Longitudinal serum and
CSF
cytokine dynamics in
NORSE
: Associations with immunotherapy exposure
Aurélie Hanin, Clémence Marois, Léa Cosme, Quentin Calonge, Zineb Hayatou, Sarah Baer, Anna‐Lena Behr, Simone Beretta, Francesca Bisulli, Serena Broggi, Michael Cardinale, Carlos Castillo‐Pinto, Adam Celier, Thomas Coppens, Anne De Saint Martin, Krista Eschbach, Susana Ferrao Santos, Elizabeth E. Gerard, Teneille Gofton, Margaret T. Gopaul, Karnig Kazazian, Jeroen Kerstens, Humberto L. Moser Filho, Lorenzo Muccioli, Roberto Santalucia, Hannah Stamberger, Eyal Muscal, Lawrence J. Hirsch, Sophie Demeret, Vincent Navarro 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.