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

EcLiPSE

Cite this article as:
Richard Appleton. EcLiPSE, Don't Forget the Bubbles, 2018. Available at:
https://doi.org/10.31440/DFTB.16679

Paediatrics has been blessed with not one, but two, really important randomised controlled trials on status epilepticus coming to fruition in the last months. PREDICT’s ConSEPT study was reported at #DFTB18 and now the EcLiPSE study, supported by PERUKI, has just released its headline results. 

Cannabinoids in Epilepsy at DFTB17

Cite this article as:
Team DFTB. Cannabinoids in Epilepsy at DFTB17, Don't Forget the Bubbles, 2018. Available at:
https://doi.org/10.31440/DFTB.16227

John Lawson is a paediatric neurologist at Sydney Children’s Hospital in Randwick. He has been Lead Investigator in the NSW Medical Cannabis in Epilepsy trial and is one of Australia’s leading experts on its use in near intractable seizures.

This is an almost evidence-free zone as the popular press has taken up the fight on behalf of patients.

So what are doctors to do, when parents come to them asking them to prescribe cannabis to their one year old child? This is not a talk about the wholesale legalisation of marijuana but about how, once again, we need to take a closer look at the evidence.


This double-blinded, placebo controlled trial reported in last years NEJM sets the scene for the the potential beneficial effects of cannabidiols.

Go ahead and watch the talk…

You can read this latest paper, a narrative review of some of the challenges facing the use of medical cannabis in the Medical Journal of Australia.

Chen KA, Farrar MA, Cardamone M, Lawson JA. Cannabis for paediatric epilepsy: challenges and conundrums. The Medical Journal of Australia. 2018 Feb 19;208(3):132-6.

Febrile seizures

Cite this article as:
Thanos Konstantinidis. Febrile seizures, Don't Forget the Bubbles, 2014. Available at:
https://doi.org/10.31440/DFTB.2560

An 8 month old baby has been referred to you by the Accident and Emergency Department with the first episode of febrile convulsion. He has been coryzal over the last couple of days with spikes of temperature up to 38oC. The episode lasted for 5 minutes, the baby felt hot at the time and following recovery he has remained well.

The First Afebrile Seizure

Cite this article as:
Ben Lawton. The First Afebrile Seizure, Don't Forget the Bubbles, 2014. Available at:
https://doi.org/10.31440/DFTB.4794

You are the paeds reg in a regional base hospital when a five-year-old girl is referred to you by the emergency department following a seizure.  She is afebrile and not known to have a seizure disorder.  By the time of your assessment, she is alert and interactive.

Bottom line

  • A detailed understanding of exactly what happened is crucial
  • Distinguish seizure from seizure mimic (see below for definition)
  • Distinguish primary from secondary seizure
  • Don’t miss a potentially fatal arrhythmia
  • Check a BSL and strongly consider an ECG
  • Ensure parents (and child if age appropriate) have received advice about what to do in the event of another seizure and safety regarding environmental hazards

How do I know if it was a seizure?

Your history should enable you to imagine a video clip of the event occurring – what was happening beforehand? How did it start? Was it symmetrical? How long did it go on for? What were the patient’s eyes doing? What was the recovery period like?

This detailed understanding of what happened may enable you to see a pattern that you recognise as a particular form of seizure or seizure mimic (any other process, pathological or not, which may mimic and thus be confused with a true seizure). In reality, the more experience you have in this area the more likely you are to recognise a particular pathology but even if you don’t a good history will also enable you to describe the event more usefully to a specialist. Watch out for DFTB’s upcoming seizure quiz for descriptions of some common seizure patterns and classic seizure mimics.

Tongue biting, incontinence of urine, a drowsy post-ictal period and occurrence during sleep or on waking are all strongly associated with seizures. When observing a patient with intermittent seizure episodes you may also see an increase in heart rate and blood pressure and pupillary dilatation during periods of seizure activity. While providing useful information unfortunately none of these observations is diagnostic in isolation. It is worth noting that tonic-clonic activity can occur following vasovagal syncope so a history of jerking movements is also not diagnostic of a seizure.

Serum prolactin is elevated immediately and at 20 minutes following many seizures, returning to baseline within an hour.  This is often discussed but NICE recommend against using it to diagnose a seizure as it is neither sensitive nor specific enough to be used for that purpose.    Consider it circumstantial evidence only and note the importance of the timing of the test in relation to the episode.

Was it a primary or secondary seizure?

i.e. was this a seizure that occurred as the primary pathology or was it a symptom of another problem?

Occurrence during exercise, after a sudden surprise or with a family history of arrhythmia, a pacemaker or sudden death which may have been due to a cardiac cause are big red flags for a dangerous cardiac arrhythmia as a cause of the event and warrant urgent assessment by a cardiologist.  This is the big one not to miss in the context of a child who has made a full recovery by the time you see them.

Intracranial bleeds, meningitis and ingestions are other things to consider in every case and may be relatively straightforward to exclude on the history or may warrant further investigation such as a CT head, LP or a tox screen and a discussion with child protection.

Careful physical exam is important looking for stigmata of a neurocutaneous syndrome, subtle neurological deficits as well as evidence of any traumatic injury which may be a cause or an effect of the seizure.

What investigations are required?

This is heavily dependent on the clinical context however a few general principles apply.

Anyone with any altered level of consciousness should get their BSL checked whatever the presumed cause.

The utility of checking electrolytes decreases with age and degree of recovery.  NICE suggest that checking electrolytes is at the discretion of the practitioner but what does this mean?  Infants are at risk of many congenital causes of electrolyte abnormality as well as errors in formula preparation.   When seizures are caused by electrolyte problems the patient is unlikely to make a full recovery until you identify and treat that abnormality.    I think it is essential to check the electrolytes (paying particular attention to Na and Ca) in anyone under 12 months of age, anyone who has not stopped seizing by the time you see them or does not go on to make a full and timely recovery and anyone who has findings on history or examination which suggest they may be at particular risk of an electrolyte disorder.  Our patient in this case is 5yrs old, alert and interactive so Us and Es in her case are unlikely to be helpful.

An ECG is non-invasive and harmless so worthy of a look for evidence of LQTS, Brugada syndrome, HOCM or pre-excitation in all but those episodes with an obvious alternate cause.

Other investigations are dictated by the history and exam, it may be appropriate to look for infections, metabolic problems, trauma or other pathologies as suggested by the clinical circumstances.

Do note, however, that a WCC may be elevated by a primary seizure with or without an infectious trigger.

Who needs a CT?

This is not required routinely unless there is a persistently altered level of consciousness, new focal neurological abnormality or particular reason to suspect an intracranial bleed.

Focal episodes are more likely to be associated with structural pathology than generalised episodes but are not a hard indication for immediate CT (provided they fully resolve).

MRI is a better test for parenchymal abnormalities so patients with seizure disorder who do not have a clear clinical/EEG based diagnosis will need an MRI regardless of whether they have had a CT.  Whether you chose to CT in some circumstances (e.g. a focal seizure with full resolution and a normal neuro exam) may be heavily influenced by your speed of access to MRI.

As alluded to above those with more experience in this area are likely to be more comfortable making a clinical diagnosis of a seizure syndrome and will consequently order less imaging. So don’t be shy about discussing the patient with your senior colleagues prior to requesting a CT in a child who has made a full recovery.

Who needs an EEG?

In reality most people who have had a seizure or seizure like episode without clear diagnosis will need an EEG.

It is important to bear in mind that it is not a screening test for epilepsy as some people with epilepsy will have normal inter-ictal EEGs and many without epilepsy will have baseline EEG abnormalities.

There is a reasonable degree of interpreter variability with paediatric EEGs and it is worth considering who will be interpreting the EEGs you request and how much experience they have in paediatrics before taking the conclusions as absolute, especially if your clinical assessment does not leave you confident about the underlying aetiology of the episode.

The NICE guideline suggests EEG should usually be undertaken after the second seizure like event, should not be performed unless you think this was a seizure on clinical grounds and should be taken to neither exclude or confirm a diagnosis of epilepsy.

The chain of events in which a non-specific episode leads to the requesting of an EEG which turns out to be abnormal and results in a child who does not have epilepsy being started on AED medication is something to be wary of.

Who should I start on anti-epileptic medications?

Acutely very few people should be started on anti-epileptic drugs (AEDs) after a single seizure.

There is a significant reported rate of over-diagnosis of epilepsy in the community and all anti-epileptic medications have significant side effect profiles including subtle impairment of cognitive function to which the developing brain is particularly sensitive.

Some AEDs are more effective for certain seizure types and contraindicated in others, they have different side effect profiles and these need to be considered in light of the individual patients lifestyle and co-morbidities.

An RCT of 1443 adult patients showed no significant long term differences in seizure control or quality of life measures with treatment at the time of the first episode versus later on.

If you are entirely confident about the diagnosis of a particular epilepsy syndrome and are sure that your patient will require AED medication it is essential you discuss this with whoever will be following the patient up as switching to a different AED will require a weaning process.  Outpatient follow up should be arranged in a relatively short time frame, NICE recommend within 2 weeks.

What else should I tell the family?

Anyone who has had a seizure is more likely than the average person to have another one.

There are some places that a seizure could prove fatal because of the environment in which they occur, a bathtub, a swimming pool, unfenced heights, on a bike in traffic. Families should be aware of the need to avoid these situations which, in the case of a 3 yr old, may not require any change to the level of supervision the child would normally receive but older children may need to start taking showers instead of baths and so on.

Obviously someone with a potentially uncontrolled seizure disorder should not be driving and while this is not relevant to most paediatric practice the required seizure free period for gaining a drivers licence is worth considering when reviewing teenagers with epilepsy in clinic.

Many parents have smartphones with video recording capability and it is really helpful if parents can get a video of these events if they are to recur.

Selected references

NICE CG137 The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Modified Dec 2013 https://www.nice.org.uk/nicemedia/live/13635/57779/57779.pdf accessed 22/12/13

Wilden J and Cohen-Gadol A. Evaluation of first non-febrile seizures. Am Fam Physician. 2012;86(4):334-340

Marson A, Jacoby A, Johnson A, Kim L, Gamble C, Chadwick D; Medical Research Council MESS Study Group. Immediate versus deferred anti-epileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet. 2005;365(9476):2007-2013.

Luef G. Hormonal alterations following seizures. Epilepsy behav 2010 Oct;19(2):131-3.