Febrile Infection-Related Epilepsy Syndrome (FIRES)

Cite this article as:
Jessica Archibald and Catherine Murphy. Febrile Infection-Related Epilepsy Syndrome (FIRES), Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32716

An 8-year-old presents to the emergency department following a first seizure episode. They had a witnessed generalised tonic-clonic seizure that morning lasting approximately 60 seconds and remain post-ictal. They have a history of being non-specifically unwell yesterday with subjective fever, lethargy and a mild headache. They have no significant past medical history and no family history of seizures. The examination is unremarkable. Whilst in the emergency department they have a further two self-terminating generalised tonic-clonic seizures.

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a rare epileptic encephalopathy that results in prolonged refractory status epilepticus in previously well patients.

Presenting Features

FIRES typically presents in children between the age of 3 to 15 years, with intractable status epilepticus, 2 to 10 days post a febrile illness. The preceding illness is most commonly an upper respiratory tract infection or gastroenteritis. Fevers may have resolved prior to the onset of the acute phase of the condition.

The acute phase of the illness is characterised by frequent seizures, rapidly progressing to status epilepticus. Although the seizures are initially focal in nature, they may evolve into secondary generalised seizures. The acute phase can be prolonged, lasting from weeks to months. An association with rash, liver derangement and arrhythmia has been noted in the literature. There is no latency period.

The chronic phase is denoted by refractory epilepsy, resulting in seizures that may cluster every 2 to 4 weeks. This is often associated with severe neurological impairment and cognitive decline.

FIRES had previously been thought to only occur in children, and New-Onset Refractory Status Epilepticus (NORSE) only in adults, however this theory has been disproven. Although FIRES is more prevalent in children, it has been known to also occur in adults. As such, FIRES is now considered a subtype of NORSE, characterised by a preceding febrile illness. It has previously been known as Acute Encephalitis with Refractory, Bepetitive Partial Seizures (AERRPS) and Devastating Epilepsy in School-age Children (DESC).

Aetiology

The aetiology of FIRES in unknown and as such the pathophysiology remains unclear.

One theory is that FIRES is a form of severe infectious encephalitis, but as yet no infectious agent has been identified, and the refractory nature of the seizures is atypical of encephalitis. Another hypothesis suggests FIRES is the result of an immune response, however, there is not enough evidence to support this theory.

A case identifying anti-GABA A receptor antibodies in the CSF of a patient who presented with severe refractory status epilepticus associated with a fever led to speculation that the condition may be autoimmune-mediated. Again this has not been proven and the case may have been an exception rather than a rule.

Other theories include genetic associations and potential links with metabolic disease, but as yet a cause has not been identified.

Diagnosis and Differentials

The diagnosis of FIRES is essentially clinical, as FIRES is a cryptogenic illness. The work up is initially general, and focused on the exclusion of other treatable causes, such as infectious or autoimmune encephalitis.

A detailed history will identify the preceding febrile illness, and would be focussed on the identification of risk factors for other causes for the presentation, including exposure to animals, drugs and toxins, recent foreign travel and immunosuppression.

Blood sampling will be used to identify an infectious cause for the presentation, through full blood count, blood cultures and a screen for atypical infective agents. Lumbar puncture should be performed for CSF sampling in order to investigate bacterial, viral, fungal or autoimmune causes. CSF may show a mildly elevated white cell count in those with FIRES.

EEGs may show a generalised slowing, in keeping with an encephalopathic picture, but do little in the way of distinguishing between other causes of seizures. However, they are useful in guiding treatment and identifying non-convulsive seizures.

Initial MRI imaging is often normal, however, follow up imaging has been associated with devastating changes. Early MRI, in the first weeks of the acute illness, has shown swelling of the mesial temporal structures and increased T2 weighted signal. Follow up MRI, greater than 6 months after onset, may be associated with bilateral mesial temporal atrophy and increased T2 weighted signal. It should be noted that MRI may be normal in 50% of cases.

Differentials to consider are Dravet Syndrome, which presents with a febrile illness associated with status epilepticus, though this tends to present within the first year of life. Also Alper’s Disease, which presents with refractory seizures in previously well children, and is often associated with liver disease.

The patient is loaded with levetiracetam (40mg/kg) as per hospital guidelines, and admitted under paediatrics locally. A CT head is unremarkable and bloods show mild LFT derangement with normal inflammatory markers. They are treated empirically with intravenous cefotaxime and aciclovir. Later that afternoon they develop a fever of 38.3.

The GCS fluctuates between 11 to 13 with no full recovery to baseline until later that evening. Following two focal seizures the next afternoon, they are transferred to the local tertiary centre for further investigation and management.

Initial Management

Initial management involves treating the seizure, and more often status epilepticus. Local hospitals have their own guideline for managing status epilepticus but the first line is typically benzodiazepines (lorazepam, diazepam, midazolam, clonazepam). Second-line treatment is standard anti-convulsants (levetiracetam, phenytoin, phenobarbitone, sodium valproate), however, FIRES does not typically respond to these medications even in high doses.


The seizure pattern in FIRES is often resistant to multiple anti-epileptics. Alternative treatment options have to be sought although there is limited evidence as to the optimal treatment.

Long-term Management

There is limited data on the treatment of FIRES, however, they all conclude the seizures are very difficult to manage and often require polytherapy. Some of the alternative treatment options include drug-induced burst-suppression comas, immunotherapy, a ketogenic diet, vagus nerve stimulation, therapeutic hypothermia and intravenous magnesium sulfate. The most commonly used and researched options are discussed below.

Burst suppression coma

Burst suppression coma induction is viewed as standard care for refractory status epilepticus. If first and second-line treatments fail the next option involves high doses of anti-convulsants along with anaesthetic agents, for example, an infusion of midazolam, barbiturates or propofol. Unfortunately when the anti-convulsants are weaned the seizures tend to reoccur. Prolonged burst suppression coma has been associated with a significantly worse cognitive outcome and poorer prognosis.

Immunotherapy

Immunotherapy has been trialled due to the suspected role of inflammation in the pathogenesis of FIRES. High dose steroids, intravenous immunoglobulin and plasmapheresis have all been used. There is limited evidence to suggest a beneficial role in the management of refractory epilepsy. A large-scale Japanese study described 2 out of 12 patients responding to steroids, although there is not enough evidence to support this as a treatment option. Treatment with immunotherapy is often associated with significant side effects

Anakinra is a recombinant and modified human interleukin-1 receptor antagonist protein. Recent evidence has shown it to be an effective and promising treatment option in patients with FIRES, though relapse has been reported after withdrawal. It has been shown to decrease the duration of mechanical ventilation and hospital length of stay, and possibly seizure reduction. Future studies are required to understand the optimum dosing regime and safety of anakinra.

Ketogenic diet

A ketogenic diet is a high fat, adequate protein and low carbohydrate diet aimed at imitating the body’s fasting state. The body, therefore, metabolises fat for energy. The early introduction of the ketogenic diet has shown to be beneficial in the management of FIRES in uncontrolled trials. It has been suggested that the ketogenic diet may have an anti-inflammatory, as well as an anti-convulsant effect. Some reports suggest it may also have a positive effect on long term cognition. Currently, it is one of the only management options shown to be effective. Future controlled studies are needed to prove this efficacy.

Vagus nerve stimulation

Vagus nerve stimulation (VNS) involves the implantation of an electrode that produces intermittent electrical stimulation into the left cervical vagus nerve. Case reports have found benefit from VNS in the cessation of seizures in patients with refractory status epilepticus and NORSE. There is limited evidence of its use in FIRES.

Long term effects

The prognosis of FIRES is poor. The outcome varies with the length of the acute phase with mortality rates up to 30%. Of those patients who survive there is 66-100% chance that they will have long term cognitive impairment due to damage of the frontal and temporal lobe functions. Survivors with a normal cognitive function will present with a spectrum of learning disabilities, behavioural disorders, memory issues and sensory changes. There is a high risk of recurrent status epilepticus. Unfortunately, only a small proportion of survivors will have no neurologic sequelae.

The patient required a lengthy PICU admission where they were managed with a burst suppression coma, ketogenic diet, high dose steroids and intravenous immunoglobulin.

They were later diagnosed with Febrile-Infection Related Epilepsy Syndrome after extensive investigations, including a normal brain MRI and a lumbar puncture which showed a mildly elevated white cell count but was otherwise unremarkable.

They are currently seizure free on a combination of oral phenobarbitone, perampanel and levetiracetam but have some cognitive sequelae.

References

  1. Fox K, Wells ME, Tennison M, Vaughn B. Febrile Infection-Related Epilepsy Syndrome (FIRES): A literature Review and Case Study. Neurodiagn J. 2017;57(3):224-233. doi: 10.1080/21646821.2017.1355181. PMID: 28898171
  2. Lee H, Chi C. Febrile infection-related epilepsy syndrome (FIRES): therapeutic complications, long-term neurological and Neuro imaging follow-up. Seizure. 2018;56:53-59.
  3. Serino D, Santarone M, Caputo D, Fusco L. Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies. Neuropsychiatric Disease and Treatment. 2019;Volume 15:1897-1903.
  4. NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome) – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/new-onset-refractory-status-epilepticus-norse
  5. Orphanet: Febrile infection related epilepsy syndrome [Internet]. Orpha.net. 2021 [cited 20 January 2021]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163703
  6. Caputo D, Iorio R, Vigevano F, Fusco L. Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABA A R antibodies. European Journal of Paediatric Neurology. 2018;22(1):182-185.
  7. Diagnostic Evaluation — NORSE INSTITUTE [Internet]. NORSE INSTITUTE. 2021 [cited 20 January 2021]. Available from: http://www.norseinstitute.org/definitions
  8. Dravet Syndrome – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum
  9. Alpers Disease – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/alpers-disease
  10. Wheless. J. Treatment of refractory convulsive status epilepticus in children: other therapies. Seminars in Paediatric Neurology (2010) 17 (3) 190-194.
  11. Kramur U et al. Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment and outcome. Epilepsia (2011) 52: 1956-65.
  12. Gaspard et al. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia (2018). 59 (4) 745-752.
  13. Sakuma et al. 2010. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 121:251–256.
  14. Hon et al. Febrile Infection-Related Epilepsy Syndrome (FIRES): An overview of treatment and recent patents. Recent Patents on Inflammation & Allergy Drug Discovery (2018). 12 (2): 128-135
  15. Maniscalco et al. The off-label use of anakinra in pediatric systemic autoinflammatory diseases. The Advance Musculoskeletal Disease (2020)
  16. Shukla N et al. Anakinra (IL-1 blockade) use in children with suspected FIRES: a single institution experience. Neurol 2018; 90: 346
  17. Lai et al. Anakinra usage in febrile infection related epilepsy syndrome: an international cohort. Annals of Clinical and Translational Neurology (2020). 7(12): 2467 – 2474
  18. Dibue-Adjei et al. 2019. Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review. Brain Stimuatlion. 12 (4) 1101-1110.
  19. Kurukumbi et al. 2019. Vagus nerve stimulation (VNS) in super refractory new onset refractory status epilepticus (NORSE). Case Reports in Neu

Hot Garbage: Mythbusting fever in children

Cite this article as:
Alasdair Munro. Hot Garbage: Mythbusting fever in children, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.22916

Juniper is a 3yr old girl brought in with her mother, with a 48hr history of fever. Her mum is particularly concerned because her fever was up to 39.8°C, didn’t come down with paracetamol and she describes an episode which sounds like a rigor. On examination, she has a temperature of 39.3°C, a runny nose and bright red tonsils, and looks otherwise well. You go to discharge her, but your colleague asks if you should wait to see if her temperature comes down with ibuprofen before sending her home?

 

Introduction

Febrile illnesses are the most common cause of presentation to acute paediatric medical services. This means that fever is the most common presenting symptom seen by paediatricians, and it is clearly a huge cause of concern for parents. Despite this fact, it is clear that in day-to-day practice that there is a widespread misunderstanding about fever, its purpose, and its clinical interpretation.

Well, no longer! Once you have finished reading, you will be a master of all things related to fevers in children. We will start with some basic understanding of the processes surrounding fever, and finish off with some mega myth-busting!

What is fever?

Fever is an elevated core body temperature, as part of a physiological response to infection regulated by the hypothalamus. This is crucial to understand – your body is in control of your temperature. This is not something an infection is doing to your body; it is something your body is doing to the infection. This is different from pathological hyperthermia, where your temperature is elevated by either hypothalamic dysfunction or external heat. These are extremely rare.

Note: there are other, non-infectious causes of fever, such as cancer, Kawasakis, and autoinflammatory conditions, but these are rare in comparison to infectious fever and are covered elsewhere.

 

What temperature counts as a fever?

At what threshold do we say a child has an elevated body temperature? This is more controversial than one might think, as actually the data from which we derive “normal” body temperature is extremely poor. The most common cut off for defining a fever is 38°C – but it is important to remember that there is nothing magic about 38°C compared to 37.9°C, and temperature is better taken in context or a trend, if possible.

How do we get fevers?

The process of developing fever is extremely complex, and our understanding is still developing. At present, our best explanation is that the process is triggered by the presence of chemicals referred to as pyrogens. Pyrogens can either be exogenous (such as parts of the microbe itself, like the lipopolysaccharide on the outside of bacteria), or endogenous, such as cytokines like IL1, TNF, Prostaglandin E2 and importantly IL6, which are released by immune cells when they detect an invader. These pyrogens act to increase body temperature peripherally, but importantly also trigger receptors in the preoptic nucleus in the brain. This releases PGE2 into the hypothalamus, which then sets a new target temperature. This target is met by many facets designed to increase heat, including:

  • Release of noradrenaline by the sympathetic nervous system, increasing thermogenesis in brown adipose tissue and causing peripheral vasoconstriction and piloerection (reducing heat loss)
  • Acetylcholine release stimulating muscle myocytes to induce shivering
  • Feeling cold”, inducing heat-seeking behaviours (warm clothes and blankets)

It is important to remember that the body is trying to get hotter. If you intervene with non-medicinal efforts to cool it down, it will work even harder to try to heat up.

Why do we get fevers?

The process of having a fever has been conserved across species from lizards to mammals, and even plants! This is because it is a beneficial response to an infection. The mechanisms by which a fever helps protect you from infection include:

  1. Higher temperatures inhibiting growth/replication of pathogens
  2. Higher temperatures promoting the immune response to infection

It is also worth noting that bacteria are killed more easily by antibiotics at higher temperatures, so there is also a potential third mechanism.

 

Summary

Fever is beneficial. When a pathogen causes infection, pyrogens stimulate the hypothalamus to increase the body temperature through several mechanisms, and this increased temperature helps inhibit the growth of the pathogen AND stimulates the immune system to fight it.

That was a lot of science. Don’t worry – it’s time to get clinical! All this science stuff is lovely, but what does this mean for our patients?

Clinical significance of fever

As we have ascertained, fever is beneficial. For this reason, when a child presents with fever, the fever itself is actually of no concern. What we are interested in is the reason for the fever. Is this fever the result of a benign, self-limiting, childhood infection – or is it associated with a serious bacterial infection? Trying to determine this is enough for its own blog article (the most important thing is the end of the bed assessment – see Andy Tagg’s excellent breakdown of the paediatric assessment triangle).

Ignore the fever itself – what’s important is ascertaining its cause.

Now, let’s get on and bust some myths that persist surrounding fever in children!

 

Myth 1 – Higher temperature indicates a serious infection

This is one of the most common concerns amongst parents. The particular height of temperature may be what prompts them to come to hospital, or even what prompts the health care provider to initiate more aggressive management or investigations.

The truth is that the relationship between the height of temperature and risk of serious illness is at best complicated, and at worst a dangerous distraction. There is a very poor correlation, with such woeful sensitivity and specificity that it will both grossly over and under-call serious infections (either if the high temperature is used to rule in, or lower temperature to rule out). The caveat to this is in younger infants (particularly under 60 or 90 days), who have a higher baseline risk of serious infections (and more to the point – once they spike a temperature will be managed aggressively regardless of how high it was). Some studies have shown an extremely weak association in older children, but not enough for it to have any meaningful influence on our management. A fever is a fever – higher temperatures should not be managed any differently than lower ones.

 

Myth 2 – Temperature not relieved by antipyretics indicates a serious infection

Another common misconception also linked to the myth above. Some fevers respond well to antipyretics, and some do not. We do not understand why this is the case, however, studies have not demonstrated that failure to respond to antipyretics is a useful indicator of a more serious infection. It is not very pleasant for the child to remain hot, but it does not mean they are at any higher risk. A child whose temperature does not respond to antipyretics should not be treated any differently to one that does.

Myth 3 – Rigors indicated a serious infection

This has been covered in-depth in a separate blog post – but to summarise; there is extremely weak evidence that rigors are associated with an increased risk of bacterial infection in children, which is irrelevant when factors that are more important are taken into account. There is also evidence of no increased risk. The presence or absence of rigors should not be a deciding factor in the management of febrile children.

Myth 4 – You must wait for a fever to come down before discharge

This may seem common practice for many of you working in acute paediatrics. If a child is febrile on arrival, people often want to wait to see the temperature come down before allowing them to be discharged (this should be differentiated from seeing observations normalize in the absence of fever – which is a more understandable if still slightly questionable practice). As we have seen, a fever merely indicates the presence of an infection. If you have ascertained the cause of the fever, or at least ruled out any red flags for serious causes, the ongoing presence or absence of a fever means nothing for the child. If it comes down before discharge, it will probably just go up again once they are home! There is no need to make them wait around for hours for no reason.

Myth 5 – Fever should be treated with antipyretics

We have established that fever is beneficial. Therefore, there is essentially no reason to treat a fever in and of itself. It will not cause harm, and it is probably helping. Some children tolerate having higher temperatures extremely well, so if they are playing happily or do not seem terribly bothered about their temperature of 39°C then you leave them well alone.

Treat the child, not the fever.

Myth 6 – Fever should not be treated with antipyretics

There is an opposing school of thought, which says that since fevers are beneficial, we should not treat them at all. Given how absolutely dreadful it can feel to have a fever (which many of us adults should be able to vouch for), many of us give medicines to try to bring the temperature down and make the child more comfortable. This is the right thing to do. Despite the potential benefits having a fever confers, there is no evidence of any clinically meaningful harms to treating temperatures in unwell children, or even in adults in ICU. If the child is distressed by the temperature, they should have antipyretics to make them feel more comfortable.

Summary

  • Fever helps your body to fight infection and is not dangerous (no matter how high)
  • The fever itself is not important. The cause of the fever is what matters
  • There is little to no evidence that higher temperatures, temperatures that don’t respond to antipyretics, or rigors indicate an increased risk of serious infection
  • Persisting fever on its own is not a reason to postpone discharge
  • Only treat fevers if they are causing distress. Treat the child, not the fever

 

Postscript: Febrile convulsions

When I posted my initial thread on twitter about fevers, there were many comments asking why I didn’t address febrile convulsions. This was mainly because these are worth a post to themselves (which they have here). In brief, febrile convulsions are extremely distressing for parents to observe, but they are common and they are very benign. We do not advise treating fevers to prevent febrile convulsions, and until recently, this was because there was no evidence that they had any effect in preventing them. A recent study from Japan did demonstrate a decrease in recurrence of febrile convulsions in children who had already had one if given regular PR paracetamol, however, there are major caveats to this study discussed in depth here.

 

For the more visual oriented, the talented Emma Buxton has created an infographic of the key reminders from this blog post:

Are rigors a sign of serious bacterial infection?

Cite this article as:
Alasdair Munro. Are rigors a sign of serious bacterial infection?, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.18150

Noah is an 18m old boy who presents with fever since yesterday evening. He’s been eating and drinking a little less than usual but wetting nappies regularly. He’s been miserable when hot, but settles when his temperature comes down. His mum presented to A&E because whilst febrile this morning, he had an episode of shivering which lasted several minutes. He was conscious during the episode.

DFTB in EMA #2 – identifying the sick febrile child

Cite this article as:
Tessa Davis. DFTB in EMA #2 – identifying the sick febrile child, Don't Forget the Bubbles, 2015. Available at:
https://doi.org/10.31440/DFTB.7321

The team at DFTB had our second article published in the series for Emergency Medicine Australasia Journal.

Healthcare professionals who do not meet sick children on a regular basis are often anxious about missing a serious bacterial infection in a child. Even for those of us working solely in paediatrics, there is still the same fear of sending home a pyrexial child without recognising how unwell they are. Each individual needs to have a system in place, and a process to work through, when assessing the child who is febrile with no focus of infection. A combination of history, physical assessment and physiological markers can be used for correct identification.