General description

Cryptogenic new-onset refractory status epilepticus (C-NORSE), also known as febrile infection-related epilepsy syndrome (FIRES), is a rare but devastating neurological emergency characterized by refractory status epilepticus without a readily identifiable cause in previously healthy individuals. NORSE is defined as a clinical presentation, not a specific diagnosis, and when the cause remains unknown despite extensive workup, it is termed cryptogenic NORSE (C-NORSE).

The pathophysiology of C-NORSE remains incompletely understood, but mounting evidence suggests an immune-mediated process. Although no specific antibodies are identified in C-NORSE by definition, an autoimmune inflammatory mechanism has been considered the most likely underlying pathophysiological process. Neuroinflammation appears to play a crucial role, with studies showing elevated levels of proinflammatory cytokines, particularly interleukin-6 (IL-6) and IL-8, in the cerebrospinal fluid (CSF) of patients with C-NORSE.

Clinical manifestations

C-NORSE typically presents in previously healthy individuals with a prodromal phase characterized by fever of unknown origin. This prodromal period can precede the onset of seizures by a couple of weeks and often includes non-specific symptoms such as headache, fatigue, and general malaise. Notably, unlike in autoimmune encephalitis, prodromal psychobehavioral or memory alterations are typically absent in C-NORSE, which is an important distinguishing clinical feature.

Following the prodromal phase, patients develop sudden-onset seizures that rapidly progress to refractory status epilepticus. The seizures in C-NORSE are characteristically:

• Highly refractory to conventional antiseizure medications
• Predominantly convulsive in nature, often requiring mechanical ventilation and continuous infusion of anesthetic drugs
• Prolonged, with status epilepticus lasting for a median of 12 days (range 3-106 days)

The clinical course of C-NORSE is typically protracted, with patients experiencing prolonged hospital stays (median 48.5 days). The mortality rate is approximately 22%, with significant morbidity among survivors. Among survivors, approximately 37-41% develop pharmacoresistant epilepsy, and many experience cognitive deficits and other neurological sequelae. Predictors of poor outcome include duration of status epilepticus, use of anesthetics, and medical complications.

References

1. Di Dier, Kelly, Lucas Dekesel, and Sven Dekeyzer. "The claustrum sign in febrile infection-related epilepsy syndrome (FIRES)." Journal of the Belgian Society of Radiology 107.1 (2023): 45.
2. Muccioli, Lorenzo, et al. "Teaching NeuroImage: claustrum sign in febrile infection–related epilepsy syndrome." Neurology 98.10 (2022): e1090-e1091.