Cytokines in New-Onset Refractory Status Epilepticus Predict Outcomes

Aurélie Hanin; Jorge Cespedes; Karim Dorgham; Yashwanth Pulluru; Margaret Gopaul; Guy Gorochov; David A Hafler; Vincent Navarro; Nicolas Gaspard; Lawrence J Hirsch

doi:10.1002/ana.26627

Cytokines in New-Onset Refractory Status Epilepticus Predict Outcomes

Ann Neurol. 2023 Jul;94(1):75-90. doi: 10.1002/ana.26627. Epub 2023 Mar 17.

Authors

Aurélie Hanin^{1

2

3}, Jorge Cespedes^{4

5}, Karim Dorgham⁶, Yashwanth Pulluru^{4

7}, Margaret Gopaul⁴, Guy Gorochov⁶, David A Hafler¹, Vincent Navarro^{2

3

8}, Nicolas Gaspard^{4

9}, Lawrence J Hirsch⁴

Affiliations

¹ Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, CT, United States.
² Sorbonne Université, Institut du Cerveau, Paris Brain Institute, ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
³ Department of Clinical Neurophysiology, Epilepsy Unit, DMU Neurosciences 6, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁴ Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.
⁵ Universidad Autonoma de Centro America, School of Medicine, San Jose, Costa Rica.
⁶ Department of Immunology, Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁷ Division of Epilepsy, Nebraska Medical Center, Omaha, NE, United States.
⁸ Center of Reference for Rare Epilepsies, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁹ Department of Neurology, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium.

PMID: 36871188
DOI: 10.1002/ana.26627

Abstract

Objective: The objective of this study was to investigate inflammation using cerebrospinal fluid (CSF) and serum cytokines/chemokines in patients with new-onset refractory status epilepticus (NORSE) to better understand the pathophysiology of NORSE and its consequences.

Methods: Patients with NORSE (n = 61, including n = 51 cryptogenic), including its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES), were compared with patients with other refractory status epilepticus (RSE; n = 37), and control patients without SE (n = 52). We measured 12 cytokines/chemokines in serum or CSF samples using multiplexed fluorescent bead-based immunoassay detection. Cytokine levels were compared between patients with and without SE, and between the 51 patients with cryptogenic NORSE (cNORSE) and the 47 patients with a known-etiology RSE (NORSE n = 10, other RSE n = 37), and correlated with outcomes.

Results: A significant increase of IL-6, TNF-α, CXCL8/IL-8, CCL2, MIP-1α, and IL-12p70 pro-inflammatory cytokines/chemokines was observed in patients with SE compared with patients without SE, in serum and CSF. Serum innate immunity pro-inflammatory cytokines/chemokines (CXCL8, CCL2, and MIP-1α) were significantly higher in patients with cNORSE compared to non-cryptogenic RSE. Patients with NORSE with elevated innate immunity serum and CSF cytokine/chemokine levels had worse outcomes at discharge and at several months after the SE ended.

Interpretation: We identified significant differences in innate immunity serum and CSF cytokine/chemokine profiles between patients with cNORSE and non-cryptogenic RSE. The elevation of innate immunity pro-inflammatory cytokines in patients with NORSE correlated with worse short- and long-term outcomes. These findings highlight the involvement of innate immunity-related inflammation, including peripherally, and possibly of neutrophil-related immunity in cNORSE pathogenesis and suggest the importance of utilizing specific anti-inflammatory interventions. ANN NEUROL 2023;94:75-90.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Chemokine CCL3
Chemokines
Cytokines* / cerebrospinal fluid
Humans
Inflammation / complications
Status Epilepticus* / diagnosis

Substances

Cytokines
Chemokine CCL3
Chemokines