Technical Report: Treatment of The Child With Simple Febrile Seizures

Technical Report: Treatment of the Child With Simple Febrile Seizures
Robert J. Baumann
Pediatrics 1999;103;e86
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AMERICAN ACADEMY OF PEDIATRICS

Robert J. Baumann, MD
ABSTRACT. Overview. Simple febrile seizures that
occur in children ages 6 months to 5 years are common
events with few adverse outcomes. Those who advocate
therapy for this disorder have been concerned that such
seizures lead to additional febrile seizures, to epilepsy,
and perhaps even to brain injury. Moreover, they note
the potential for such seizures to cause parental anxiety.
We examined the literature to determine whether there
was demonstrable benefit to the treatment of simple
febrile seizures and whether such benefits exceeded the
potential side effects and risks of therapy. The therapeutic approaches considered included continuous anticonvulsant therapies, intermittent therapy, or no anticonvulsant therapy.
Methods. This analysis focused on the neurologically
healthy child between 6 months and 5 years of age whose
seizure is brief (<15 minutes), generalized, and occurs
only once during a 24-hour period during a fever. Children whose seizures are attributable to a central nervous
system infection and those who have had a previous
afebrile seizure or central nervous system abnormality
were excluded. A review of the current literature was
conducted using articles obtained through searches in
MEDLINE and additional databases. Articles were obtained following defined criteria and data abstracted using a standardized literature review form. Abstracted
data were summarized into evidence tables (Tables 1
through 7).
Results. Epidemiologic studies demonstrate a high
risk of recurrent febrile seizures but a low, though increased, risk of epilepsy. Other adverse outcomes either
dont occur or occur so infrequently that their presence is
not convincingly demonstrated by the available studies.
Although daily anticonvulsant therapy with phenobarbital or valproic acid is effective in decreasing recurrent
febrile seizures, the risks and potential side effects of
these medications outweigh this benefit. No medication
has been shown to prevent the future onset of recurrent
afebrile seizures (epilepsy). The use of intermittent diazepam with fever after an initial febrile seizure is likely to
decrease the risk of another febrile seizure, but the rate of
side effects is high although most families find the perceived benefits to be low. Although antipyretic therapy
has other benefits, it does not prevent additional simple
febrile seizures.
Conclusions. The Febrile Seizures Subcommittee of
the American Academy of Pediatrics Committee on
Quality Improvement used the results of this analysis to
derive evidence-based recommendations for the treatment of simple febrile seizures. The outcomes anticipated as a result of the analysis and development of the
The recommendations in this statement do not indicate an exclusive course
of treatment or serve as a standard of medical care. Variations, taking into
account individual circumstances, may be appropriate.
PEDIATRICS (ISSN 0031 4005). Copyright 1999 by the American Academy of Pediatrics.
practice guideline include: 1) to optimize practitioner

understanding of the scientific basis for using or avoiding various proposed treatments for children with simple
febrile seizures; 2) to improve the health of children with
simple febrile seizures by avoiding therapies with high
potential for side effects and no demonstrated ability to
improve childrens eventual outcomes; 3) to reduce costs
by avoiding therapies that will not demonstrably improve childrens long-term outcomes; and 4) to help the
practitioner educate caregivers about the low risks associated with simple febrile seizures. Pediatrics 1999;103(6).
URL: http://www.pediatrics.org/cgi/content/full/103/6/e86;
febrile seizures, epilepsy, valproic acid, carbamazepine, phenytoin, diazepam, phenobarbital, sodium valproate, pyridoxine.
ABBREVIATION. NCPP, National Collaborative Perinatal Project.
he debate over whether children with recurrent febrile seizures benefit from anticonvulsant therapy began early in this century.1 An
important advance was the identification of the subgroup of children with simple febrile seizures; a subgroup that is large, remarkably homogeneous, and
healthy at 7- and 10-year follow-ups.2,3 Furthermore,
the recognition of such favorable outcomes has accentuated the need to balance the risk of any treatment with an expected benefit. Epidemiologic studies helped to identify this subgroup, demonstrated
their predominantly favorable outcomes, and confirmed what has long been known: febrile seizures
are common events. Of youngsters in a British birth
cohort, 2.7% had febrile seizures, 88% of whom had
simple febrile seizures.3,4
DEFINITION OF THE PROBLEM
This parameter is limited to children with simple

febrile seizures defined as neurologically healthy infants and children between 6 months and 5 years of
age whose seizure is brief (,15 minutes), generalized, and occurs only once during a 24-hour period
in a febrile child. This definition is easily applied in
the usual clinical circumstances and has the additional advantages of encompassing most children
with febrile seizures and defining a relatively homogeneous group of patients.4 This practice parameter
excludes children whose seizures are attributable to
a central nervous system infection (symptomatic febrile seizures) and those who have had a previous
afebrile seizure or central nervous system abnormality (secondary febrile seizures).
http://www.pediatrics.org/cgi/content/full/103/6/e86
PEDIATRICS Vol. 103 No. 6 June 1999
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BACKGROUND
Proponents of therapy for simple febrile seizures

have worried that repeated simple febrile seizures
will lead to more febrile seizures and possibly to
afebrile seizures (epilepsy). They also have been apprehensive that these seizures will cause brain injury
and thus diminish intelligence or impair motor coordination.5
A child who has experienced a single simple febrile seizure is likely to experience another. As epidemiologic data indicate, this recurrence rate is
strongly age-related. The younger the child at the
time of the first event, the more likely there will be
subsequent events. In the National Collaborative
Perinatal Project (NCPP), half the subjects with onset
of febrile seizures during the first year versus approximately 30% with onset after the first year had
one or more additional febrile seizures.2 This project
included 1706 prospectively studied children with febrile seizures from approximately 54 000 pregnancies.
The risk of experiencing a single afebrile seizure or
two or more afebrile seizures (defined as epilepsy) is
elevated when comparing children with simple febrile seizures with the general age-matched population.3,6,7 In the NCPP, the risk factors for epilepsy
after a febrile seizure were a positive family history
of afebrile seizures, preexisting neurologic abnormality, and a complicated initial febrile seizure. Interestingly, the age at first febrile seizure and the number
of febrile seizures did not alter this risk.6 At age 7
years, only 1.9% of children with simple febrile seizures and negative family histories of epilepsy had
experienced a single afebrile seizure, and epilepsy
had developed in 0.9%. The comparable figures for
study children who never experienced a febrile seizure were 0.9% for a single afebrile seizure and 0.5%
for epilepsy.2,6 Similar rates were seen in the large
British cohort study that included all surviving neonates born in the United Kingdom during 1 week in
April 1970. These children were followed until age 10
years, and 305 had an initial simple febrile seizure.
Of the 305 children, 8 (2.6%) subsequently had an
afebrile seizure and epilepsy eventually developed
in 5 (1.6%). The comparable number with epilepsy
among the 14 278 children who never had febrile
seizures was 53 (0.4%).3
Although the risk of epilepsy among children with
simple febrile seizures is elevated, the rate is still low,
and the number of children in any given study is
small. These numbers provide some understanding
of the difficulty of designing a population-based
study to determine if any treatment for the prevention of simple febrile seizures would subsequently
prevent the development of epilepsy.
Investigators have attempted to look at this issue.
At the Kaiser Foundation Hospitals in Southern California, Wolf and colleagues8,9 studied 400 children
who had febrile seizures (identified from lumbar
puncture reports). They divided the children into
three study groups: those who received phenobarbital daily, those who received phenobarbital only
with fever, and those who received no therapy. Follow-up lasted a mean of 6.3 years. No difference was
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found in the rate of afebrile seizures. This study

included children with complex as well as simple
febrile seizures, many children did not receive the
prescribed medication (approximately one third),
and the study was small and could have missed a
statistically valid effect.
In another study, 289 children with febrile seizures
were randomized to rectal diazepam prophylaxis at
the onset of any fever or rectal diazepam therapy
during any febrile seizure. At age 14 years, there was
no difference in intelligence, coordination, or occurrence of epilepsy between the two groups. The number of study patients was small, there are questions
regarding compliance, and patients with complex
and simple febrile seizures were included.10
Evidence for adverse outcomes other than epilepsy
has been sought. The NCPP had the benefit of longitudinal examination of a predefined group of children. No evidence of death in relation to asymptomatic febrile seizures was found, and examination of
the children revealed no evidence for the development of motor deficits.2 There also has been concern
about cognitive deficits in relation to febrile seizures.
The NCPP found no effect on intelligence among 431
children with febrile seizures who were compared
with their siblings.2 Comparisons of children with
simple febrile seizures with the general population
also have found no adverse effect.11,12 Smith and
Wallace13 believed that they found an adverse effect
of repeated febrile seizures on intelligence as measured by the Griffith Mental Development Scale. Because they studied children with simple and complex febrile seizures, it is possible that underlying
neurologic disease predisposed to further seizures
and to lower scores on retesting.
METHODS
Pertinent articles previously obtained by a MEDLINE search
and a search of the Epilepsy Foundation of America database4
were reviewed and supplemented by references suggested by
members of the Committee and the Committees consultants.
More than 300 articles were reviewed.
The goal of the review was to identify articles that met the
following criteria:
The study children had simple febrile seizures that were convincingly differentiated from afebrile seizures and other types
of febrile seizures.
The subjects with simple febrile seizures were reasonably representative of children with simple febrile seizures.4,5
A suitable control group was included in the study. Preference
was given to blinded protocols.
CONTINUOUS ANTICONVULSANT THERAPY

Phenobarbital
There are several studies in which phenobarbital

administered daily successfully prevented recurrent
febrile seizures. Camfield and associates14 randomized 79 children who had had a first simple febrile
seizure to receive phenobarbital at 5 mg/kg per day
in a single dose or a placebo. Compliance was monitored by use of the urine fluorescence of a riboflavin
additive and by measurements of serum phenobarbital levels. There was a significant difference in the
incidence of recurrent febrile seizures between the
phenobarbital recipients (2/39 [5%]) and the placebo
TECHNICAL REPORT: TREATMENT OF THE CHILD WITH SIMPLE FEBRILE SEIZURES

group (10/40 [25%]). Neither parents nor investigators knew which subjects received the active drug.14
Investigators found no significant difference in IQ
(using Stanford-Binet or Bayley Scales) between the
placebo and phenobarbital groups after 8 to 12
months of therapy. Nevertheless, phenobarbital was
demonstrated to decrease memory and concentration in proportion to higher serum phenobarbital
levels. Transient sleep disturbances and daytime
fussiness were more common among phenobarbital
recipients, but by 1 year, the two groups were indistinguishable. This was partially accounted for by 4
children receiving phenobarbital whose side effects
resolved after the dosage was reduced.
In a controlled trial comparing phenobarbital (5
mg/kg per day) with phenytoin (8 mg/kg per day)
and placebo, Bacon and associates15 also found phenobarbital to be effective. In younger children, the
febrile seizure recurrence rate was 9% (2/22) for
phenobarbital recipients versus 44% (12/27) placebo
recipients. This trial included subjects with complicated febrile seizures who were stratified proportionally into the three groups. The study had major problems with compliance. All phenobarbital-treated
children with a recurrence for whom drug levels
were obtained at the time of recurrence had a plasma
level ,15 mg/L. Interestingly the reported behavioral changes were similar in the subjects treated
with phenobarbital and a placebo.
Mamelle et al16 compared phenobarbital (3 to 4
mg/kg per day), valproate (30 to 40 mg/kg per day
in 2 doses), and placebo in a randomized single-blind
study of infants with a first simple febrile seizure.
They found significantly fewer recurrences in the
valproate (1/22 [4.5%]) and phenobarbital (4/21
[19%]) groups compared with the placebo group
(9/26 [35%]). Compliance was measured by serum
drug levels. Only 5 subjects were removed from
therapy because of side effects; all were described as
having agitation and all were receiving phenobarbital. Other studies, some with designs that were less
rigorous, also found phenobarbital to be effective,1720
including the previously mentioned Kaiser Foundation study.8
Not all studies have found phenobarbital to be
effective. Heckmatt et al21 found recurrent febrile
seizures in 14 (19%) of 73 control subjects, 10 (11%) of
88 children for whom phenobarbital was prescribed,
and 4 (8%) of 49 who actually took the prescribed
phenobarbital (4 to 5 mg/kg per day in divided
doses). These last 4 subjects had plasma phenobarbital levels .16 mg/L at the time of recurrence. Although the differences between the treatment groups
are not statistically important, they seem to suggest
that an effect favoring phenobarbital might have
been evident had the numbers been larger or the
duration of the study longer.
Children who had complicated febrile seizures analyzed by intention to treat experienced no difference
in recurrence rate between phenobarbital-treated
subjects and controls.22 The study described a poor
rate of compliance and seemed to show that a medication is not effective if parents are unable to administer it. Early in the study when compliance was
high, 56% of phenobarbital recipients (4 to 5 mg/kg

once per day) and 35% of placebo recipients were
reported to have side effects. The study found that
the mean IQ was 8.4 points lower in the phenobarbital group than in the placebo group (95% CI:
213.323.5, P 5 .0057) at the end of the 2-year study,
with an IQ differential that persisted 6 months after
the taper of medication had begun. The analysis of
these data was complicated by the low compliance
rates, the fact that 24 (26%) of 94 placebo recipients
and 53 (64%) of 83 phenobarbital recipients were
prescribed phenobarbital after the study ended, and
the inclusion of subjects with complicated febrile
seizures.22
Phenobarbital is associated with impairment of
short-term memory and concentration and worsening of behavior.2325 Most data on the effects of phenobarbital have been obtained from adults or from
children with epilepsy.23,24 The drugs effect seems
most prominent at the onset of therapy.23 The reported effect in children with simple febrile seizures
varies among studies. In the study by Camfield et
al,14 parents were only aware of side effects early in
the study, but higher serum levels were associated
with decreased memory concentration. Smith and
Wallace13 found no effect of therapy but believed that
repeated seizures in children with complicated febrile seizures were associated with lower mental development scores. Wolf and Forsythe26 reported hyperactivity in 46 (42%) of 109 children treated with
phenobarbital (initial dose, 3 to 4 mg/kg per day,
adjusted to give a serum level of 10 to 15 mg/mL) for
febrile seizures compared with 21 (17.5%) of 120 not
receiving phenobarbital. As in other studies, a substantial rate of improvement was noted in both
groups with time. When 25 children from each group
were extensively tested, no cognitive differences
could be detected.27
Valproic Acid
A number of studies have demonstrated the effectiveness of this agent in preventing recurrent febrile
seizures.18,19 The study by Mamelle et al16 typifies the
studies that found valproic acid to be more effective
than phenobarbital.28 Although no severe adverse
effects are described among the children participating in the febrile seizure trials, the numbers in these
trials are small. Valproic acid therapy is associated
with fatal hepatotoxicity,29,30 pancreatitis,31 renal toxicity,32 hematopoietic disturbances,33 and other problems.
Carbamazepine
Carbamazepine was not effective for febrile seizures in preliminary trials and, thus, has not been
studied widely.34,35 In a double-blind trial of carbamazepine (20 mg/kg per day in twice daily doses) vs
phenobarbital (4 to 5 mg/kg per day) involving children with complicated febrile seizures, Antony and
Hawke17 reported recurrent febrile seizures in 9
(47%) of 19 carbamazepine recipients and 2 (10%) of
21 phenobarbital recipients.
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Phenytoin
As with carbamazepine, preliminary studies

showed no evidence that phenytoin was effective for
febrile seizures, so it has not been studied extensively.36 In a randomized, controlled study of children
with simple and complex febrile seizures, the recurrence rate in the phenytoin group (8 mg/kg per day)
of younger children was 33% (9/27) compared with
9% (2/22) for the phenobarbital group (5 mg/kg per
day) and 44% (12/27) for the equivalent placebo
group.15
INTERMITTENT THERAPY
Antipyretic Agents
Because simple febrile seizures occur only in conjunction with a fever, it has seemed logical to try to
prevent these seizures by using aggressive antipyretic therapy. In the randomized, double-blind study
by Camfield and associates,14 all subjects received
detailed instruction about temperature control, including antipyretic use with any rectal temperature
higher than 37.2C (99F). Ten (25%) of 40 subjects
using only temperature control had recurrences compared with 2 (5%) of 39 receiving continuous phenobarbital. A randomized, controlled trial using a complicated study design with placebo, low-dose
diazepam, and acetaminophen also found no evidence that acetaminophen prevented recurrent febrile seizures.37 In this protocol, the diazepamtreated children who had previously experienced a
febrile seizure received a rectal diazepam solution (if
they weighed ,7 kg, they received 2.5 mg; if 7 to 15
kg, 5 mg; and if .15 kg, 10 mg) followed in 6 hours
by 0.2 mg/kg three times a day whenever they were
febrile. The antipyretic treatment group received 10
mg/kg of acetaminophen four times per day.
In children hospitalized after a simple febrile seizure, Schnaiderman et al38 found that acetaminophen
(15 to 20 mg/kg per dose) given every 4 hours did
not prevent a second febrile seizure during that admission any better than giving acetaminophen sporadically. The two groups also had the same frequency, duration, and height of temperature
elevations. There is no evidence that aggressive antipyretic therapy prevents recurrent febrile seizures.
Diazepam
The use of intermittent diazepam prophylaxis for

febrile seizures is well-reported in the literature.39
Autret and colleagues,40 in a randomized, controlled
multicenter study, found that oral diazepam (0.5
mg/kg initially, then 0.2 mg/kg every 12 hours) was
no more effective than a placebo in preventing recurrent febrile seizures. Most of the children had simple
febrile seizures, and the data were analyzed by intention to treat. Recurrence was experienced by 15
(16%) of 93 children in the diazepam group compared with 18 (20%) of 92 children in the placebo
group. Although parents were instructed verbally,
in writing, and by demonstration, there were major
problems with compliance. In children with recurrences, only 1 (7%) of/15 diazepam recipients and 7
(39%) of 18 placebo recipients received the medica4 of 57
tion or placebo as prescribed. The difference between

these two groups is significant. The reasons that the
subjects did not receive their assigned treatment included the following: 1) 7 in each group had a seizure as the first sign of illness, 2) 5 parents in the
diazepam group and 4 in the placebo group did not
give the medication, and 3) 2 children in the diazepam group would not take their medication. Because
14 (93%) of the 15 children for whom diazepam was
prescribed who had a recurrence had not received
their prescribed medication, these data demonstrate
that a treatment is not effective if parents cannot or
will not administer it before the febrile seizure occurs. The only noted side effect was hyperactivity,
which was significantly more frequent in the diazepam group (138 vs 34 days).
By contrast, in a similarly well-designed, randomized, double-blind, placebo-controlled trial, Rosman
et al41 found oral diazepam to be significantly more
effective than placebo when analyzed by intention to
treat. A 44% reduction in the risk of febrile seizures
per person-year occurred with diazepam. Children
in the diazepam group had 675 febrile episodes and
41 febrile seizures, of which 7 occurred while receiving the study medication. Comparable figures for the
placebo group were 526 febrile episodes and 72 febrile seizures, of which 38 occurred while receiving
the placebo. These investigators describe febrile seizures as highly upsetting to the parent population,
which may have influenced adherence. Not surprisingly, they found that a higher rate of side effects
accompanied their subjects better compliance. Of
the diazepam recipients, 59 (39%) had at least one
moderate side effect and a similar number had a
mild side effect.
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REFERENCESTREATMENT TABLES
Phenobarbital
Antony JH, Hawke S. Phenobarbital compared with carbamazepine in
892 895
Bacon CJ, Hierons AM, Mucklow JC, Webb JKG, Rawlins MD, Weightman
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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AMERICAN ACADEMY OF PEDIATRICS

practice guideline include: 1) to optimize practitioner

This parameter is limited to children with simple

Proponents of therapy for simple febrile seizures

found in the rate of afebrile seizures. This study

CONTINUOUS ANTICONVULSANT THERAPY

There are several studies in which phenobarbital