Febrile seizures

Abstract

Introduction

Simple febrile seizures are generalised in onset and have a brief duration. The American Academy of Pediatrics defines this brief duration to be <15 minutes; whereas, in the UK, a maximum duration of 10 minutes is used. Simple febrile seizures do not occur more than once in 24 hours and resolve spontaneously. Complex febrile seizures are longer lasting, have focal symptoms (at onset or during the seizure), and can recur within 24 hours or within the same febrile illness. This review only deals with simple febrile seizures. About 2% to 5% of children in the US and Western Europe, and 6% to 9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. A very small number of children with simple febrile seizures may develop afebrile seizures, but simple febrile seizures are not associated with any permanent neurological deficits.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments given during episodes of fever in children (aged 6 months to 5 years) with one or more previous simple febrile seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 4 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: intermittent anticonvulsants (clobazam, diazepam, lorazepam), antipyretic drug treatments (paracetamol, ibuprofen), and conservative measures (watchful waiting, physical antipyretic measures [tepid sponging, removing clothes, cooling room, direct fanning of child]).

Key Points

Febrile seizures are defined as events in infancy or childhood usually occurring between 3 months and 5 years of age associated with a fever, but without evidence of intracranial infection or defined cause for the seizure.

• Simple febrile seizures are generalised in onset and have a brief duration. They do not occur more than once in 24 hours and resolve spontaneously. Complex seizures are longer lasting, have focal symptoms (at onset or during the seizure), and can recur within 24 hours or within the same febrile illness. This review only deals with simple febrile seizures.

• About 2% to 5% of children in the US and Western Europe, and 6% to 9% of infants and children in Japan will have experienced at least one febrile seizure by age 5 years.

• A very small number of children with simple febrile seizures may develop afebrile seizures, but simple febrile seizures are not associated with any permanent neurological deficits.

Evidence is lacking on whether antipyretic drug treatments (paracetamol, ibuprofen) or physical methods of temperature reduction (tepid sponging, removing clothing, cooling room, direct fanning of child) are useful in treating episodes of fever to prevent seizure recurrence in children with one or more previous simple febrile seizures.

Intermittent anticonvulsants (clobazam, diazepam) may be effective in reducing seizure recurrence at some time points, but the lack of consistency of results over time and weak methods of RCTs make it difficult to draw any definitive conclusions on their effectiveness, and any long-term clinical benefits are unclear.

• Also, adverse effects, such as hyperactivity, lethargy, ataxia, and sedation, may often be associated with the use of intermittent anticonvulsants (clobazam, diazepam, lorazepam).

About this condition

Definition

Febrile seizures are divided into three types: simple febrile seizures, complex febrile seizures, and febrile status epilepticus. This review focuses on children with simple febrile seizures. The National Institutes of Health (NIH) definition of a febrile seizure is "an event in infancy or childhood usually occurring between 3 months and 5 years of age associated with a fever, but without evidence of intracranial infection or defined cause for their seizure", after having excluded children with previous afebrile seizures. Another definition from the International League Against Epilepsy (ILAE) is that of "a seizure occurring in childhood after 1 month of age associated with a febrile illness not caused by an infection of the central nervous system (CNS), without previous neonatal seizures or a previous unprovoked seizure, and not meeting the criteria for other acute symptomatic seizures". In addition, following updates to ILAE classification and terminology, febrile seizures are now categorised under "conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se". In working practice, the lower age limit for febrile seizures is generally taken to be 6 months, given concerns regarding the possibility of an underlying serious but treatable infection in younger infants masquerading as a febrile seizure (e.g., meningitis). A simple febrile seizure is a generalised seizure that has a brief duration. The American Academy of Pediatrics has defined this brief duration to be <15 minutes; whereas, in the UK, a maximum duration of 10 minutes is used. A simple febrile seizure does not occur more than once in 24 hours and resolves spontaneously. Treatment for the actual seizure is generally not indicated, given the short duration. In >80% of children the duration of the febrile seizure is <10 minutes, and in only about 9% of children do they last >15 minutes. Often, by the time the child presents to hospital, the seizure has already stopped. A febrile seizure may also be the presenting sign of a fever episode. This review does not include children experiencing complex febrile seizures, which are characterised by any of the following features: >10 or 15 minutes in duration (depending on the definition used), focal symptoms (at onset or during the seizure), and recurrence within 24 hours or within the same febrile illness. Investigations, including neuro-imaging and lumbar puncture, are often warranted. Also excluded from this review are children experiencing febrile status epilepticus, which lasts >30 minutes and requires treatment. Addressing parental anxiety forms a key part of the management of febrile seizures because parents' (unspoken) worry with a first seizure is often that their child might have died. It is good practice to support families with information on simple febrile seizures and contact details of medical services, and reassure them of the benign nature of simple febrile seizures.

Incidence/ Prevalence

About 2% to 5% of children in the US and Western Europe, and 6% to 9% of infants and children in Japan will have experienced at least one febrile seizure, simple or complex, by the age of 5 years. Elsewhere the incidence varies, it is between 5% to 10% in India and as high as 14% in Guam. There are no specific data available for simple febrile seizures.

Aetiology/ Risk factors

While the exact cause of simple febrile seizures is unknown, it is thought to be multifactorial, with both genetic and environmental factors having been shown to contribute to its pathogenesis. Increasingly, a genetic predisposition is recognised with febrile seizures occurring in families. However, the exact mode of inheritance is not known, and seems to vary between families. While polygenic inheritance is likely, there is a small number of families identified with an autosomal-dominant pattern of inheritance of febrile seizures, leading to the description of a 'febrile seizure susceptibility trait' with an autosomal-dominant pattern of inheritance with reduced penetrance. In addition, mutations in several genes have been found that account for enhanced susceptibility to febrile seizures. A familial epilepsy syndrome exists (generalised epilepsy with febrile seizures plus [GEFS+]), in which people can have classical febrile seizures, febrile seizures that persist beyond 5 years (hence FS+), and/or epilepsy. The revised ILAE classification refers to FS+ as an ‘electroclinical syndrome’ that usually starts in childhood but can occasionally have its onset in infancy. Similar genetic factors have been identified that are involved in both febrile seizures and FS+. Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the gamma-aminobutyric acid A receptor and the sodium channel (e.g., sodium channel, voltage-gated, type I, alpha subunit [SCN1A]). The latter, in particular, is associated with an early epilepsy syndrome and epileptic encephalopathy called Dravet syndrome (also known as severe myoclonic epilepsy of infancy [SMEI]), which often begins with prolonged seizures triggered by fever or the first presentation of epilepsy. Certain SCN1A mutations have also been associated with increased susceptibility to febrile seizures and FS+. As most of the mutations in SCN1A-related epilepsies occur de novo, when an infant presents initially with febrile seizures, there is uncertainty as to whether they will have simple febrile seizures only, develop FS+, or develop severe epilepsy, such as Dravet syndrome. In the UK, genetic testing for SCN1A mutations is currently not routinely carried out in clinical practice for infants and children with simple febrile seizures, but it is increasingly being considered and performed in infants and children with complex febrile seizures, febrile status, and FS+.With regards to risk factors, febrile seizures are more frequent in children attending day-care centres, and in those with a first- or second-degree relative with a history of febrile seizures. The risk of another child having febrile seizures is 1 in 5 if one sibling is affected, and 1 in 3 if both parents and a previous child have had febrile seizures. Other risk factors associated with an increased rate of febrile seizure recurrence include young age at onset (<12 months), history of simple or complex febrile seizures, and body temperature at onset of <40°C. Among these, age at onset seems the most constant predictive factor, with 50% of children aged <12 months and 30% of children aged >12 months presenting with a recurrent febrile seizure. Positive family history of epilepsy is not consistently associated with increased simple febrile seizure recurrence.

Prognosis

A very small number of children with simple febrile seizures may develop afebrile seizures, but simple febrile seizures are not associated with any permanent neurological deficits. Furthermore, simple febrile seizures do not appear to have any known long-term adverse effects or sequelae. Whereas traditionally understood to be a ‘benign’ condition, the ILAE cautions against this terminology, stating that ‘benign’ can be misleading and leave physicians, patients, and families unaware of and unprepared to address the wide variety of brain disorders that may be associated with febrile seizures, such as cognitive, behavioural, and psychiatric illnesses, as well as sudden death and suicide. Nonetheless, there is very little evidence to suggest that simple febrile seizures have any adverse effects on behaviour or learning. The risk of developing epilepsy is increased further in children with a history of complex febrile seizures. A strong association exists between febrile status epilepticus or febrile seizures characterised by focal symptoms and later development of temporal lobe epilepsy.

Aims of intervention

To prevent seizure recurrence with minimal adverse effects in children with one or more previous simple febrile seizures.

Outcomes

Recurrence of febrile seizures and adverse effects.

Methods

Clinical Evidence search and appraisal July 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2013, Embase 1980 to July 2013, and The Cochrane Database of Systematic Reviews 2013, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in English (including open studies) and containing more than 20 individuals (at least 10 per arm), of whom more than 80% were followed up. There was no minimum length of follow-up. A regular surveillance protocol was used to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which were added to the review as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Febrile seizures.

Important outcomes	Recurrence of febrile seizures
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments given during episodes of fever in children (aged 6 months to 5 years) with one or more previous simple febrile seizures?
2 (at least 230)	Recurrence of febrile seizures	Antipyretic drugs (paracetamol, ibuprofen) versus placebo	4	-2	0	0	0	Low	Quality points deducted for incomplete reporting of results and unclear follow-up (no absolute numbers reported).
10 (at least 1429)	Recurrence of febrile seizures	Intermittent anticonvulsants (clobazam, diazepam, lorazepam) versus placebo or no treatment	4	-2	0	-2	0	Very low	Quality points deducted for weak methods (blinding, treatment allocation, randomisation) and using no treatment as a comparator. Directness points deducted for inconsistent effects over time, unclear clinical importance, and significant heterogeneity.
1 (72)	Recurrence of febrile seizures	Intermittent anticonvulsants (clobazam, diazepam, lorazepam) versus each other	4	-2	0	0	0	Low	Quality points deducted for methodological issues (treatment allocation and blinding not reported) and sparse data.

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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