Abstract
Introduction: Refractory Status Epilepsy Syndrome is a heterogeneous group of diseases associated with status epilepsy. Literature and definition have been conflicting and confusing in terms of their nomenclatures. New-onset refractory status epilepticus (NORSE) is a syndrome characterized by new onset refractory seizures in a previously health child. Febrile infection-related epilepsy syndrome (FIRES) is a similar syndrome now considered a variant of NORSE and is defined as a febrile event taking place between twenty-four hours and two weeks prior to the commencement of refractory status epilepticus. An autoimmune or inflammatory etiology is often implied in both conditions because infection is rarely identified. Aim: This review provides an update on hypotheses, etiology, pathophysiology, clinical features, diagnosis, laboratory evaluation, treatment, and perspectives for NORSE/FIRES. Methods: A PubMed Clinical Queries search is performed using keywords of NORSE and FIRES, on human subjects up to May 2025. All reviews, systematic reviews, case series and case reports were included. Results: Seizures are typically recalcitrant in NORSE/FIRES. Treatments include anti-seizure medications (ASM), ketogenic diet, immunotherapy (intravenous immunoglobulin ± plasmapheresis ± corticosteroid). The prognosis is usually poor. Most children would suffer refractory epilepsy and associated cognitive impairment if they survived. Guidelines and new consensus on NORSE/FIRES terminology have aided clinicians in managing status epilepticus in a previously healthy child that occurs ± a minor febrile episode. When an autoimmune or paraneoplastic condition is subsequently identified, the condition will be named accordingly. Conclusions: NORSE and FIRES are similar conditions except that vagus nerve stimulation appears to be more efficacious in NORSE than FIRES. We propose to define these heterogeneous and confusing conditions as "NOSES" as a two-criteria syndrome: New Onset + Status Epilepticus Syndrome, lasting for over 24 h despite the use of two standard ASM. Autoimmune, paraneoplastic and infectious encephalitis are specific diagnoses of NOSES with etiology subsequently identified.