Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study

Abstract

Background: Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet. The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years.

Methods: This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients. Forty consecutive OCB-negative (OCB-) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB- MS, 11 OCB+ MS and 10 patients with other neurological conditions.

Results: Increased number of CLs was found in OCB+ compared to OCB- patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36). The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163. Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view.

Conclusions: OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years. Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflammatory immune response in the CSF of OCB+ patients support the hypothesis of crucial role played by compartmentalized, intrathecal B cell response in the pathogenesis of CLs and OCB production.

Keywords: CSF; Cytokines; Grey matter; IgG; MRI; Multiple sclerosis; Neurodegeneration; Neuroinflammation; OCB; Oligoclonal bands.

Fig. 1

3D double inversion recovery images of three RRMS OCB+ patients (a–c) and three RRMS OCB− patients (d–f). OCB+ patients show both white and grey matter demyelination (arrows) including insular lesions (arrows, c). OCB− patients do not show any grey matter lesion despite the severe white matter demyelination especially in the periventricular region (arrowheads, d–f)

Fig. 2

Protein analysis of the presence and levels of neurofilament light chains (NF-L) and inflammatory mediators in CSF. a NF-L protein levels have been analysed in the CSF of controls, OCB− and OCB+ MS patients by using ELISA assessment, showing significant increased levels in OCB+ MS patients compared to both controls and OCB− MS patients. b Cluster analysis showing the level of expression of the 28 inflammatory mediators examined in OCB− and OCB+ MS patients: the red rectangle outlines a cluster of molecules significantly overexpressed only in OCB+ MS patients. c Statistical representation of the presence and levels of inflammatory mediators significantly overexpressed in OCB+ compared to controls and to OCB− MS patients. (Statistical analysis performed by using Mann-Whitney test; p value *<0.05; **<0.01; ***<0.001)

Fig. 3

Pearson correlation analysis between the CSF levels of overexpressed proteins and the number of cortical lesions detected by 3 T MRI in the subgroup of the 21 MS patients. All the represented correlations involve molecules related to B cell chemo-attraction (CXCL13, CXCL12) and activity (IL6, OPN, TWEAK). The r and p values are reported for each examined correlation in the correspondent graph

Fig 4

Pearson correlation analysis between the CSF levels of overexpressed proteins and the EDSS values of the subgroup of the 21 MS patients at the follow-up. The r and p values are reported for each examined correlation in the correspondent graph