Time-dependent changes in cerebrospinal fluid cytokines in NORSE and FIRES: A systematic review

New-onset refractory status epilepticus (NORSE) describes patients with no prior history of epilepsy who develop refractory status epilepticus. A subtype of NORSE with prior fever is known as febrile infection-related refractory status epilepticus (FIRES). This systematic review summarises the temporal dynamics of cytokine profiles in cerebrospinal fluid (CSF) throughout the course of these conditions.

We conducted a comprehensive search of PubMed, Scopus, and Web of Science studies published between 1st January 2006 and 30th March 2025. Studies reporting cytokine profiles before and/or after immunotherapies in NORSE and FIRES were included.

We reviewed a total of 42 studies. Interleukin (IL) IL-6, IL-8, and IL-1β were most consistently reported and showed observable temporal changes. Mean CSF levels of IL-1β increased from 1.3 ± 1.9 pg/ml at week 1 to a peak of 2.8 ± 2.5 pg/ml at week 2 and declined to 2.6 ± 2.2 pg/ml at week 3. A similar trend was noted in CSF IL-8 level, which increased from 974.7 ± 1489.7 pg/ml at week 1 to 1336.0 ± 2082.2 pg/ml at week 2, then declined to 391.1 ± 284.4 pg/ml at week 3. In contrast, CSF IL-6 level rose markedly to 349.7 ± 559.5 pg/ml at week 1 and declined substantially to 93.1 ± 182.7 pg/ml at week 2, and 83.2 ± 27.9 pg/ml at week 3.

Proinflammatory cytokines in CSF were markedly elevated within the first two weeks after seizure onset, highlighting this as a critical window for cytokine profiling and the importance of interpreting cytokine levels in a time-dependent manner to guide immunotherapy in NORSE and FIRES.