent simple febrile seizures. Another theoretical risk of recurrent simple febrile seizures is an adverse effect on intelligence. In two large studies from the United States and Britain, no relationship was identified between the presence of recurrent febrile seizures and learning. Ellenberg and Nelson [8] studied 431 children who experienced febrile seizures and observed no significant difference in their intellectual abilities. In a similar British study by Verity et al. [9], 303 children with febrile seizures were compared with control children. No difference in learning was identified, except in those children who were neurologically abnormal before their first febrile seizure. A third theoretical risk of simple febrile seizures is death caused by aspiration, but to our knowledge, no deaths associated with simple febrile seizures have been reported. The only remaining risk of simple febrile seizures is recurrence. The overall risk of a first recurrence is 30%; it is 50% for two or more recurrences and is also

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Table 2.

Valproic acid trials Design RC, NB 1. Cont. 2. VPA RC, SB 1 Cont. 2. Cont. VPA 3. Placebo Comparison 1. VPA 2. Comparison 1. VPA 2. 3. No Rx RC, NB 1. VPA 2. No Rx Children (n) SZ Type SFS and CFS 33 32 First generalized FS 24 24 25 First SFS 18 21 First FS 48 46 27 Second SFS 30 28 Outcome did not 2 rec. VPA sig 2 rec. Recurrence 1. 19% 2. 4% 3. 35% VPA Both better than placebo Both VPA and sig. better than no Rx (if levels therapeutic) VPA not effective Comments 24% discontinued because of side effects; all tolerated VPA Sig. difference between VPA vs placebo but not between and placebo or VPA and

Investigators Lee and Melchior [16], 1981 Mamelle et al. [17], 1984

Ngwane and Bower [18], 1980 Wallace and Smith [19], 1980

Williams et al. [31], 1979

Two of 21 subtherapeutic

Abbreviations: CFS Complex febrile seizure Cont. Continuous DB Double-blind 2 Decreased FS Febrile seizure NB No blinding Phenobarbital RC Randomized controlled

Rec. Rx SB SFS Sig. SZ VPA

Recurrence Therapy Single blind Simple febrile seizure Significant Seizure Valproic acid

50% for those children younger than 12 months of age at the time of their first febrile seizure [1] In summary, with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. Prevention of Recurrent Febrile Seizures With Continuous Antiepileptic Therapy In most studies, phenobarbital has been proved to be effective in preventing recurrent febrile seizures. Camfield et al. [10] randomized 79 children who had experienced a first simple febrile seizure to either phenobarbital or placebo and monitored compliance. They reported a significant benefit to phenobarbital because 5% of the treated children had a recurrence compared with 25% in the placebo group. For the drug to be effective, however, it must be given daily and blood levels must be within the therapeutic range. Wolf et al. [11] randomized children with a history of febrile seizures to either continuous, intermittent, or no phenobarbital. Although no significant difference in recurrence was evident between those children receiving either intermittent or no phenobarbital, those children who received phenobarbital on a daily basis had a significant reduction in seizures. Studies in which continuous phenobarbital has not been effective generally have reflected noncompliance. For example, in the study of Farwell et al. [12], children whose phenobarbital levels were therapeutic had a reduction in seizures, but because

noncompliance was high, an overall benefit to phenobarbital was not identified. In contrast to most studies, Heckmatt et al. [13] did not observe a significant advantage to phenobarbital even in those children with therapeutic levels (although the dropout rate in the phenobarbital arm was high). Recurrences occurred in 19% of the control children, in 11% of those for whom phenobarbital was prescribed, and in 8% of those who completed treatment. Whether larger numbers might have identified a significant benefit to phenobarbital is unclear. Carbamazepine has not been demonstrated to be effective in preventing febrile seizure recurrence. Antony and Hawke [14] compared children who had been treated with therapeutic levels of either carbamazepine or phenobarbital. Forty-seven percent of the carbamazepine group had recurrence compared with only 10% of the phenobarbital group. Similar results were reported by Camfield et al. [15] who prescribed carbamazepine for those children with febrile seizures who had either been unable to tolerate phenobarbital or in whom phenobarbital had not been effective. Despite good compliance, 13 of 16 children had a recurrent febrile seizure within 18 months of beginning carbamazepine therapy [15]. Several studies have compared valproic acid with phenobarbital in the prevention of recurrent febrile seizures. Lee and Melchior [16] evaluated three groups of children: those treated with phenobarbital; those treated with valproic acid; and those who received no therapy. Valproic acid provided significantly better control than no therapy.

Baumann and Duffner: Treatment of Simple Febrile Seizures 13

Table 3.

Diazepam trials Design RC prospective 1. Int. diazepam 2. Placebo RC 1. Int. diazepam 2. Continuous Comparison, NB 1. Int. diazepam 2. VPA RC, DB 1. Int. diazepam 2. Int. placebo RC, DB 1. Int. diazepam* 2. Placebo Children (n) SZ Type SFS and CFS 93 92 SFS and CFS 99 96 44 50 202 204 81 80 First FS 70-73% SFS Complicated seizures FS Rec. rate same in both groups VPA rec. Diazepam in 2 15-16% had rec. (poor comp. with diazepam) No randomization No comp. checks for diazepam SFS vs CFS not specified 50 diazepam and 55 placebo patients withdrawn Low doses of acetaminophen or diazepam, or both, ineffective Outcome Diazepam ineffective Comments Poor comp. with diazepam

Investigators Autret et al. [25], 1990 Knudsen and Vestermark [27], 1978 Lee [33], 1986

Rosman et al. [23], 1993 Uhari et al [26], 1995

Int. by mouth Diazepam 2 rec. Diazepam acetaminophen ineffective

* Subjects also received antipyretics, alternating acetaminophen or placebo every other febrile episode (four groups of subjects). Abbreviations: CFS Complex febrile seizure Comp. Compliance DB Double-blind 2 Decreased FS Febrile seizure Int. Intermittent NB No blinding

RC Rec. SZ SFS VPA

Phenobarbital Randomized controlled Recurrence Seizure Simple febrile seizure Valproic acid

Of interest, significant differences were not identified in seizure prevention between those patients treated with phenobarbital and the control children [16]. Mamele et al. [17] randomized children with a previous febrile seizure to valproic acid, phenobarbital, or placebo. They found a statistically significant difference among the three groups, with recurrence rates of 4%, 19%, and 35%, respectively. Significant differences (P 0.05) were evident between the treated children (valproic acid and phenobarbital) and placebo and between children treated with valproic acid and those treated with placebo (P 0.01) [17]. A similar study was performed by Ngwane and Bower [18] in which a randomized double-blind trial was performed on children between 6 and 18 months of age who had experienced a previous simple febrile seizure. Children were randomized to valproic acid, phenobarbital, or placebo. Treatment with valproic acid and phenobarbital provided significantly better results than placebo, and valproic acid was as effective as phenobarbital in that study [18]. Wallace and Smith [19] also determined that both phenobarbital and valproic acid were equally effective, and both were significantly better than placebo in preventing recurrence of febrile seizures. As might be anticipated, those children who had less than optimal blood levels did not fare as well because seizures occurred with fever during eight of 58 6-month periods with phenobarbital and during six of 35 periods in those taking valproic acid. The data on the use of phenytoin in febrile seizures are limited. In a study by Bacon et al. [20] the efficacy of phenobarbital, phenytoin, and placebo were compared in

children with febrile seizures. Phenytoin did not offer an advantage over placebo in 33% of younger subjects or in 35% of older subjects. In their study, phenobarbital significantly reduced the recurrence of febrile seizures in children younger than 14 months of age but was not effective in children beyond that age [20]. The lack of efficacy of phenytoin in preventing febrile seizures in children younger than 3 years was also reported by Melchior et al. [21] in a study in which blood levels were monitored. In summary, most studies demonstrate that when either phenobarbital or valproic acid are administered continuously and maintained in the usual therapeutic range, febrile seizure recurrence can be prevented in up to 90% of patients. In actual usage the high rate of noncompliance leads to more frequent failures. In contrast, carbamazepine and phenytoin are ineffective even when the agents are in the usual therapeutic range. Intermittent Therapy Antipyretic Agents Antipyretic agents are routinely given to ill children who have a history of febrile seizures to reduce the fever and hence (theoretically) reduce the likelihood of recurrence. Camfield et al. [10] reported, however, that although treatment with acetaminophen and phenobarbital was effective in preventing recurrent febrile seizures, acetaminophen and placebo were not. It is even unclear

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Table 4.

Side Effects Study Comparison 1. CBZ 2. RC, DB 1. 2. Placebo RC, DB 1. 2. Control (no SZ) Comparison, DB 1. 2. VPA Comparison, matched pairs 1. 2. No Rx RC 1. cont. 2. int. 3. No Rx Children (n) Side Effects 42% side effects (23% discontinued ) CBZ 30% risk effects (17% stopped CBZ) 23% transient, 11% doserelated, 8.6% unacceptable Placebo 23% side effects ? neg. effect on cognition; at 2 yr mean IQ 8.4 less than placebo; 15% side effects; placebo 11% side effects 2 performance with VPA superior to No sig. difference in psychometric results vs no Rx 42% taking cont had behavioral problems, especially hyperactivity Sig. 1 hyperactivity vs no Comments CBZ less effective than

Investigators Antony and Hawke [14], 1983

19 21

Camfield et al. [28], 1979 Farwell et al. [12], 1990

35 30 217 ( or placebo) 150

Vining et al. [29], 1987 Wolf and Forsythe [34], 1981 Wolf and Forsythe [30], 1978

No difference in IQ after 8-12 mo 2 comprehension No sig. difference in rec. rate levels at rec. mostly unavailable 13 noncompliant at time of rec. More behavior problems with

21

25 25 109 142 120

No Rx 18% behavior problems

Abbreviations: CBZ carbamazepine Cont. Continuous DB Double-blind 2 Decreased 1 Increased Int. Intermittent IQ Intelligence quotient Neg. Negative

RC Rec. Rx Sig. SZ VPA

Phenobarbital Randomized controlled Recurrence Therapy Significant Seizure Valproic acid

whether administration of acetaminophen on a routine basis at the time of a febrile illness is effective in reducing fever episodes. Schnaiderman et al. [22] reported that administration of acetaminophen every 4 hours was no more effective in either reducing the number of febrile episodes or in reducing the mean duration of the fever than sporadic dosing of acetaminophen when the body temperature was greater than 37.9C. Therefore although acetaminophen may make the child more comfortable, it will not prevent recurrent febrile seizures. Diazepam Rosman et al. [23] compared the use of oral diazepam with placebo in children who had a history of febrile seizures. Patients were treated during febrile illnesses with 0.33 mg/kg of diazepam given orally every 8 hours for 48 hours. The intention-to-treat analysis revealed a reduction of 44% in the risk of febrile seizures per person per year with diazepam. The cumulative incidence of first recurrences of febrile seizures in the placebo group was 32%; the incidence of seizures in the diazepam-treated group was 21% overall. Thus, in their study, treatment with diazepam was effective in preventing recurrent febrile seizures. The efficacy of intermittent diazepam had previ-

ously been suggested [24]. Continuous valproic acid was compared with intermittent diazepam given only during febrile illnesses. No significant differences were identified between the recurrence rates in the two treatment groups. In contrast to these studies, Autret et al. [25] compared intermittent diazepam with placebo and observed no efficacy for the children treated with diazepam. Recurrent seizures occurred in 16% of the diazepam group and in 19.5% of the placebo group. The dose of diazepam used in the study of Autret et al., however, was only 0.2 mg/kg. Perhaps more importantly, prophylactic treatment was given correctly to only one of 15 in the diazepam-treated group and seven of the 18 of the placebo group, suggesting it may have been a failure of the method rather than a failure of the agent. Uhari et al. [26] conducted a placebocontrolled double-blind trial of diazepam 0.2 mg/kg and placebo, acetaminophen and placebo, diazepam and acetaminophen, and two kinds of placebo. The combination of acetaminophen and low-dose diazepam did not reduce the incidence of recurrence [26]. In summary, intermittent therapy with diazepam, if given in sufficient doses, is likely to be effective in preventing febrile seizure recurrence. Acetaminophen is ineffective as a preventative agent.

Baumann and Duffner: Treatment of Simple Febrile Seizures 15

Risks of Antiepileptic Therapy If one concludes that continuous treatment with either phenobarbital or valproic acid and intermittent treatment with diazepam are effective in preventing the recurrence of simple febrile seizures, an analysis of the risk factors associated with these drugs must also be performed. Phenobarbital is the most commonly used antiepileptic drug in the prevention of recurrent febrile seizures, but its side effects can be substantial. These adverse effects include hyperactivity, irritability, and idiosyncratic reactions. Antony and Hawke [14] observed that nine of their subjects (43%) who received phenobarbital as prophylaxis had side effects and five (24%) had problems severe enough to discontinue the agent. Knudsen and Vestermark [27] also observed side effects in 45% of their phenobarbital-treated group. Side effects included hyperkinesia, irritability, and listlessness; also, side effects were so severe at times that some of the patients discontinued the study [27]. Lee and Melchior [16] evaluated children treated with phenobarbital and observed that 21% of families discontinued the drug because of side effects that included hyperactivity and sleep disturbances. Camfield et al. [28] performed a study comparing the side effects of phenobarbital and placebo. Transient side effects occurred in 23% of the children taking a placebo. Unacceptable side effects in the phenobarbital group were primarily related to sleep disturbances and irritability [28]. Of more concern was a study by Farwell et al. [12], in which they determined that phenobarbital might have a lasting negative effect on cognitive performance. At 2 years of age the mean intelligence quotient (IQ) of the phenobarbital-treated children was 8.4 points lower than in the placebo group. Moreover, the changes persisted after the medication was discontinued, such that the mean IQ was 4 points lower in the phenobarbital-assigned group. Vining et al. [29] also evaluated the effects of phenobarbital on neuropsychologic function. They observed significant differences when children treated with phenobarbital were compared with those treated with valproic acid. Patients who received valproic acid had superior results on block design, performance, full scale IQ (according to the Wechsler Intelligence Scale for Children, Revised), and on paired/association learning tasks compared with those taking phenobarbital. Moreover, the patients taking phenobarbital also scored significantly higher on a hyperactivity index score [29]. In contrast, Wolf and Forsythe [30] compared psychometric tests of children receiving phenobarbital with those receiving no therapy. The initial testing and the 3-month follow-up revealed no significant differences on any of the measures between the two groups [30]. The evidence, therefore, suggesting that phenobarbital has a permanent adverse effect on intelligence (even after the agent is discontinued) is not strong, but reduced performance while taking therapy has been identified in several studies. Good data are also available to suggest that from 20% to 40% of phenobarbital-treated children develop

significant behavioral side effects, particularly hyperactivity, irritability, and sleep disorders, and a smaller percentage may develop idiosyncratic reactions in the form of rash, including Stevens-Johnson syndrome. Valproic acid is not generally recommended for children in the first 2-3 years after birth (without a major indication) because of the potential for life-threatening hepatotoxicity. Additional complications associated with valproic acid include thrombocytopenia (particularly in the face of viral infections), pancreatitis, and weight disturbances. In those studies in which valproic acid was given to children with febrile seizures, toxicity was limited to alterations in appetite, vomiting, and increases in daytime activity [16,31]. No cases of hepatic failure were identified. The intermittent use of diazepam has also been associated with side effects. In the study of Rosman et al. [23], 25-30% of children developed ataxia, lethargy, and irritability, and approximately one in 20 children had moderate side effects, including speech abnormalities, depressed or heightened activity level, or sleep disorders. Only three of the 135 children in that study had side effects of such significance to require discontinuation of the agent. An additional concern raised by the committee who developed the Practice Parameter was that diazepam given at the time of fever could mask a serious underlying infection because the family might attribute the lethargy to the diazepam and not bring the child in for pediatric evaluation. Conclusions The committee determined that the major risk of simple febrile seizures is recurrence. The risk of developing epilepsy is extremely low and, even in these cases, no evidence is available that recurrent simple febrile seizures produce structural central nervous system damage. In addition, no evidence that recurrent simple febrile seizures cause either learning problems or premature death has been identified. Although data are convincing that continuous antiepileptic therapy with phenobarbital or valproic acid and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the Committee determined that the potential toxicities associated with antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. Recommendation On the basis of the risks and benefits of the effective therapies, neither continuous nor intermittent antiepileptic therapy is recommended for children with one or more simple febrile seizures. The AAP recognizes that recurrent episodes of febrile seizures can create anxiety in some parents and their children. As such, appropriate education and emotional support should be provided. In those situations in which parental anxiety associated with febrile seizures is severe, intermittent oral diazepam at the onset

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of febrile illness may be effective in preventing recurrence. Evidence is not convincing, however, that any therapy will alleviate the possibility of future epilepsy. Although antipyretic agents may improve the comfort of the child, they will not prevent febrile seizures.
The AAP Subcommittee that formulated the Practice Parameter included Patricia K. Duffner, MD (Chair), Robert Baumann, MD (methodologist), Peter Berman, MD (child neurologist), John Green, MD (pediatrician), and Sanford Schneider, MD (child neurologist). Our AAP liaison was Ms. Carla Herrerias, without whose help this Parameter would not have been possible. We also thank the AAP Committee on Quality Improvement and the Board of Directors for their valuable input. Finally, we would like to acknowledge the superb secretarial skills of Ms. Marilyn Thomasula.

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[15] Camfield PR, Camfield CS, Tibbles JA. Carbamazepine does not prevent febrile seizures in phenobarbital failures. Neurology 1982; 32:288-9. [16] Lee K, Melchior JC. Sodium valproate versus phenobarbital in the prophylactic treatment of febrile convulsions in childhood. Eur J Pediatr 1981;137:151-3. [17] Mamelle N, Mamelle JC, Plasse JC, Revol M, Gilly R. Prevention of recurrent febrile convulsions: A randomized therapeutic assay: Sodium valproate, phenobarbitone and placebo. Neuropediatrics 1984;15:37-42. [18] Ngwane E, Bower B. Continuous sodium valproate or phenobarbitone in the prevention of simple febrile convulsions. Arch Dis Child 1980;55:171-4. [19] Wallace SJ, Smith JA. Successful prophylaxis against febrile convulsions with valproic acid or phenobarbitone. BMJ 1980;280:353-4. [20] Bacon CJ, Hierons AM, Mucklow JC, Webb JK, Rawlins MD, Weightman D. Placebo-controlled study of phenobarbitone and phenytoin in the prophylaxis of febrile convulsions. Lancet 1981;2:600-4. [21] Melchior JC, Buchthal F, Lennox-Buchthal M. The ineffectiveness of diphenylhydantoin in preventing febrile convulsions in the age of greatest risk, under three years. Epilepsia 1971;12:55-62. [22] Schnaiderman D, Lahat E, Sheefer, T, Aladjem M. Antipyretic effectiveness of acetaminophen in febrile seizures: Ongoing prophylaxis versus sporadic usage. Eur J Pediatr 1993;152:747-9. [23] Rosman NP, Colton T, Labazzo J. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-84. [24] Lee K, Taudorf K, Hvorslev V. Prophylactic treatment with valproic acid or diazepam in children with febrile convulsions. Acta Pediatr Scand 1986;75:593-7. [25] Autret E, Billard C, Bertrand P, Motte J, Pouplard F, Jonville AP. Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. J Pediatr 1990;117:490-4. [26] Uhari M, Rantala H, Vainionpaa L, Kurttila R. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. J Pediatr 1995;126:991-5. [27] Knudsen FU, Vestermark S. Prophylactic diazepam or phenobarbitone in febrile convulsions: A prospective, controlled study. Arch Dis Child 1978;53:660-3. [28] Camfield CS, Chaplin S, Doyle AB, Shapiro SH, Cummings C, Camfield PR. Side effects of phenobarbital in toddlers: Behavioral and cognitive aspects. J Pediatr 1979;95:361-5. [29] Vining EPG, Mellits ED, Dorsen MM. Psychologic and behavioral effects of antiepileptic drugs in children: A double-blind comparison between phenobarbital and valproic acid. Pediatrics 987;80:165-74. [30] Wolf SM, Forsythe A. Behavior disturbance, phenobarbital and febrile seizures. Pediatrics 1978;61:728-31. [31] Williams AJ, Evans-Jones LG, Kindley AD, Groom PJ. Sodium valproate in the prophylaxis of simple febrile convulsions. Clin Pediatr 1979;18:426-30. [32] van den Berg BJ, Yerushalmy J. Studies on convulsive disorders in young children. II. Intermittent phenobarbital prophylaxis and recurrence of febrile convulsions. J Pediatr 1971;78:1004-12. [33] Lee K. Prophylactic treatment with valproic acid or diazepam in children with febrile convulsions. Acta Paediatr Scand 1986;75:593-7. [34] Wolf SM, Forsythe A, Studen AA, Friedman R, Diamond H. Long-term effect of phenobarbital on cognitive function in children with febrile convulsions. Pediatrics 1981;68:820-3.

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