Febrile Infection-Related Epilepsy Syndrome (FIRES)

Managing seizures and seizure disorders in children is a required skill for emergency medicine providers. Clearly we know to never let hypoglycemia fool us and to always consider other seizure mimics. Fortunately, most seizures will spontaneously resolve and then we need to ponder their potential etiologies (ex, simple febrile seizure). Some will require emergent management with benzodiazepines and other second-line and third line anti-epileptic medications for Status Epilepticus. Clearly, while seemingly straight forward, the seizing brain is a complex problem and comes in innumerable forms that can be equally perplexing and challenging to manage (ex, neonatal seizures, Pyridoxine Deficiency, Eclampsia, Rickets, Toxins). Furthermore, there are many epilepsy syndromes that are managed with unique therapies that may present to our emergency departments and require some knowledge of to manage appropriately. One such condition was recently reviewed by Koh et al (PMID 33681649). Let us take a minute to familiarize ourselves with this nutritious educational morsel – Febrile Infection-Related Epilepsy Syndrome (FIRES):

Febrile Infection-Related Epilepsy Syndrome (FIRES): Basics

Known by many names, but now FIRES is preferred.
  • Prior names include:
    • “Devastating Epileptic Encephalopathy in School Age Children (DESC)”
    • “Fever Induced Refractory Encephalopathy in School Age Children”
    • “Acute Encephalitis with Refractory Repetitive Partial Seizures (AERRPS)”
  • Clearly, FIRES is a better acronym… but the prior names also point out key characteristics:
    • Age – while it can affect young adults, it typically is seen in children older than 2 years of age with a median age of onset of ~ 8 years of age.
    • Refractory nature – seizure episodes increase in frequency and duration and progress to refractory status epilepticus
    • Encephalopathy / Encephalitis – significant cognitive deterioration is common
    • Fever – associated with recent febrile illness
FIRES is a subcategory of New-Onset Refractory Status Epilepticus (NORSE).
  • NORSE defines a clinical presentation, not a specific diagnosis.
  • It affects previously healthy children and adults who did not have prior seizures.
  • The seizures develop Suddenly and Explosively!
  • The seizures are difficult to control / refractory.
  • The seizures do not have a clear etiology (structural, toxic, metabolic, or infectious).
FIRES is defined as:
  • Subcategory of NORSE that has had a prior febrile infection.
  • Fever needs to have been within 24 hours to up to 2 weeks prior to the onset of the seizures.
  • Fever may be present at onset of seizure.

Febrile Infection-Related Epilepsy Syndrome: Presentation

  • Begins as New onset seizure that has is intermittent or stuttering
    • (so, we may see this early on and think it to be a simple febrile seizure or complex febrile seizure or even just a new onset seizure.)
  • Episodes then crescendo with increasing frequency and duration over a 2 to 7 day period.
  • Eventually culminates in refractory status epilepticus.
    • Has minimal response to conventional therapies.
    • Has stereotypic EEG findings (which I want try to understand).
  • Eventually, seizure activity reduces, but patients are left with lasting morbidity.
    • Significant cognitive deterioration
    • Chronic intractable epilepsy
    • There is a 9-18% mortality rate as well.

Febrile Infection-Related Epilepsy Syndrome: Therapies

  • The exact pathogenesis of FIRES is not yet understood, so targeted therapies are still being developed.
    • There is an apparent fulminant inflammatory process (encephalitis) involved.
    • A non-specific, febrile infectious process is believed to be the culprit (but no agent yet defined).
    • The infectious agent may not be the problem, but rather the immune response to it that leads to the inflammatory process.
  • Therapies that are currently used (and we should be on the look out for):
    • Alternative strategies are used since common anti-epileptic medications are often ineffective.
    • Cannabidiol (CBD)
      • May have anti-inflammatory effects.
      • Has also been used for Dravet Syndrome and Lennox-Gastaut Syndrome.
    • Ketogenic Diets
      • Ketogenic diets exhibit anti-inflammatory properties and are often used in other difficult to control seizure disorders.
      • Be aware of this as giving glucose to a child who is on a ketogenic diet may be detrimental.
    • Immunomodulatory / Anti-inflammatory medications
      • IVIG has been used.
      • Monoclonal antibodies against IL-1 (Anakinra)and IL-6 (Tocilizumab) to manipulating cytokines may be beneficial.
      • Other immunomodulators like Tacrolimus and Rituximab have been also used.

Moral of the Morsel:

  • Suspect FIRES when there is smoke. Smoke being equal to new-onset seizures without a clear etiology, especially when there is increasing frequency and severity of the episodes.
  • History matters (like always). Inquire about fevers occurring in the past 2 weeks.
  • CSF matters too! Obtaining CSF to rule out infection is clearly important, but that CSF may also offer clues (ask your friendly neurologist what other fancy tests may be helpful).
  • Knowledge always matters! Knowing is half the battle (I learned that from GI Joe).

References

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Sean M. Fox
I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renowned educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.
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