BMJ
2001;323:1111-1114 ( 10 November )
Evidence based
paediatrics
Martin Offringa
a Emma Children's Hospital, Academic
Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands, b Department
of Pediatrics, University of Texas, Houston Health Science Center, Houston, TX
77030, USA
Correspondence to: V A Moyer [log in to unmask]
|
THE CASE |
A previously healthy 19 month old boy was rushed to the
emergency department after being found unconscious at home by his mother.
As she went to wake him from his afternoon nap she heard a short
cry. She found him lying on his back, rigid and unresponsive, with
blue lips and apparently not breathing. His breathing and circulation
were adequate on arrival in the emergency room. His pulse rate was
110 per minute, blood pressure 100/60 mm Hg, and temperature
39.9°C. The boy was lethargic and confused but seemed to recognise
his mother. Apart from a slightly red pharynx there was no obvious
focus of infection and no rash. Neck rigidity was difficult to
evaluate because he actively resisted examination and refused to
sit.
Summary points Seizures
occurring in association with fever affect approximately 4% of all children In children
with a seizure associated with fever the probability of bacterial meningitis
is low but not zero (ranging between 0-4%) A normal
physical examination and history make bacterial meningitis highly improbable After a
first febrile seizure the probability of seizure recurrence in subsequent
fever episodes is related to age, and is highest between 1 and
3 years After a
first febrile seizure prophylactic treatment with antiepileptic drugs does
not decrease the likelihood of future febrile seizures |
|
Background |
A febrile seizure is defined as a seizure occurring in a
neurologically healthy child aged 6 months to 5 years. Simple febrile
seizures are brief (under 15 minutes' duration), are generalised,
and occur in association with fever and only once during any 24 hours.1 Seizures
occurring with fever are the most common neurological disorder in
paediatrics, affecting 2-4% of all children in Britain and the
United States.2
Children whose seizures are attributable to a central nervous system
infection and those who have had a previous afebrile seizure or
central nervous system abnormality are not considered to have simple
febrile seizures.
|
Finding
the evidence |
A number of questions arise in this case. You wonder how likely it
is that this boy has meningitis and whether lumbar puncture is
necessary. If this is a simple febrile seizure, what is the likelihood
of future febrile seizures, epilepsy, or brain damage? You also
wonder whether you should begin treatment with anticonvulsants. You
wish to use an evidence based approach, so you frame your questions
to maximise the yield from searching.
Questions and search strategies
Question 1: In young children with a seizure associated with fever
(patient/population, event) what is the probability of bacterial
meningitis (outcome)? [baseline risk]
Search: Medline (PubMed: www.ncbi.nlm.nih.gov/entrez/static/clinical.html):
Clinical queriesaetiologysensitivity:
"fever and seizures
and meningitis"
Question 2: In young children with a
seizure associated with fever (patient/population, event) can a normal physical
examination and history (intervention/test) reliably exclude
bacterial meningitis (outcome)? [diagnosis]
Search: Medline(PubMed: www.ncbi.nlm.nih.gov/entrez/query.fcgi):
"fever and seizures and meningitis and (clinical signs or
diagnosis)"
Question 3: In children with a first
febrile seizure (patient/population, event), can prophylactic treatment with
antiepileptic drugs (intervention) as compared to no therapy
(comparison) decrease the likelihood of future febrile seizures
(outcome)? [therapy]
Search: PubMed: Clinical queriestherapysensitivity
"seizures and fever and recurrence"
Question 4: In children with a first
febrile seizure (patient/population, event), what is the likelihood of future
febrile or afebrile seizures (outcome)? [prognosis]
Search: PubMed: Clinical queriesprognosissensitivity
"seizures and fever and epilepsy".
|
Results |
Prevalence of meningitis
In trying to determine the likelihood of meningitis, you are looking
for cross sectional studies or follow up studies of children with
seizures and fever that identify children who developed meningitis.
Your "clinical queries" search nets 30 articles, most
of which are informal reviews and letters. One article, a decision
analysis, seems relevant.3
You then click on the "related articles"the hyperlink next to this referenceand find two more articles which seem to be
relevant surveys. 4
5
Wears et al reviewed seven studies
performed in urban hospital emergency rooms in the United States.4 All were
retrospective surveys of charts documenting the disease outcome
after a seizure with fever. Among 2100 such cases of seizures
associated with fever the overall prevalence of meningitis was 1.2%,
ranging from 0-4% in the seven studies. It was not stated, however,
whether all children underwent lumbar puncture in these emergency
rooms, or whether meningitis was excluded on clinical grounds at
follow up.
In the second study, 7% of the children
who visited the emergency rooms of two Dutch hospitals with a first seizure
associated with fever had either bacterial or viral meningitis.5 As this
study was done in the hospital setting in a country where general practitioners
manage up to 50% of all seizures with fever, 6 7 its
results may not apply to the situation where is no family physician
or general practitioner to evaluate the child before referral to
hospital.
From these two studies it can be concluded
that the prevalence of meningitis among children with seizures and fever in
North American paediatric emergency wards is between 1% and 2% and,
through selective referral, it may be as high as 7% in a European country.
These figures indicate that a large number of "unnecessary" lumbar
punctures would be done if lumbar puncture were to be carried out in
all children with a seizure associated with fever.
Seizures in "well" children
Your next question is whether a seizure can be the sole
manifestation of meningitis in a child who seems otherwise well. You
are looking for studies that investigate the relations of various
signs and symptoms with meningitis in children with seizures and
fever, preferably in the form of likelihood ratios. One study
provides sensitivity, specificity, and likelihood ratios for the
various clinical indicators of meningitis.5 This study
tried to identify criteria, based on age, specific clinical indicators,
or the results of initial blood tests, that could serve as indications
for performing lumbar puncture. Meningitis was diagnosed in 23 (7%)
of 309 children aged 3 months to 6 years with a first seizure
associated with fever who were seen consecutively in the emergency rooms
of two major children's hospitals in the western part of the
Netherlands. These 23 children were then compared with a reference group
of 69 children with seizures associated with fever but without meningitis,
selected at random from the remaining 286 children.
Discriminant factors
Several clinical signs and symptoms were examined for their ability
to discriminate between children with and without meningitis. The
clinical risk factors shown in table 1 were evaluated. The
presence of one or more of the major signspetechiae, nuchal rigidity, coma identified 16 out of the 23 children with meningitis
(70%). In the absence of meningitis, these major signs of the disease
were not found; the likelihood ratio when any of these signs is
present (LR +) is therefore infinite (95% confidence interval
6.0 to ) and the
probability of meningitis approaches 100% (31 to 100%). In the
absence of meningeal irritation, petechiae, or complex features of
the seizure there were no cases of meningitis in the study. A
child's age, sex, degree of fever, and results of routinely
performed blood tests did not have any diagnostic value. The
likelihood ratios of the negative and positive tests can separate
children into two groups, a group in which the risk of meningitis is
very high and lumbar puncture should be done regardless of other
history or physical findings, and a group in which the risk of
meningitis is low and the need for lumbar puncture will depend on
other clinical findings.
|
Generalisability
The Dutch study was a retrospective review of the medical records of
children presenting with a first episode of seizure and fever.5 The study
population was limited to children aged 3 months to
6 years. The pretest probability of meningitis would be likely
to be different in another population of children. In addition,
nuchal rigidity may not be as strong a predictor of meningitis in
young as in older children; in this patient population the mean age
was 18 months. However, these results indicate that it is very
unusual for a child with meningitis to present with only a seizure.
Also, a fair number of children without meningitis will present with
the risk factors mentioned abovethat is, the specificity of these "clinical tests" is
far from 100%.
Value of prophylactic treatment
To determine whether prophylactic treatment with an antiepileptic
drug or an antipyretic as compared with no treatment decreases the
likelihood of future febrile seizures, you are looking for studies
in which patients with febrile seizures were randomised to different
treatment regimens and followed over time to see how many developed
subsequent febrile seizures. Of the 55 articles that result
from your search, five papers specifically address your question;
they are either meta-analyses of randomised controlled trials 8 9 or are
reports of randomised controlled trials.10-12
Newton assessed the efficacy of
phenobarbitone and valproate for the prophylactic treatment of febrile
convulsions by summarising the results from all eight British
clinical trials that were done before 1988.8 Data were
pooled and analysed on an intention to treat basis. The overall odds
ratio of recurrent febrile seizures for treatment with
phenobarbitone was 0.8 and for valproate 1.42. Neither of
these results was statistically significant. The author therefore
concluded that neither treatment is to be recommended.
A second meta-analysis summarised four
published non-British, randomised placebo controlled trials that had been
carried out using phenobarbitone to prevent febrile seizures.9 The risk
of recurrences was lower in children receiving continuous phenobarbitone
than placebo (odds ratio 0.54, 95% confidence interval 0.33 to
0.90). On average, eight children would have to be given continuous phenobarbitone
prophylaxis for two years to prevent one febrile seizure (number
needed to treat=8.5-27).13
However, in view of the adverse effects of phenobarbitone, such as
irritability, hyperactivity, somnolence, and possibly diminished
cognitive development,10
the authors of this second review also concluded that phenobarbitone
prophylaxis of febrile seizures cannot be recommended.
Treatment in febrile periods only
To avoid the adverse effects of giving antiepileptic drugs for
prolonged periods, rapidly acting anticonvulsants given only during
fever periods have been used in an attempt to reduce the risk of
recurrent febrile seizures. Phenobarbitone given at times of fever
has been proved ineffective, probably because of the delay in
achieving appropriate serum and tissue concentrations. Thus far, only
prophylactic diazepam, given orally or rectally, has been studied in
placebo controlled trials.
DiazepamRosman et al conducted a randomised, double blind, placebo
controlled trial among 406 children with a mean age of 24 months
who had had at least one febrile seizure, comparing diazepam
(0.33 mg per kg body weight), given orally every eight hours
during febrile illnesses, with placebo.11 During a
mean follow up of two years, the relative risk of subsequent febrile
seizures per person year was 0.56 (0.38 to 0.81). Many parents
did not give the treatment as directed, and an analysis restricted to
children who had seizures while definitely receiving the study drug
showed an 82% reduction in the risk of febrile seizures with diazepam.
Between 25% and 30% of the children in the study by Rosman were
irritable, lethargic, or ataxic after taking diazepam, which might
interfere with parents' and clinicians' ability to distinguish
benign childhood febrile illness from more serious disease; one in
every 3.5-4 children taking diazepam develops these symptoms
(number needed to harm=3.5-4). The decision to recommend this
treatment will depend on balancing these potential harms against the
potential benefits to each specific child, and on the family's values.
IbuprofenTo assess whether antipyretic drugs given intermittently
prevent recurrence of febrile seizures, a randomised placebo controlled
trial was conducted in the Netherlands.12 Children
aged 1 to 4 years who had at least one risk factor for
recurrence of a febrile seizure (see below) were randomly assigned
to receive either ibuprofen syrup, 5 mg per kg body weight per
dose, or placebo every six hours during fever, defined as a
temperature >38.4°C. Median follow up time was 12 months.
The relative risks for recurrence in the two groups did not differ
significantly.
Prognosis after first seizure
To address the parents' concerns about the prognosis, you are
looking for a large cohort of patients with first simple febrile
seizures who have been followed over time to see how many develop
recurrent febrile or non-febrile seizures. Your search strategy
yields 157 articles, only two of which meet your study design
criteria. 14
15
In a collaborative study, the individual
data from five follow up studies that used similar definitions of febrile
seizures and risk factors were pooled and reanalysed to estimate the
risk of frequent recurrent seizures and occurrence of complex
seizures in previously healthy, untreated children.14 Of a
total of 2496 children with 1410 episodes of recurrent
seizures, 32% had one, 15% two, and 7% three or more recurrent
seizures after a first febrile seizure; 7% had a complex recurrence.
The hazard of recurrent seizures was highest between the ages of
12 and 24 months. A history of febrile or unprovoked
seizures in a first degree family member, a relatively low
temperature at the first seizure, young age at onset (<12
months), a family history of unprovoked seizures, and a partial
initial febrile seizure were all associated with an increased risk
of subsequent complex seizures. Although complex features of the
first seizurethat is, a
seizure which is partial, is multiple, or lasts for more than
15 minuteshave long been
thought to predict recurrence, the follow up studies included in
this review showed that only multiple initial seizures are associated
with an increased risk (1.6-fold) for a first recurrence.14 Prolonged
or focal initial seizures were not associated with this increased
risk, as long as they had not led to permanent neurological abnormalities.
Risk factors for the occurrence of
unprovoked seizures were assessed in a cohort of 428 children followed
prospectively for at least two years from their first febrile
seizure.15
Unprovoked seizures occurred in 26 (6%). Neurodevelopmental
abnormalities, complex febrile seizures, and a family history of
epilepsy were associated with an increased risk of unprovoked
seizures. Recurrent febrile seizures and brief duration of fever
before the initial febrile seizure were also risk factors. A family
history of febrile seizures, temperature and age at the time of the
initial febrile seizure, sex, and race were not associated with
unprovoked seizures. This high quality evaluation of predictors gives
an insight into the risk of epilepsy and may be used to counsel
patients. However, no studies have examined the possibility of
preventing epilepsy by pharmacological interventions after a first
or a second febrile seizure. 15 16 The
evidence you have gathered is summarised in table 2.
|
|
Applying
the evidence |
From the history and the physical examination you consider this
child to be at a low risk of meningitis and you decide to observe
him without a lumbar puncture. After resolution of the acute
episode, you reassure the parents and counsel them at a follow up
visit on the risk of future seizures. For this child, the
probability of frequent or potentially threatening recurrences is
low. You decide that the evidence does not support using a daily
anticonvulsant like phenobarbitone or sodium valproate, and that intermittent
diazepam or an antipyretic agent during fever are not effective in
preventing recurrence of seizures. You know you will need to spend
time with the parents to help them overcome the fears and anxiety
that seizures provoke and to educate them about the clinical course
of febrile seizures and their consequences. You know that they may
still request treatment with anticonvulsants. This will depend on
the values they place on different outcomes such as risk of a
subsequent seizure and the adverse effects of use of
anticonvulsants. You counsel these parents that the risk of
recurrence declines rapidly after six months from the previous
seizure and instruct them to position the child for optimal airway
patency in case of a new seizure, which is especially important in
the event of vomiting. A prescription for rectal diazepam should
also be given, and the parents should be instructed how to
administer it in the rare event of a prolonged recurrence lasting
>15 minutes. 17
18 This
approach, it has been suggested, also reduces parental fear. 19 20
|
Acknowledgments |
MO wrote the original chapter for Evidence Based Pediatrics and Child Health;
VAM edited the chapter for publication in the BMJ
and wjm (Western Journal of Medicine).
|
Footnotes |
Series editor: Virginia A Moyer
Competing interests: None declared.
This article is adapted from a chapter in "Evidence
Based Pediatrics and Child Health," which can be purchased through the
BMJ Bookshop (www.bmjbookshop.com);
further information and updates for the book are available on www.evidbasedpediatrics.com
|
References |
1. |
Nelson KB, Ellenberg JH, eds. Febrile seizures. New York: Raven Press,
1981. |
2. |
Verity CM, Butler NR, Golding J. Febrile
convulsions in a national cohort followed up from birth. 1. Prevalence
and recurrence in the first five years of life. BMJ 1985; 290: 1307-1310 |
3. |
Joffe A, McCormick M, DeAngelis C. Which
children with febrile seizures need lumbar puncture? A decision analysis
approach. Am J Dis Child 1983;
137: 1153-1156 |
4. |
Wears RL, Luten RC, Lyons RG. Which
laboratory tests should be performed on children with apparent febrile
convulsions? An analysis and review of the literature. Pediatr Emerg Care 1986; 2: 191-196 |
5. |
Offringa M, Beishuizen A, Derksen-Lubsen
G, Lubsen J. Seizures and fever: Can we rule out meningitis on clinical
ground alone? Clin Pediatr
1992; 9: 514-522 |
6. |
Offringa M, Hazebroek-Kampschreur AAJM,
Derksen-Lubsen G. Prevalence of febrile seizures in Dutch schoolchildren. Paediatr Perinat Epidemiol 1991; 5:
181-188 |
7. |
Verburgh ME, Bruijnzeels MA, van der
Wouden JC, van Suijlekom-Smit LW, van der Velden J, Hoes AW, et al. Incidence
of febrile seizures in the Netherlands. Neuroepidemiology
1992; 11: 169-172 |
8. |
Newton RW. Randomised controlled trials
of phenobarbitone and valproate in febrile convulsions. Arch Dis Child 1988; 63: 1189-1191 |
9. |
Rantala H, Tarkka R, Uhari M. A
meta-analytic review of the preventive treatment of recurrences of febrile
seizures. J Pediatr 1997; 131:
922-925 |
10. |
Farwell JR, Lee YJ, Hirtz DG, Sulzbacher
SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizureseffects on intelligence and on seizure recurrence. N Engl J Med 1990; 332: 364-369 |
11. |
Rosman NP, Colton T, Labazzo J, Gilbert
PL, Gardella NB, Kaye EM, et al. A controlled trial of diazepam administered
during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993; 329: 79-85 |
12. |
Van Stuijvenberg M, Derksen-Lubsen G,
Steyerberg EW, Habbema JD, Moll HA. Randomized, controlled trial of ibuprofen
syrup administered during febrile illnesses to prevent febrile seizure
recurrences. Pediatrics 1998;
102(5): pE51 |
13. |
Altman DG. Confidence intervals for the
number needed to treat. BMJ
1998; 317: 1309-1312 |
14. |
Offringa M, Bossuyt PM, Lubsen J,
Ellenberg JH, Nelson KB, Knudsen FU, et al. Risk factors for seizure
recurrence in children with febrile seizures: a pooled analysis of individual
patient data from five studies. J Pediatr
1994; 124: 574-584 |
15. |
Berg AT, Shinnar S. Unprovoked seizures
in children with febrile seizures: short-term outcome. Neurology 1996; 47: 562-568 |
16. |
Freeman JM. The best medicine for
febrile seizures. N Engl J Med
1992; 327: 1161-1163 |
17. |
Knudsen FU. Rectal administration of
diazepam in solution in the acute treatment of convulsions in infants and
children. Arch Dis Child 1979;
54: 855-857 |
18. |
Dreifuss FE, Rosnan NP, Cloyd JC,
Pellock JM, Kuzniecky RI, Lo WD, et al. A comparison of rectal diazepam gel
and placebo for acute repetitive seizures. N
Engl J Med 1998; 338: 1869-1875 |
19. |
Rossi LN, Rossi G, Bossi A, Cortinovis
I, Brunelli G. Behaviour and confidence of parents instructed in home
management of febrile seizures by rectal diazepam. Helv Paediatr Acta 1989; 43: 273-281 |
20. |
Camfield CS, Camfield PR. Febrile seizures:
a Rx for parent fears and anxieties. Contemp
Pediatr 1993; 10: 26-44 |
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.