Objective Intrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. Methods We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing‐remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. Results Forty‐one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p < 0.001). In the multivariate analysis, CXCL13 (hazard ratio [HR] = 1.35; p = 0.0002), LIGHT (HR = 1.22; p = 0.005) and APRIL (HR = 1.78; p = 0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model, including CSF variables, predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C‐index at 4 years = 71% vs 44%). Finally, higher CSF levels of CXCL13 (β = 4.7*10−4; p < 0.001), TNF (β = 3.1*10−3; p = 0.004), LIGHT (β = 2.6*10−4; p = 0.003), sCD163 (β = 4.3*10−3; p = 0.009), and TWEAK (β = 3.4*10−3; p = 0.024) were associated with more severe cortical thinning. Interpretation A specific CSF profile, mainly characterized by elevated levels of B‐cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. ANN NEUROL 2020;88:562–573

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti-inflammatory effect and/or to a direct effect on neuronal cells. Areas covered: In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS. Expert opinion: Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect.

DMF appeared generally safe and no carryover PML among investigated cases was observed. Although DMF did not eliminate the possibility of disease reactivation, it seems anyway a promising drug for those patients who shall discontinue NTZ. The clinical and radiological activity preceding the DMF treatment might be used as a prognostic marker of therapy response.

Background: The underlying pathogenesis of surface-in grey matter abnormalities in MS, demonstrated by both neuropathology and advanced MRI analyses, is under investigation and it might be related to CSF-mediated mechanism of inflammation and/or damage. Objective: To examine the link of CSF inflammatory profile with the damage of three regions early-involved in MS and bordering with CSF: thalamus, hippocampus and cerebellum. Methods: In this longitudinal, prospective study, we evaluated, in 109 relapsing–remitting MS patients, at diagnosis and after 2-year follow-up, the association between the baseline CSF level of 19 inflammatory mediators and the volume changes of thalamus, hippocampus, cerebellar cortex and control regions (globus pallidus, putamen). Results: The multivariable analysis showed that the CXCL13 and sCD163 CSF levels at baseline were independent predictors of thalamus ([Formula: see text]; p < 0.001) and hippocampus ([Formula: see text]; p < 0.001) volume change after 2-year follow-up. These molecules, plus CCL25, IFN-γ and fibrinogen, were independent predictors of the cerebellar cortex volume loss ([Formula: see text]; p < 0.001). No independent predictors of volume changes of the control regions were found. Conclusion: Our results indicate an association between the CSF inflammatory profile and grey matter volume loss of regions anatomically close to CSF boundaries, thus supporting the hypothesis of a surface-in GM damage in MS.

These results suggest a possible protective effect of fingolimod on focal and diffuse GM damage.