Epilepsy Res., 5 (1990) 209-216
209
Elsevier EPIRES 00.299
Recurrence of febrile convulsions in a population-based cohort*
J o h n F. A n n e g e r s , Sally A . B l a k l e y a, W. A l l e n H a u s e r b a n d L e o n a r d T. K u r l a n d c Division of Epidemiology, Universityof Texas Health Science Centerat Houston, School of Public Health, Houston, TX (U.S.A.), aDepartment of Epidemiology, 7)dane University, New Orleans, LA (U. S.A.), bDepartmentsof Epidemiology and Neurology, G.H. Sergievsky Center, Columbia MedicalSchool, New York, NY (U.S.A.), and CDepartmentof Medical Statisticsand Epid.'miology, Mayo Clinic, Rochester, MN (U.S.A.) (Received 19 May 1989; revision received 8 July 1989; accepted 11 July 1989)
Key words: Febrile convulsion; Prognosis; Recurrence
The risk of recurrence after an initial febrile seizure was 25% in a population-based cohort of 639 children followed from their first febrile seizure. Prognostic factors were an increasing risk of recurrence with younger age at first febrile seizure, a first degree relative with febrile seizures and complex features of the first febrile seizure. The effect of complex features was modified by age at first febrile seizure and family history in that complex features alone did not increase risk of recurrence but further increased the risk for children under 18 months at first seizure and/or with a positive family history. The prognostic factors for all febrile convulsions recurrences were also prognostic for having subsequent complex febrile convulsions. Children with none of the prognostic factors had only a 3% risk of a future complex febrile seizure while children under 18 months at first febrile convulsion and a positive family history or complex features had about a ~~3%risk of a subsequent comp!ex febrile seizure.
INTRODUCTION Febrile convulsions are a common childhood condition affecting 2-4% of children and they tend to recur. A few population-based studies have reported recurrence risks of 31-48% after an initial febrile seizure 1'4'9'n'13. Although in agreement on some prognostic factors, e.g., young age at onset and a family history of febrile convulsions, these studies are discrepant regarding complex features of the initial febrile convulsion. More= * Presented in part at the 39th annual meeting of the American Academy of Neurology, New York, NY, April 1987.
Correspondence to.: Dr. J.F. Annegers, University of Texas Health Science Center at Houston, School of Public Health, P.O. Box 20186, Houston, TX 77225, U.S.A.
over, the risks and prognostic factors for a recurrent febrile seizure with complex features have not been evaluated. Based on the follow-up of a large cohort of children with an initial febrile seizure while residents of Rochester, Minnesota, we have addressed the following questions in this paper: (1) What is the overall probability of recurrence after an initial febrile seizure? (2) Do potential prognostic factors examined in other studies, e.g., age at first seizure, sex, family history of seizure disorders, the presence of complex features, show a similar pattern of association with subsequent seizures? (3) Given a second febrile convulsion what are the risks for further recurrences? (4) What is the risk of a subsequent complex febrile seizure? (5) Are there any factors which identify children at high
0920-1211/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
210 risk of subsequent complex febrile seizures? METHODS The design and methods of this investigation have been described in detail previously and will only be summarized here 4. The resources of the medical record linkage system of the Rochester Project of the Mayo Clinic were utilized to identify residents of Rochester, Minnesota with a diagnosis of febrile seizure between 19.~5 and 1984. Under the record linkage system all contacts with medical care facilities in the Rochester, Minnesota area including records of all inpatient, outpatient, emersency room and home visits have been indexed by diagnostic code. For this study, we retrieved all records indexed to a diagnosis of seizure or to selected conditions potentially related to seizure occurrence and reviewed the records to validate the diagnosis of seizure and to determine the clinical circumstances of the seizure. This process provided for comprehensive identification of the occurrence of febrile seizures among Rochester residents who received medical attention and were indexed as such. Febrile seizure was defined as a convulsion with febrile illness in childhood in the absence of intracranial infection or other acute cause or of a prior history of unprovoked seizure in accordance with the recommendations of the National Institutes of Health Consensus Conference s. A total of 817 (Table I) children were identified as having febrile convulsions while residents of Rochester, Minnesota between 1935 and 1984. Of these 33 were not Rochester residents for the first febrile convulsions but satisfied residency criteria for later convulsions. Because these patients were not followed from the initial febrile convulsion they were TABLE !
Febrile convulsions, Rochester, Minnesota, 1935-1984 exclusions for evaluation of febrile recurrences Total cases Less non-residents for initial febrile seizure (33) l.ess not ascertained at initial seizure (124) Less neuro-defici~ from birth (16) Less cases without, foUow-up (5)
817 784 660 644 633
not included in the study. An additional 124 children were excluded because they were not ascertained at the time of the initial febrile convulsion but as a result of sequelae including subsequent febrile or afebrile convulsions or through an affected relative. Finally, 16 additional febrile convulsion cases with cerebral palsy or mental retardation, i.e., IO less than 70, were excluded. Children were not excluded solely on the basis of having had neonatal convulsions (n - 6). No age criteria for the first febrile seizure were imposed; however, 98.5% of the children in the cohort were aged 6 years or less with 11 children having their first febrile seizure between ages 7 and 11. We identified 644 children meeting clinical, residency and ascertainment criteria for a first febrile seizure during the period 1935-1984. Information was abstracted from the medical records of these eligible cases which included: age at initial febrile convulsion; the dates of subsequent febrile convulsions; and for each febrile convulsion, whether long-term anticonvulsant medications were prescribed, the presence or absence of focal features (including Todd's paralysis), the duration of the febrile seizure and whether there were repeated episodes of seizures within 24 h. Multiple seizures within a 24 h period were not classified as recurrences but as a single seizure characterized by repeated episodes. Seizures were classified as complex if characterized by any one or more of the following: focal features, duration longer than 10 min, or repeated episodes within 24 h. A family history of seizure disorders among first degree relatives was obtained by reviewing the medical records of the parents and siblings of the index cases. Twelve cases with a family history of both febrile and unprovoked seizures were classified as having both a positive family history of febrile seizures and a positive family history of unprovoked seizures. Children were followed from the initial febrile seizure for subsequent febrile seizures via the medical records linkage system. Afebrile convulsions and seizures due to other acute causes, e.g., central nervous system infections or head trauma, were not included as recurrences of febrile seizure. Follow-up was terminated by migration from southeastern Minnesota, the development of un-
211
provoked seizures, death or the close of the study in 1987. Of the 6 ~ children, five without followup after the initial febrile convulsions were excluded. Among the remaining 639 children, 96% were under follow-up at 2 years after the initia! seizure and 91% at the end of 4 years. Risks of a recurrent febrile seizure were computed by life-table methods for a second, third, fourth and fifth seizure after the first seizure and for a complex seizure on either the second or third seizure after the first seizure s . Cumulative risks are presented for the total follow-up of this cohort, which is essentially equivalent to 48 months of follow-up inasmuch as there was only one recurrence after this time. Because the time to recurrence is short and losses from the cohort during the initial
years of follow-up were few in this study, the lifetable risks are similar to the simple proportions of children with recurrences. Potential prognostic factors were evaluated by stratified life-tables, and the Mantel-Cox statistic was used to test for differences in the risk of recurrence ~. The proportional hazards model was also used for multivariate analysis of the simultaneous effect of the factors under study on recurrence s . RESULTS
Risk of a second febrile seizure Of the 639 children, 148, or 23.2%, experienced a recurrence (Table II). The life-table risk of recurrent febrile seizure was 12% within 6 months
TABLE II
Cumulative risk of second febrile seizure by characteristics at first febrile seizure
Total
No. characteristic children
Recurrence
639
6 months
I year
2 years
Total
148
11.8
17.3
23.2
26.0
128 336 107 68
36 86 20 6
13.5 13.2 8.7 6.6
20.2 18.6 13.7 10.1
30.0 25.3 15,9 10,1
30.0 27,6 22,1 10,1'
150 489
52 96
17.6 10.1
25,9 !4.5
33,8 19.8
36,2* 22,0
170 469
52 96
13.3 11.3
19.0 16.6
29.9 20.8
35.0 22.1
28 52 559
9 17 122
18.5 5.9 12.1
18,5 22.2 16.7
29.6 32.8 21.9
35.0 35,1 24.0
30 609
10 138
20.2 11.5
27.2 16.8
31.0 22.9
38.0 24.4
94 545
31 117
17.5 10.9
22,2 16.5
32.3 21.7
38,7* 23,4
Age I year 1-2 2-3 3+
FamilyHxFC Yes No
Complex features Yes No
Duration 30+ 10-29 10
Focal features Yes No
Repeated episodes Yes No *P < 0.05.
Cumulative risk (%)
212 after the first febrile convulsion, 17% within I year and 23% within 2 years. In all, 95% of second febrile seizures occurred within 2 years of the first seizure and consequently the cumulative risk increased only to 26% for the entire follow-up. As expected, the risk of recurrence was inversely associated with the child's age at first seizure (Table II). Children whose first seizure occurred under 1 year of age had the highest risk, or 30%, while that risk declined to 10% for those over 3 years at first seizure. A positive history of febrile seizures in a first degree relative was identified in 150 or 23% of the children. The risk of a recurrence was 36% in these children and was significantly higher than the risk of 22% for children without a family history of febrile seizures (Table II). In contrast, the 33 children with a family history of unprovoked seizures did not experience recurrences more frequently than children without such family history (25% vs. 23%, respectively). Age at initial febrile seizure and family history of febrile convulsions were both independently associated with recurrence risk. The risk associated with eithex~of these prognostic indicators alone of 28-29% was about twice that of children without either factor. The joint effect of a positive family history and young age at first febrile convulsion was additive as the risk for these children was 42%. In 170, or 26.6% of the children, the first febrile convulsion was complex. The risk of recurrence after a complex initial seizure of 35% was significantly higher than that of 22% after an initial simple seizure. Each of the individual characteristics of complex seizure-- focal features, repeated episodes, and long d u r a t i o n - was similarly associated with increased recurrences: 38% and 24% for focal vs. generalized seizures; 39% and 23% for repeated seizures vs. single seizures within 24 h; and 35% more than 10 min duration compared to 24% for those less than 10 min (Table II). To examine whether the effect of complex features was attenuated by confounding or interaction by age and family history, the cohort was stratiffed by combinations of these risk factors (Table III). These results show baseline risk of 15% for children with none of the risk factors. Children
T A B L E III
Cumulative risk of second febrile seizure by combination of characteristics at first seizure Age F a m i l y Corn- No. No. Cumula- Risk under Hx plex childrenrecur- tire ratio 18 FC features rences risk (%) (%) months -
-
-
192
26
15.1
-
-
+
47
5
9.0
0.6
1.0"
-
+
-
52
13
26.8
1.8
+
-
-
175
39
23.6
1.6
-
+
+
20
7
36.6
2.4
+
-
+
75
26
40.1
2.7
+
+
-
50
18
37.2
2.5
+
+
+
28
14
52.2
3.5
* R e f e r e n c e group.
with young age at first febrile convulsion have a 1.6-fold increased risk over those with none of the factors while children with a positive family history alone have a 1.8-fold increased risk. However, there is no independent effect of complex seizures as the risk for children with complex seizures alone of 9% was slightly less than that for children without any of the prognostic factors. However, the presence of complex features modified the effect of age at initial febrile seizures. The relative risk for children with complex features and age under 18 months was 2.7 compared to 1.6 for age under 18 months alone. The relative risk for children with all 3 factors was 3.5 compared to 2.5 for children under age 18 months with a positive family history. Thus, although not a prognostic factor alone the presence of complex features increased the recurrence risk of younger children with initial febrile convulsions. Boys were only slightly more likely to experience an initial recurrence than girls (26% vs. 23%). Because this study included patients with an initial febrile seizure over a 50 year period, recurrence risks were determined by time periods. There was no secular trend in the recurrence risks as the risks were 20%, 23%, 27%, 25% and 26% for the 5 successive decades of the study. The risks of recurrence varied littly by type of illness associated with the febrile convulsion. Among the more frequent known illnesses, the risks were 28% with upper respiratory infections (330 cases), 31% with otitis media (n - 131), 28%
213 with roseola (n = 44) and 26% for post-vaccination febrile convulsions (n = 19). We also considered the potential role of anticonvulsant medications as a confounder in our analysis. Overall 131 or 20% of children were prescribed continuous anticonvulsant medication after the first seizure. Selection for such treatment was primarily related to time period, more common during the late 1960s and early 1970s, and to the clinical characteristics of the seizure as those who experienced a complex first seizure were more likely to be prescribed anticonvulsants. However, prophylactic treatment was not related to age at seizure or to family history of febrile seizures. The frequency of recurrences did not differ by medication status according to the univariate a n a l y s i s - - 27% with continuous anticonvulsants compared to 25% without, or in the multivariate analysis, rate ratio for continuous anticonvulsants adjusting for age, family history of febrile convulsions and complex features was 0.9 (95% CI 0.6-1.3). Consequently, adjustment for anticonvulsant status did nc,t affect our findings. However, no information on compliance with therapy was available for these analyses, and therefore these findings should not be interpreted as evidence against the efficacy of anticonvulsant medications. Only 105 of the 635 children ascertained at their first febrile convulsions had an E E G performed at that time. Of these, 86 were classified as normal and 19 as abnormal. The cumulative risk of a recurrence was 29% for those classified as normal compared to 13% for those classified as abnormal. Thus, EEG abnormalities were not predictive of febrile seizure recurrence for the limited number of patients on whom an E E G was performed at the time of the initial febrile convulsions. R i s k o f a third febrile seizure
There; were 205 children followed from second febrile seizure. These patients include the 146 patients under follow-up from the first febrile seizure plus 59 patients who were not residents or not ascertained as the result of the first febrile convulsions but were Rochester residents and ascertained at the tim~ of the second febrile seizure. Among the 205 children 62 went on to have a third
febrile convulsion. The cumulative risk of a third seizure was 13% within 6 months after the second seizure, 21% within 1 year, 27% within 2 years, and 32% for the entire follow-up. As was the case with a first recurrence, the younger the child at the time of the second seizure the greater the risk of yet another febrile seizure. The risk was 43% for children under 2 years of age at the second seizure compared to 22% for those over 2 years. The risk was also increased for children with a positive family history of febrile convulsions, 39-28% over those without a positive history; but the difference was no longer statistically significant. There was a greater sex difference, 35% for boys compared to 28% for girls. Complex seizures were less predictive as the risk was 26% for those with complex features compared to 29% for those without. In contrast to initial recurrences stratified analysis, Table IV shows increased risks of a similar magnitude for individual prognostic factors as well as combinations. The likelihood of a third seizure (32%) after a second was greater overall than the 25% risk of an initial recurrence. The risk for a fourth recurrence increased to 40% for the 88 patients uader followup after the third febrile convulsion but decreased to 32% for a fifth after a fourth seizure (34 patients). Although the numbers were too small to detect significant differences, additional recurrences were still associated with a positive family
TABLE IV Cumulative risk of third febrile seizure by combination of characteristics at first 2 seizures Age Family Corn- No. No. Cumula- Risk under Hx plex children recur, tive ratio 18 FC features rences risk (%) (%) months -
-
-
32
+ + + +
+ + + +
+ + + +
28 i7 34 18 30 13 20
* Reference group.
2
6.4
1.0'
9 5 12 5 10 8 10
36.0 30.3 38.9 27.8 35.9 61.5 50.0
4.2 3.5 4.5 3.2 4.2 7.1 6.1
214 history. None of the other factors considered were prognostic of additional recurrences.
Risk of complex recurrences Of the 639 children followed from an initial febrile seizure, 57 children experienced a subsequent complex seizure, i.e., a second through fifth febrile seizure with complex features, for a lifetable cumulative risk of 10.5%. As for all recurrences, complex features, age under 18 months at initial febrile seizure and a family history of febrile convulsions, were predictors of complex recurrences. Among the 170 children with a complex first seizure, the risk of an additional complex seizure of 15.6% was significantly increased over the risk of 8.6% for those with a simple first febrile convulsion. In the stratified analysis (Table V), the risk of a complex recurrence was only 3% for children with none of the 3 prognostic factors while the risk ranged from 9 to 24% for those with any combinations of a positive family history or under 18 months of age at initial febrile convulsion. A complex initial seizure alone did not increase the risk of a complex recurrence over the baseline risk. As with all recurrences the presence of complex: ~eatures at initial seizure, in addition to young age, increased the risk of further complex recurrences.
TABLE
V
Cumulative risk of complex recurrence by combination of factors at first seizure Age Family Com- No. No, tinder Hx plex children recur18 FC features rences months
Cumulative risk (%)
Risk ratio (%)
-
-
-
192
5
3.0
1.0"
-
-
+
47
1
2,6
0,9
-
+
-
52
7
15.5
5.1
+
-
-
175
14
9.0
3.0
-
+
+
20
2
12.1
4.0
+
-
+
75
15
24.5
8.0
+
+
-
50
9
20.9
6.9
+
+
+
28
4
18.4
6.1
* Reference group.
DISCUSSION The proportion of children experiencing febrile seizure recurrences has been presented in numerous studies; however, most of these studies were of patients referred to specialty clinics whose basis for referral in many cases may have been multiple febrile convulsions. Therefore, We have limited the comparison of our findings for subjects ascertained through inpatient and outpatient medical contacts with other cohort studies whose subjects were not ascertained through referral centers (Table Vl). The overall life-table risk of a second febrile seizure in our study (25%) is slightly less than the proportion of children with a second seizure of 31% in the National Institute of Neurological and Communicative Disorders and Stroke Collaborative Perinatal Project (NCPP) 9. Recurrences were more frequent in the British National Birth Cohort Study 13 (36%), the Kaiser-Oakland n birth cohort of 40% and in children followed from hospitalization for a first febrile seizure, 37% and 4 8 % 6'14. The lower recurrence risk in the current study is due, at least in part, to the exclusions of patients whose initial febrile convulsions were ascertained as a result of a subsequent febrile or afebrile seizure. In fact, if all 817 patients identified as having febrile convulsions while residents of Rochester were included in this study the cumulative recurrence risk would be 33%. This, however, would be a biased estimate because some of these patients were ascertained only because a recurrence occurred. The higher risks reported in studies of hospitalized cases are presumably due also to the selection of a greater proportion of patients with complex features who are at greater risk. The risks of a third febrile convulsion, in the Oakland u cohort 40% and for a fourth 42%, are similar to the risks of 38% and 40%, respectively, found in the present study while the Oakland study reported much higher risks of an initial recurrence, i.e., 40% vs. 25%. This difference may be due to a greater number of initial seizures in the Oakland study being ascertained through subsequent seizures which were not included in the Rochester study. Progressively higher rates of recurrence were reported by Verity et al. 13 of 36%
215
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for the second, 54% and 62% for a fourth. All investigations have found that children with a first febrile seizure at younger ages are at higher risk of recurrence. The proportion of children with a recurrence is in the order of 2-fold higher in children less than 18 months compared to children over 18 months at first seizure. Nelson and Ellenberg 9 and Verity et al. 13reported a decreasing proportion of children with recurrences with each successive year of age at first seizure from a high of 50% with recurrences in children less than 1 year of age to a low of 12-18% in children over 3 years of age. In the present study, the risk of recurrence was somewhat lower for childrca under 1 year (30%) when compared to the other studies; but was similar for children 3 years and over (10%). A family history of febrile convulsions has been shown to be a strong risk factor for an initial febrile seizure, and there is general agreement among the studies reviewed here that the risk of an initial recurrence is increased 1.8-fold among children with a family history of febrile convulsions (Table VI). Our findings also show an effect of a family history of febrile convulsions on subsequent recurrences which is independent of the effect of young age at first seizure. The increased risk of recurrence associated with a family history is presumably due to an underlying predisposition to febrile convulsions which is related not only to a higher risk of febrile convulsions in relatives3'1° but also to recurrences. There is less agreement on the effect of a family history of afebrile convulsions on recurrence of febrile seizures. Knudsen 6 reported an increase in recurrence risk associated with a family history of afebrile convulsions similar to that for a family history of febrile convulsions, but this was based on only 8 cases with a family history of afebrile seizures. Nelson and Ellenberg 9 reported a significant association of recurrence with a history of afebrile seizures in the immediate family, but it is not known to what extent these included family members with febrile seizures as well. We did not find children with a family history of only afebrile seizures to be at increased risk of recurrence. Males have a higher incidence of febrile seizures as is evidenced by the higher proportion of males in the 5 studies summarized in Table VI. All studies are in agreement, however, that the higher in-
216 cidence of first febrile convulsions in males does not imply a propensity for more frequent recurrences. However, in the present study, males did have a higher risk of a third febrile seizure than females (38% vs. 29%) although this was not statistically significant. Children with febrile convulsions with complex features - - focal features, long duration and repeated episoacs - - have been shown to be at increased risk for subsequent unprovoked seizures t°. However, the relation between an initial febrile convulsion with complex features and febrile seizure recurrence has been less certain. Wallace t4 and Knudsen 6 found children whose initial seizure was complex to be at increased risk of recurrence, however, Nelson and Ellenberg 9 and Verity et al.t3 did not find a statistically significant increase. The results reported by Verity et al. 13, however, coui' also be interpreted as being consistent with an increased risk, as the risk was 34% among those with an initial simple febrile convulsion compared to 44% when the first febrile convuision was complex. Our findings show a statistically significant univariate association between complex features and recurrence. However, stratified analysis reveals that complex febrile seizures were not an independent prognostic factor but a modifier of the effect of the other prognostic factors, particularly young age at first seizure. Data were not reported from the other studies which REFERENCES 1 Annegers, J.F., Hauser, W.A., Elveback, L.R. and Kurland, L.T., The risk of epilepsy following febrile convulsions, Neurology, 29 (19'19) 297-303. 2 Cutler, S.J. and Ederer, F., Maximum utilization of the life table method in analyzing survival, J. Chron. Dis., 8 (1959) 699-712. 3 Hauser, W.A., Annegers, J.F., Anderson, V.E. and Kurland, L.T., The risk of seizure disorders among relatives of children with febrile convulsions, Neurology, 35 (1985) 1268-1273. 4 Hauser, W.A. and Kurland, F.T., The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967, Epilepsia, 16 (1975) 1-66. 5 Kalbfleisch, J.D. and Prentice, R.L., Statistical Analysis of Failure Time Data, Wiley, New York, 1980. 6 Knudsen, F.U., Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis, Arch. Dis. Child., 60 (1985) 1045-1049. 7 Mantel, N., Evaluation of survival data and two new rank order statistics arisin~ in its consideration, Cancer Che-
would allow us to evaluate whether a complex initial seizure is a factor which modifies the effect of age at first seizure on recurrence. While children with complex febrile seizures have been shown to be at an increased risk of subsequent epilepsy compared to children with simple febrile seizures, the identification of children at high risk of complex febrile seizures remains largely unaddressed in prior studies. Nelson and Ellenberg9 have emphasized that the vast majority of complex febrile convulsions, 75% in the NCPP, occur as a child's first seizure before preventive measures can be taken. Among children followed from the initial febrile seizure, 83% of those with one or more complex febrile seizures experienced a complex first seizure. The overall risk of complex recurrences was 10% but it was 15-24% for those who had a positive family history, 18-24% for those whose first seizure was complex, while the risk was only 3% for those of young age at initial febrile seizure and no family history. ACKNOWLEDGEMENTS This research was supported in part by the Minnesota Comprehensive Epilepsy Program, Grant NS-16308 from the National Institute of Neurological and Communicative Disorders and Stroke. We thank Ms. Pat Perkins and Ms. Sally Book for assistance in the data collection. mother. Rep., 50 (1966) 163-170. 8 National Institutes of Health Consensus Development Conference, Consensus statement on febrile seizures. In: K.B. Nelson and J.H. Ellenberg (Eds.), Febrile Seizures, Raven Press, New York, 1981, pp. 302-306. 9 Nelson, K.B. and EUenberg, J.H., Prognosis in children with febrile seizures, Pediatrics, 61 (1978) 720-727. 10 Tsuboi, T., Genetic aspects of febrile convulsions, Hum. Genet., 38 (1977) 169-173. 11 Van den Berg, B.J., Studies on convulsive disorders in young children. IV. Incidence of convulsions among siblings, Dev. Med. Child. Neurol., 16 (1974) 457-464. 12 Van den Berg, B. and Yerushalmy, J., Studies on convulsive disorders in young children. III. Recurrence of febrile convulsions, Epilepsia, 15 (1974) 177-190. 13 Verity, C.M., Butler, N.R. and Golding, J., Febrile convulsions in a national cohort followed from birth. I. Prevalence and recurrence in the first five years of life, Br. Med. J., 290 (1985) 1307-1310. 14 Wallace, S.J., Recurrence of febrile convulsions, Arch. Dis. Child., 49 (1974) 763-765.
209
Elsevier EPIRES 00.299
Recurrence of febrile convulsions in a population-based cohort*
J o h n F. A n n e g e r s , Sally A . B l a k l e y a, W. A l l e n H a u s e r b a n d L e o n a r d T. K u r l a n d c Division of Epidemiology, Universityof Texas Health Science Centerat Houston, School of Public Health, Houston, TX (U.S.A.), aDepartment of Epidemiology, 7)dane University, New Orleans, LA (U. S.A.), bDepartmentsof Epidemiology and Neurology, G.H. Sergievsky Center, Columbia MedicalSchool, New York, NY (U.S.A.), and CDepartmentof Medical Statisticsand Epid.'miology, Mayo Clinic, Rochester, MN (U.S.A.) (Received 19 May 1989; revision received 8 July 1989; accepted 11 July 1989)
Key words: Febrile convulsion; Prognosis; Recurrence
The risk of recurrence after an initial febrile seizure was 25% in a population-based cohort of 639 children followed from their first febrile seizure. Prognostic factors were an increasing risk of recurrence with younger age at first febrile seizure, a first degree relative with febrile seizures and complex features of the first febrile seizure. The effect of complex features was modified by age at first febrile seizure and family history in that complex features alone did not increase risk of recurrence but further increased the risk for children under 18 months at first seizure and/or with a positive family history. The prognostic factors for all febrile convulsions recurrences were also prognostic for having subsequent complex febrile convulsions. Children with none of the prognostic factors had only a 3% risk of a future complex febrile seizure while children under 18 months at first febrile convulsion and a positive family history or complex features had about a ~~3%risk of a subsequent comp!ex febrile seizure.
INTRODUCTION Febrile convulsions are a common childhood condition affecting 2-4% of children and they tend to recur. A few population-based studies have reported recurrence risks of 31-48% after an initial febrile seizure 1'4'9'n'13. Although in agreement on some prognostic factors, e.g., young age at onset and a family history of febrile convulsions, these studies are discrepant regarding complex features of the initial febrile convulsion. More= * Presented in part at the 39th annual meeting of the American Academy of Neurology, New York, NY, April 1987.
Correspondence to.: Dr. J.F. Annegers, University of Texas Health Science Center at Houston, School of Public Health, P.O. Box 20186, Houston, TX 77225, U.S.A.
over, the risks and prognostic factors for a recurrent febrile seizure with complex features have not been evaluated. Based on the follow-up of a large cohort of children with an initial febrile seizure while residents of Rochester, Minnesota, we have addressed the following questions in this paper: (1) What is the overall probability of recurrence after an initial febrile seizure? (2) Do potential prognostic factors examined in other studies, e.g., age at first seizure, sex, family history of seizure disorders, the presence of complex features, show a similar pattern of association with subsequent seizures? (3) Given a second febrile convulsion what are the risks for further recurrences? (4) What is the risk of a subsequent complex febrile seizure? (5) Are there any factors which identify children at high
0920-1211/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
210 risk of subsequent complex febrile seizures? METHODS The design and methods of this investigation have been described in detail previously and will only be summarized here 4. The resources of the medical record linkage system of the Rochester Project of the Mayo Clinic were utilized to identify residents of Rochester, Minnesota with a diagnosis of febrile seizure between 19.~5 and 1984. Under the record linkage system all contacts with medical care facilities in the Rochester, Minnesota area including records of all inpatient, outpatient, emersency room and home visits have been indexed by diagnostic code. For this study, we retrieved all records indexed to a diagnosis of seizure or to selected conditions potentially related to seizure occurrence and reviewed the records to validate the diagnosis of seizure and to determine the clinical circumstances of the seizure. This process provided for comprehensive identification of the occurrence of febrile seizures among Rochester residents who received medical attention and were indexed as such. Febrile seizure was defined as a convulsion with febrile illness in childhood in the absence of intracranial infection or other acute cause or of a prior history of unprovoked seizure in accordance with the recommendations of the National Institutes of Health Consensus Conference s. A total of 817 (Table I) children were identified as having febrile convulsions while residents of Rochester, Minnesota between 1935 and 1984. Of these 33 were not Rochester residents for the first febrile convulsions but satisfied residency criteria for later convulsions. Because these patients were not followed from the initial febrile convulsion they were TABLE !
Febrile convulsions, Rochester, Minnesota, 1935-1984 exclusions for evaluation of febrile recurrences Total cases Less non-residents for initial febrile seizure (33) l.ess not ascertained at initial seizure (124) Less neuro-defici~ from birth (16) Less cases without, foUow-up (5)
817 784 660 644 633
not included in the study. An additional 124 children were excluded because they were not ascertained at the time of the initial febrile convulsion but as a result of sequelae including subsequent febrile or afebrile convulsions or through an affected relative. Finally, 16 additional febrile convulsion cases with cerebral palsy or mental retardation, i.e., IO less than 70, were excluded. Children were not excluded solely on the basis of having had neonatal convulsions (n - 6). No age criteria for the first febrile seizure were imposed; however, 98.5% of the children in the cohort were aged 6 years or less with 11 children having their first febrile seizure between ages 7 and 11. We identified 644 children meeting clinical, residency and ascertainment criteria for a first febrile seizure during the period 1935-1984. Information was abstracted from the medical records of these eligible cases which included: age at initial febrile convulsion; the dates of subsequent febrile convulsions; and for each febrile convulsion, whether long-term anticonvulsant medications were prescribed, the presence or absence of focal features (including Todd's paralysis), the duration of the febrile seizure and whether there were repeated episodes of seizures within 24 h. Multiple seizures within a 24 h period were not classified as recurrences but as a single seizure characterized by repeated episodes. Seizures were classified as complex if characterized by any one or more of the following: focal features, duration longer than 10 min, or repeated episodes within 24 h. A family history of seizure disorders among first degree relatives was obtained by reviewing the medical records of the parents and siblings of the index cases. Twelve cases with a family history of both febrile and unprovoked seizures were classified as having both a positive family history of febrile seizures and a positive family history of unprovoked seizures. Children were followed from the initial febrile seizure for subsequent febrile seizures via the medical records linkage system. Afebrile convulsions and seizures due to other acute causes, e.g., central nervous system infections or head trauma, were not included as recurrences of febrile seizure. Follow-up was terminated by migration from southeastern Minnesota, the development of un-
211
provoked seizures, death or the close of the study in 1987. Of the 6 ~ children, five without followup after the initial febrile convulsions were excluded. Among the remaining 639 children, 96% were under follow-up at 2 years after the initia! seizure and 91% at the end of 4 years. Risks of a recurrent febrile seizure were computed by life-table methods for a second, third, fourth and fifth seizure after the first seizure and for a complex seizure on either the second or third seizure after the first seizure s . Cumulative risks are presented for the total follow-up of this cohort, which is essentially equivalent to 48 months of follow-up inasmuch as there was only one recurrence after this time. Because the time to recurrence is short and losses from the cohort during the initial
years of follow-up were few in this study, the lifetable risks are similar to the simple proportions of children with recurrences. Potential prognostic factors were evaluated by stratified life-tables, and the Mantel-Cox statistic was used to test for differences in the risk of recurrence ~. The proportional hazards model was also used for multivariate analysis of the simultaneous effect of the factors under study on recurrence s . RESULTS
Risk of a second febrile seizure Of the 639 children, 148, or 23.2%, experienced a recurrence (Table II). The life-table risk of recurrent febrile seizure was 12% within 6 months
TABLE II
Cumulative risk of second febrile seizure by characteristics at first febrile seizure
Total
No. characteristic children
Recurrence
639
6 months
I year
2 years
Total
148
11.8
17.3
23.2
26.0
128 336 107 68
36 86 20 6
13.5 13.2 8.7 6.6
20.2 18.6 13.7 10.1
30.0 25.3 15,9 10,1
30.0 27,6 22,1 10,1'
150 489
52 96
17.6 10.1
25,9 !4.5
33,8 19.8
36,2* 22,0
170 469
52 96
13.3 11.3
19.0 16.6
29.9 20.8
35.0 22.1
28 52 559
9 17 122
18.5 5.9 12.1
18,5 22.2 16.7
29.6 32.8 21.9
35.0 35,1 24.0
30 609
10 138
20.2 11.5
27.2 16.8
31.0 22.9
38.0 24.4
94 545
31 117
17.5 10.9
22,2 16.5
32.3 21.7
38,7* 23,4
Age I year 1-2 2-3 3+
FamilyHxFC Yes No
Complex features Yes No
Duration 30+ 10-29 10
Focal features Yes No
Repeated episodes Yes No *P < 0.05.
Cumulative risk (%)
212 after the first febrile convulsion, 17% within I year and 23% within 2 years. In all, 95% of second febrile seizures occurred within 2 years of the first seizure and consequently the cumulative risk increased only to 26% for the entire follow-up. As expected, the risk of recurrence was inversely associated with the child's age at first seizure (Table II). Children whose first seizure occurred under 1 year of age had the highest risk, or 30%, while that risk declined to 10% for those over 3 years at first seizure. A positive history of febrile seizures in a first degree relative was identified in 150 or 23% of the children. The risk of a recurrence was 36% in these children and was significantly higher than the risk of 22% for children without a family history of febrile seizures (Table II). In contrast, the 33 children with a family history of unprovoked seizures did not experience recurrences more frequently than children without such family history (25% vs. 23%, respectively). Age at initial febrile seizure and family history of febrile convulsions were both independently associated with recurrence risk. The risk associated with eithex~of these prognostic indicators alone of 28-29% was about twice that of children without either factor. The joint effect of a positive family history and young age at first febrile convulsion was additive as the risk for these children was 42%. In 170, or 26.6% of the children, the first febrile convulsion was complex. The risk of recurrence after a complex initial seizure of 35% was significantly higher than that of 22% after an initial simple seizure. Each of the individual characteristics of complex seizure-- focal features, repeated episodes, and long d u r a t i o n - was similarly associated with increased recurrences: 38% and 24% for focal vs. generalized seizures; 39% and 23% for repeated seizures vs. single seizures within 24 h; and 35% more than 10 min duration compared to 24% for those less than 10 min (Table II). To examine whether the effect of complex features was attenuated by confounding or interaction by age and family history, the cohort was stratiffed by combinations of these risk factors (Table III). These results show baseline risk of 15% for children with none of the risk factors. Children
T A B L E III
Cumulative risk of second febrile seizure by combination of characteristics at first seizure Age F a m i l y Corn- No. No. Cumula- Risk under Hx plex childrenrecur- tire ratio 18 FC features rences risk (%) (%) months -
-
-
192
26
15.1
-
-
+
47
5
9.0
0.6
1.0"
-
+
-
52
13
26.8
1.8
+
-
-
175
39
23.6
1.6
-
+
+
20
7
36.6
2.4
+
-
+
75
26
40.1
2.7
+
+
-
50
18
37.2
2.5
+
+
+
28
14
52.2
3.5
* R e f e r e n c e group.
with young age at first febrile convulsion have a 1.6-fold increased risk over those with none of the factors while children with a positive family history alone have a 1.8-fold increased risk. However, there is no independent effect of complex seizures as the risk for children with complex seizures alone of 9% was slightly less than that for children without any of the prognostic factors. However, the presence of complex features modified the effect of age at initial febrile seizures. The relative risk for children with complex features and age under 18 months was 2.7 compared to 1.6 for age under 18 months alone. The relative risk for children with all 3 factors was 3.5 compared to 2.5 for children under age 18 months with a positive family history. Thus, although not a prognostic factor alone the presence of complex features increased the recurrence risk of younger children with initial febrile convulsions. Boys were only slightly more likely to experience an initial recurrence than girls (26% vs. 23%). Because this study included patients with an initial febrile seizure over a 50 year period, recurrence risks were determined by time periods. There was no secular trend in the recurrence risks as the risks were 20%, 23%, 27%, 25% and 26% for the 5 successive decades of the study. The risks of recurrence varied littly by type of illness associated with the febrile convulsion. Among the more frequent known illnesses, the risks were 28% with upper respiratory infections (330 cases), 31% with otitis media (n - 131), 28%
213 with roseola (n = 44) and 26% for post-vaccination febrile convulsions (n = 19). We also considered the potential role of anticonvulsant medications as a confounder in our analysis. Overall 131 or 20% of children were prescribed continuous anticonvulsant medication after the first seizure. Selection for such treatment was primarily related to time period, more common during the late 1960s and early 1970s, and to the clinical characteristics of the seizure as those who experienced a complex first seizure were more likely to be prescribed anticonvulsants. However, prophylactic treatment was not related to age at seizure or to family history of febrile seizures. The frequency of recurrences did not differ by medication status according to the univariate a n a l y s i s - - 27% with continuous anticonvulsants compared to 25% without, or in the multivariate analysis, rate ratio for continuous anticonvulsants adjusting for age, family history of febrile convulsions and complex features was 0.9 (95% CI 0.6-1.3). Consequently, adjustment for anticonvulsant status did nc,t affect our findings. However, no information on compliance with therapy was available for these analyses, and therefore these findings should not be interpreted as evidence against the efficacy of anticonvulsant medications. Only 105 of the 635 children ascertained at their first febrile convulsions had an E E G performed at that time. Of these, 86 were classified as normal and 19 as abnormal. The cumulative risk of a recurrence was 29% for those classified as normal compared to 13% for those classified as abnormal. Thus, EEG abnormalities were not predictive of febrile seizure recurrence for the limited number of patients on whom an E E G was performed at the time of the initial febrile convulsions. R i s k o f a third febrile seizure
There; were 205 children followed from second febrile seizure. These patients include the 146 patients under follow-up from the first febrile seizure plus 59 patients who were not residents or not ascertained as the result of the first febrile convulsions but were Rochester residents and ascertained at the tim~ of the second febrile seizure. Among the 205 children 62 went on to have a third
febrile convulsion. The cumulative risk of a third seizure was 13% within 6 months after the second seizure, 21% within 1 year, 27% within 2 years, and 32% for the entire follow-up. As was the case with a first recurrence, the younger the child at the time of the second seizure the greater the risk of yet another febrile seizure. The risk was 43% for children under 2 years of age at the second seizure compared to 22% for those over 2 years. The risk was also increased for children with a positive family history of febrile convulsions, 39-28% over those without a positive history; but the difference was no longer statistically significant. There was a greater sex difference, 35% for boys compared to 28% for girls. Complex seizures were less predictive as the risk was 26% for those with complex features compared to 29% for those without. In contrast to initial recurrences stratified analysis, Table IV shows increased risks of a similar magnitude for individual prognostic factors as well as combinations. The likelihood of a third seizure (32%) after a second was greater overall than the 25% risk of an initial recurrence. The risk for a fourth recurrence increased to 40% for the 88 patients uader followup after the third febrile convulsion but decreased to 32% for a fifth after a fourth seizure (34 patients). Although the numbers were too small to detect significant differences, additional recurrences were still associated with a positive family
TABLE IV Cumulative risk of third febrile seizure by combination of characteristics at first 2 seizures Age Family Corn- No. No. Cumula- Risk under Hx plex children recur, tive ratio 18 FC features rences risk (%) (%) months -
-
-
32
+ + + +
+ + + +
+ + + +
28 i7 34 18 30 13 20
* Reference group.
2
6.4
1.0'
9 5 12 5 10 8 10
36.0 30.3 38.9 27.8 35.9 61.5 50.0
4.2 3.5 4.5 3.2 4.2 7.1 6.1
214 history. None of the other factors considered were prognostic of additional recurrences.
Risk of complex recurrences Of the 639 children followed from an initial febrile seizure, 57 children experienced a subsequent complex seizure, i.e., a second through fifth febrile seizure with complex features, for a lifetable cumulative risk of 10.5%. As for all recurrences, complex features, age under 18 months at initial febrile seizure and a family history of febrile convulsions, were predictors of complex recurrences. Among the 170 children with a complex first seizure, the risk of an additional complex seizure of 15.6% was significantly increased over the risk of 8.6% for those with a simple first febrile convulsion. In the stratified analysis (Table V), the risk of a complex recurrence was only 3% for children with none of the 3 prognostic factors while the risk ranged from 9 to 24% for those with any combinations of a positive family history or under 18 months of age at initial febrile convulsion. A complex initial seizure alone did not increase the risk of a complex recurrence over the baseline risk. As with all recurrences the presence of complex: ~eatures at initial seizure, in addition to young age, increased the risk of further complex recurrences.
TABLE
V
Cumulative risk of complex recurrence by combination of factors at first seizure Age Family Com- No. No, tinder Hx plex children recur18 FC features rences months
Cumulative risk (%)
Risk ratio (%)
-
-
-
192
5
3.0
1.0"
-
-
+
47
1
2,6
0,9
-
+
-
52
7
15.5
5.1
+
-
-
175
14
9.0
3.0
-
+
+
20
2
12.1
4.0
+
-
+
75
15
24.5
8.0
+
+
-
50
9
20.9
6.9
+
+
+
28
4
18.4
6.1
* Reference group.
DISCUSSION The proportion of children experiencing febrile seizure recurrences has been presented in numerous studies; however, most of these studies were of patients referred to specialty clinics whose basis for referral in many cases may have been multiple febrile convulsions. Therefore, We have limited the comparison of our findings for subjects ascertained through inpatient and outpatient medical contacts with other cohort studies whose subjects were not ascertained through referral centers (Table Vl). The overall life-table risk of a second febrile seizure in our study (25%) is slightly less than the proportion of children with a second seizure of 31% in the National Institute of Neurological and Communicative Disorders and Stroke Collaborative Perinatal Project (NCPP) 9. Recurrences were more frequent in the British National Birth Cohort Study 13 (36%), the Kaiser-Oakland n birth cohort of 40% and in children followed from hospitalization for a first febrile seizure, 37% and 4 8 % 6'14. The lower recurrence risk in the current study is due, at least in part, to the exclusions of patients whose initial febrile convulsions were ascertained as a result of a subsequent febrile or afebrile seizure. In fact, if all 817 patients identified as having febrile convulsions while residents of Rochester were included in this study the cumulative recurrence risk would be 33%. This, however, would be a biased estimate because some of these patients were ascertained only because a recurrence occurred. The higher risks reported in studies of hospitalized cases are presumably due also to the selection of a greater proportion of patients with complex features who are at greater risk. The risks of a third febrile convulsion, in the Oakland u cohort 40% and for a fourth 42%, are similar to the risks of 38% and 40%, respectively, found in the present study while the Oakland study reported much higher risks of an initial recurrence, i.e., 40% vs. 25%. This difference may be due to a greater number of initial seizures in the Oakland study being ascertained through subsequent seizures which were not included in the Rochester study. Progressively higher rates of recurrence were reported by Verity et al. 13 of 36%
215
..=
i
ie
V^
VAVAVAVA
,-k
i o e~
=
o
for the second, 54% and 62% for a fourth. All investigations have found that children with a first febrile seizure at younger ages are at higher risk of recurrence. The proportion of children with a recurrence is in the order of 2-fold higher in children less than 18 months compared to children over 18 months at first seizure. Nelson and Ellenberg 9 and Verity et al. 13reported a decreasing proportion of children with recurrences with each successive year of age at first seizure from a high of 50% with recurrences in children less than 1 year of age to a low of 12-18% in children over 3 years of age. In the present study, the risk of recurrence was somewhat lower for childrca under 1 year (30%) when compared to the other studies; but was similar for children 3 years and over (10%). A family history of febrile convulsions has been shown to be a strong risk factor for an initial febrile seizure, and there is general agreement among the studies reviewed here that the risk of an initial recurrence is increased 1.8-fold among children with a family history of febrile convulsions (Table VI). Our findings also show an effect of a family history of febrile convulsions on subsequent recurrences which is independent of the effect of young age at first seizure. The increased risk of recurrence associated with a family history is presumably due to an underlying predisposition to febrile convulsions which is related not only to a higher risk of febrile convulsions in relatives3'1° but also to recurrences. There is less agreement on the effect of a family history of afebrile convulsions on recurrence of febrile seizures. Knudsen 6 reported an increase in recurrence risk associated with a family history of afebrile convulsions similar to that for a family history of febrile convulsions, but this was based on only 8 cases with a family history of afebrile seizures. Nelson and Ellenberg 9 reported a significant association of recurrence with a history of afebrile seizures in the immediate family, but it is not known to what extent these included family members with febrile seizures as well. We did not find children with a family history of only afebrile seizures to be at increased risk of recurrence. Males have a higher incidence of febrile seizures as is evidenced by the higher proportion of males in the 5 studies summarized in Table VI. All studies are in agreement, however, that the higher in-
216 cidence of first febrile convulsions in males does not imply a propensity for more frequent recurrences. However, in the present study, males did have a higher risk of a third febrile seizure than females (38% vs. 29%) although this was not statistically significant. Children with febrile convulsions with complex features - - focal features, long duration and repeated episoacs - - have been shown to be at increased risk for subsequent unprovoked seizures t°. However, the relation between an initial febrile convulsion with complex features and febrile seizure recurrence has been less certain. Wallace t4 and Knudsen 6 found children whose initial seizure was complex to be at increased risk of recurrence, however, Nelson and Ellenberg 9 and Verity et al.t3 did not find a statistically significant increase. The results reported by Verity et al. 13, however, coui' also be interpreted as being consistent with an increased risk, as the risk was 34% among those with an initial simple febrile convulsion compared to 44% when the first febrile convuision was complex. Our findings show a statistically significant univariate association between complex features and recurrence. However, stratified analysis reveals that complex febrile seizures were not an independent prognostic factor but a modifier of the effect of the other prognostic factors, particularly young age at first seizure. Data were not reported from the other studies which REFERENCES 1 Annegers, J.F., Hauser, W.A., Elveback, L.R. and Kurland, L.T., The risk of epilepsy following febrile convulsions, Neurology, 29 (19'19) 297-303. 2 Cutler, S.J. and Ederer, F., Maximum utilization of the life table method in analyzing survival, J. Chron. Dis., 8 (1959) 699-712. 3 Hauser, W.A., Annegers, J.F., Anderson, V.E. and Kurland, L.T., The risk of seizure disorders among relatives of children with febrile convulsions, Neurology, 35 (1985) 1268-1273. 4 Hauser, W.A. and Kurland, F.T., The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967, Epilepsia, 16 (1975) 1-66. 5 Kalbfleisch, J.D. and Prentice, R.L., Statistical Analysis of Failure Time Data, Wiley, New York, 1980. 6 Knudsen, F.U., Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis, Arch. Dis. Child., 60 (1985) 1045-1049. 7 Mantel, N., Evaluation of survival data and two new rank order statistics arisin~ in its consideration, Cancer Che-
would allow us to evaluate whether a complex initial seizure is a factor which modifies the effect of age at first seizure on recurrence. While children with complex febrile seizures have been shown to be at an increased risk of subsequent epilepsy compared to children with simple febrile seizures, the identification of children at high risk of complex febrile seizures remains largely unaddressed in prior studies. Nelson and Ellenberg9 have emphasized that the vast majority of complex febrile convulsions, 75% in the NCPP, occur as a child's first seizure before preventive measures can be taken. Among children followed from the initial febrile seizure, 83% of those with one or more complex febrile seizures experienced a complex first seizure. The overall risk of complex recurrences was 10% but it was 15-24% for those who had a positive family history, 18-24% for those whose first seizure was complex, while the risk was only 3% for those of young age at initial febrile seizure and no family history. ACKNOWLEDGEMENTS This research was supported in part by the Minnesota Comprehensive Epilepsy Program, Grant NS-16308 from the National Institute of Neurological and Communicative Disorders and Stroke. We thank Ms. Pat Perkins and Ms. Sally Book for assistance in the data collection. mother. Rep., 50 (1966) 163-170. 8 National Institutes of Health Consensus Development Conference, Consensus statement on febrile seizures. In: K.B. Nelson and J.H. Ellenberg (Eds.), Febrile Seizures, Raven Press, New York, 1981, pp. 302-306. 9 Nelson, K.B. and EUenberg, J.H., Prognosis in children with febrile seizures, Pediatrics, 61 (1978) 720-727. 10 Tsuboi, T., Genetic aspects of febrile convulsions, Hum. Genet., 38 (1977) 169-173. 11 Van den Berg, B.J., Studies on convulsive disorders in young children. IV. Incidence of convulsions among siblings, Dev. Med. Child. Neurol., 16 (1974) 457-464. 12 Van den Berg, B. and Yerushalmy, J., Studies on convulsive disorders in young children. III. Recurrence of febrile convulsions, Epilepsia, 15 (1974) 177-190. 13 Verity, C.M., Butler, N.R. and Golding, J., Febrile convulsions in a national cohort followed from birth. I. Prevalence and recurrence in the first five years of life, Br. Med. J., 290 (1985) 1307-1310. 14 Wallace, S.J., Recurrence of febrile convulsions, Arch. Dis. Child., 49 (1974) 763-765.
