Craig S, and Roland D. Hot and shaking truths…, Don't Forget the Bubbles, 2018. Available at:
It’s always nice to come across a paper that makes you pause. A paper that challenges, until you read it, what you know to be “true”.
This recent paper by Murata et al. on febrile seizures may just do that.
Murata S, Okasora K, Tanabe T, Ogino M, Yamazaki S, Oba C, Syabana K, Nomura S, Shirasu A, Inoue K, Kashiwagi M. Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode. Pediatrics. 2018 Oct 8:e20181009.
Have you ever really reviewed the literature on febrile seizures? We know everything there is to know don’t we? This has led to a pattern of standard advice handed down by generations of Paediatricians to both parents and their juniors.
These are pretty common. Although they’re frightening, they are rarely dangerous…. We need to ensure we know where the fever is coming from [its nearly always a viral illness] but after a period of observation [to both confirm the diagnosis and allow the parents to recover] we’ll be able to send you home.
“There’s not much we can do to stop them happening… The vast majority of children with seizures and a fever do not go on to develop epilepsy, and they grow out of febrile seizures, often by the age of 5 or 6. If a seizure does happen again, here’s what you do…”
This newly published RCT of over 400 children from Japan challenges this near universal approach to febrile seizure advice but before we go through the paper, a little background and context is important.
What is the prognosis for febrile seizures?
A nice review in the BMJ provides the following key points:
- Up to 1/3 of children will have recurrence of a febrile seizure; most of these occur in the next year.
- Risk factors for recurrence include family history of febrile seizure, going to child care, and younger age (<18 months) at onset. Also, multiple seizures in the one illness, a “low” fever (<39C), and a shorter duration of fever prior to the seizure increase risk for recurrence.
- There is a low risk of subsequent epilepsy in simple febrile seizures. However, complex seizures, a family history of epilepsy, and neurodevelopmental impairment increase the risk of unprovoked seizures.
What can be done to prevent seizure recurrence?
While standard advice (often provided on handouts) highlights that “Nothing can be done to prevent a febrile convulsion from occurring.” the evidence, however, is more nuanced.
The most recent Cochrane review on medications to prevent febrile seizures in children found
- 40 articles describing 30 RCTs
- 4256 randomised participants.
The following tables provide a very brief overview of the findings of the Cochrane review. Briefly, a tick in a box suggests a benefit of treatment, a cross suggests no benefit, and an empty box means there isn’t any data one way or the other.
There have also been comparisons of continuous phenobarbitone to intermittent rectal/oral diazepam (no difference), and intermittent rectal diazepam to intermittent rectal valproate (no difference).
So – there is a statistical benefit to treatment with intermittent diazepam, intermittent diazepam, or continuous phenobarbitone. However, most children with a febrile seizure don’t have a recurrence. The Cochrane authors estimate that “up to 16 children would have to be treated over a year or two to save just one child a further seizure.”
Importantly, these drugs are not benign. In fact, two studies of children given continuous phenobarbitone demonstrated lower comprehension scores, and around 1/3 of children treated with either barbiturates or benzodiazepines had adverse effects.
Finally, the authors conclude with the suggestion that “Parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.”
So – what do the guidelines tell us to do?
Interestingly, the same evidence has led to varying guidelines, which seem to depend upon the prevailing medical culture where you practice.
Australians, Canadians and the English appear to accept the inevitability of febrile convulsions:
Australia: “Long term anticonvulsants are not indicated except in rare situations with frequent recurrences.”
Canada: “Pending further research, intermittent prophylactic therapy to prevent recurrent febrile seizures cannot be recommended at this time.”
English: “Providing drug treatment to prevent or manage future seizures may be considered appropriate in some circumstances, such as when the child has a history of prolonged or frequent seizures. However, these circumstances are an indication for urgent admission for specialist assessment and management, including the decision to prescribe drugs to manage or prevent future seizures”
The USA and Ireland suggest that there are occasions where intermittent diazepam might be reasonable.
USA: “…the potential toxicities associated with antiepileptic drugs outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term therapy is not recommended. In situations in which parental anxiety associated with febrile seizures is severe, intermittent oral diazepam at the onset of febrile illness may be effective in preventing recurrence…. Although antipyretics may improve the comfort of the child, they will not prevent febrile seizures.”
Ireland: “There is no evidence that antipyretics influence the recurrence of febrile seizures…. Use of intermittent prophylactic oral or rectal diazepam at the time of illness or fever, may help reduce the risk of recurrent febrile seizures. This should only be prescribed in conjunction with a paediatric specialist…. Continuous prophylactic treatment is now not generally advised for children with febrile convulsions, or at very least is rarely indicated and should be prescribed only by a paediatric specialist.”
Japan’s guidelines seem to propose a lower threshold for treatment. They provide recommendations for when to commence prophylactic diazepam (during a subsequent febrile illness). Listed indications include:
- A febrile seizure lasting 15 minutes or longer, or
- Repeated febrile seizures and two or more of the following risk factors:
- Focal or repeated seizures within 24 h
- Preexisting neurological abnormality or developmental delay
- Family history of FS or epilepsy
- Age younger than 12 months
- Seizure within 1 h after onset of fever
- Seizure occurring with body temperature less than 38 °C
What did the study tell us?
Please do read the full paper but in summary this prospective, open randomised control trial randomised 219 patients to receive regular per rectal paracetamol (10mg/kg) and 204 to receiving no treatment. The latter group were advised NOT to give further antipyretic medication following arrival in hospital with only 3 patients breaching protocol. The power calculation had been based on same fever episode recurrence rate of 15% which had been derived from a previous study looking at the impact of per rectal diazepem. This is relevant as this ‘study’ recurrence rate is likely to be different than a whole population recurrence rate and therefore reduces the external validity of the findings. Of note 188 patients were excluded from the 794 patients who had a Febrile Convulsion during the study period because they had already received a diazepam suppository to prevent a further seizure.
The recurrence rate was significantly lower in the intervention arm (9.1%) compared to the no treatment group (23.5%) with 7 patients needed to be treated to prevent one febrile seizure
Why is this important?
This study highlights that a common perspective, the fatalistic acceptance of the inevitability of febrile seizure, is not necessarily the only reasonable approach.
“Each person does see the world in a different way. There is not a single, unifying, objective truth. We’re all limited by our perspective”
While there may be numerous reasons why this study may not be applicable in your local practice it does appear that controlling the fever can reduce recurrence rates however uncomfortable it might be to admit this isn’t what we previously believed
However, the interpretation and application of evidence depends on context. For a parent terrified of their child having another seizure, this study (and the evidence for intermittent diazepam) may be compelling. On the other hand, a parent who accepts the low likelihood of an adverse outcome from another seizure may have a more relaxed approach
Once this illness has resolved, we don’t have evidence for the use of paracetamol or ibuprofen to reduce the recurrence of febrile seizures with subsequent febrile illnesses. In fact, there’s pretty good evidence that it won’t help.
In an RCT of 231 children who were followed for two years after their first febrile seizure, antipyretics were found to be ineffective in preventing subsequent seizures, with similar rates for placebo, ibuprofen and paracetamol. So for the parent whose child has a febrile convulsion and then two weeks later spikes a solitary fever – rushing for paracetamol is probably not sage advice.
Usual practice isn’t to withhold paracetamol or ibuprofen in the child who has unpleasant symptoms associated with a febrile illness. Most clinicians recommend treating “as needed” (when the child is grumpy, upset, irritable or lethargic). The control arm, the absence of any treatment, is not normal practice in many healthcare settings and given you are potentially denying a child a treatment for pain and distress something an ethics committee in an different environment may not approve. A control arm of normal care may have resulted in a different recurrence rate (especially in this population which appears to be proactive in the control of fever) i.e. we don’t really know the difference between regular paracetamol and as needed paracetamol on the incidence of early febrile convulsion recurrence,
Ultimately a 1 in 4 recurrence rate is high and difficult to determine from other population studies and so the external validity of this study in other populations does require further study
The bottom line
There is so much to discuss in this study. However, it’s unlikely that any society that doesn’t normally use per rectal medications will be changing guidance on febrile convulsions any time soon. Also, we don’t know how “as needed” antipyretics compares to “regular” antipyretics for this indication.
It is very unlikely that the differences occurred by chance alone, so the impact of regular antipyretic may well have a short term impact, even though the clinical course of the disease is not changed (i.e. febrile seizures will recur in a significant proportion of children).
The next question is should parents and carers have a right to utilise this evidence (and the existing evidence for diazepam for prevention of seizures in future febrile episodes) in treatment options for their own children?
Want to read more?
Read Casey Parker’s take on paracetamol PR for febrile seizures.