Febrile infection-related epilepsy syndrome

Overview

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a rare and severe neurological condition characterized by the sudden onset of status epilepticus, prolonged or repeated seizures, that occurs in previously healthy children following a mild febrile illness. The seizures are typically resistant to standard antiepileptic treatments and can lead to significant neurological impairment. FIRES is considered a subcategory of New-Onset Refractory Status Epilepticus (NORSE) and is a medical emergency requiring intensive care.

Causes

The exact cause of FIRES remains unknown. It typically follows a nonspecific febrile illness such as a respiratory or gastrointestinal infection, occurring within a few days before seizure onset. Potential contributing factors include:

• Post-infectious inflammation: An abnormal immune response to a prior infection may trigger widespread brain inflammation.

• Genetic predisposition: Some genetic mutations affecting neuronal excitability or immune function may increase susceptibility.

• Autoimmune response: FIRES may involve an unidentified autoimmune reaction, though standard autoimmune markers are often absent.

• No identifiable cause: In most cases, extensive testing fails to pinpoint a definitive infectious or autoimmune etiology.

Symptoms

FIRES generally affects school-aged children and progresses rapidly from a mild febrile illness to severe neurological symptoms. Common features include:

• Sudden onset of seizures: Multiple focal or generalized seizures that quickly escalate to status epilepticus.

• Fever history: Usually a mild fever 1–14 days prior to seizure onset.

• Refractory seizures: Seizures that are resistant to standard antiepileptic drugs (AEDs).

• Neurological deterioration: Coma, confusion, or cognitive regression as seizures continue.

• Long-term complications: Chronic epilepsy, developmental delay, and cognitive deficits after the acute phase.

Diagnosis

Diagnosing FIRES is challenging due to its rarity and the need to exclude other causes. Key diagnostic steps include:

• Clinical history: Sudden refractory seizures in a previously healthy child following a recent febrile illness.

• Electroencephalogram (EEG): Shows frequent epileptiform discharges and electrical status epilepticus.

• MRI brain imaging: May be normal initially or show diffuse cortical swelling or signal changes in later stages.

• CSF analysis: Typically normal or nonspecific; used to rule out infections or autoimmune encephalitis.

• Blood tests and infectious workup: Negative for common pathogens or autoimmune antibodies.

• Genetic and metabolic screening: Performed to exclude underlying metabolic or genetic disorders.

Treatment

FIRES is extremely difficult to treat, and management requires a multidisciplinary approach in an intensive care setting. Treatment options include:

• Antiepileptic drugs (AEDs): High-dose and multiple agents, though seizures are often drug-resistant.

• Anesthetics: Medications like midazolam, propofol, or pentobarbital may be used to induce coma and suppress seizure activity.

• Immunotherapy: Corticosteroids, intravenous immunoglobulin (IVIG), or plasmapheresis may be attempted, though often with limited success.

• Ketogenic diet: A high-fat, low-carbohydrate diet that has shown promise in reducing seizure frequency in FIRES patients.

• Anti-inflammatory and neuroprotective agents: Experimental treatments, including anakinra (IL-1 receptor antagonist), are being studied.

• Supportive care: Management of complications, nutritional support, mechanical ventilation if needed, and rehabilitation.

Prognosis

The prognosis for FIRES is generally poor. Although the initial febrile illness is mild, the subsequent status epilepticus is often severe and prolonged. Most survivors develop chronic epilepsy and suffer from long-term neurological impairments, including intellectual disability, behavioral problems, and motor deficits. Mortality rates vary but can be significant. Early recognition, aggressive seizure control, and experimental therapies like the ketogenic diet may improve outcomes in some cases.