Recognizing NORSE and FIRES - clinical course, diagnosis and evaluation.

New-onset refractory status epilepticus (NORSE) is a rare but severe neurological condition affecting both children and adults without prior epilepsy and without an identifiable acute cause at presentation. A substantial proportion of patients progress to super-refractory status epilepticus, which is associated with high morbidity and mortality. Despite its clinical severity, diagnostic strategies remain heterogeneous and are largely based on expert consensus due to limited high-quality evidence. This article summarizes current concepts in the definition, clinical recognition, and diagnostic evaluation of NORSE and its subtype febrile infection-related epilepsy syndrome (FIRES). Early identification is critical, as the clinical course, often characterized by a prodromal phase followed by rapidly escalating, treatment-refractory seizures, may provide important diagnostic clues. A structured diagnostic approach is essential and should include early, broad investigation for infectious, autoimmune, paraneoplastic, metabolic, and genetic etiologies, combined with continuous reassessment as new clinical information emerges. Key diagnostic tools include comprehensive blood and cerebrospinal fluid analyses, continuous EEG monitoring, and early neuroimaging, supplemented by advanced techniques such as cytokine panels, metagenomic sequencing and genetic testing when indicated. However, in more than half of cases, no etiology is identified, and patients are classified as having cryptogenic NORSE. Given the potential for treatable causes and the impact of early targeted therapy, timely and systematic evaluation is essential. We here provide an overview of current diagnostic strategies and propose a practical framework to support clinicians managing this complex condition.