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. 2008 May 22;2008:0324.

Febrile seizures

Leena D Mewasingh 1
PMCID: PMC2907951  PMID: 19450310

Abstract

Introduction

Simple febrile seizures are generalised in onset, last less than 15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures. About 2-5% of children in the USA and Western Europe, and 6-9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments given during episodes of fever in children with one or more previous simple febrile seizures? What are the effects of long-term (daily, for more than 1 month) anticonvulsant treatment in children with a history of simple febrile seizures? What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2007 (BMJ 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 19 systematic reviews, RCTs, or observational studies 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: anticonvulsants (intermittent or continuous), and antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen).

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, last less than 15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures.

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

  • Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.

We do not know whether antipyretics are useful in treating episodes of fever to prevent seizure recurrence in children with one or more previous simple febrile seizures.

  • Intermittent anticonvulsants used in treating episodes of fever to prevent seizure recurrence in children are associated with adverse effects, including hyperactivity, irritability, and difficulties with speech, activity level, or sleep.

Continuous anticonvulsant treatment may be effective for reducing recurrence in children with a history of simple febrile seizures, but is associated with adverse effects: for example, phenobarbital is associated with cognitive impairments and behavioural adverse effects, including hyperactivity, irritability, and aggressiveness.

  • Anticonvulsants do not appear to reduce the risk of epilepsy up to 12 years later in children with a history of simple febrile seizures.

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 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, often tonic-clonic, lasting less than 15 minutes in duration, which does not occur more than once in 24 hours, and is followed by full recovery within 1 hour. Treatment for the actual seizure is generally not indicated, given the short duration. In over 80% of children the duration of the febrile seizure is less than 10 minutes, and in only about 9% of children do they last longer than 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: greater than 15 minutes in duration, focal symptoms, recurrence within 24 hours, and not followed by full consciousness within 1 hour. Investigations including neuroimaging and lumbar puncture are often warranted. Also excluded from this review are children experiencing febrile status epilepticus, which lasts longer than 30 minutes and requires treatment. Addressing parental anxiety forms a key part of the management of simple febrile seizures, as parents' (unspoken) worry with a first seizure is that their child might have died. However, there is little in the medical literature about this aspect of education and reassurance in management of simple febrile seizures.

Incidence/ Prevalence

About 2-5% of children in the USA and Western Europe, and 6-9% 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, being 5-10% 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 patients can have classical febrile seizures, febrile seizures that persist beyond 5 years (hence FS+), and/or epilepsy. Similar genetic factors have been identified that are involved in both febrile seizures and GEFS+. Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor. Both of these channels are also associated with another early epilepsy syndrome, Severe Myoclonic Epilepsy of Infancy (SMEI) which often begins with prolonged febrile seizure (either complex febrile seizure or febrile status) with subsequent seizures precipitated by fever. With regards 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 one in five if one sibling is affected, and one in three 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 (less than 12 months), history of simple or complex febrile seizures, and body temperature at onset of less than 40 °C. Among these, age at onset seems the most constant predictive factor, with 50% of children aged less than 12 months, and 30% of children aged more than 12 months, presenting with a recurrent febrile seizure. Positive family history of epilepsy is not consistently associated with increased simple febrile seizure recurrence.

Prognosis

Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no adverse effects on behaviour, scholastic performance, or neurocognition. 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 reduce febrile seizures and prevent recurrence, and to prevent the development of epilepsy, with minimal adverse effects.

Outcomes

Febrile seizures; development of epilepsy; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal August 2007. The following databases were used to identify studies for this review: Medline 1966 to August 2007, Embase 1980 to August 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this chapter were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We included all studies described as "blinded", "open", "open label", or not blinded. We also searched for cohort studies on specific harms of named interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. Some systematic reviews meta-analysed RCTs of children with both simple febrile seizures and complex febrile seizures, and in some RCTs the type of febrile seizure is unspecified; we have reported this throughout the text. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for febrile seizures

Important outcomes Febrile seizures, development of epilepsy, adverse effects
Number of 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 with one or more previous simple febrile seizures?
2 (410) Recurrence of febrile seizures Antipyretics v placebo 4 −3 0 0 0 Very low Quality points deducted for incomplete reporting of results and methodological weaknesses
5 (1850) Recurrence of febrile seizures Intermittent anticonvulsants (diazepam) v placebo/no treatment 4 −1 −1 −2 0 Very low Quality points deducted for weak methodologies. Consistency point deducted for conflicting results. Directness points deducted for differences in doses, methods of administration, and compliance
2 (100) Recurrence of febrile seizures Intermittent anticonvulsants (clobazam) v placebo/no treatment 4 −3 0 0 0 Very low Quality points deducted for sparse data, and methodological flaws (no intention-to-treat- analysis, not reporting method of randomisation, and uncertainty about follow-up)
What are the effects of long-term (daily, longer than 1 month) anticonvulsant treatment in children with a history of simple febrile seizures?
8 (1573) Recurrence of febrile seizures Continuous phenobarbital v placebo/no treatment 4 0 −1 −1 0 Low Consistency point deducted for heterogeneity among studies. Directness point deducted for differences in doses used
3 (216) Recurrence of febrile seizures Continuous sodium valporate v placebo/no treatment 4 0 −1 −1 0 Low Consistency point deducted for heterogeneity among studies. Directness point deducted for differences in doses used
1 (43) Recurrence of febrile seizures Continuous anticonvulsants v each other 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures?
1 (290) Incidence of epilepsy Intermittent diazepam v no prophylaxis 4 −2 0 0 0 Low Quality points deducted for quasi-randomisation and incomplete reporting of results
1(400) Incidence of epilepsy Phenobarbital (daily or intermittent) v no treatment 4 −1 0 −1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for underlying differences in risk of developing epilepsy
Open in a new tab

Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds 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.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2008 May 22;2008:0324.

Antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen)

Summary

RECURRENCE OF FEBRILE SEIZURES Antipyretic drugs compared with placebo: Ibuprofen or paracetamol may be no more effective at 1–2 years at reducing the proportion of children (who have previously had 1 simple febrile seizure) with recurrence of febrile seizures ( very low-quality evidence ). NOTE We found no direct information about physical methods of temperature reduction in the treatment of children with simple febrile seizures.

Benefits

Physical methods of temperature reduction:

We found no systematic review or RCTs in children with febrile seizures (see comment below).

Antipyretic drugs versus placebo:

We found one systematic review (search date 2003), which identified two RCTs. The first RCT (230 children with 1 previous simple febrile seizure) found no significant difference in the proportion of children who had recurrence of febrile seizures at 1 year between ibuprofen given during episodes of fever and placebo (31/111 [28%] with ibuprofen v 36/119 [30%] with placebo; reported as not significant). The second RCT (180 children with 1 previous simple febrile seizure) compared four interventions: paracetamol plus placebo, paracetamol plus diazepam, diazepam plus placebo, and placebo plus placebo. It found no significant difference in the number of recurrent febrile seizures at 2 years between paracetamol given during episodes of fever and placebo (5.2% with paracetamol plus placebo v 8.2% with placebo plus placebo; reported as not significant). The review had weak methods; it used inadequate search methods that are difficult to replicate, and had no specific inclusion/exclusion criteria.

Harms

Physical methods of temperature reduction:

We found no RCTs in children with previous simple febrile seizures (see comment below).

Antipyretic drugs versus placebo:

The systematic review gave no information on adverse effects. We found one systematic review (search date 2004, 3 RCTs, 254 people) comparing paracetamol versus placebo in children with fever. It found no significant difference in the proportion of children who had adverse effects between paracetamol and placebo (9/130 [7%] with paracetamol v 4/124 [3%] with placebo; RR 1.84, 95% CI 0.65 to 5.18).

Comment

Physical methods of temperature reduction:

We found one systematic review (search date 2004), which identified two RCTs (120 children) comparing tepid sponging versus paracetamol in children with an axillary temperature of 38.5–40.0 °C with UTI, malaria, or both. One of the RCTs (80 children) assessed febrile seizures. It found no significant difference in febrile seizures at 2 hours between sponging and paracetamol (1/40 [3%] with tepid sponging v 0/40 [0%] with paracetamol; RR 0.33, 95% CI 0.01 to 7.95). The review found no significant difference in adverse effects, including shivering, goose pimples, and discomfort, between sponging and paracetamol (6/55 [11%] with tepid sponging v 2/65 [3%] with paracetamol; RR 0.26, 95% CI 0.07 to1.01). As this review excluded children with previous simple febrile seizures, we have not reported it in the previous section.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 22;2008:0324.

Anticonvulsants (intermittent)

Summary

RECURRENCE OF FEBRILE SEIZURES Compared with placebo: We don't know whether intermittent diazepam given to children during a febrile episode is more effective at reducing the risk of febrile seizure recurrence in children with a history of simple or complex febrile seizures ( very low-quality evidence ). Clobazam given during a febrile episode may be more effective at reducing the risk of recurrence of febrile seizures (very low-quality evidence). NOTE Diazepam has been associated with increased hyperactivity, lethargy, irritability, and with difficulties with speech, activity level, or sleep. We found no clinically important results about intermittent compared with continuous anticonvulsants for treating children with febrile seizures.

Benefits

We found two systematic reviews and two subsequent RCTs assessing intermittent anticonvulsants (diazepam and clobazam) given during a febrile episode to reduce recurrence in children with a history of simple or complex febrile seizures.

Intermittent anticonvulsants versus placebo or no treatment:

The first review (search date not reported, 4 RCTs, 791 children) compared intermittent diazepam versus placebo. It found that diazepam given during a febrile episode significantly reduced the proportion of children with febrile seizure recurrence compared with placebo (44/393 [11%] with intermittent diazepam v 68/398 [17%] with placebo; OR for recurrence 0.60, 95% CI 0.40 to 0.90). The second review (search date not reported) identified three of the same RCTs as the first systematic review, and one additional RCT comparing intermittent diazepam versus no treatment (1060 children). It found no significant difference in febrile seizure recurrence at up to 24 months between diazepam given during a febrile episode and placebo or no treatment (92/537 [17%] with intermittent diazepam v 134/522 [26%] with placebo or no treatment; P = 0.20; see comment below). The first subsequent RCT (40 children with 1 or more episodes of febrile seizure) compared clobazam given during episodes of fever versus placebo. The children had 108 episodes of fever over a mean of 9.9 months; 60 episodes were treated with clobazam and 48 with placebo. The RCT found that clobazam given during a febrile episode significantly reduced the rate of seizure recurrence compared with placebo (6/48 [12%] episodes with placebo v 1/60 [2%] episodes with clobazam; P = 0.01).The RCT randomised children and analysed episodes of fever; it is unclear whether adjustments were made to allow for this, but it is likely that results would remain significant even with adjustment. The second subsequent RCT (60 children who completed the study, aged 6 months to 5 years, presenting with 1 or more episodes of febrile seizure) also compared clobazam given during febrile episodes versus placebo. The children had 312 episodes of fever over a period of 6 months; 151 episodes were treated with clobazam and 161 with placebo. In both groups, parents were advised to treat temperatures above 38 °C with antipyretic (paracetamol) and cold sponging. The RCT found that clobazam given during a febrile episode significantly reduced the recurrence of seizures compared with placebo (recurrence of seizures with febrile episodes: 9/30 [30%] people with clobazam v 25/30 [83%] people with placebo; P less than 0.001). In this RCT, each arm was also treated with antipyretic measures as described above, so that the significant results in the treatment group would appear to be attributable to clobazam only. However, the RCT did not report the method of randomisation used, and stated that the analysis was not by intention to treat; in addition, the number of children lost to follow-up after randomisation into the RCT is not clear.

Intermittent anticonvulsants versus continuous anticonvulsants:

We found no systematic review or RCTs comparing intermittent anticonvulsants (diazepam) versus continuous anticonvulsants (phenobarbital or sodium valproate).

Harms

Intermittent anticonvulsants versus placebo or no treatment:

The reviews gave no information on adverse effects. However, when we assessed individual papers, two RCTs included in the reviews reported information on adverse events. The first RCT (185 children with simple or complex febrile seizures) found that diazepam significantly increased the number of days that children were hyperactive (defined as agitation and inability to keep still) compared with placebo (138 days with diazepam v 34 days with placebo; P less than 0.0003). The second RCT found that 59/153 (39%) children taking intermittent diazepam had adverse effects, including: ataxia; lethargy; irritability; or difficulties with speech, activity level, or sleep. One child taking placebo had a rash. In the first subsequent RCT, clobazam significantly increased ataxia compared with placebo (5 [8.3%] with clobazam v 0 [0%] with placebo; P = 0.04), while the second subsequent RCT reported that "no significant difference in adverse drug-reaction profile was observed except irritability, which was occasionally more in clobazam group" (irritability: 4/30 [13%] with clobazam v 1/30 [3%] with placebo; further details and statistical analysis between groups not reported). We found one further prospective controlled study (139 children who entered the study after their first febrile seizure) which compared intermittent rectal diazepam given during the first 2 days of a febrile illness (68 children) with a group that received no prophylaxis during fever (71 children). Treatments were allocated by odd and even dates (further details not reported), and follow-up was 3 years. Children with complex febrile seizures (approximately 19%) and febrile status epilepticus (approximately 3%) were also included. The study reported that adverse effects with diazepam were mild and transient, and no long-term side effects were recorded during the 3-year follow-up (no further numerical data or statistical analysis of adverse effects between groups reported).

Intermittent anticonvulsants versus continuous anticonvulsants:

We found no RCTs.

Comment

Intermittent anticonvulsants versus placebo or no treatment:

The two reviews identified three of the same RCTs. However, one of these RCTs has been reported differently in each review. In the first systematic review the recurrence rates for this RCT are reported as 7/202 (3.5%) in children taking diazepam and 29/204 (14.2%) in children taking placebo; in the second systematic review, they are reported as 37/202 (18.3%) in children taking diazepam compared with 53/204 (30%) in children taking placebo. This may explain how reviews with predominantly the same included RCTs came to different conclusions. The mode, dose, and frequency of administration of diazepam varied in each RCT. Most of the RCTs identified by the reviews had weak methods. The first RCT was small. In the second RCT, 50 children (25%) taking diazepam and 55 children (27%) taking placebo were lost to follow-up. The third RCT reported poor compliance in children taking diazepam, which was significantly different from those taking placebo.

Substantive changes

Anticonvulsants (intermittent) One small RCT (60 children) comparing clobazam versus placebo added to the two systematic reviews already reported, and benefits and harms data enhanced. One prospective study (139 children) comparing diazepam versus placebo added to the harms section, and harms data enhanced.Categorisation of 'Anticonvulsants (intermittent)' unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2008 May 22;2008:0324.

Anticonvulsants (continuous)

Summary

RECURRENCE OF FEBRILE SEIZURES Continuous phenobarbital compared with placebo/no treatment: Phenobarbital may be more effective at reducing febrile seizure recurrence in children with a history of simple or complex febrile seizures ( low-quality evidence ). Continuous sodium valproate compared with placebo/no treatment: Continuous sodium valproate may be no more effective at reducing febrile seizure recurrence in children with a history of simple or complex febrile seizures (low-quality evidence). Continuous anticonvulsants compared with each other: We don’t know whether phenobarbital is more effective than sodium valproate at reducing the proportion of children with febrile seizure recurrence (low-quality evidence). NOTE Phenobarbital may be associated with cognitive impairment, and with behavioural problems including hyperactivity, irritability, and aggression. Serious adverse events which may be associated with sodium valproate include hepatotoxicity and haematological toxicity, both of which may occasionally be fatal.

Benefits

We found two systematic reviews, which between them identified eight RCTs assessing continuous anticonvulsants given during a febrile episode in children with a history of simple or complex febrile seizures.

Continuous phenobarbital versus placebo or no treatment:

The first review (search date not reported) identified six RCTs (598 children) comparing continuous phenobarbital versus placebo. It found that continuous phenobarbital significantly reduced the proportion of children with febrile seizure recurrence compared with placebo (71/290 [24%] with phenobarbital v 114/308 [37%] with placebo; OR 0.54, 95% CI 0.38 to 0.76; NNT 17, 95% CI 10 to 85). However, there was significant statistical heterogeneity among the trials (P less than 0.01). The second review (search date not reported, 8 RCTs, 6 included in the previous review, 975 children) also found that phenobarbital significantly reduced the proportion of children with febrile seizure recurrence compared with placebo or no treatment (90/483 [19%] with phenobarbital v 184/492 [37%] with placebo or no treatment; RR 0.51, 95% CI 0.32 to 0.82; P less than 0.01). The second review also found heterogeneity among the trials (figures not reported; see comment below).

Continuous sodium valproate versus placebo or no treatment:

We found one systematic review (search date not reported), which identified three RCTs (278 children) comparing sodium valproate versus placebo or no treatment. It found no significant difference between groups in the proportion of children with febrile seizure recurrence (29/102 [28%] with sodium valproate v 34/114 [30%] with placebo or no treatment; RR 0.74, 95% CI 0.24 to 2.23, P = 0.59; calculated by random-effects model). The authors of the review suggest that, if only the small (48 children), placebo-controlled RCT is considered, there is a significant decrease in recurrent febrile seizures with sodium valproate compared with placebo (1/22 [4%] with sodium valproate v 9/26 [35%] with placebo; RR 0.13, 95% CI 0.02 to 0.96, P = 0.01).

Continuous anticonvulsants versus each other:

We found one systematic review (search date not reported), which identified one RCT (69 children with 1 previous febrile seizure, type not reported) comparing three interventions: daily sodium valproate, daily phenobarbital, and placebo. It found no significant difference in the proportion of children with febrile seizure recurrence between phenobarbital and sodium valproate (4/21 [19%] with phenobarbital v 1/22 [4%] with sodium valproate; reported as not significant, P value not reported).

Harms

Continuous phenobarbital versus placebo or no treatment:

The reviews gave no information on adverse effects. However, when we assessed individual papers, five RCTs identified by the review included information on adverse effects. We also found one additional RCT assessing cognitive and behavioural adverse effects. All of the RCTs found that phenobarbital increased cognitive and behavioural adverse effects compared with placebo (see table 1 ).

Table 1.

Adverse effects reported in RCTs comparing phenobarbital (PHB) versus placebo or no treatment in children with at least one previous simple febrile seizure.

Ref Population Adverse events
  217 children with at least 1 previous simple febrile seizure Negative effect on cognition: 2-year follow-up mean IQ, PHB v placebo: –8.4 points, 95% CI –13.3 points to –3.5 points; P = 0.0057). 6 months after weaning and discontinuation of PHB, mean IQ PHB v placebo: –5.2 points, 95% CI –10.5 points to 0.04 points; P = 0.052)
  90 children with 2 or more previous simple febrile seizures (60 taking PHB v 30 taking placebo) Adverse effects necessitating withdrawal: 3/60 (5%) PHB-treated children had “intolerable” adverse effects (defined as effects persistent for longer than 1 month), including hyperkinetic behaviour, extreme irritability, fussiness, aggressiveness, all of whom withdrew from the study owing to the adverse effects. 1/30 (3.3%) of children taking placebo withdrew for unknown reasons
  138 children with 1 previous simple febrile seizure Negative effects on behaviour: Many parents of children taking PHB reported deterioration in behaviour, as did many parents of children taking placebo (absolute numbers and P value not reported); 20% reported slight improvement in some aspects of behaviour when PHB was withdrawn
  79 children with 1 previous simple febrile seizure Adverse effects necessitating withdrawal: 4/39 (10%) in both groups withdrew because of intolerable adverse effects
  371 children with 1 previous simple febrile seizure (109 taking continuous PHB v 142 intermittent PHB v 120 no treatment) Negative effects on behaviour: 46/109 (42%) children taking continuous PHB developed a behaviour disorder, usually hyperactivity, compared with 22/120 (18%) having no treatment. Hyperactivity spontaneously disappeared in 52% of children. Continuous PHB was prematurely discontinued in 25/46 (54%) of the children with behaviour abnormality (20% of those treated)
  65 children with 1 previous simple febrile seizure Negative effects on behaviour (increased fussiness and sleep disturbance classed as transient, dose related, or unacceptable): transient: 8/35 (23%) with PHB v 7/30 (23%) with placebo; dose related: 4/35 (11%) with PHB v 0/30 (0%) with placebo; unacceptable: 3/35 (9%) with PHB v 1/30 (3%) with placebo. Decreased comprehension: Children taking PHB had lower scores on memory concentration items on the Stanford–Binet Intelligence scale at 8- to 12-month follow-up compared with children taking placebo, although the difference between groups was not significant (absolute numbers not reported; P = 0.07).
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IQ, intelligence quotients; PHB, phenobarbital; Ref, reference.

Continuous sodium valproate versus placebo or no treatment:

The systematic review gave no information on adverse effects. Known rare, serious adverse effects of sodium valproate include hepatotoxicity and haematological toxicity. Although valproate hepatotoxicity may be dose dependent, it can, more rarely, be an idiosyncratic phenomenon — which means that it is often irreversible and difficult to predict on the basis of laboratory monitoring. Blood disturbances can also be dose dependent, with direct bone marrow suppression leading to aplastic anaemia or peripheral cytopenia affecting one or more cell lines, or even fatal bone marrow failure.

Continuous anticonvulsants versus each other:

The review and RCT gave no information on adverse effects.

Comment

Searches in the first review included studies in Spanish, and English language RCTs; searches in the second review were restricted to English language. Inclusion criteria were stated in both reviews. Methods for data extraction were also stated in both reviews, albeit more briefly in one than the other. Doses of phenobarbital or sodium valproate differed across RCTs. Most RCTs did not assess compliance and, although the adverse effects associated with anticonvulsants are well known, potential adverse events associated with their use were not routinely monitored or investigated. Despite this lack of formal monitoring of adverse effects, the authors of the individual RCTs and the reviews often concluded that the benefit : harm ratios for phenobarbital and sodium valproate were unfavourable.

Heterogeneity among RCTs identified:

Tests for statistical heterogeneity were carried out in both reviews; both found significant heterogeneity among the phenobarbital and sodium valproate RCTs. However, the authors of the first review concluded that the effectiveness of phenobarbital could not be shown. This is not quite in keeping with the findings of a significantly lower recurrence of febrile seizures in children taking phenobarbital. The second review found that, even taking the heterogeneity of the trials of phenobarbital into account, the overall effect remained positive, with inconsistencies among RCTs being ascribed rather to the degree of seizure preventing effect.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 22;2008:0324.

Anticonvulsants (intermittent and continuous)

Summary

INCIDENCE OF EPILEPSY Intermittent diazepam compared with no prophylaxis: Intermittent diazepam given during a febrile episode may be no more effective at reducing the incidence of epilepsy at 12 years in children with one previous simple or complex febrile seizure ( low-quality evidence ). Continuous Phenobarbital (daily/intermittent) compared with no treatment: Phenobarbital given daily or intermittently may be no more effective at reducing the proportion of children who develop epilepsy at 6.3 years (low-quality evidence).

Benefits

We found no systematic review of anticonvulsants for preventing the development of epilepsy in children with simple febrile seizures.

Intermittent diazepam:

We found one quasi-randomised RCT (289 children with one previous simple or complex febrile seizure), comparing intermittent diazepam (given during a febrile episode) versus no prophylaxis (diazepam only in case of febrile seizure) that followed up the children at 12 years after the initial study had finished. It found no significant difference between groups in the incidence of epilepsy at 12 years (0.8% with intermittent diazepam v 0.7 % with diazepam during seizure; reported as not significant, P value not reported). The RCT found that the risk of having epilepsy at the mean age of 14 years was 1/250 (0.4%) after simple febrile seizures and 1/40 (2.5%) after complex febrile seizures. There was no significant difference in the incidence of epilepsy with different types of seizure (reported as not significant, P value not reported). The quasi-randomised RCT assigned groups alternatively, depending on whether the child was admitted on an odd or even date.

Continuous phenobarbital:

We found one RCT (355 children with 1 previous simple or complex febrile seizure) comparing three interventions: daily phenobarbital, intermittent phenobarbital (given at the onset of fever), and no treatment. It found that, although continuous phenobarbital significantly reduced recurrent febrile seizures compared with no treatment, there was no significant difference in the proportion of children who developed epilepsy over a mean 6.3 years (7/116 [6%] with daily phenobarbital v 6/158 [4%] with intermittent phenobarbital v 1/126 [1%] with no treatment; reported as not significant, P value not reported).

Continuous sodium valproate:

We found no systematic review or RCTs about the effects of sodium valproate on preventing epilepsy in children with simple febrile seizures.

Harms

Intermittent diazepam:

The quasi-randomised RCT found no significant difference in full scale, verbal, or performance intelligence quotients (IQ; measured by the Wechsler Intelligence Scale for Children [WISC] general intelligence test), memory, reading tests, and overall scholastic performance at 12 years between intermittent diazepam and diazepam during seizures (absolute results tabulated; P value not significant for all outcomes).

Continuous phenobarbital:

The RCT gave no information on adverse effects.

Continuous sodium valproate:

We found no RCTs.

Comment

The RCT assessing children who had taken phenobarbital for febrile seizures suggested that children who subsequently developed epilepsy differed from those who did not in the frequency of neonatal abnormality, family history of mental retardation, focal initial febrile seizures, and delay in psychomotor milestones before the initial febrile seizure. It also suggested that half of the children who developed mental retardation had histories of delay in psychomotor milestones before the initial febrile seizure.

Substantive changes

No new evidence

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