What is the recommended management of FIRES (Febrile infection‑related epilepsy syndrome)?

Management of FIRES (Febrile Infection-Related Epilepsy Syndrome)

FIRES requires immediate aggressive multimodal therapy combining early ketogenic diet initiation, IL-1 receptor antagonist (anakinra), intensive seizure management with anesthetics, and consideration of intrathecal dexamethasone when conventional approaches fail, though outcomes remain poor despite treatment.

Disease Recognition and Initial Assessment

FIRES should be suspected in any previously healthy patient older than 2 years presenting with explosive onset of seizures rapidly progressing to refractory status epilepticus (RSE) following a febrile illness within the preceding two weeks 1, 2. The condition is characterized by super-refractory status epilepticus that is resistant to multiple antiseizure medications and continuous anesthetic infusions 1.

Critical diagnostic steps include:

• Comprehensive autoimmune and inflammatory workup completed before initiating second-line therapies to guide cytokine-directed treatment 3
• Brain MRI (abnormal in 84.2% of cases) 4
• Continuous EEG monitoring showing complete loss of normal background activity in acute phase 4
• CSF analysis for inflammatory markers 1

Acute Phase Management: Seizure Control

First-Line Antiseizure Medications

The median number of ASMs required is 7 (range 2-12) before pharmacologic coma becomes necessary 5. Standard status epilepticus protocols should be followed initially, though seizure control is typically not achieved with conventional ASMs alone 5.

Pharmacologic Coma

All patients ultimately require pharmacologic coma 5. The following agents should be used sequentially:

• Midazolam (most commonly used, though only 17% achieve seizure resolution) 5
• Ketamine (21% seizure resolution rate; preferred due to anti-inflammatory properties) 6, 5
• Thiopentone (16.6% seizure resolution) 5
• Isoflurane (for refractory cases) 5

The median duration of pharmacologic coma is 11 days (range 1-125 days) 5. A critical pitfall: prolonged barbiturate use produces respiratory depression and drug hypersensitivity syndrome, complicating seizure control 6.

Early Disease-Modifying Therapies (Initiate Immediately)

Ketogenic Diet

The ketogenic diet should be started early in the clinical course 2, 6. This is one of the few interventions that may reduce convulsions and improve intellectual prognosis 6. In the reviewed cohort, 56% received ketogenic diet 5.

Anakinra (IL-1 Receptor Antagonist)

Early administration of anakinra is recommended as soon as FIRES is suspected 2. This blocks the biologic activity of IL-1β, which is implicated in the pathophysiology of FIRES through overproduction of inflammatory cytokines in the CNS 6. Anakinra has shown effectiveness in multiple case reports 7, 3.

First-Line Immunotherapy

High-Dose Corticosteroids

• Methylprednisolone administered in 97% of patients 5
• Used as first-line systemic immunotherapy but ineffective in most cases 3

Intravenous Immunoglobulin (IVIG)

• Administered in 63% of patients 5
• Also considered first-line but rarely effective as monotherapy 3

Important caveat: First-line systemic immunotherapy (steroids and IVIG) fails to control super-refractory status epilepticus in the majority of FIRES cases 3.

Second-Line Immunomodulatory Therapies

When first-line immunotherapy fails (which is typical), cytokine-directed therapies should be considered based on inflammatory workup:

IL-6 Receptor Antagonist (Tocilizumab)

• Effective in select cases when IL-6 elevation is documented 3
• Administered in conjunction with other immunomodulators 1

Intrathecal Dexamethasone

For patients with continued seizures despite anakinra, multiple ASMs, and continuous anesthetic infusions, intrathecal dexamethasone should be initiated 7. A recent case report demonstrated:

• 6 doses of IT-DEX resulted in resolution of RSE 7
• Rapid wean off continuous infusions 7
• Improved inflammatory markers and cognitive outcomes when initiated early 7

Other Second-Line Options

• Rituximab (32% of patients) 5
• Cyclophosphamide (32% of patients) 5
• Baricitinib (JAK inhibitor) showed effectiveness in one case 3
• Plasmapheresis 7

Chronic Phase Management

Ongoing Seizure Management

At median follow-up of 37 months, epilepsy remains poorly controlled in 67% of survivors 5. Multifocal spikes and slow waves persist on EEG in 94.7% of patients, with extreme delta brush noted in 36.8% 4.

Seizure-freeness is difficult to achieve and should not be the primary goal for cryptogenic FIRES 8. The clinical approach should focus on:

• Optimizing quality of life over complete seizure freedom 8
• Avoiding overly aggressive ASM regimens that worsen cognitive outcomes 8

Emerging Chronic Therapies

• Minocycline (100 mg twice daily for 12 weeks): preliminary data suggest potential benefit for seizure duration and quality of life in select patients 9
• Cannabidiol 9
• Vagus nerve stimulation 9
• Responsive neurostimulation 9
• Deep brain stimulation (centro-median thalamic nuclei) 9

Prognosis and Outcomes

Mortality is 34% in pediatric cohorts, with death occurring at median follow-up of 37 months 5. Among survivors:

• Moderate-to-severe neurologic and cognitive impairment is universal at discharge 3
• Only 52% achieve good outcome (CASE score ≤5) 5
• The outcome depends more on clinical spectrum than on therapy 8
• The clinical course may depend more on time than on specific interventions 8

Critical limitation: There is no statistically significant difference in outcomes with ketogenic diet, pharmacologic coma, or conventional immunomodulatory therapies across outcome groups 5. This underscores the devastating nature of FIRES and the urgent need for novel therapeutic approaches.

Key Clinical Pitfalls

• Delayed recognition: FIRES must be included in the broad differential for RSE to allow empiric therapies to start early 2
• Incomplete workup: Autoimmune and inflammatory evaluation is seldom completed prior to treatment, limiting ability to direct cytokine-specific therapies 3
• Over-reliance on conventional ASMs: Waiting too long before initiating ketogenic diet and anakinra 2
• Barbiturate complications: Prolonged use causes respiratory depression and drug hypersensitivity syndrome 6
• Unrealistic seizure-freedom goals: Pursuing complete seizure control may worsen cognitive outcomes through medication toxicity 8