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

Danielle deCampo; Julie Xian; Alexis Karlin; Katie R Sullivan; Sarah M Ruggiero; Peter Galer; Mark Ramos; Nicholas S Abend; Alex Gonzalez; Ingo Helbig

doi:10.3389/fneur.2023.1161161

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

Front Neurol. 2023 Apr 3:14:1161161. doi: 10.3389/fneur.2023.1161161. eCollection 2023.

Authors

Danielle deCampo^{1

2

3}, Julie Xian^{1

2

3}, Alexis Karlin^{1

2

3}, Katie R Sullivan^{1

2

3}, Sarah M Ruggiero^{1

2

3}, Peter Galer^{1

2

3}, Mark Ramos³, Nicholas S Abend^{1

2

3}, Alex Gonzalez³, Ingo Helbig^{1

2

3

4

4}

Affiliations

¹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
² The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, United States.
³ Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, United States.
⁴ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

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.