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Background and purpose: Different biological and radiological biomarkers predict clinical conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS). The aim was to explore their role in predicting the outcome of patients with optic neuritis (ON), a CIS considered to have a benign prognosis. Methods: Sixty‐eight consecutive ON patients were followed prospectively. Magnetic resonance imaging (MRI) and cerebrospinal fluid studies including oligoclonal immunoglobulin G (IgG) bands (OCGBs), lipid‐specific oligoclonal IgM bands (LS‐OCMBs) and neurofilament light chain quantification were performed at disease onset. Conversion to clinically definite MS (CDMS) was monitored. Results: The mean time of follow‐up of our series was 46.4 months. Twenty‐five patients (36.7%) developed CDMS during follow‐up. Neurofilament light chain levels did not predict clinical conversion. By contrast, an abnormal MRI increased the risk of CDMS [hazard ratio (HR) 12.5, P = 0.013]. The clearest association was found in patients with more than three T2 lesions. OCGBs also predicted the onset of CDMS (HR 21.3, P = 0.003) and LS‐OCMBs were associated with a shorter time to CDMS (HR = 116.6, P < 0.001). Conclusions: Magnetic resonance imaging and OCGBs predicted conversion to CDMS after an ON episode. In addition, LS‐OCMBs identified the ON patients more likely to develop MS early. These results, applicable to the everyday clinical setting, may be of interest for therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background and purpose: Chitinase 3‐like 1 (CHI3L1) and neurofilament light chain (NF‐L) are promising biomarkers of disability in multiple sclerosis (MS). However, their role in cognitive dysfunction remains elusive. Here, we aimed to correlate cerebrospinal fluid (CSF) levels of CHI3L1 and NF‐L with cognitive status in MS. Methods: Fifty one recently diagnosed patients were cognitively evaluated and CSF was collected. Levels of CHI3L1 and NF‐L were determined by ELISA. Spearman's partial correlation coefficient was performed. Results: After adjusting cognitive scores by age, anxiety and EDSS, association was detected between CHI3L1 levels and Trail Making Test A (rs = 0.348; p = 0.016) and between NF‐L levels and Word List Generation (rs = −0.324; p = 0.025). Conclusion: High levels of CSF CHI3L1 and NF‐L are associated with cognitive impairment in the early phases of MS. [ABSTRACT FROM AUTHOR]

Background and purpose Cerebrospinal fluid ( CSF) neurofilament light protein ( NFL) is a promising biomarker of axonal injury and neurodegeneration. Here CSF lymphocyte subpopulations and antibodies, potential players of neurodegeneration, are examined in relation to CSF NFL shedding in MS. Methods Cerebrospinal fluid NFL from 127 consecutive untreated MS patients was analysed. Samples from 37 age-matched patients with other central nervous system non-inflammatory neurological diseases ( NIND) were also assessed. CD4+, CD8+, CD56+ and CD19+ cell subsets were studied by flow cytometry. Oligoclonal Ig G and Ig M bands ( OCMB) against lipids were studied by isoelectric focusing and immunoblotting. These data were analysed in relation to clinical and magnetic resonance imaging features. Results A CSF NFL cut-off value of 900 ng/l (mean + 3 SD of NIND values) was calculated. MS patients with increased NFL values showed significantly higher Multiple Sclerosis Severity Score and magnetic resonance imaging lesion number. The presence of OCMB ( P < 0.0001) and elevated T and B lymphocyte counts was associated with increased levels of CSF NFL. Conclusions High CSF NFL levels are associated with elevated CSF lymphocyte cell counts and intrathecal synthesis of Ig M against lipids. These findings support a role for OCMB in the axonal damage of MS offering a rationale for the association of these antibodies with disability and brain atrophy progression in MS. [ABSTRACT FROM AUTHOR]

Changes in blood natural killer ( NK) cells, important players of the immune innate system, have been described in multiple sclerosis ( MS). We studied percentages and total cell counts of different effector and regulatory NK cells in cerebrospinal fluid ( CSF) of MS patients and other neurological diseases to gain clearer knowledge of the role of these cells in neuroinflammation. NK cell subsets were assessed by flow cytometry in CSF of 85 consecutive MS patients (33 with active disease and 52 with stable MS), 16 with other inflammatory diseases of the central nervous system ( IND) and 17 with non-inflammatory neurological diseases ( NIND). MS patients showed a decrease in percentages of different CSF NK subpopulations compared to the NIND group. However, absolute cell counts showed a significant increase of all NK subsets in MS and IND patients, revealing that the decrease in percentages does not reflect a real reduction of these immune cells. Remarkably, MS patients showed a significant increase of regulatory/effector ( CD56bright/ CD56dim) NK ratio compared to IND and NIND groups. In addition, MS activity associated with an expansion of NK T cells. These data show that NK cell subsets do not increase uniformly in all inflammatory neurological disease and suggest strongly that regulatory CD56bright and NK T cells may arise in CSF of MS patients as an attempt to counteract the CNS immune activation characteristic of the disease. [ABSTRACT FROM AUTHOR]

Background and purpose Different data show an association between human herpesvirus 6 ( HHV-6) and multiple sclerosis ( MS). Intrathecal anti- HHV-6 immunoglobulin G (IgG) was detected in MS patients, but the antigen recognized by cerebrospinal fluid ( CSF) IgG has not been characterized yet. Our objective was to identify the HHV-6 antigens recognized by IgG present in the CSF of patients with MS. Methods Cerebrospinal fluid IgG of 15 MS patients and eight patients with other neurological diseases was purified on protein G Sepharose columns. Purified IgG from every patient was linked to a CNBr-activated Sepharose 4B column. Fifty micrograms of viral extract was applied to each column. Bound proteins were eluted and analysed by SDS- PAGE and silver staining. The viral protein was characterized by mass spectrometry. Results A protein of 150 kD was eluted from CSF IgG columns of three of eight patients with primary progressive MS and one of seven with relapsing−remitting MS. After digestion and mass spectrometry analysis 10 peptides were found with 100% homology with the major capsid protein of the HHV-6A. Discussion These findings confirm the presence of anti- HHV-6 IgG in CSF of MS patients, particularly in progressive forms, and identify major capsid protein as the major antigen recognized by CSF IgG from MS patients. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing-remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1-3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p<0.0001), higher relapse rate in the first year (0.8 versus 0.2; p=0.001), lower proportion of relapse-free patients (25% versus 61.3%; p=0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p=0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment. [ABSTRACT FROM AUTHOR]

Background and Objective The presence of lipid-specific immunoglobulin M bands in the cerebro-spinal fluid (CSF) predicts an aggressive course in patients with relapsing-remitting multiple sclerosis (MS) during early stages of the disease. This study examined whether it is also a predictor of long- term prognosis in MS. Methods Eighty-one patients with MS and 22 headache controls were analyzed for anti-lipid IgM reactivity in CSF samples. The correlation between the presence of lipid-specific immunoglobulin M bands in CSF and disease progression was assessed in patients with MS who had been followed longitudinally for, on average, more than 11 years. Results Lipid-specific immunoglobulin M bands were detected in the CSF of 24 of 81 patients with MS and were absent in the CSF of all headache controls. Median time to conversion to a secondary progressive course was 11 years in patients with bands and 22 years in patients without bands. Median time to an Expanded Disability Status Scale score of 4 was 14 years in patients with bands and 24 years in patients without bands. Conclusion The presence of lipid-specific immunoglobulin M bands in CSF predicts a more adverse long-term outcome in patients with MS; it may thus define a subset of patients who might benefit from aggressive treatment during the early phase of the disease. [ABSTRACT FROM AUTHOR]

TREM-2 is a membrane bound receptor expressed by microglia and macrophages and its engagement reduces inflammation. In this study, a soluble form of TREM 2 (sTREM-2) is identified. Cerebrospinal fluid (CSF) sTREM-2 levels were found to be higher in relapsing-remitting multiple sclerosis patients (n = 52) compared with noninflammatory neurologic diseases cases (n = 41; p = 0.004). Primary-progressive multiple sclerosis patients (n = 21) and other inflammatory neurologic diseases subjects (n = 19) also had high CSF TREM-2 levels (p < 0.001). Furthermore a subset of CSF monocytes expressed TREM-2 which was also highly expressed on myelin-laden macrophages in active demyelinating lesions. The elevated levels of sTREM-2 in the CSF of multiple sclerosis patients may inhibit the anti Inflammatory function of the membrane bound receptor. Therefore, sTREM-2 may be a possible target for future therapies. [ABSTRACT FROM AUTHOR]