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

Abstract

BackgroundAlthough 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.MethodsThis 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.ResultsIncreased 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.ConclusionsOCB 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0812-y) contains supplementary material, which is available to authorized users.

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

“…In such a process, the tissue in closest proximity to the CSF becomes saturated early and atrophies at a higher rate, and the effect exponentially decreases moving in depth, finally leveling off again where the concentration gradient no longer contributes to damage. The imaging evidence of such an injury gradient on the ventricular side of the thalamus of children with MS thus supports the theory put forth based on observations in adult MS that the subpial cortical damage may reflect the presence of one or more inflammatory, cytotoxic, and/or myelinotoxic soluble CSF factors, possibly released by immune cells within the CSF or situated within meningeal infiltrates . Several in vitro studies further support this hypothesis; cultured neurons exposed to CSF of MS patients (but not CSF from non‐MS controls) exhibited oxidative stress and axonal damage, with the implication of particular ceramides (C16:0 and C24:0) enriched in the CSF of the MS patients as possible mediators of this injury .…”

Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis

“…In particular, CSF abundance of B cell‐linked inflammatory mediators, such as CXCL13, CXCL12, CXCL10, BAFF, IL6, IL10, GM‐CSF, and TNF, supports the hypothesis of a prominent role of B cells in the pathogenesis of CLs . These inflammatory mediators as well as one or more cyto‐ and/or myelinotoxic soluble CSF factors could then diffuse through the cortex and mediate a “surface‐inward” pattern of subpial cortical damage . A number of in vitro studies further support this hypothesis, showing that cultured neurons exposed to CSF of MS patients, but not of controls, undergo oxidative stress and axonal damage and that ceramides (C16:0 and C24:0) enriched in MS CSF patients may represent possible mediators of this injury .…”

“…The IgG index and the presence/absence of oligoclonal bands (OCB) for each MS patient are reported in Table . The levels of 69 inflammatory mediators (Table ) were assessed using a combination of immune‐assay multiplex techniques (Bio‐Plex X200 System, BioRad, Hercules, CA) as previously optimized and described in Data S1.…”

“…The levels of neurofilament light chain (NF‐L) in CSF were measured using Human NF‐light enzyme‐linked immunosorbent assays (ELISA) kit (MyBioSource, San Diego, CA) according to procedures previously optimized …”

“…In a recent combined ex vivo and in vivo study, compartmentalized inflammation in meningeal infiltrates and cerebrospinal fluid (CSF) was found significantly associated with increased subpial demyelination . In particular, a distinctive CSF pro‐inflammatory pattern, including increased levels of CXCL13, TNF, IFN γ , CXCL12, IL6, IL8, and IL10, has been associated with a higher GM lesion load both at the time of diagnosis and at death …”