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

Seizures Module

Cite this article as:
Peter Tormey. Seizures Module, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.27858
TopicSeizures
AuthorPeter Tormey
DurationUp to 2 hours
Equipment requiredNone

Basics (10 mins)

Main session: (2 x 15 minute) case discussions covering the key points and evidence

Advanced session: (2 x 20 minutes) case discussions covering grey areas, diagnostic dilemmas; advanced management and escalation

Quiz (10 mins)

Infographic sharing (5 mins): 5 take home learning points

We also recommend sharing a copy of your local guideline.

Unprovoked seizures are common in children with around 8% having a seizure by 15 years of age

  • Most seizures are brief, self-limiting and generally cease within 5 minutes
  • Convulsive status epilepticus is the most common paediatric neurological emergency worldwide and the 2nd most common reason for PICU admission in the UK.
  • A seizure is the clinical expression of abnormal, excessive, synchronous discharges of neurons residing primarily in the cerebral cortex

Was the seizure a primary event or secondary to something else?

Seizures can be due to an underlying epilepsy or can be acute symptomatic seizures due to:

  • Hyponatraemia
  • Hypoglycaemia
  • Hypocalcaemia
  • High fever
  • Toxin exposure
  • Intracranial bleeding
  • Meningitis

Was this really a seizure or should I consider other differentials?

Tonic clonic activity and incontinence are not specific for seizures so always consider differential diagnoses.

  • Differential diagnosis of a seizure:
    • Vasovagal syncope
    • Blue breath holding spell
    • Reflex anoxic seizure
    • Arrhythmia
    • Non-epileptic paroxysmal event

Seek out clues in the history:

A sudden fright or minor trauma followed by the child turning pale and seizing is suggestive of a reflex anoxic event secondary to a vagal reflex. Hypoxia can induce a short tonic-clonic event that looks like a generalized tonic-clonic seizure but the child will recover quickly.

A history of a temper tantrum crescendo-ing into the child holding their breath, turning blue and then seizing might make you think of a breath holding attack. Again, this child will recover quickly.

Standing in a hot, stuffy room, feeling lightheaded with some visual changes and echoey hearing sounds vasovagal. Compare this to a child who describes palpitations or is exercising before the event; this child could have had an arrhythmia.

A 7-year-old boy called Simon is brought to the ED by his parents. At approximately 7am they were awoken by noises coming from his room. They ran in and noticed that the left side of his face was jerking and he was drooling and making gurgling sounds. He wasn’t responding to them.

The movements stopped after 2 minutes. He was drowsy for a few minutes after and had difficulty talking and expressing himself for 15-20minutes after. They also noticed there was a slight drooping on one side of his mouth for 15-20 minutes.

He has now fully recovered and is bright and alert in ED with GCS 15/15 and a normal neurological exam.

What are some of the key elements of Simon’s past medical history that you must ascertain?

How would you classify his seizure? 

Are there clues in the history as to what specific seizure disorder he may have?

Would you perform any investigations at this point?

Does he need to be admitted? Does he need treatment? What follow up will you arrange?

Any history of hypoxic injury at birth?

Did he have any delay in meeting his developmental milestones?

How does his school performance compare to that of his peers?

Is there any history of similar events? Or unusual behaviours or word-finding difficulties on waking from sleep?

The key here is to determine if Simon is an otherwise well child or if there are details in his medical history, such as developmental delay, that may make him more prone to developing epilepsy

It is also important to determine if he perhaps has had more subtle seizures in the past that may have been missed

This is an opportunity to look at the International League Against Epilepsy infographic.

Simon has had a focal motor seizure with impaired awareness.

Specific seizure disorder: Simon’s seizure would be most in keeping with a clinical diagnosis of benign childhood epilepsy with centrotemporal spikes (BCETS) also known as benign rolandic epilepsy.

BCETS usually presents in early school age children with normal development. The most common seizure type is a focal motor seizure involving the face. There may or may not be impaired awareness. They can also be associated with facial numbness, hypersalivation, drooling, dysphasia and speech arrest. Motor activity in the upper, but not lower, limbs is common.  They may also progress to a generalized tonic-clonic seizure. Approximately 75% of seizures occur at night or on awakening and, therefore, can be easily missed. Patients may have a post-ictal paresis, often of one side of the face which can be concerning for a cerebrovascular accident. 


A blood glucose should be checked. 

Electrolytes are often checked with a first seizure but their utility decreases with patient age and degree of recovery. 5

As this history is strongly in keeping with a diagnosis of BCETS, an EEG is not strictly necessary to confirm the diagnosis, however, your local guideline for first seizure management should be followed.

There is no indication for neuroimaging at present.

Patients generally do not need to be admitted after a first seizure with no red flags:

  • Seizure related to head injury
  • Developmental delay or regression
  • Headache prior to seizure   
  • Bleeding disorder or on anticoagulant medication
  • Drug or alcohol use
  • Focal neurological signs or incomplete recovery
  • Seizure >5 minutes
  • Social concerns e.g. parental coping mechanisms or concerns over parental ability to recognize and seek medical attention if another seizure were to occur

Patients with an uncomplicated first seizure generally do not need to be commenced on treatment. BCETS in particular generally has a benign course and rarely requires treatment. 

All children who have a first seizure episode should be referred for paediatric follow up. This may be General Paediatric or Paediatric Neurology follow up and local referral pathways should be consulted. 

The International League Against Epilepsy have a useful infographic for managing a first seizure:

https://www.ilae.org/patient-care/first-seizure

For more information on managing a 1st afebrile seizure see: 

https://dontforgetthebubbles.com/first-afebrile-seizure/

Emily is a 4-year-old girl brought to ED with episodes of disturbed sleep for the last 3 weeks. This is her 4th visit to ED. She was previously diagnosed with “night terrors” and reassured. Her mum is concerned because the episodes are now occurring each night, having previously been 1-2 per week.

Her mum has videos of the episodes, which she shows you. The events usually occur shortly after going asleep. In the videos Emily wakes from sleep, looks terrified and stares straight ahead. The episodes go on for 2-3minutes. She usually vomits or retches towards the end of the episode. She goes back to sleep after. She is well during the day.

What could be going on here?

What interesting details in the history might lead you towards a specific diagnosis?

What could help differentiate between epileptic and non-epileptic events in this case?

What is the prognosis for these patients?

These episodes sound unusual and their frequency and severity seems more pronounced that what could be put down to normal variance in sleep pattern and arousal. Emily’s symptoms are not likely to be simple night terrors.

Seizures commonly occur in sleep and as a result can be missed or present subtly or without characteristic features.

There are several features in the history that would suggest Panayiotopoulous Syndrome (PS). 

PS is a focal epilepsy that occurs in children aged 1-14 years with a mean age of 5 years. The seizures are usually nocturnal

It is thought PS accounts for 6% of children with epilepsy.

There is a strong association with vomiting (70-85%) of patients. Visual symptoms are also closely related, given the seizures originate in the occipital lobe. Autonomic features can also be seen: pallor, tachycardia, miosis, coughing and hypersalivation.

They may also have head or eye deviation and focal or generalized clonic activity.

The diagnosis of PS is often delayed due to misdiagnosis with other causes of vomiting and autonomic manifestatons e.g encephalitis, migraine, syncope or gastroenteritis.

PS could easily be clinically misdiagnosed as night terrors. Night terrors are dramatic awakenings that usually happen during the first few hours of sleep. They share several characteristics with PS but there are also some subtle differences highlighted in the table below:

Clinical FeaturePSNight Terrors
Usual duration 5-10min++
Occur during the first few hours of sleep++
Autonomic Symptoms e.g tachycardia, tachypnea, sweating+++
Impaired awareness++
Child looks scared++
Starring+++
Running or walking around during episode++
Screaming++
Vomiting++
Thrashing of arms and legs++

Table 1. Clinical characteristics of PS and night terrors

It is not unreasonable to clinically diagnose night terrors if they present with characteristic events, more in keeping with night terrors than PS. However, if there are unusual features, such as vomiting, or exaggerated autonomic symptoms, or in a child who represents, then an alternative diagnosis should be considered. 

An inter-ictal EEG will usually be diagnostic in PS with occipital spikes, which are enhanced in sleep, the characteristic feature. In a child with unusual events occurring in sleep and a normal EEG, a video telemetry EEG may be useful to try and capture and characterise the events and outrule seizures as a possibility.

PS usually has a benign course with spontaneous remission commonly occurring within 2-3 years of onset. 

Seizures are generally infrequent but oxcarbazepine may be required to reduce seizure frequency.

Emma is a 3-year-old girl with a background of refractory epilepsy and developmental delay. Her current medications include levetiracetam, sodium valproate, clobazam and lamotrigine.

She is PEG fed but has been vomiting up her feeds for the last 2 days and mum is unsure if her medications have been staying down.

She normally has up to 20 short seizures per day at home, but this has been increasing in the last 2 days.

You get a pre-alert from the ambulance service: Emma has been having a generalised tonic clonic seizure for 15 minutes. Her mum gave her buccal midazolam at 5 minutes, but it has not had any effect.

The ambulance crew ask you can they repeat the dose of buccal midazolam?

Emma arrives in resus with the seizure ongoing. What is your management plan?

Emma has had two doses of benzodiazepines. What would be your next line agent? Who else should you be calling at this stage?

You decide to suggest 2 papers, the ConSEPT and EcLiPSE papers for your department’s next journal club and to discuss what effect they will have on your department’s practice. One issue you foresee is that a lot of the patients you see are already on maintenance levetiracetam.

Does this preclude children on maintenance levetiracetam from receiving IV levetiracetam in status epilepticus, as is the case with the use of phenytoin in patients who take it as maintenance treatment?

Emma’s seizure terminated with the second line agent and she was admitted under neurology for IV fluids and ongoing management of her seizures until she could tolerate her medications by PEG again. In this case her status epilepticus was likely due to her vomiting up her medications.

Had Emma’s seizure not stopped after the loading dose of phenytoin, what would your next steps be?

There is a risk of respiratory depression with any benzodiazepine. 

A Cochrane review9 in 2018 found that 25/346 (7.2%) patients treated with buccal midazolam experienced respiratory depression. There was no statistically significant difference in risk of respiratory depression between buccal midazolam and other benzodiazepines, administered via various routes. 

The drug information leaflet or Summary of Product Characteristics (SPC) for Buccolam® and Epistatus® recommend that only a single dose be administered at home by a caregiver and that additional doses should only be administered after seeking medical advice and, preferably, under medical supervision.

In this case, it would be reasonable to advise a second dose of buccal midazolam, presuming the paramedics had the necessary equipment and skillset to manage any respiratory depression that may occur. 

Factors that may influence your decision are: the ETA of the ambulance and if the child has a history of respiratory depression with benzodiazepines.

She should be managed as per the APLS guideline (please note this is the Australian APLS guideline and has been updated to include the use of levetiracetam as a second line agent. This has not yet been included in the UK APLS guideline, see discussion below):

At this point you should be informing PICU about the patient and your PEM consultant if you haven’t done so already.

The CONCEPT and ECLIPSE trials were published concurrently in May 2019.

These two studies looked at whether levetiracetam is non-inferior to phenytoin as a second line treatment in the management of convulsive status epilepticus in children.

This question was posed as phenytoin is linked to many adverse events including liver damage, Steven-Johnson syndrome, extravasation and reports of death due to dosing errors. As a result, and because of its biopharmacology, it is a resource-intensive drug to make up in an emergency.

Levetiracetam can be given over 5 minutes (phenytoin takes 20 minutes to infuse), is more compatible with IV fluids, has less drug interactions, and has a lower risk of adverse events.

The infographic below provides a nice summary:

You can find a more detailed summary at: https://dontforgetthebubbles.com/consept-eclipse-status-epilepticus/

It’s important to note that the primary outcomes of the two studies were different:

ConSEPT – The primary outcome was seizure cessation 5 minutes after the drug infusion and where possible the seizure cessation was verified independently via a video recording to reduce observer bias between the two groups.

EcLiPSE – In a key difference to the ConSEPT study the primary outcome was time “from randomisation to cessation of all visible signs of convulsive activity, defined as cessation of all continuous rhythmic clonic activity, as judged by the treating clinician”. As per the inclusion criteria this a very real world pragmatic approach.

The two studies concluded:

ConSEPT – Levetiracetam is not superior to phenytoin as a second line agent for convulsive status epilepticus

EcLiPSE – There is no significant difference between phenytoin and levetiracetam in the second-line treatment of paediatric convulsive status epilepticus for any outcome, including time to seizure cessation

Here is a section of the commentary from the post:

“While there were differences between the study designs, the primary outcome measure of timing being the largest, the fact that both studies found no difference probably means head-to-head there is little difference.

The nature of the statistical analysis means that both groups rightly point out that in their cohorts levetiracetam wasn’t superior in outcomes to phenytoin. A future pooled analysis could still demonstrate a difference, but it seems unlikely that a critical difference will be seen (especially for the safety element).

Given the wealth of evidence on the side effects of phenytoin it is surprising the incident rates were relatively low. Whether in study conditions more care was taken with drawing up and delivering the drug or that previous safety reviews were heterogenous in their inclusion criteria is difficult to know. However, the time to draw up phenytoin, and the background concerns on its potential harm, will lead some to suggest that the switch to levetiracetam is a logical one, regardless of its effectiveness against phenytoin.

The challenge faced by many units is a capacity for PICU beds. Because phenytoin is given over 20 minutes there is time to prepare for airway/anaesthetic intervention if it is unsuccessful in terminating the seizure. The use of levetiracetam may cause some to wonder if they should then try phenytoin either as a stop gap to bed availability or because the time in status now seems ‘shorter’ than normal. These are not statistical issues, these are pragmatic clinical conundrums.

The absence of a clear winner will further fuel this debate meaning it is unlikely in the immediate future we are going to see a change from the ALSG or similar organisations. However, local units may decide, in the clear absence of harm from levetiracetam, that it is a drug they should be adding into their treatment protocols.”

The EcLiPSE trial2 did not report any increase in adverse events in children who were on maintenance leveltiracetam and received a loading dose of IV levetiracetam. The ConSEPT trial excluded all patients who were on maintenance levetiracetam and phenytoin.

The use of phenytoin in status epilepticus in patients who are on maintenance phenytoin is avoided due to its potential cardiovascular side effects. As levetiracetam does not share these side effects and is generally safe and well tolerated it is reasonable to use it in children who are already on maintenance therapy. 

The EcLiPSE trial2 did not report any increase in adverse events in children who were on maintenance leveltiracetam and received a loading dose of IV levetiracetam. The ConSEPT trial excluded all patients who were on maintenance levetiracetam and phenytoin.

The use of phenytoin in status epilepticus in patients who are on maintenance phenytoin is avoided due to its potential cardiovascular side effects. As levetiracetam does not share these side effects and is generally safe and well tolerated it is reasonable to use it in children who are already on maintenance therapy. 

The current APLS guidance in the UK would be to proceed with RSI. As we have discussed above, the Australian APLS guidelines have changed, in view of the results of the ConSEPT and EcLiPSE, to include the use of an additional second line agent prior to proceeding to RSI. As reported in the ConSEPT trial, treatment with one drug and then the other reduced the failure rate by more than 50% at the expense of only an additional 10 minutes. 

For further discussions on advanced seizure management and RSI, the following podcast is recommended:

https://broomedocs.com/2019/06/paediatric-status-epilepticus-debate/

Caroline is a 13-year old girl who presents to ED with a first seizure. Her parents describe a generalised tonic clonic seizure that lasted 20 minutes.

She is an otherwise well girl who is doing well in school. The only concern in her past medical history is that she has been having frequent syncopal episodes for the last 12 months. She has been seen by her GP for this who reassured her that syncopal events were common on her age group and advised her to drink plenty of fluids and try and avoid triggers.

Her neurological exam is normal.

How would you proceed? 

Are there any investigations you could perform in the department to investigate the syncopal episodes she reports?

Is there any link between syncope or arrhythmogenic events and seizures?

Caroline is admitted for further cardiac investigations. She also has an EEG diagnostic for frontal lobe epilepsy which is linkced to ion channel abnormalities.

A blood glucose should be checked. If she has returned to her baseline and there were no red flags with regard to the seizure it would be reasonable to arrange outpatient follow up as per departmental protocol and advise her parents what to do if she should have further seizures.

An ECG and a lying-standing blood pressure should be performed.

Caroline has an ECG performed which has features consistent with Type 1 Brugada syndrome.

Seizures may be triggered by cerebral hypoperfusion due to an arrhythmic event. They can often be treated as a primary seizure and the underlying cardiac abnormality may be missed. Long QT syndrome in particular can present with seizures and almost half of affected patients are initially misdiagnosed and treated for epilepsy before the correct diagnosis is made.

Seizures can also be seen as a primary neurological abnormality, related to the cardiac abnormality. Brugada Syndrome is an autosomal dominant condition characterized by ECG alterations and a predisposition to tachyarrhythmias and sudden death. It is caused by a mutation in the genes SCNA5 and SCN1A. SCN5A codes for the alpha subunit of the voltage-gated sodium channel. As the condition is a channelopathy it can also be associated with epileptic seizures with the channelopathy affecting neuronal pathways. 

Caroline has a ECG which is consistent with features of Type 1 Brugada Syndrome.

There is coved ST segment elevation in V1 and V2 with a negative T wave. This is the only ECG abnormality that is potentially diagnostic and is often referred to as Brugada sign.

For an approach to the paediatric ECG have a look at the following DFTB post:

https://dontforgetthebubbles.com/approaching-the-paediatric-ecg/

For further reading on the specific ECG findings in Brugada Syndrome, please see:

https://litfl.com/brugada-syndrome-ecg-library/

Which symptom is more commonly seen with Panayiotopoulos syndrome than night terrors?

A: Staring

B: Terrified expression

C: Vomiting

D: Thrashing of arms and legs

E: Tachypnoea

70-85% of seizures in PS are associated with vomiting. Vomiting is not usually described in night terrors. The diagnosis of night terrors should be carefully applied to children having events disturbing their sleep that have a strong
association with vomiting.

Which of the following are side effects of phenytoin but not levetiracetam?

A: Mood disturbance

B: Cardiovascular toxicity 

C: Purple glove syndrome

D: Gingival hypertrophy

E: Stevens Johnson syndrome

The correct answers as B, C, & D

Although levetiracetam and phenytoin have several common side effects, cardiovascular toxicity, purple glove syndrome and gingival hypertrophy are more specific to phenytoin and are not generally seen with levetiracetam. Mood
disturbance is one of the most common side effects of levetiracetam. Stevens Johnson syndrome is also reported with levetiracetam.



Which of the following ECG findings are seen in Brugada syndrome:

A: Coved ST segment elevation in V1-3, >2mm

B: Prolonged PR interval

C: Negative T wave

D: Saddleback ST elevation, >2mm

E: LVH voltage criteria

The correct answers are A, C, & D

  • Brugada Type 1 has coved ST segment elevation in V1-3, >2mm, followed by a negative T wave. This is often referred to as Brugada sign.
  • Brugada Type 2 has >2mm of saddleback-shaped ST elevation
  • Brugada Type 3 can have the morphology of type 1 or 2 but with <2mm ST segment
  • elevation
  • Prolonged PR interval and LVH voltage criteria are not characteristic features of Brugada syndrome

1. Clinical Practice Guidelines : Afebrile seizures [Internet]. [cited 2020 Apr 20]. Available from: https://www.rch.org.au/clinicalguide/guideline_index/Afebrile_seizures/

2. Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet. 2019 May 25;393(10186):2125–34

3. https://www.uptodate.com/contents/seizures-and-epilepsy-in-children-classification-etiology-and-clinical-features?search=seizures%20in%20children&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

4. https://www.ilae.org/education/infographics

5. https://dontforgetthebubbles.com/first-afebrile-seizure/

6. Michael M, Tsatsou K, Ferrie CD. Panayiotopoulos syndrome: An important childhood autonomic epilepsy to be differentiated from occipital epilepsy and acute non-epileptic disorders. Vol. 32, Brain and Development. Elsevier; 2010. p. 4–9.

7. Ferrie CD, Grünewald RA. Panayiotopoulos syndrome: A common and benign childhood epilepsy. Vol. 357, Lancet. Elsevier Limited; 2001. p. 821–3.

8. Weir E, Gibbs J, Appleton R. Panayiotopoulos syndrome and benign partial epilepsy with centro-temporal spikes: A comparative incidence study. 2018 [cited 2020 May 4]; Available from https://doi.org/10.1016/j.seizure.2018.03.002

9. Mctague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Vol. 2018, Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd; 2018.

10. Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019 May 25;393(10186):2135–45.

11. Sandorfi G, Clemens B, Csanadi Z. Electrical storm in the brain and in the heart: Epilepsy and Brugada syndrome. Mayo Clin Proc. 2013 Oct 1;88(10):1167–73.

12. Camacho Velásquez JL, Rivero Sanz E, Velazquez Benito A, Mauri Llerda JA. Epilepsy and Brugada syndrome. Neurol (English Ed. 2017 Jan 1;32(1):58–60.



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Prepare for transport: Costas Kanaris at DFTB19

Cite this article as:
Team DFTB. Prepare for transport: Costas Kanaris at DFTB19, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.22605

Costas Kanaris is a paediatric intensivist working in Manchester. He is also internet-famous for his challenging #fridayquiz in which he presents a case, drip-feeding information, as the Twitter audience figure out the diagnosis and the best way to treat the patient in front of them.

This time he tries it in front of a live studio audience. Here is a teaser to tickle your brain.

 

This talk was recorded live at DFTB19 in London, England. With the theme of  “The Journey” we wanted to consider the journeys our patients and their families go on, both metaphorical and literal.

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ConSEPT and EcLiPSE – Levetiracetam versus Phenytoin for Status Epilepticus

Cite this article as:
Roland D, Davis T. ConSEPT and EcLiPSE – Levetiracetam versus Phenytoin for Status Epilepticus, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.18696

This week sees the publication of two hugely anticipated randomised controlled trials both published in the Lancet simultaneously which DFTB have been given exclusive access to.  

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.