Long-Term Effect of Phenobarbital on Cognitive Function in Children with Febrile

Convulsions
Sheldon M. Wolf, Alan Forsythe, Alastair A. Stunden, Robert Friedman and Harriet
Diamond
Pediatrics 1981;68;820-823

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 Long-Term Effect of Phenobarbital on
Cognitive Function in Children with Febrile
Convulsions

Sheldon M. Wolf, MD, Alan Forsythe, PhD, Alastair A. Stunden, PhD,

Robert Friedman, PhD, and Harriet Diamond, PhD

From the Departments of Neurology and Psychiatry, Kaiser Foundation Hospital;

Department of Biomathematics, University of California at Los Angeles; Glendale
Guidance Clinic; and North Los Angeles Regional Center, Los Angeles

ABSTRACT. Psychometric tests were performed on 50 reported previously.4 Children receiving phenobar-
children with a history of febrile convulsions. Twenty- bital began with a daily dose of 3-4 mg/kg. This
five of these had received daily phenobarbital for a mean
dosage was adjusted to attempt to maintain a
of 35 months; 25 had received no phenobarbital. The two
groups were matched for sex, age at the time of testing,
phenobarbital level of 10 to 15 jig/mi. In the chil-
race, and socioeconomic status. The tests used were the then receiving phenobarbital, the initial psycholog-
Wechsler Preschool and Primary Scale of Intelligence ical testing was done just prior to the planned
(WPPSI), the Matching Familiar Figures Test, and the termination of drug treatment. Parents were then
Children’s Embedded Figures Test. There were no signif-
instructed to taper the drug gradually over a period
icant differences in test results between the two groups.
Pediatrics 68:820-823, 1981; phenobarbital, cognitive of one to two months. The interval between the
I unction, convulsions. initial testing and retesting ranged from 1 1 to 19
weeks. The modal period between test administra-
tions was 12 weeks (46 subjects) with the mean
period being 13 weeks. Four children in the drug-
Daily phenobarbital therapy is effective in pre- treated group had only one set of psychological
venting recurrent febrile convulsions. 1-5 However, tests; these were given while the children were
adverse effects of phenobarbital on behavior, mem- receiving barbiturate therapy. Phenobarbital ther-
ory, attention, and performance on psychometric apy had not completely stopped in two children at
tests have been reported.’2 A major concern is the time of the second test. There were 26 girls and
whether phenobarbital given for several years to 24 boys; 32 children were white, eight were black,
prevent recurrent febrile convulsions may affect the and ten fell into other categories. The mean age at
intellectual development of children. the time of the initial testing was 57.5 months for
In this study of children with febrile convulsions, phenobarbital-treated children (SD 8.1 months,
we compared the performance, in several psycho- range 45 to 71 months) and 59.6 months for children
logical tests, of children who had received daily not receiving phenobarbital (SD 7.8 months, range
phenobarbital prophylaxis with those who had re- 48 to 73 months).
ceived no anticonvulsants. A psychologist (H.D.) with special training in the
testing of young children tested all subjects. We
METHODS attempted to test every English-speaking child who
had completed a course of phenobarbital. As this
The details of drug dosage and of selection and
part of the study was conceived and begun several
randomization of children into groups given pheno-
years after the main portion, only a minority of
barbital daily or not given phenobarbital have been
children treated with phenobarbital could be tested.
At no time did anyone other than the chief inves-
Received for publication Oct 27, 1980; accepted Feb 25, 1981. tigator know the group to which the child belonged.
Reprint requests to (5MW.) 1526 N Edgemont St, Los Angeles,
Every ninth test session was audiotaped to permit
CA 90027.
PEDIATRICS (ISSN 0031 4005). Copyright © 1981 by the
evaluation of the uniformity of test administration.
American Academy of Pediatrics. Typically a testing session lasted 2#{189}
hours with a

820 PEDIATRICS Vol. 68 No. 6 December 1981

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20-minute break. The order of test administration mum = 14.3 years.
was uniform throughout the study. There were no significant differences between the
Three instruments were used in the study. The two groups in: (1) family history of febrile convul-
first, the Wechsler Preschool and Primary Scale of sions or afebrile seizures; (2) age at the initial febrile
Intelligence (WPPSI) is a widely used intelligence convulsion; (3) family history of neurologic disease;
test standardized on a stratified random sample of (4) abnormalities of pregnancy, delivery, or neo-
1,200 children ranging in age from 4 to 6#{189}
years. natal period; (5) birth weight; (6) duration of the
Q uotas for each stratum of the sample were drawn initial febrile seizure; (7) multiplicity of the initial
from 1960 census data. Test-retest data indicate febrile seizure; (8) type of initial febrile convulsion
that the instrument has sufficient stability over (generalized, akinetic, focal); and (9) initial EGG
time to warrant its use in a pre- and posttest design results.
of the kind used in this study. The WPPSI yields No children in either group had a delay in devel-
three scores, verbal IQ, performance IQ, and full- opmental milestones. One child in the group not
scale IQ. The test-retest coefficients published by given phenobarbital had an abnormal neurologic
the Psychological Corporation in 1967 are .86 verbal examination, with clumsiness and increased tone of
IQ, .89 performance IQ, and .92 full-scale IQ. The the limbs, when tested at age 3#{189}
years. Since age 6,
Matching Familiar Figures Test (MFFT), and Chil- the neurological examination has been normal and
dren’s Embedded Figures Test (CEFT) were in- school grades have been above average. No children
eluded to assess problem-solving abilities. They are had hyperactivity prior to the initial febrile convul-
largely independent of general intelligence, but sion. No child in either group have developed afe-
rather reflect differences in attentiveness and im- brile seizures. Two children, both in the group not
pulse control. The MFFT is a visual matching task given phenobarbital, had one recurrent febrile sei-
measuring speed of decision making and accuracy zure prior to the psychologic testing. In one child
of responses. It has been characterized as a measure the seizure lasted less than five minutes; in the
of reflectivity-impulsiveness in which reflectivity other it lasted between 16 and 20 minutes. In both
refers to the degree to which a subject considers the children, the seizure was generalized major in type.
possible responses simultaneously available to the The 25 children in the group given phenobarbital
solution ofa problem. The CEFT reflects the ability daily received the drug for a mean of 35 months
to separate an item from the field in which it is (SD 11 months, median 35 months, mode 33
embedded. The raw data collected from the CEFT months).
for analysis was the total test score or the combi- Statistical analysis used the matched sample t
nation of the number of correct responses from the test. All data were also analyzed and included in a
‘Tent” subscale added to the number of correct three-way factorial analysis of covariance (treat-
responses from the ‘House” subscale. ment group by gender by race with age and socio-
The raw data collected from the MFFT for anal- economic status as covariates). Inasmuch as essen-
ysis was the mean of the latencies to the first tially identical results come from both forms of
response the child made to each item to the nearest analysis, we shall present the matched t test rather
half second, and the mean number of errors made than the unbalanced analysis of covariance. Hotell-
by the child to all items. ing’s T2 statistic was used to compare multivar-
A matched pair design was used, in which 25 iately the matched pairs on all six tests simultane-
children from the group treated daily with pheno- ously.
barbital were matched with 25 from the group not Two subgroups of the children treated with con-
given phenobarbital. The matching was done with- tinuous phenobarbital were defined on the basis of
out any knowledge of psychological test results. The serum phenobarbital levels drawn throughout the
criteria used were: (1) same sex, (2) same race, (3) study. The more compliant group consisted of 14
age at time of test, and (4) socioeconomic status as children with 50% or more of phenobarbital levels
measured by average educational level of the census 15 jig/mi. The less compliant group consisted of
tract of residence. 11 children with less than 50% of phenobarbital
Age and socioeconomic status were matched as levels 15 j.tg/ml. The test results of these two
closely as possible within gender and racial groups. subgroups were compared.
The census tract educational levels for those chil-
dren in the matched pair design were as follows: RESULTS
continuous phenobarbital, median = 12.4 years;
Compliance with Drug Regimen
minimum = 10.8 years; maximum = 13.8 years.
Values for the group not given phenobarbital were: In the 25 children treated with phenobarbital 172
median = 12.5 years; minimum = 10.8 years; maxi- phenobarbital level determinations were per-

ARTICLES 821
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formed. Of these 73% were >10 tg/mi, and 45% phenobarbital. However, species difference, as well
were >15 Lg/mi; 84% of the children had levels >10 as the very high dosage and levels of drug involved,
zg/ml more than 50% of the time, and 86% had sharply limit the validity of extrapolating this data
>50% of the levels greater than 10 ig/m1 during the to children receiving clinically used dosages of
last year of phenobarbital treatment when the tests phenobarbital.
were given. Behavioral abnormalities in children with febrile
seizures receiving daily phenobarbital are common.
Although no evidence of adverse effect on cognitive
Psychological Test Results
function in children receiving daily phenobarbital
1. Initial testing during phenobarbital treatment was observed in the studies of Ellenberg and Ne!-
(Table 1) indicated no significant differences be- son’5 or Wallace,’6 blood levels were not monitored,
tween the two groups on any of the six psychological and it cannot be assumed that the drug was actually
test measurements when considered separately or being taken.
multivariately. Several studies in epileptic adults and children
2. In the retesting, three months after treatment have shown impairment of either psychomotor per-
stopped (Table 2), again there were no significant formance or short-term memory.9”7 Other studies’82#{176}
differences observed between the treatment and no- have not found any impairment of cognitive func-
treatment groups. tion associated with phenobarbital, but serum levels
3. There was no significant difference in degree were not measured. Hirtz2’ has pointed out that
of change of test scores from the initial to the later these studies in epileptics are often difficult to
tests when the two groups were compared. evaluate because of variability in etiology and type
The comparison of the more compliant with the of seizure disorder, degree of seizure control, age of
less compliant groups did not yield any significant the patients, drug levels, and usage of multiple
differences. The multivariate tests had P values drugs.
greater than 0.55, and the individual t tests on the The only study systematically testing cognitive
six test scores all had values greater
P than 0.19. function in children with febrile convulsions treated
with daily phenobarbital was reported by Camfield
et al.7 In this study, children with simple febrile
DISCUSSION
seizures who had completed either eight or 12
Animal studies’3”4 have shown deleterious effects months of therapy with phenobarbital or a placebo
on brain weight and chemical composition due to were tested with either the Bayley scale (if the child

TABLE 1 . Initial Test Results of Children Receiving Treatment*

Group Means Differences of Matched Pairs

With No Means ± SEM t P

Pheno- Pheno-
barbital barbital
Verbal IQ 99.3 100.1 -0.80 ± 3.41 -0.23 .82
Performance IQ 110.6 103.4 7.24 ± 4.83 1.50 .75
Full-scale IQ 105.3 102.0 3.28 ± 4.07 0.81 .43
Children’s Embedded Figures 5.76 5.12 0.640 ± 0.571 1.12 .27
Matching Familiar Figures (time) 5.44 5.07 0.364 ± 0.691 0.53 .60
Matching Familiar Figures (errors) 2.18 2.25 -0.062 ± 0.136 -0.45 .66
0 Multivariate results: Hotelling T2 = 8.16; P = .43.

TABLE 2. Retesting Three Months After Termination of Treatment0

Group Means Differences of Matched Pairs

With No Means±SEM t P
Pheno- Pheno-
barbital barbital
Verbal IQ 101.4 102.7 -1.26 ± 4.30 -0.29 .77
Performance IQ 115.2 113.7 1.43 ± 4.27 0.34 .74
Full-scale IQ 109.0 108.9 0.087 ± 4.44 0.02 .98
Children’s Embedded Figures 7.83 7.17 0.652 ± 1.01 0.64 .52
Matching Familiar Figures (time) 5.81 4.95 0.852 ± 0.727 1.17 .25
Matching Familiar Figures (errors) 2.32 2.16 0.153 ± 0.157 0.97 .34
0 Multivariate results: Hotelling T2 = 15.24; P = .128.

822 EFFECT OF PHENOBARBITAL ON COGNITIVE FUNCTION

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was less than 2 years of age) or the Stanford Binet 4. Wolf S, Carr A, Davis DC, et al: The value of phenobarbital
if the child was older. The treated and placebo in the child who has had a single febrile seizure: A controlled
prospective study. Pediatrics 59:378, 1977
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negative correlation between the serum levels of seizure-Antipyretic instruction plus either phenobarbital or
phenobarbital and the Binet subscore of “memory.” placebo to prevent a recurrence. J Pediatr 97: 16, 1980
6. Wolf SM, Forsythe A: Behavior disturbance, phenobarbital
Also, children tested after 12 months of phenobar- and febrile seizures. Pediatrics 61:728, 1978

bital therapy had significantly lower “general com- 7. Camfield C, Chaplin 5, Doyle A, et al: Side effects of pheno-
prehension” scores than those tested after eight barbital in toddlers: Behavioral and cognitive aspects. J
Pediatr 95:361, 1979
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the longer exposure to phenobarbital might have barbitone to prevent febrile convulsions. Br Med J 1:559,
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9. MacLeod C, Dekaban A, Hunt E, et a!: Memory impairment
in an editorial critique of this paper, stated that the in epileptic patients: Selective effects of phenobarbit.al con-
Binet test does not yield meaningful test scores in centration..Scien.ce 202:1102, 1978
individual subcategories and considered that any 10. Hutt S, Jackson P, Beisham A, et al: Perceptual-motor
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ACKNOWLEDGMENTS performance. Arch Neurol 35:17, 1978

16. Wallace 5: Neurological and intellectual deficits: Convul-

This work was supported by grants from Southern
sions with fever viewed as acute indications of life long
California Permanente Medical Group and the Epilepsy
developmental defects in brain dysfunction in infantile feb-
Foundation of America. rile convulsions, in Brazier M, Coceani F (eds): Brain Dys-
This work was partly based on a cooperative multicen- function in Infantile Febrile Convulsions. New York, Raven
ter study done in the Kaiser Foundation Hospitals in Los Press, 1976
Angeles. The physicians who participated in the study 17. Ozdirim E, Renda Y, Epir 5: Effects of phenobarbital and
were Drs A. Carr, D. Davis, S. Davidson, E. Dale, E. phenytoin on the behavior of epileptic children. Adv Epilep-
Goldenberg, R. Hanson, G. Lulejian, M. Nelson, P. Treit- tology 13:120, 1978
18. Chaudhry M, Pond D: Mental deterioration in epileptic
man, and A. Weinstein.
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Long-Term Effect of Phenobarbital on Cognitive Function in Children with Febrile
Convulsions
Sheldon M. Wolf, Alan Forsythe, Alastair A. Stunden, Robert Friedman and Harriet
Diamond
Pediatrics 1981;68;820-823
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