Febrile Infection-Related Epilepsy Syndrome (FIRES) is a rare and devastating neurological disorder, primarily affecting children, characterized by the sudden onset of severe, prolonged seizures following a non-specific fever or mild infection. It is a catastrophic form of epilepsy and a subcategory of New-Onset Refractory Status Epilepticus (NORSE). FIRES is a medical emergency due to its high mortality rate and the profound, long-lasting neurological damage it inflicts, stemming from continuous seizure activity that resists conventional anti-epileptic medications.
Defining Characteristics and Onset
The clinical presentation of FIRES is typically biphasic. The first stage is a brief, non-specific febrile illness, such as a common cold or gastroenteritis, which precedes the neurological crisis. This initial fever, the “F” in FIRES, usually begins between 24 hours and two weeks before the onset of seizures and may have resolved by the time seizures start.
The second stage is the catastrophic onset of seizures, often starting as frequent focal events that quickly escalate. These seizures rapidly progress into refractory status epilepticus—continuous seizure activity that does not stop despite the administration of two different standard anti-epileptic drugs. This acute phase of continuous seizures can persist for weeks or months, leading to extensive brain injury.
The typical age of onset is in school-aged children, averaging around eight years, though cases occur into adulthood. The syndrome shows a slight male predominance. This rapid, non-stop seizure activity makes the acute phase of FIRES destructive.
The Underlying Pathophysiology
The precise cause of FIRES remains unknown, but the prevailing hypothesis centers on a massive, misguided inflammatory response within the central nervous system, known as neuroinflammation. Although triggered by a preceding infection, the syndrome is not caused by the active presence of a microbe or virus in the brain tissue, distinguishing it from infectious meningitis or encephalitis. The initial infection appears to act as a spark, setting off an overwhelming immune system reaction.
This immune system overreaction leads to the release of high levels of proinflammatory cytokines and chemokines, which are signaling molecules that mediate inflammation. These markers are found in the blood and cerebrospinal fluid, suggesting the inflammation occurs primarily inside the brain. The resulting neuroinflammation creates a pro-convulsive environment, significantly lowering the brain’s seizure threshold and sustaining continuous seizure activity.
The inflammatory cascade is thought to involve the overactivation of immune cells in the brain, particularly microglia, which then drive the production of inflammatory molecules like Interleukin-1 (IL-1). This sustained inflammation, rather than an infection, is believed to be the primary mechanism of brain injury and the development of intractable epilepsy. This understanding highlights FIRES as an autoinflammatory condition where the body’s own immune response is the source of the pathology.
Diagnostic Procedures
Diagnosing FIRES is largely a process of exclusion, as there is no single definitive laboratory test or biomarker. Physicians must perform extensive testing to rule out other causes of new-onset refractory status epilepticus, including infectious, metabolic, autoimmune, and genetic disorders. A lumbar puncture is performed to analyze the cerebrospinal fluid (CSF), crucial for excluding active central nervous system infections like encephalitis.
Continuous electroencephalogram (EEG) monitoring is an obligatory diagnostic tool used to characterize seizure activity and confirm status epilepticus. The EEG often reveals a complete loss of normal background activity during the acute phase, along with frequent focal seizures and characteristic patterns. Brain imaging, specifically magnetic resonance imaging (MRI), is required to rule out structural abnormalities like tumors or stroke. Initial MRIs are often normal, but changes such as atrophy or signal abnormalities in the mesial temporal structures may become apparent weeks or months later.
The diagnosis of FIRES is ultimately a clinical one, made when a previously healthy individual develops refractory status epilepticus following a febrile illness. This diagnosis is confirmed only after all other known causes have been systematically eliminated through a comprehensive battery of tests.
Acute and Chronic Management
The treatment of FIRES is extremely challenging and requires an aggressive, multi-pronged approach due to the refractory nature of the seizures. Acute management focuses on immediately breaking the status epilepticus. This typically begins with high-dose intravenous anti-epileptic drugs (AEDs) such as benzodiazepines, administered in a stepwise fashion.
When seizures continue despite two or more standard AEDs, the condition is termed super-refractory status epilepticus, necessitating continuous intravenous anesthetic agents. Medications like midazolam, propofol, or barbiturates are infused to induce a pharmacologically-induced coma, suppressing all electrical seizure activity. This process is managed in an intensive care unit setting, but prolonged use carries risks and does not guarantee permanent seizure cessation.
Given the suspected inflammatory mechanism, immunomodulatory therapies are often initiated early, though their effectiveness is variable. These include high-dose corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange. Newer targeted therapies, such as the anti-interleukin-1 agent anakinra, have shown promise by directly targeting the inflammatory cascade. The ketogenic diet, a high-fat, low-carbohydrate regimen, is also sometimes introduced early due to its demonstrated anti-seizure and potentially anti-inflammatory effects.
Long-Term Outcomes
Despite aggressive intervention, the long-term prognosis for survivors of FIRES is generally poor. The relentless seizure activity causes significant brain damage, leading to severe, chronic neurological sequelae in the majority of individuals. Most survivors are left with severe, drug-resistant epilepsy that is difficult to control with standard medications.
Significant neurodevelopmental delays and cognitive impairment affect an estimated two-thirds to all survivors. This manifests as learning disabilities, memory issues, and a regression of previously acquired developmental milestones. The damage often impacts intellectual ability and motor skills, necessitating long-term supportive care and specialized rehabilitation services.
The chronic phase is characterized by persistent, refractory epilepsy and the need for ongoing management of cognitive and physical disabilities. While the acute, life-threatening seizures eventually subside, the patient transitions into a life with severely affected neurological function. The mortality rate associated with FIRES can be up to 30%.