The role of CSF IL-6 levels in diagnosis and outcome prediction of autoimmune encephalitis

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Background: Autoimmune encephalitis (AE) is clinically heterogeneous, and its early diagnosis and prognostication remain challenging. We aimed to determine whether cerebrospinal fluid (CSF) interleukin-6 (IL-6), a marker of central nervous system inflammation, can improve AE diagnosis and predict treatment outcomes. Methods: This retrospective cohort study (April 2014-August 2024) included patients who fulfilled the criteria for at least possible AE according to the 2016 Graus criteria and had their CSF IL-6 measured. The patients with infectious encephalitis were excluded. We collected clinical, laboratory, brain MRI, and tumor screening data. In a subset of AE patients with repeat CSF testing approximately 1 month after initiation of immunotherapy, we obtained post-treatment laboratory data, hospitalization length, and modified Rankin Scale (mRS) score at discharge. Diagnostic performance was assessed using receiver operating characteristic (ROC) analyses, and multivariable regression was used to identify predictors of discharge mRS score and hospitalization length. In antibody-negative AE, we also examined the association between post-treatment CSF IL-6 (CSF IL-6_1M) and the RAPID score, a prognostic tool for antibody-negative AE. Results: The cohort comprised 55 AE cases (25 antibody-positive). ROC analysis of CSF parameters suggested that IL-6 showed the highest sensitivity, whereas the immunoglobulin G (IgG) index demonstrated the highest specificity. In an additional analysis that included CSF IL-6 as an additional inflammatory CSF parameter within the 2016 Graus criteria, the diagnostic sensitivity increased from 73% to 85% with a specificity of 88%. Among the 35 AE patients with post-treatment CSF measurements, multivariable regression showed that only CSF IL-6_1M significantly predicted both mRS score at discharge (p = 0.0444, 95% CI 0.00104-0.0702) and hospitalization length (p = 0.0143, 95% CI 0.425-3.13). Specifically, patients with CSF IL-6_1M of < 6 pg/mL had significantly shorter hospital stays than those with higher levels (generalized Wilcoxon test, p = 0.0361). CSF IL-6_1M was also significantly associated with the RAPID score (p = 0.0492). Conclusion: CSF IL-6 is a useful marker for early AE diagnosis and CSF IL-6_1M may serve as a practical biomarker for treatment response and prognosis, particularly for antibody-negative AE. Thus, CSF IL-6 and CSF IL-6_1M assessment may facilitate more precise, timely, and individualized therapeutic interventions.

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