Investigating the genetic contribution in febrile infection-related epilepsy syndrome and refractory status epilepticus

Abstract

Introduction: Febrile infection-related epilepsy syndrome (FIRES) is a severe childhood epilepsy with refractory status epilepticus after a typically mild febrile infection. The etiology of FIRES is largely unknown, and outcomes in most individuals with FIRES are poor.

Methods: Here, we reviewed the current state-of-the art genetic testing strategies in individuals with FIRES. We performed a systematic computational analysis to identify individuals with FIRES and characterize the clinical landscape using the Electronic Medical Records (EMR). Among 25 individuals with a confirmed FIRES diagnosis over the last decade, we performed a comprehensive review of genetic testing and other diagnostic testing.

Results: Management included use of steroids and intravenous immunoglobulin (IVIG) in most individuals, with an increased use of immunomodulatory agents, including IVIG, plasma exchange (PLEX) and immunosuppressants such as cytokine inhibitors, and the ketogenic diet after 2014. Genetic testing was performed on a clinical basis in almost all individuals and was non-diagnostic in all patients. We compared FIRES with both status epilepticus (SE) and refractory status epilepticus (RSE) as a broader comparison cohort and identified genetic causes in 36% of patients with RSE. The difference in genetic signatures between FIRES and RSE suggest distinct underlying etiologies. In summary, despite the absence of any identifiable etiologies in FIRES, we performed an unbiased analysis of the clinical landscape, identifying a heterogeneous range of treatment strategies and characterized real-world clinical practice.

Discussion: FIRES remains one of the most enigmatic conditions in child neurology without any known etiologies to date despite significant efforts in the field, suggesting a clear need for further studies and novel diagnostic and treatment approaches.

Keywords: febrile infection-related epilepsy syndrome; genetics; new onset refractory status epilepticus; pediatric epilepsy; refractory status epilepticus.

Figure 1

Framework for the identification of individuals with Febrile Infection Related Epilepsy Syndrome (FIRES). Natural language processing was applied across a large pediatric institution Electronic Medical Record database followed by manual chart review, leading to identification of 25 individuals with confirmed FIRES based on formal consensus criteria. FIRES is a subset of New Onset Refractory Status Epilepticus (NORSE), showing the hierarchy of FIRES and NORSE with broader subgroups of individuals with SE related epilepsies and epilepsies with a presumed underlying genetic cause (inset).

Figure 2

Clinical histories of 25 individuals with FIRES identified in the Electronic Medical Records (EMR), highlighting in (A) time at hospital admission and discharge in addition to transfer of care and time of first genetic test results received in the first year following first status epilepticus event. Individuals whose genetic testing results were received more than a year after first hospital admission are indicated with a green asterisk. (B) Overview of treatment strategies for each individual presenting with FIRES, ordered by year of FIRES diagnosis, showing common use of steroids and intravenous immunoglobulins (IVIG) and an increased use of immunosuppressants (ISx) and plasmapheresis (PLEX) after 2014.

Figure 3

Genetic testing in FIRES has been heterogeneous over the years. (A) Distribution of FIRES diagnoses in the past decade. (B) Overview of genetic testing including karyotype, single gene testing, microarray, whole exome sequencing (with mitochondrial testing indicated), and gene panel in 25 individuals with FIRES, ordered from the oldest diagnosis in 2010 to most recent diagnosis in 2021.

Figure 4

The genetic architecture of status epilepticus and refractory status epilepticus (RSE) differs from FIRES. (A) 166,301 time-stamped encounters from the Electronic Medical Records (EMR) across 959 individuals identified with RSE in a broader cohort of 32,112 individuals with childhood epilepsy, showing in red the encounters at which RSE was first documented for each individual. Only the encounter of first RSE onset is captured for each individual, as later encounters with RSE documented could either refer to a new or prior RSE event, and we found that the majority of individuals presenting with RSE have onset within the first 3 months of life. (B) Status epilepticus and RSE in the most common genetic etiologies in a cohort of 1,894 individuals with known or presumed genetic epilepsies. NLP was performed only on patient notes prior to a genetic diagnosis to adjust for bias in clinical impression following a molecular diagnosis. Inset shows numbers of individuals with genetic diagnoses who presented with RSE as first seizure presentation. (C) Clinical features in 1,158 individuals with status epilepticus stratified by individuals with a genetic diagnosis (n = 389) compared to individuals without a genetic diagnosis (n = 769), highlighting a difference in overall disease severity between the two subgroups. Red indicates phenotypic features with nominal significance (p < 0.05) while size of points indicate −log10(p-value). The landscape of FIRES were distinct from both subgroups, with characteristic severe clinical presentations and no currently identified genetic etiology.