Longitudinal serum and CSF cytokine dynamics in NORSE : Associations with immunotherapy exposure

Year: 2026

Type: article

Abstract: OBJECTIVE: To characterize serum and cerebrospinal fluid (CSF) cytokine dynamics according to immunotherapy exposure in cryptogenic new-onset refractory status epilepticus (cNORSE). METHODS: We analyzed cytokine profiles in 94 serum and 42 CSF samples from 29 and 14 patients, respectively, with cNORSE. Nine contributed both sample types, resulting in 34 patients. Samples were categorized according to immunotherapy exposure as no immunotherapy (NT), first-line (FL), and second-line (SL), and stratified by innate- or adaptive-directed therapies. SL represented cumulative exposure, as all SL samples followed initiation of both FL and SL therapies. Linear mixed-effects models accounted for repeated measures and time from cNORSE onset. A systematic literature review included 27 studies and 63 patients. RESULTS: Serum cytokine levels were generally lower during FL (n = 24) than NT (n = 9), whereas most cytokines were higher during SL (n = 61) than FL. CXCL8 (C-X-C motif ligand 8)/IL-8 and CCL2 (C-C motif chemokine ligand 2) were higher during SL than FL, with CCL2 remaining significant after multiple-testing correction. No serum differences remained significant when analyses were restricted to samples collected 7-30 days after onset. CSF levels were generally lower during FL (n = 10) and SL (n = 25) than NT (n = 7). Innate-directed therapies were associated with higher serum IL-6, CXCL8/IL-8, and CCL2 and CSF IL-4, whereas adaptive-directed therapies were associated with lower CSF MIP-1α (Macrophage Inflammatory Protein-1 alpha). The association with higher serum IL-6 was no longer observed after excluding tocilizumab-treated patients. No temporal association after SL initiation or status epilepticus resolution remained significant after multiple-testing correction. The literature review showed more frequent reductions in pro-inflammatory cytokines in CSF than serum following immunotherapy initiation. SIGNIFICANCE: Cytokine profiles in cNORSE differ by treatment exposure and compartment. Persistent serum inflammation during SL may reflect disease severity, systemic inflammation, treatment effects, or their combination, whereas CSF showed more consistent reductions after immunotherapy exposure. These findings highlight the importance of treatment timing and compartment when interpreting cytokine measurements and support prospective studies integrating baseline immune phenotypes and standardized clinical outcomes.

Source: Epilepsia

DOI: 10.1002/epi.70566

Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Cité, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Institut de génétique et de biologie moléculaire et cellulaire, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, University of Augsburg, University of Milano-Bicocca, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Aziende Socio Sanitarie Territoriale dei Sette Laghi, Hôpital d'Instruction des Armées Sainte-Anne, University of Washington, Clinique Saint Pierre, Children's Hospital Colorado, University of Colorado Anschutz, Cliniques Universitaires Saint-Luc, UCLouvain, Northwestern University, Western University, London Health Sciences Centre, Yale University, Erasmus MC, Antwerp University Hospital, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, Baylor College of Medicine, Texas Children's Hospital

Language: English

Topic: Epilepsy research and treatment

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,360

Funder: Yale University

OpenAlex ID: W7225313610