Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

Abstract

BackgroundDespite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications.AimTo study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis.MethodsWe measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups.ResultsIn descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α.ConclusionA combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.

CSF TACI and BAFF levels in patients with primary CNS lymphoma as novel diagnostic biomarkers

“…TACI and BCMA play major roles in normal and malignant B cells in B cell homeostasis and lymphoid cancers 12. Other studies reported that CSF levels of TACI and BCMA have potential as useful diagnostic biomarkers 13, 14. In the present study, CSF BAFF and TACI levels in patients with PCNSL were significantly higher than those in other groups.…”

Herpes simplex virus‐induced anti‐N‐methyl‐d‐aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases

“…Finally, while remaining vigilant for the possibility of new viral replication, high clinical suspicion toward an autoimmune aetiology should be maintained in case of relapses of HSE, in view of the different treatment and the good response to immune therapy. The identification of early predictors of autoimmune relapse post‐HSE would allow early intervention and, possibly, prevention of secondary autoimmunity, and it remains among future challenges …”

Relapse risk factors in anti‐N‐methyl‐D‐aspartate receptor encephalitis

“…Indeed, it is unclear how long the inflammatory component of disease lasts. In this respect, the correlation between anti‐NMDAR antibodies and clinical course is unclear, and the correlation of disease severity and relapse with other markers, such as C‐X‐C motif chemokine ligand 13 (CXCL13), C‐X‐C motif ligand 10 (CXCL10), Fas, Fas ligand, T‐helper cell 17 (Th17), B cell activating factor from the tumor necrosis factor family (BAFF), and a proliferation‐inducing ligand (APRIL) is being investigated …”

“…Neuroimaging and neurophysiologic data were not reviewed centrally, impeding a more accurate description of EEG and MRI abnormalities detected. Moreover, CSF neuroinflammatory biomarkers were inconsistently available, and data on newer markers whose utility has been suggested in the literature, such as neopterins and cytokines, were not collected . The study of these markers with regards to disease course and the occurrence of relapses would be of utmost clinical interest.…”