Immune dysregulation in new-onset refractory status epilepticus (NORSE): current insights and therapeutic perspectives

Objective

Emerging evidence suggests that cryptogenic new-onset refractory status epilepticus (c-NORSE) arises from innate immunity dysfunction leading to exacerbated inflammation. While immunotherapies have been administered, their efficacy remains variable and unpredictable.

Methods

We conducted a comprehensive literature review of studies reporting inflammation biomarkers in patients with NORSE or evaluating targeted immunotherapies. Additionally, we discussed future research directions and therapeutic perspectives.

Results

A total of 29 studies reporting inflammation biomarkers in at least five patients were analyzed. Most focused on c-NORSE, frequently describing cerebrospinal fluid pleocytosis, often lymphocytic and usually mild, upon admission. Elevated levels of innate immunity-related pro-inflammatory cytokines were consistently reported in c-NORSE. A large international study further demonstrated significantly higher cytokine levels in c-NORSE compared to other refractory status epilepticus patients, suggesting the importance of innate immunity in c-NORSE pathophysiology. One recent study identified subgroups with distinct inflammatory profiles among c-NORSE, suggesting different treatment approaches.

More than 30 case series or reports have documented the use of targeted immunotherapies in NORSE. The most commonly used are anakinra (IL1 antagonist) and tocilizumab (IL6 antagonist), both showing seemingly comparable efficacy in seizure control. Recently, intrathecal dexamethasone has gained interest, particularly in pediatric cases, showing promising efficacy with no reported side effects. Other emerging approaches include canakinumab (anti-IL1 antibody), Janus kinase (JAK) inhibitors, and tumor necrosis factor alpha (TNFα) inhibitors.

Conclusions

Recent studies have advanced our understanding of innate immunity disturbances in c-NORSE onset and progression. Moreover, they highlight patient heterogeneity, emphasizing the need for personalized strategies targeting specific inflammatory pathways.