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Original Contribution
The Long-Term Risk of Epilepsy after Febrile Seizures in Susceptible Subgroups
Mogens Vestergaard1,2, Carsten Bcker Pedersen3, Per Sidenius4, Jrn Olsen2,5, and Jakob
Christensen4,6
1
Department of General Practice, Institute of Public Health, Aarhus University, Aarhus, Denmark.
Department of Epidemiology, Institute of Public Health, Aarhus University, Aarhus, Denmark.
3
National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
4
Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
5
Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA.
6
Department of Clinical Pharmacology, Aarhus University, Aarhus, Denmark.
2
A family history of seizures, preexisting brain damage, or birth complications may modify the long-term risk of
epilepsy after febrile seizures. The authors evaluated the association between febrile seizures and epilepsy in
a population-based cohort of 1.54 million persons born in Denmark (19782002), including 49,857 persons with
febrile seizures and 16,481 persons with epilepsy. Overall, for children with febrile seizures compared with those
without such seizures, the rate ratio for epilepsy was 5.43 (95% condence interval: 5.19, 5.69). The risk remained
high during the entire follow-up but was particularly high shortly after the rst febrile seizure, especially in children
who experienced early (<1 year of age) or late (>3 years of age) onset of febrile seizures. At 23 years of follow-up,
the overall cumulative incidence of epilepsy after febrile seizures was 6.9% (95% condence interval: 6.5, 7.3). In
conclusion, persons with a history of febrile seizures had a higher rate of epilepsy that lasted into adult life, but less
than 7 percent of children with febrile seizures developed epilepsy during 23 years of follow-up. The risk was higher
for those who had a family history of epilepsy, cerebral palsy, or low Apgar scores at 5 minutes.
Apgar score; birth weight; cerebral palsy; Denmark; epilepsy; follow-up studies; premature birth; seizures, febrile
Abbreviations: CI, condence interval; ICD-8, International Classication of Diseases, Eighth Revision; ICD-10, International
Classication of Diseases, Tenth Revision.
Correspondence to Dr. Mogens Vestergaard, Department of General Practice, Institute of Public Health, Aarhus University, Vennelyst Boulevard
6, DK-8000 Aarhus C, Denmark (e-mail: mv@soci.au.dk).
911
Am J Epidemiol 2007;165:911918
Received for publication January 12, 2006; accepted for publication October 5, 2006.
Study variables
RESULTS
Information on febrile seizures, cerebral palsy, and epilepsy for the study population, their parents, and their siblings was obtained from the National Hospital Register (14),
which contains data on all discharges from Danish hospitals
since 1977. Diagnoses resulting from visits to emergency
rooms and outpatient clinics have been included in the register since 1995. Diagnostic information in the National
Hospital Register is based on the International Classification of Diseases, Eighth Revision (ICD-8) from 1978 to
1993 and the International Classification of Diseases, Tenth
Revision (ICD-10) from 1994 to 2002. We classified children as having a febrile seizure when they were registered
with ICD-8 code 780.21 or ICD-10 code R56.0, were between 3 months and 5 years of age at the time of discharge,
and had no recorded history of epilepsy or intracranial infection (ICD-8 codes 320323; ICD-10 codes G00G09).
Persons were categorized as having epilepsy when they
were registered with ICD-8 code 345 or ICD-10 code
G40 or G41 and as having cerebral palsy when they were
registered with ICD-8 code 343.99 or 344.99 or ICD-10
code G80. Information on Apgar score at 5 minutes, birth
weight, and gestational age at birth was obtained from the
Danish Medical Birth Register.
Statistical analyses
Am J Epidemiol 2007;165:911918
913
TABLE 1. Estimated rate ratios of epilepsy according to febrile seizures and the risk factors investigated
based on data for the 1,540,725 persons born in Denmark between 1978 and 2002 and followed for epilepsy
until 2002
Overall
First adjustmenty
Full adjustmentz
Febrile
seizures
in study
subject
No. of
cases*
No
17,496,653
14,332
1.00
Reference
1.00
Reference
497,477
2,149
5.98
5.71, 6.26
5.43
5.19, 5.69
17,016,095
13,790
1.00
Reference
1.00
Reference
Yes
Rate
ratio
95% CI
Rate
ratio
95% CI
No
Yes
444,736
1,914
6.04
5.75, 6.34
5.62
5.35, 5.90
Yes
No
480,559
542
1.41
1.29, 1.53
1.31
1.20, 1.43
Yes
52,740
235
6.17
5.42, 7.03
5.15
4.52, 5.87
Reference
17,111,777
13,365
1.00
Reference
1.00
Yes
479,623
1,974
6.01
5.73, 6.30
5.60
5.34, 5.88
No
384,876
967
3.37
3.15, 3.60
3.22
3.02, 3.44
Yes
17,854
No
17,478,619
14,272
1.00
Reference
1.00
Reference
Yes
495,142
2,123
5.96
5.69, 6.24
5.62
5.36, 5.89
No
18,034
60
4.27
3.32, 5.51
4.21
3.26, 5.42
Yes
2,335
Cerebral palsy
No
Yes
No
17,467,858
13,838
1.00
Reference
1.00
Reference
Yes
495,303
2,042
5.95
5.68, 6.24
5.65
5.38, 5.93
No
28,796
Yes
2,173
No
17,142,887
13,649
1.00
Reference
1.00
Reference
Yes
487,423
2,085
6.09
5.81, 6.38
5.59
5.33, 5.86
No
97,074
370
4.69
4.23, 5.20
2.97
2.67, 3.30
Yes
3,337
7.20
5.19, 9.97
1.00
Reference
No
Yes
461,356
1,927
6.09
5.80, 6.39
5.74
5.46, 6.03
<2,500
No
856,897
1,376
2.08
1.97, 2.20
1.54
1.43, 1.65
Yes
33,468
212
9.34
8.15, 10.70
5.61
4.85, 6.49
15,407,024
12,236
1.00
Reference
1.00
Reference
16,525,191
12,827
1.00
Reference
No
Yes
434,971
1,841
6.07
5.78, 6.38
5.68
5.40, 5.97
<37
No
796,126
1,226
1.89
1.78, 2.00
1.22
1.13, 1.32
Yes
31,027
203
9.35
8.14, 10.75
4.96
4.28, 5.76
* Because of missing values, the numbers of cases of epilepsy in each category do not always add to 16,481.
y Estimates were adjusted for calendar period and for age and its interaction with gender.
z Estimates were adjusted for calendar period, age and its interaction with gender, febrile seizures in siblings,
epilepsy in parents or siblings, cerebral palsy, Apgar score, birth weight, and gestational age.
CI, condence interval.
{ These estimates were adjusted for neither epilepsy in parents or siblings nor febrile seizure in a sibling.
Am J Epidemiol 2007;165:911918
Yes
No
4.8), 5.6 percent (95 percent CI: 5.3, 5.8), 6.4 percent (95
percent CI: 6.1, 6.7), and 6.9 percent (95 percent CI: 6.5,
7.3) 1, 5, 10, 15, 20, and 23 years after the first febrile
seizures, respectively. Among persons with no history of
febrile seizures, the cumulative incidence of epilepsy was
1.8 percent (95 percent CI: 1.8, 1.9) at the age of 25 years,
that is, the mean age of persons followed up for 23 years
after the first febrile seizures. The cumulative incidence
varied according to the subgroups under study. The highest
risk was found among children with cerebral palsy, Apgar
score of less than 7 at 5 minutes, or a family history of
epilepsy, especially in siblings of children in whom epilepsy
developed after febrile seizures (table 2).
DISCUSSION
We found that febrile seizure was associated with an increased risk of epilepsy that lasted into adulthood. The rate
was highest shortly after the first febrile seizure, especially
for children who experienced early (<1 year) or late onset
(>3 years) of febrile seizures. The overall cumulative incidence of epilepsy after febrile seizures was 6.9 percent at
23 years of follow-up. The risk was particular high for persons with cerebral palsy, low Apgar scores, or a family history of epilepsy.
The association between febrile seizures and epilepsy
may be explained by at least four different mechanisms.
Am J Epidemiol 2007;165:911918
FIGURE 1. Adjusted rate ratios of epilepsy after febrile seizures according to time since rst febrile seizure among persons born in Denmark.
Estimates were based on data for the 1,540,725 persons born in Denmark between 1978 and 2002 and followed until 2002. Rate ratios were
adjusted for age, gender, calendar period, history of febrile seizures in siblings, history of epilepsy in parents or siblings, cerebral palsy, birth weight,
gestational age at birth, and Apgar score at 5 minutes. Point estimates are given, with error bars representing 95% condence intervals.
915
First, seizures occurring during fever may be the first manifestation of epilepsy and not febrile seizures. Dravets syndrome (severe myoclonic epilepsy of infancy) is an example
of a rare condition that appears within the first year of life,
often during a febrile episode and with unprovoked seizures
following shortly after (17). Misclassification of epilepsy as
febrile seizures could explain at least some of the high rate
of epilepsy we and others (6) found shortly after the first
febrile seizures. It is difficult to avoid this misclassification
in the clinical setting because no other factors besides fever
may separate the two conditions. However, our data indicate
that children may need special attention if the first febrile
seizure occurs at an uncommon age: before 1 year of age or
after 3 years of age (18). Others have found a higher rate of
epilepsy associated with febrile seizures occurring before
1 year of age, perhaps because the more severe febrile seizures tend to occur early (6, 7).
Second, febrile seizure may be an age-specific marker of
seizure susceptibility if febrile seizures and epilepsy share
causes. We adjusted for age, gender, calendar period, history
of febrile seizures in siblings, family history of epilepsy,
cerebral palsy, birth weight, gestational age at birth, and
Apgar score at 5 minutes and found little change in the
estimates, but other confounders may be present. Genetic
analyses of familial epilepsies have identified mutations in
ion channel genes that result in a wide range of phenotypes
from febrile seizures to severe forms of childhood epilepsy
Am J Epidemiol 2007;165:911918
FIGURE 2. Adjusted rate ratios of epilepsy after febrile seizures according to time since rst febrile seizure. Estimates were based on data for all
children born in Denmark between 1995 and 2002 and followed until 2002. Rate ratios were adjusted for age, gender, calendar period, history of
febrile seizures in siblings, history of epilepsy in parents or siblings, cerebral palsy, birth weight, gestational age at birth, and Apgar score at
5 minutes. Point estimates are given, with error bars representing 95% condence intervals.
seizures and epilepsy. Clinical case series tend to overestimate the frequencies of adverse outcomes after febrile
seizures (22), but our study was based on a nationwide cohort with virtually complete follow-up. Bias due to selection
of study participants and nonresponse can therefore not
All children
Yes
95% CIy
95% CI
1.8
1.8, 1.9
6.9
6.5, 7.3
2.3
2.1, 2.6
7.3
6.3, 8.2
5.5
5.1, 5.8
16.7
14.6, 18.8
6.9
5.7, 8.1
21.0
14.1, 27.9
21.0
18.8, 23.3
56.6
48.3, 64.8
5.3
4.4, 6.2
20.0
10.4, 29.6
3.0
2.8, 3.2
8.7
7.4, 10.1
2.8
2.5, 2.9
8.7
7.2, 10.2
* The cumulative incidence was assessed 23 years after the rst febrile seizure for persons
with a history of febrile seizures and at the 25th birthday for persons with no history of febrile
seizures.
y CI, condence interval.
Am J Epidemiol 2007;165:911918
FIGURE 3. Rate ratios of epilepsy after febrile seizures according to age at rst febrile seizure and time since rst febrile seizure. Estimates were
based on data for the 1,540,725 persons born in Denmark between 1978 and 2002 and followed until 2002. Point estimates are given, with error
bars representing 95% condence intervals.
Am J Epidemiol 2007;165:911918
Thus, our estimates are too high for some children and too
low for others. Previous studies have shown that the risk of
epilepsy tends to increase with increasing duration of febrile
seizures, that children with focal febrile seizures are prone
to develop partial-onset epilepsy, and that children with recurrent febrile seizures are prone to develop generalizedonset epilepsy (7). One of the most controversial issues
within the field of epileptology is whether prolonged febrile
seizures damage the hippocampus and cause temporal lobe
epilepsy. To address this important issue, we need neuroimaging studies with long-term follow-up of children with
a history of prolonged febrile seizures (28).
In this study, we found that persons with a history of
febrile seizures had a higher rate of epilepsy that lasted into
adult life, but less than 7 percent of children with febrile
seizures developed epilepsy during 23 years of follow-up.
The risk was higher for those who had a family history of
epilepsy, cerebral palsy, or low Apgar scores at 5 minutes.
ACKNOWLEDGMENTS
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