
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.13.24310337
preprint
1
Article
Altered Cytokine Profile in Clinically Suspected Seronegative Autoimmune Associated Epilepsy
Motovilov Katherine http://orcid.org/0000-0002-0679-9584

Maguire Cole http://orcid.org/0000-0001-8986-9762

Briggs Deborah
Melamed Esther http://orcid.org/0000-0001-5571-3591

14 9 2024
2024.09.13.24310337https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.13.24310337
nihpp-2024.09.13.24310337.pdf
Abstract

Background and Objectives

Autoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies.

Methods

To identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases.

Results

We found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA).

Discussion

Overall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.
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