Background and Objective
The presence of lipid-specific immunoglobulin M bands in the cerebrospinal 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.
Oligoclonal IgM bands (OCMB) against myelin lipids predict an aggressive multiple sclerosis (MS) course. However, the clinical significance of OCMB without lipid specificity, present in other MS ...patients, remains unknown. We describe here a characterization of these antibodies and study their role in MS progression. Fifty-four MS patients showing CSF-restricted OCMB were included in this study at disease onset and followed-up during 61.1 ± 2.7 months. The specificity of OCMB and the CSF B-cell profile were investigated. A second CSF IgM study was performed in a group of eight patients. Thirty-eight patients showed OCMB against myelin lipids (M+L+) and other sixteen had OCMB lacking this specificity (M+L-). The CD5+ B cell subpopulation, responsible for most persistent IgM responses, was considerably higher in M+L+ than in M+L- patients (3.3 ± 0.6% versus 0.8 ± 0.2, P = 0.009). In addition, M+L+ bands persisted during disease course, while M+L- disappeared during follow-up. M+L+ patients suffered more relapses (4.2 ± 0.6 versus 1.6 ± 0.3, P = 0.002) and reached higher disability (EDSS score of 2.2 ± 0.2 versus 1.2 ± 0.2, P = 0.02) than M+L- group. These data corroborate that anti-lipid OCMB associate with an aggressive MS course and show that OCMB that do not recognize myelin lipids represent a transient immune response related to a more benign disease course. Multiple Sclerosis 2008; 14: 183—187. http://msj.sagepub.com
Objective:
To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS).
Methods:
We performed a multicenter study ...including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes.
Results:
The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2–138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5–22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85–0.90) was higher than OCB (0.82; 95%CI = 0.79–0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78–0.88) was lower (OCB = 0.92; 95% CI = 0.89–0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB.
Conclusion:
Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.
Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the ...finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.
The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control ...groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.
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.
Oligoclonal IgM bands restricted to cerebrospinal fluid are an unfavorable prognostic marker in MS, the most common demyelinating disease of the CNS. We have attempted to identify the B cell ...subpopulation responsible for oligoclonal IgM secretion and the specificity of these bands. In addition, we explored the relationship between specificity and disease evolution. Intrathecal B cell subpopulations present in 29 MS patients with oligoclonal IgM bands and 52 without them were analyzed. A considerable increase in CD5(+) B lymphocytes was found in patients with oligoclonal IgM bands. These cells mostly secrete IgM antibodies recognizing nonproteic molecules. We also studied whether oligoclonal IgM bands present in cerebrospinal fluid of 53 MS patients were directed against myelin lipids. This was the case in most patients, with phosphatidylcholine being the most frequently recognized lipid. Disease course of 15 patients with oligoclonal IgM against myelin lipids and 33 patients lacking them was followed. Patients with anti-lipid IgM suffered a second relapse earlier, had more relapses, and showed increased disability compared with those without anti-lipid IgM. The presence of intrathecal anti-myelin lipid IgM antibodies is therefore a very accurate predictor of aggressive evolution in MS.
Patients with a clinically isolated demyelinating syndrome (CIS) are at risk of developing a second attack, thus converting into clinically definite multiple sclerosis (CDMS). Therefore, an accurate ...prognostic marker for that conversion might allow early treatment. Brain MRI and oligoclonal IgG band (OCGB) detection are the most frequent paraclinical tests used in MS diagnosis. A new OCGB test has shown high sensitivity and specificity in differential diagnosis of MS.
To evaluate the accuracy of the new OCGB method and of current MRI criteria (MRI-C) to predict conversion of CIS to CDMS.
Fifty-two patients with CIS were studied with OCGB detection and brain MRI, and followed up for 6 years. The sensitivity and specificity of both methods to predict conversion to CDMS were analyzed.
OCGB detection showed a sensitivity of 91.4% and specificity of 94.1%. MRI-C had a sensitivity of 74.23% and specificity of 88.2%. The presence of either OCGB or MRI-C studied simultaneously showed a sensitivity of 97.1% and specificity of 88.2%.
The presence of oligoclonal IgG bands is highly specific and sensitive for early prediction of conversion to multiple sclerosis. MRI criteria have a high specificity but less sensitivity. The simultaneous use of both tests shows high sensitivity and specificity in predicting clinically isolated demyelinating syndrome conversion to clinically definite multiple sclerosis.
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