European Journal of Paediatric Neurology (2004) 8, 131134

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ORIGINAL ARTICLE

Intermittent oral diazepam prophylaxis in febrile convulsions: its effectiveness for febrile seizure recurrence
Alberto Verrottia,*, Giuseppe Latinib, Giovanna di Corciaa, Raffaella Giannuzzib, Carmela Salladinia, Daniela Trottaa, Francesco Chiarellia
a

Section of Pediatrics, Department of Medicine, University of Chieti-Ospedale Policlinico, Via dei Vestini 5, Chieti 66013, Italy b Department of Pediatrics, Perrino Hospital of Azienda Ospadaliera Di Summa, Brindisi, Italy
Received 30 September 2003; accepted 27 January 2004

KEYWORDS
Febrile seizures; Diazepam

Summary In order to evaluate the effectiveness of diazepam for the reduction in the recurrence of febrile seizures we carried out a prospective study in two groups of children; Group A: 45 children (25 female, 20 male), receiving oral prophylaxis with diazepam, and Group B: 65 children (35 female, 30 male) who did not receive any oral prophylaxis. All subjects of both groups were followed for at least 4 years and nally re-evaluated at the mean age of 6.7 ^ 1.4 years. Among the patients of Group A, recurrent febrile seizures (FS) occurred in ve of the 45 children (11.1%). Among the 65 children of Group B, 20 (30.7%) went on to have one or more additional episodes. In conclusion, our study demonstrates that oral diazepam, given only when fever is present, is an effective means of reducing the risk of recurrences of FS. Q 2004 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Introduction
Febrile seizures (FS) are the most common type of seizures and occur in 2 4% of children. One of the greatest concern of the parents of children with FSs is the possibility of other convulsions during other febrile infections.1 3 In spite of many large epidemiological studies,4,5 there is no agreement about when, or in what circumstances, to carry out an intermittent diazepam prophylaxis is justiable.
*Corresponding author. Tel.: 39-871-574-538; fax: 39-871574-831. E-mail address: averrott@unich.it (A. Verrotti).

There are some uncontrolled studies4,5 and one large randomized study which demonstrated that administration of oral diazepam could reduce the recurrence of FS.6 The aim of study was to evaluate the effectiveness of administration of oral diazepam for the reduction of the recurrence of FS.

Materials and methods

We carried out a prospective study in two groups of children. Group A: 45 children (25 female, 20 male)

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who had one simple FS; the inclusion criteria were: no personal history of afebrile seizures, normal neurophychomotor development, age from 6 months to 5 years, no previous anticonvulsant therapy. After a careful and detailed information about the pathogenesis and the treatment of FS, the parents of these patients received written instructions explaining how to give the oral prophylaxis with diazepam, according to the body weight of the child (0.35 mg/kg every 8 h), during each episode of fever higher than 38 8C, continuing until the child had been afebrile for 24 h. Moreover, instructions to stop seizure by diazepam administered rectally at the dosage of 0.5 mg/kg were given to the parents of these children. The diazepam was effective in all children after the rst dose. Group B: 65 (35 female, 30 male) children who had one simple FS; the inclusion criteria were the same of the Group A patients, but they did not receive any oral prophylaxis. All children of both groups were Caucasian. A FS was dened in accordance with the National Institutes of Health consensus statement. Complex seizures were dened as either focal or multiple seizures or seizures with duration . 15 min, or a combination of these; simplex seizures were dened as generalised seizures that lasted less than 15 min and did not recur within a day. A statistician randomly assigned each child to Group A or B and the doctors who followed these children did not know the randomization. All children of both groups were recruited after the rst FS from the Paediatric Department of Chieti University and the Division of Pediatrics of Di Summa Hospital, Brindisi, admitted in these hospitals for FS; the age at the hospital admission (in occasion of the rst FS) ranged from 1.7 to 3.9 years (mean ^ SD 2.5 ^ 1.4); the pregnancy and neonatal period were normal. No patients had clinical or laboratory signs of progressive central nervous system disease, nor associated psychiatric disorders and all children showed normal cerebral computed tomography or magnetic resonance imaging (performed in six patients). In the large majority of cases, FS were brief, generalised, tonic clonic. EEG was performed in all patients within a week after the rst seizure and in the majority of the patients (90/110) in the third day after the FS; aspecic anomalies (e.g. mild background dysrhythmia, slow rhythms, background instability, moderate rhythm asymmetry) were found in 10 children; in particular, the most frequent anomaly was background instability, but all these anomalies disappeared after few days. Remaining children showed normal EEG.

Cerebrospinal uid examination, performed in two cases with suspected meningeal infection, showed normal results. All subjects of both groups were followed for at least 4 years and nally re-evaluated at the mean age of 6.7 ^ 1.4 years. During these 4 years, we met the families of the children every 6 months in order to have all information about FS of the patients (and the eventual side effects of diazepam) and to reinforce the study program. The duration of fever preceding the FS was usually less than 24 h in all patients of both groups, in particular it ranged from 2 h (seven patients) to 64 h (one patient). During each episode of fever higher than 38 8C all of the patients were treated with paracetamol. EEG recordings were performed during waking and spontaneous sleep, as previously described.7

Statistical analysis
Comparison between two groups was analysed by independent-sample t-tests for quantitative variables and the x 2 test for categorical variables. P values , 0.05 were considered statistically signicant. For the analysis of the time to the rst recurrence of a febrile seizure, we used the Kaplan Meier method to plot the incidence curves.

Results
There were 113 children who met all the entry criteria. Three children were excluded because no follow-up information could be obtained after the initial evolution. This report is, therefore, based on the remaining 110 children for whom a follow-up contact was made. In most instances, their seizures were associated with upper respiratory tract infections, and all children recovered without complications within a few days. Of the 110 children, 30 (27.2%) presented with an initial complex febrile seizure; in particular in Group A we found 15 children with complex seizures, while 20 children of Group B showed complex seizures. The mean ^ SD follow-up time all cases were 50.2 months (range, 48.0 66.2 months). Among the patients of Group A, recurrent FS occurred in ve of the 45 children (11.1%). In these ve FS, parents did not administer oral diazepam to them. Parents were asked why the medication had not been given. The main reasons were that the parents did not take the childs temperature, that

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the seizure was the rst sign of illness, and that the last recorded temperature had been normal. On other occasions, the medication was not with the parent, the parents misunderstood the instructions, the child spat up the medicine, or the parents were worried about the side effects. The most common side effects are: ataxia, lethargy and irritability. In particular, 14 children (31.1%) had ataxia, 13 (28.8%) presented lethargy and 11 children (24.4%) had irritability. In all cases, these side effects lasted no more than 36 h. Among the 65 children of Group B, 20 (30,7%) children showed at least one recurrence of FS during the follow-up. In detail among the 20, it is interesting to report that eight had at least three, and ve at least four recurrent FS. Hence, of children with an initial recurrence, 31% went on to have one or more additional episodes. Most recurrent FS were simple ones. Only two children with an initial complex febrile seizure and three children with an initial simple febrile seizure had complex recurrent ones during the follow-up period. The rate of recurrence declined gradually as the children aged. None of the 110 children had abnormal neurological or developmental sequelae. Multiple recurrences were also related to early onset; of children whose FS occurred during the rst 24 months of life, 22% later experienced more than one recurrence, whereas only 4% of those whose onset was after the second year of age had more than a single recurrence. The interval between rst and second febrile seizure varied little with the age at which the initial seizure took place; 40% of second attacks occurred during the 3 months after the initial one, 60% within 6 months, 72% within 12 months, and 96% within 24 months after the rst febrile seizure (see Fig. 1). We found no signicant differences (evaluated by chi-square) between the Groups A and B patients in the presence of the risk factors for febrile convulsions: sex, gestational age, fetal distress

instrumental vaginal delivery, caesarean section, birth trauma, early age at onset, epilepsy in a rstdegree relative, and complex initial febrile seizure.

Discussion
FS are the most common seizures of childhood, and recurrences of such seizures are by far the largest associated risk.7 In the present study, about 76.1% of the children had their rst febrile convulsion in the rst 2 years of age, and this nding correlates well with the data of the previous reports.8 11 We decided to carry out an intermittent prophylaxis randomly in one of the two groups of our children. In the Group A children, we evaluated the usefulness of diazepam administration. In literature there are many studies on the prevention of FS4 6,12 15 but few of these studies have evaluated the use of oral diazepam; among these studies, Rosman et al.6 have demonstrated a signicant reduction in the risk of febrile convulsions with diazepam prophylaxis. Our experience conrms the efcacy of this prophylaxis with oral diazepam. In fact, the ndings of our prospective study demonstrate that oral diazepam reduces signicantly the percentage of recurrence of FS. As in other studies,15,16 we chose to study oral diazepam because it is easy and safe to give to children. Furthermore, with oral diazepam, peak serum levels occur more quickly in children than in adults,16 with absorption rates that are as rapid as those with the rectal solution17 and more rapid than with rectal suppositories.15 Our study demonstrates that although side effects of diazepam were not infrequent, these effects (usually ataxia, lethargy, or irritability) are always mild and reversible. This study has examined a spectrum of adverse outcomes following FS, and has found those other than recurrences to be infrequent. All children of this series were followed for at least 48 months after the rst febrile seizure; more than half of rst recurrences occurred within 6 months after the rst febrile seizure, three quarters within 12 months, and 96% of rst recurrence took place within 24 months of the onset. Similar trends were observed in previous studies.7,9,18,19 Recurrences of FS are usually benign, and the most severe are the initial ones.7 In the present cohort of children with rst recurrence, complex febrile seizure followed initial simple or complex FS in only 4 and 8% of children, respectively. Similar ndings were reported by others.7 Neither death nor persisting hemiplegia occurred as sequelae of FS in none of our children. Death has been infrequent in other recent studies,6

Figure 1 Cumulative incidence of recurrent febrile seizures, according to treatment group.

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except where pre-existing abnormalities of the child, or the nature of the provoking illness, were related. In conclusion, our study demonstrates that oral diazepam, given only when fever is present, is an effective means of reducing the risk of recurrences of FS. This drug may be useful in children whose parents are very anxious; a detailed parental education about FS may play an important role in relieving anxiety.

References
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7. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978;61:7207. 8. Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth. I-Prevalence and recurrence in the rst ve years of life. BMJ 1985;290: 130710. 9. Offringa M, Derksen-Lubsen G, Bossuyt PM, Lubsen J. Seizure recurrence after a rst febrile seizure: a multivariate approach. Dev Med Child Neurol 1992;34:1524. 10. Airede AI. Febrile convulsions: factors and recurrence rate. Trop Geogr Med 1992;44:2337. 11. Al-Eissa YA, Familusi JB, Al-Zamil FA, et al. Prole of children hospitalized for their rst febrile convulsion in Riyadh, Saudi Arabia. J Trop Geogr Neurol 1992;2: 1248. 12. Rosman NP. The case for treating febrile seizures. Contemp Pediatr 1992;9:1234. 13. Freeman JM. The best medicine for febrile seizures. N Engl J Med 1992;327:11613. 14. Autret E, Billard C, Bertrand P, et al. Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. J Pediatr 1990;117: 4904. 15. Minagawa K, Mizuno S, Shirai H, Miura H. A pharmacokinetic study on the effectiveness of intermittent oral diazepam in the prevention of recurrent febrile convulsions (in Japanese). No To Hattatsu (Tokyo) 1985;17:1627. 16. Schmidt D. Benzodiazepine: diazepam. In: Levy RH, Dreifuss FE, Mattson RH, Meldrum BS, Penry JK, editors. Antiepileptic drugs, 3rd ed. New York: Raven Press; 1989. p. 73564. 17. Lombroso CT. Intermittent home treatment of status and clusters of seizures. Epilepsia 1989;30:1114. 18. Berg AT, Shinnar S, Hauser WA. A prospective study of recurrent febrile seizures. N Engl J Med 1992;327:11227. 19. McKinlay I, Newton R. Intention to treat febrile convulsions with rectal diazepam, valproate, or phenobarbitone. Dev Med Child Neurol 1989;31:61725.