Febrile infection-related epilepsy syndrome (ORPHA:163703)
A rare, potentially fatal , epileptic encephalopathy characterized by explosive-onset of recurrent multifocal and bilateral tonic-clonic seizures following an unspecific febrile illness. The syndrome develops without a clear acute structural, toxic or metabolic cause, in a patient without previous epilepsy. FIRES is a subgroup of new-onset refractory status epilepticus (NORSE), and requires a preceding febrile infection as a mandatory feature.
Epidemiology
Based on a small cohort study, in Germany the prevalence is estimated at 1/100,000 and annual incidence at 1/1,000,000 in children and adolescents. Global epidemiological date is lacking. In pediatric cases there is a male predominance, while females seem to be more frequently affected in adulthood. Familial cases have not been reported.
Clinical description
Febrile infection-related epilepsy syndrome (FIRES) is most common in school-age children. Typically, a previously healthy individual manifests with a sudden onset of recurrent multifocal and bilateral tonic-clonic seizures, following an unspecific febrile illness. Refractory, and usually superrefractory, status epilepticus develops. The acute phase can last for weeks or months. A chronic phase follows, without a latent period, characterized by refractory focal epilepsy along with, often severe, impairments in memory, cognition and behavior. Motor disability is less common.
Etiology
The etiology is not fully known. Most likely FIRES is an immune-inflammatory-mediated epileptic encephalopathy, with a vicious circle of inflammation and hyperexcitability. Findings in cerebrospinal fluid (CSF), and the poor response to immune therapies, point to the innate immune system and autoinflammatory rather than autoimmune mechanisms. Variants in known epilepsy genes do not seem to predispose to FIRES.
Diagnostic methods
An extensive work-up is needed to exclude treatable conditions. Initial magnetic resonance imaging is normal or shows temporal lobe signal abnormalities. Diffuse brain atrophy and mesial temporal lobe changes are common in the chronic phase. Analysis of CSF shows normal findings or mild pleocytosis but no presence of pathogens and usually no oligoclonal bands or neuronal antibodies. Metabolic investigations are negative. Genetic investigations to exclude genetic epilepsies such as those related to POLG. Continuous electroencephalogram (cEEG) is required to monitor seizures and depth of anesthesia. Beta-delta complexes resembling extreme delta brush is recorded in some patients in the early phase.
Differential diagnosis
Differential diagnoses include, but are not limited to, infectious or autoimmune encephalitis (e.g. anti-NMDAR encephalitis and other antineuronal antibody-related encephalitides, acute disseminated encephalomyelitis), primary angiitis of the central nervous system, acute necrotizing encephalopathy, other infection-induced encephalopathies, metabolic diseases (e.g. mitochondrial disorders, citrullinemia, thiamin metabolism disorders) and genetic epilepsies (e.g. Dravet syndrome, PCDH19 epilepsy).
Management and treatment
Monitoring in intensive care during the acute phase is mandatory. Anti-seizure medications are often ineffective. High-dose benzodiazepines can have a transient efficacy. Usually, general anesthesia with barbiturates (titrated to burst suppression) are needed to stop seizures, even if prolonged burst-suppression can be associated with a worse cognitive outcome. Recurrence is common on awakening, necessitating repeated anesthesia. Immune therapy is usually disappointing but anakinra or tocilizumab has been highly effective in a few cases. So far, the ketogenic diet has seemed most beneficial, especially if initiated early, but no controlled trials exist. Ketamine, inhalation anesthetics, cannabidiol, hypothermia and neurostimulation have shown transient efficacy in a few cases.
Prognosis
FIRES has a poor prognosis with a high risk of chronic drug-resistant epilepsy and significant cognitive impairment, but a few patients have fully recovered. The mortality rate is around 12% in children.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE* - Pr Tommy STÖDBERG | EpiCARE*


                                * European Reference Network