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

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.

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Publication Details

Journal
Epilepsia
Published
2026-11-05
DOI
https://doi.org/10.1002/epi.70566
Primary Topic
Epilepsy research and treatment
Type
article
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article

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

Michaël Cardinale, Eyal Muscal, Lorenzo Muccioli, Roberto Santalucia et al.
Epilepsia
Epilepsy research and treatment
article

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

Michaël Cardinale, Eyal Muscal, Lorenzo Muccioli, Roberto Santalucia, Jeroen Kerstens, Aurélie Hanin, Zineb Hayatou, Francesca Bisulli, Teneille Emma Gofton, Serena Broggi, Karnig Kazazian, Simone Beretta, Sophie Demeret, Clémence Marois, Elizabeth E. Gerard, Susana Ferrão Santos, Anne de Saint Martin, Krista L. Eschbach, Sarah Baer, Vincent Navarro, Adam Celier, Margaret Gopaul, Lawrence J. Hirsch, Hannah Stamberger, Carlos Castillo-Pinto, Quentin Calonge, Anna-Lena Behr, Léa Cosme, Thomas Coppens, Humberto L. Moser Filho
article en

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.

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