009-1 intermittent oral diazepam prophylaxis in febrile convulsions its effectiveness for febrile...

8/3/2019 009-1 Intermittent Oral Diazepam Prophylaxis in Febrile Convulsions Its Effectiveness for Febrile Seizure Recurrence

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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

aSection of Pediatrics, Department of Medicine, University of Chieti-Ospedale Policlinico, Via dei Vestini 5,

Chieti 66013, ItalybDepartment 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 therecurrence of febrile seizures we carried out a prospective study in two groups ofchildren; Group A: 45 children (25 female, 20 male), receiving oral prophylaxis withdiazepam, and Group B: 65 children (35 female, 30 male) who did not receive any oralprophylaxis. All subjects of both groups were followed for at least 4 years and finallyre-evaluated at the mean age of 6.7 ^ 1.4 years. Among the patients of Group A,recurrent febrile seizures (FS) occurred in five of the 45 children (11.1%). Among the 65children 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 ispresent, is an effective means of reducing the risk of recurrences of FS.Q 2004 European Paediatric Neurology Society. Published by Elsevier Ltd. All rightsreserved.

Introduction

Febrile seizures (FS) are the most common type ofseizures and occur in 24% of children. One of thegreatest concern of the parents of children with FSsis the possibility of other convulsions during otherfebrile infections.13 In spite of many large epide-miological studies,4,5 there is no agreement aboutwhen, or in what circumstances, to carry out anintermittent diazepam prophylaxis is justifiable.

There are some uncontrolled studies4,5 and onelarge randomized study which demonstrated thatadministration of oral diazepam could reduce therecurrence of FS.6

The aim of study was to evaluate the effective-ness of administration of oral diazepam for thereduction of the recurrence of FS.

Materials and methods

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

1090-3798/$ - see front matter Q 2004 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ejpn.2004.01.008

European Journal of Paediatric Neurology (2004) 8, 131134

www.elsevier.com/locate/ejpn

*Corresponding author. Tel.: 39-871-574-538; fax:39-871-574-831.

E-mail address: [email protected] (A. Verrotti).
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who had one simple FS; the inclusion criteria were:no personal history of afebrile seizures, normalneurophychomotor development, age from 6months to 5 years, no previous anticonvulsanttherapy. After a careful and detailed informationabout the pathogenesis and the treatment of FS,the parents of these patients received writteninstructions explaining how to give the oral prophy-laxis with diazepam, according to the body weightof the child (0.35 mg/kg every 8 h), during eachepisode of fever higher than 38 8C, continuing untilthe child had been afebrile for 24 h. Moreover,instructions to stop seizure by diazepam adminis-tered rectally at the dosage of 0.5 mg/kg weregiven to the parents of these children. The

diazepam was effective in all children after thefirst dose. Group B: 65 (35 female, 30 male) childrenwho had one simple FS; the inclusion criteria werethe same of the Group A patients, but they did notreceive any oral prophylaxis. All children of bothgroups were Caucasian.

A FS was defined in accordance with the NationalInstitutes of Health consensus statement. Complexseizures were defined as either focal or multipleseizures or seizures with duration .15 min, or acombination of these; simplex seizures weredefined as generalised seizures that lasted lessthan 15 min and did not recur within a day.

A statistician randomly assigned each child toGroup A or B and the doctors who followed thesechildren did not know the randomization.

All children of both groups were recruited afterthe first FS from the Paediatric Department ofChieti University and the Division of Pediatrics of DiSumma Hospital, Brindisi, admitted in these hospi-tals for FS; the age at the hospital admission (inoccasion of the first FS) ranged from 1.7 to 3.9 years(mean^ SD 2.5 ^ 1.4); the pregnancy and neonatalperiod were normal. No patients had clinical orlaboratory signs of progressive central nervoussystem disease, nor associated psychiatric disorders

and all children showed normal cerebral computedtomography or magnetic resonance imaging (per-formed in six patients).

In the large majority of cases, FS were brief,generalised, tonic clonic.

EEG was performed in all patients within a weekafter the first seizure and in the majority of thepatients (90/110) in the third day after the FS;aspecific anomalies (e.g. mild background dys-rhythmia, slow rhythms, background instability,moderate rhythm asymmetry) were found in 10children; in particular, the most frequent anomalywas background instability, but all these anomaliesdisappeared after few days. Remaining childrenshowed normal EEG.

Cerebrospinal fluid examination, performed intwo cases with suspected meningeal infection,showed normal results.

All subjects of both groups were followed for atleast 4 years and finally re-evaluated at the meanage of 6.7^ 1.4 years. During these 4 years, we metthe families of the children every 6 months in orderto have all information about FS of the patients (andthe eventual side effects of diazepam) and toreinforce the study program.

The duration of fever preceding the FS wasusually less than 24 h in all patients of both groups,in particular it ranged from 2 h (seven patients) to64 h (one patient). During each episode of feverhigher than 38 8C all of the patients were treated

with paracetamol.EEG recordings were performed during wakingand spontaneous sleep, as previously described.7

Statistical analysis

Comparison between two groups was analysedby independent-sample t-tests for quantitativevariables and the x2 test for categorical variables.P values ,0.05 were considered statisticallysignificant.

For the analysis of the time to the first recurrenceof a febrile seizure, we used the KaplanMeiermethod to plot the incidence curves.

Results

There were 113 children who met all the entrycriteria. Three children were excluded because nofollow-up information could be obtained after theinitial evolution. This report is, therefore, based onthe remaining 110 children for whom a follow-upcontact was made.

In most instances, their seizures were associated

with upper respiratory tract infections, and allchildren recovered without complications within afew days. Of the 110 children, 30 (27.2%) presentedwith an initial complex febrile seizure; in parti-cular in Group A we found 15 children withcomplex seizures, while 20 children of Group Bshowed complex seizures. The mean^ SDfollow-up time all cases were 50.2 months (range,48.0 66.2 months).

Among the patients of Group A, recurrent FSoccurred in five of the 45 children (11.1%). In thesefive FS, parents did not administer oral diazepam tothem. Parents were asked why the medication hadnot been given. The main reasons were that theparents did not take the childs temperature, that

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the seizure was the first sign of illness, and that thelast recorded temperature had been normal. Onother occasions, the medication was not with theparent, the parents misunderstood the instructions,the child spat up the medicine, or the parents wereworried about the side effects. The most commonside effects are: ataxia, lethargy and irritability. Inparticular, 14 children (31.1%) had ataxia, 13(28.8%) presented lethargy and 11 children (24.4%)had irritability. In all cases, these side effectslasted no more than 36 h.

Among the 65 children of Group B, 20 (30,7%)children showed at least one recurrence of FSduring the follow-up. In detail among the 20, it isinteresting to report that eight had at least three,

and five at least four recurrent FS. Hence, ofchildren with an initial recurrence, 31% went on tohave one or more additional episodes. Most recur-rent FS were simple ones. Only two children with aninitial complex febrile seizure and three childrenwith an initial simple febrile seizure had complexrecurrent ones during the follow-up period. Therate of recurrence declined gradually as thechildren aged. None of the 110 children hadabnormal neurological or developmental sequelae.

Multiple recurrences were also related to earlyonset; of children whose FS occurred during the first24 months of life, 22% later experienced more than

one recurrence, whereas only 4% of those whoseonset was after the second year of age had morethan a single recurrence. The interval between firstand second febrile seizure varied little with the ageat which the initial seizure took place; 40% ofsecond attacks occurred during the 3 months afterthe initial one, 60% within 6 months, 72% within 12months, and 96% within 24 months after the firstfebrile seizure (see Fig. 1).

We found no significant differences (evaluatedby chi-square) between the Groups A and B patientsin 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 first-degree relative, and complex initial febrile seizure.

Discussion

FS are the most common seizures of childhood, andrecurrences of such seizures are by far the largestassociated risk.7 In the present study, about 76.1%of the children had their first febrile convulsion inthe first 2 years of age, and this finding correlateswell with the data of the previous reports.811 Wedecided to carry out an intermittent prophylaxisrandomly in one of the two groups of our children.In the Group A children, we evaluated the useful-ness of diazepam administration. In literature thereare many studies on the prevention of FS46,1215

but few of these studies have evaluated the use oforal diazepam; among these studies, Rosman et al.6

have demonstrated a significant reduction in therisk of febrile convulsions with diazepam prophy-laxis. Our experience confirms the efficacy of thisprophylaxis with oral diazepam. In fact, the findingsof our prospective study demonstrate that oraldiazepam reduces significantly the percentage ofrecurrence of FS. As in other studies,15,16 we chose

to study oral diazepam because it is easy and safe togive to children. Furthermore, with oral diazepam,peak serum levels occur more quickly in childrenthan in adults,16 with absorption rates that are asrapid as those with the rectal solution17 and morerapid than with rectal suppositories.15 Our studydemonstrates that although side effects of diaze-pam were not infrequent, these effects (usuallyataxia, lethargy, or irritability) are always mild andreversible.

This study has examined a spectrum of adverseoutcomes following FS, and has found those otherthan recurrences to be infrequent. All children of

this series were followed for at least 48 monthsafter the first febrile seizure; more than half of firstrecurrences occurred within 6 months after the firstfebrile seizure, three quarters within 12 months,and 96% of first recurrence took place within 24months of the onset. Similar trends were observedin previous studies.7,9,18,19 Recurrences of FS areusually benign, and the most severe are the initialones.7 In the present cohort of children with firstrecurrence, complex febrile seizure followed initialsimple or complex FS in only 4 and 8% of children,respectively. Similar findings were reported byothers.7 Neither death nor persisting hemiplegiaoccurred as sequelae of FS in none of our children.Death has been infrequent in other recent studies,6

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

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except where pre-existing abnormalities of thechild, or the nature of the provoking illness, wererelated.

In conclusion, our study demonstrates that oraldiazepam, given only when fever is present, is aneffective means of reducing the risk of recurrencesof FS. This drug may be useful in children whoseparents are very anxious; a detailed parentaleducation about FS may play an important role inrelieving anxiety.

References

1. Annegers JF,Hauser WA,ElvebackLR, Kurland LT.The risk ofepilepsy following febrile convulsions. Neurology 1979;29:297303.

2. Berg AT, Shinnar S, Shapiro ED,Salomon ME,CrainEF, HauserA. Risk factors for a first febrile seizure: a matched case-control study. Epilepsia 1995;36:33441.

3. Berg AT, Shinnar S. Unprovoked seizures in children withfebrile seizures: short-term outcome. Neurology 1996;47:5628.

4. Knudsen FU. Intermittent diazepam prophylaxis in febrileconvulsions with valproic acid or phenobarbitone. BMJ 1980;280:3534.

5. Hohjo M, Miura H, Minagawa K. A clinical study on theeffectiveness of intermittent therapy with oral diazepamsyrups for the prevention of recurrent febrile convulsions: apreliminary report (in Japanese). No To Hattatsu (Tokyo)1986;18:2345.

6. Rosman NP, Colton T, Labazzo J, Gilbert PL, et al. Acontrolled trial of diazepam administered during febrileillnesses to prevent recurrence of febrile seizures. N Engl JMed1993;329:7984.

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 andrecurrence in the first five years of life. BMJ 1985;290:

130710.

9. Offringa M, Derksen-Lubsen G, Bossuyt PM, Lubsen J. Seizure

recurrence after a first 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. Profile of

children hospitalized for their first febrile convulsion in

Riyadh, Saudi Arabia. J Trop Geogr Neurol 1992;2:

1248.

12. Rosman NP. The case for treating febrile seizures. Contemp

Pediatr1992;9:1234.

13. Freeman JM. The best medicine for febrile seizures. N Engl J

Med1992;327:11613.14. Autret E, Billard C, Bertrand P, et al. Double-blind,

randomized trial of diazepam versus placebo for preven-

tion 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 Japa-

nese). 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 Med1992;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.

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