The Long-Term Risk of Epilepsy after Febrile Seizures in Susceptible Subgroups

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1 American Journal of Epidemiology Advance Access published January 30, 2007 American Journal of Epidemiology Copyright ª 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A. DOI: /aje/kwk086 Original Contribution The Long-Term Risk of Epilepsy after Febrile Seizures in Susceptible Subgroups Mogens Vestergaard 1,2, Carsten Bøcker Pedersen 3, Per Sidenius 4, Jørn Olsen 2,5, and Jakob Christensen 4,6 1 Department of General Practice, Institute of Public Health, Aarhus University, Aarhus, Denmark. 2 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. Received for publication January 12, 2006; accepted for publication October 5, 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 ( ), 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% confidence interval: 5.19, 5.69). The risk remained high during the entire follow-up but was particularly high shortly after the first 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% confidence 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, confidence interval; ICD-8, International Classification of Diseases, Eighth Revision; ICD-10, International Classification of Diseases, Tenth Revision. Febrile seizures are the most common type of seizures in childhood, affecting 2 5 percent of all children, but the long-term impact of these seizures on the developing brain is unsettled. Retrospective studies of persons with intractable temporal lobe epilepsy (1, 2), neuroimaging studies of those with prolonged febrile seizures (2, 3), and experimental studies of laboratory animals with hyperthermia-induced seizures (4, 5) suggest that some febrile seizures may cause epilepsy. These results, however, may apply to only a small proportion of children with febrile seizures. Populationbased studies show that the absolute risk of unprovoked seizures after febrile seizures is low (2 7 percent) (6 10) and indicate that most febrile seizures are age-specific markers of seizure susceptibility. Early identification of susceptible subgroups could have clinical implications because these children may need special attention (11). It has been suggested that preexisting brain damage, family history of seizures, and early environmental factors may increase the susceptibility to seizure-induced brain lesions (11, 12). However, no studies so far have been large enough to evaluate whether the risk of epilepsy after febrile seizures is modified by these factors. Correspondence to Dr. Mogens Vestergaard, Department of General Practice, Institute of Public Health, Aarhus University, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark ( mv@soci.au.dk). 1

2 2 Vestergaard et al. We evaluated the association between febrile seizures and epilepsy in a large population-based birth cohort with up to 25 years of follow-up. We examined whether age at first febrile seizure, time since first febrile seizure, number of febrile seizures, family history of febrile seizures, family history of epilepsy, cerebral palsy, low Apgar score, low birth weight, and preterm birth modify the association between febrile seizures and epilepsy. MATERIALS AND METHODS Study population We used data from the Danish Civil Registration System (13) to identify all persons born in Denmark between January 1, 1978, and December 31, 2002 (1,540,725 persons). All liveborn children and new residents of Denmark are assigned a unique personal identification number, which is stored in the Danish Civil Registration System together with information on vital status, emigration, disappearance, and personal identification numbers of mothers, fathers, and siblings. The personal identification number is used as a key to individual information in all other national registries. Study variables 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 Diagnoses resulting from visits to emergency rooms and outpatient clinics have been included in the register since 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 We classified children as having a febrile seizure when they were registered with ICD-8 code 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 ; ICD-10 codes G00 G09). 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 or 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 The study population was followed from birth until onset of epilepsy, death, emigration, or December 31, 2002, whichever occurred first. The rate ratio of epilepsy was estimated by log-linear Poisson regression (15) with the GENMOD procedure in SAS version 8.1 software (SAS Institute, Inc., Cary, North Carolina). All rate ratios were adjusted for age and its interaction with gender and calendar year. Age, calendar year, number of febrile seizures, time since first febrile seizure, history of epilepsy in a parent or sibling, and history of febrile seizures in siblings were treated as time-dependent variables, whereas all other variables were treated as variables independent of time. Time since first febrile seizure was classified in 3-month periods from 0 to 1 year, in 6-month periods from 1 to 5 years, in 1-year periods from 5 to 20 years, and as 20 or more years. Age was categorized in 3-month periods from 0 to 11 months, in 1-year periods from 1 to 21 years, and as 22 or more years. Calendar year was categorized in 1-year periods. p values were based on likelihood ratio tests, and 95 percent confidence limits were calculated by Wald s test. The cumulative incidence was calculated as the proportion of persons registered with epilepsy in the population at a given time. We accounted for death by other causes by using competing-risk Cox regression (16). Because the association between febrile seizures and epilepsy depends strongly on time since first febrile seizure, we used this time scale in the competing-risk Cox regression among persons with a history of febrile seizures. By contrast, we estimated the cumulative incidence according to age among children with no history of febrile seizures. RESULTS In the cohort of 1,540,725 persons, 49,857 children were diagnosed with febrile seizures and 16,481 persons were diagnosed with epilepsy, including 2,149 who developed epilepsy after febrile seizures. Overall, for persons with a history of febrile seizures compared with those without such seizures, the rate ratio for epilepsy was 5.98 (95 percent confidence interval (CI): 5.71, 6.26) when we adjusted for age and its interaction with gender and calendar year. The rate ratio decreased slightly after further adjustments for history of febrile seizures in siblings, epilepsy in parents or siblings, cerebral palsy, Apgar score at 5 minutes, birth weight, and gestational age at birth (rate ratio ¼ 5.43, 95 percent CI: 5.19, 5.69) (table1). The association between febrile seizures and epilepsy was modified by time since first febrile seizure. The rate of epilepsy was 26-fold higher during the first 3 months after onset of febrile seizure and declined to a threefold higher rate 8 years after the first febrile seizure and throughout the study period (figure 1). The rate ratios shown in figure 1 were adjusted for several factors, but the adjustments caused little change in the estimate of interest (data not presented). Furthermore, excluding persons with a history of febrile seizure in siblings, epilepsy in parents or siblings, cerebral palsy, low Apgar score (<7), low birth weight (<2,500 g), and low gestational age (<37 weeks) had no impact on the results presented in figure 1 (11,419 persons developed epilepsy during 14,498,957 person-years at risk) (data not presented). Information on visits to emergency rooms and outpatient clinics was not included in the National Hospital Register until However, we found little change in the estimate of interest when restricting the cohort to children born between 1995 and 2002 (2,712 persons developed epilepsy during 2,134,875 person-years at risk) (figure 2).

3 Long-Term Risk of Epilepsy after Febrile Seizures 3 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 Febrile seizures in study subject No. of personyears at risk No. of cases* First adjustmenty Rate ratio 95% CI Rate ratio Full adjustmentz 95% CI Overall No 17,496,653 14, Reference 1.00 Reference Yes 497,477 2, , , 5.69 Febrile seizures in siblings No No 17,016,095 13, Reference 1.00 Reference Yes 444,736 1, , , 5.90 Yes No 480, , , 1.43 Yes 52, , , 5.87 Epilepsy in parents or siblings No No 17,111,777 13, Reference 1.00 Reference Yes 479,623 1, , , 5.88 Yes No 384, , , 3.44 Yes 17, , , Epilepsy after febrile seizures in the same sibling{ No No 17,478,619 14, Reference 1.00 Reference Yes 495,142 2, , , 5.89 Yes No 18, , , 5.42 Yes 2, , , Cerebral palsy No No 17,467,858 13, Reference 1.00 Reference Yes 495,303 2, , , 5.93 Yes No 28, , , Yes 2, , , Apgar score at 5 minutes 7 No 17,142,887 13, Reference 1.00 Reference Yes 487,423 2, , , 5.86 <7 No 97, , , 3.30 Yes 3, , , 9.97 Birth weight (g) 2,500 No 16,525,191 12, Reference 1.00 Reference Yes 461,356 1, , , 6.03 <2,500 No 856,897 1, , , 1.65 Yes 33, , , 6.49 Gestational age (weeks) at birth 37 No 15,407,024 12, Reference 1.00 Reference Yes 434,971 1, , , 5.97 <37 No 796,126 1, , , 1.32 Yes 31, , , 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, confidence interval. { These estimates were adjusted for neither epilepsy in parents or siblings nor febrile seizure in a sibling.

4 4 Vestergaard et al. FIGURE 1. Adjusted rate ratios of epilepsy after febrile seizures according to time since first 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 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% confidence intervals. Children who experienced early (<1 year) or late (>3 years) onset of febrile seizures had a higher rate of epilepsy within the 2 years after the first seizure compared with children whose onset occurred between ages 1 and 3 years. Age at onset of febrile seizures had no effect on the rate of epilepsy 2 or more years after the first febrile seizures (figure 3). The rate ratio for epilepsy after febrile seizures increased with increasing number of admissions for febrile seizures. The rate ratios were 4.52 (95 percent CI: 4.27, 4.79), 8.10 (95 percent CI: 7.36, 8.92), and (95 percent CI: 17.88, 21.65) for children registered one, two, and three or more times with febrile seizures compared with children with no history of febrile seizures. Persons with a family history of epilepsy, a family history of febrile seizures, cerebral palsy, an Apgar score of less than 7 at 5 minutes, a birth weight of less than 2,500 g, or a gestational age at birth of less than 37 completed weeks had a higher rate of epilepsy than that for the general population (table 1). After we adjusted for several confounding factors, the rate ratio of epilepsy was particularly high for persons with both a history of febrile seizures and a family history of epilepsy, cerebral palsy, or low Apgar score. The combined effect seemed to be higher than the sum but lower than the product of the two separate effects (table 1). The cumulative incidence of epilepsy after febrile seizures was 1.3 percent (95 percent CI: 1.2, 1.4), 3.2 percent (95 percent CI: 3.0, 3.4), 4.6 percent (95 percent CI: 4.4, 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.

5 Long-Term Risk of Epilepsy after Febrile Seizures 5 FIGURE 2. Adjusted rate ratios of epilepsy after febrile seizures according to time since first febrile seizure. Estimates were based on data for all children born in Denmark between 1995 and 2002 and followed until 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% confidence intervals. First, seizures occurring during fever may be the first manifestation of epilepsy and not febrile seizures. Dravet s 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 (19). We adjusted for family history of seizures, but that is only a crude proxy for genetic susceptibility. We found that siblings of children with febrile seizures had a higher rate of epilepsy even if they had no personal history of febrile seizures, indicating that genetic and environmental factors shared by family members may play a role. Third, prolonged febrile seizures may damage the developing brain and cause epilepsy. Neuroimaging studies have demonstrated acute swelling and edema of the hippocampus after prolonged febrile seizures (2, 3), and animal studies suggest that hyperthermia-induced seizures may cause longlasting modifications of channels, synapses, and neuronal networks within the hippocampus, leading to sustained dysfunction of these cells and a decreased seizure threshold (4, 5). One would expect a particularly high risk of complex partial epilepsy after febrile seizures if febrile seizure damages the hippocampus. Unfortunately, we did not have sufficiently detailed information on type of epilepsy to address this discussion. However, the rate of epilepsy after febrile seizures remained high into adulthood, where partial seizures are the most common type of seizures. Our data and those of others (6, 7, 9) indicate that the rate of epilepsy increases with increasing number of febrile seizures. A dose-response-like pattern need not imply causality, however. (20) The number of febrile seizures may be a marker of seizure susceptibility, and children admitted several times for febrile seizures may be a selected group experiencing

6 6 Vestergaard et al. FIGURE 3. Rate ratios of epilepsy after febrile seizures according to age at first febrile seizure and time since first febrile seizure. Estimates were based on data for the 1,540,725 persons born in Denmark between 1978 and 2002 and followed until Point estimates are given, with error bars representing 95% confidence intervals. more severe febrile seizures. Moreover, randomized studies have shown that preventing recurrent febrile seizures does not alter the subsequent risk of epilepsy (21). Fourth, results may be biased by systematic errors in the selection of study subjects or in the information on febrile 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 TABLE 2. Cumulative incidence* of epilepsy according to selected characteristics among persons born in Denmark between 1978 and 2002 and followed until 2002 No Febrile seizures Yes % 95% CIy % 95% CI All children , , 7.3 Siblings of children who had febrile seizures , , 8.2 Children who had parents or siblings with epilepsy , , 18.8 Siblings of children who developed epilepsy after febrile seizures , , 27.9 Children with cerebral palsy , , 64.8 Children with an Apgar score of <7 at 5 minutes , , 29.6 Children whose birth weight was <2,500 g , , 10.1 Children whose gestational age at birth was <37 weeks , , 10.2 * The cumulative incidence was assessed 23 years after the first 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, confidence interval.

7 Long-Term Risk of Epilepsy after Febrile Seizures 7 explain our findings. We recently evaluated the quality of the diagnoses in the Danish National Hospital Register and found that the predictive value of a febrile seizure diagnosis was 93 percent (95 percent CI: 89, 96) (23) and that the predictive value of an epilepsy diagnosis was 81 percent (95 percent CI: 75, 87) (Christensen et al., Department of Neurology, Aarhus University Hospital, Denmark, unpublished manuscript). Forty percent of those who did not fulfill the criteria for epilepsy (at least two unprovoked seizures on separate days) had experienced a single unprovoked seizure. Because some of these seizures signify yet-undiagnosed epilepsy, the true validity of the epilepsy diagnosis is even higher. We found that the completeness of febrile seizure registration was 72 percent (95 percent CI: 66, 76) (23), but we lacked data on the completeness of the epilepsy diagnosis. Incomplete registration of epilepsy causes underestimation of the cumulative incidence of epilepsy, but rate ratios are affected only if the completeness of the registration is different for persons with a history of febrile seizures compared with those with no such history. In Denmark, most inhabitants have easy access to a hospital, and all hospital treatment is paid by taxes and is free of charge for the patient. The National Hospital Register holds information on all public hospitals and on the only private center in Denmark treating epilepsy patients. Thus, our study included all persons with epilepsy who had been hospitalized ( ) or treated as outpatients ( ) in Denmark. The age-specific incidence rates of epilepsy in our study (Christensen et al., Department of Neurology, Aarhus University Hospital, Denmark, unpublished manuscript) are similar to those found in other population-based studies (24). We found no significant difference in epilepsy rate ratios with regard to time since first febrile seizure when restricting the cohort to persons born from 1995 through 2002 and followed exclusively during a time period when information on both inpatients and outpatients was available. Information in the National Hospital Register is collected on a routine basis for administrative purposes, which means that our study did not affect the diagnostic process or introduce surveillance bias (25). Given this background, we find it unlikely that the data quality biased our results significantly. To determine the need for treatment of febrile seizures, the natural history of the condition should be understood. In keeping with previous population-based studies (6 10), our study showed that the majority of children with febrile seizures do not develop epilepsy. However, the risk of epilepsy was significantly higher for persons with a family history of epilepsy, cerebral palsy, or low Apgar score shortly after birth. Even after adjusting for several confounding factors, these characteristics seem to contribute independently to the rate of epilepsy; the combined effect seems more than additive but less than multiplicative. Recent studies suggest that the cause of the febrile illness may modify the subsequent risk of epilepsy (26). We have shown previously that febrile seizures provoked by vaccination against measles, mumps, and rubella were associated with a similar rate ratio of epilepsy compared with febrile seizures provoked by fever of a different etiology (27). Our study was limited by lack of clinical information such as on duration of febrile seizures and type of epilepsy. 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. 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