Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis

Elevated CSF free kappa light chains (FKLCs) may predict disability in multiple sclerosis (MS). We reviewed records of 57 patients with MS with 15-year median follow-up for correlations of disability and CSF FKLCs. Levels > or = 1.53 microg/mL predicted progression to need for ambulatory assistance during follow-up (specificity 87.5%, positive predictive value 88.9%) or within 10 years (specificity 78.6%, positive predictive value 66.7%).     

Identification of IgG subclasses'' oligoclonal bands in multiple sclerosis CSF

IgG subclasses' oligoclonal bands in unconcentrated CSF from MS patients were detected by isoelectric focusing in agarose gel with subsequent immunoblotting using mouse monoclonal antibodies to human IgG subclasses and double-antibody avidin-biotin-alkaline phosphatase system. All MS CSF showed presence of oligoclonal bands specific to the IgG1 subclass; in addition, several of these samples also had oligoclonal bands specific to IgG3, IgG2, or IgG4, in order of decreasing frequency. Since the CSF of a greater number of MS patients showed oligoclonal bands specific to the IgG1 and IgG3 subclasses, the findings are consistent with those reported in patients with chronic viral infections and autoimmune diseases.     

Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis

Background   Numerous studies have demonstrated elevated kappa free light chains (KFLCs) in CSF of multiple sclerosis (MS) patients. However, so far only small cohorts have been examined, and generally only through qualitative KFLCs analysis. Using a recently developed free light chain (FLC) immunoassay, it is now possible to quantitatively measure KFLCs by automated nephelometry. Our objective was to determine the extent to which KFLC levels in CSF correlated with the diagnosis of MS and CISSMS (clinically isolated syndrome suggestive of MS) compared to oligoclonal banding (OCB) and the immunoglobulin G (IgG) index. Methods   CSF and serum samples from 438 unselected patients, including a MS group of 70 patients (41 MS, 29 CISSMS), were analysed using nephelometry and isoelectric focusing. We then retrospectively correlated results with patients’ diagnoses. Results   Of the MS group (n = 70), 67 patients had elevated KFLCs using the KFLC index (≥ 5.9), 64 patients showed OCB and 56 patients presented with an elevated IgG index (≥ 0.6). Sensitivities were 0.96 for the KFLC index, 0.91 for OCB and 0.80 for the IgG index. The specificity of the KFLC index for the MS group (0.86) was lower than that of OCB (0.92) but distinctly higher compared to the IgG index (0.77). Conclusion   In this study, an elevated KFLC-index represented the most sensitive and specific quantitative diagnostic parameter for MS. As it is measured by automated, routinely available laboratory methods, KFLC quantitation can provide a rapid and reproduceable indication of intrathecal immunological processes supporting current MS diagnostic criteria. The study was performed in accordance with the ethical standards. An erratum to this article can be found at     

Identification of light chain type bands in CSF and serum oligoclonal IgG from patients with multiple sclerosis

The light (L) chain types (kappa and lambda) of oligoclonal IgG bands of matching CSF and serum from 10 MS patients were identified in immunofixation after isoelectric focusing in polyacrylamide gel. Each specimen showed 10-15 oligoclonal bands in pH region of 7.5-9.3. In 7 MS CSF and 5 sera a greater number of oligoclonal IgG bands were of kappa (kappa)-type whereas in 3 CSF and 2 sera the majority was of lambda (lambda)-type. In 3 sera a clearcut correlation of bands with either type of L chain was not observed due to diffuse staining background. Only a small number of oligoclonal IgG bands in 7 of 10 CSF and serum pairs had identical isoelectric points and the same type of L chain. The results show that the individual MS patient had oligoclonal IgG bands in serum, differ with respect to number, isoelectric point and L chain type from the oligoclonal IgG profile seen in the patient's CSF.     

Urine free light chains kappa in multiple sclerosis]

The evaluation of free light chains kappa in urine was performed in 77 cases of multiple sclerosis, including 52 patients before and after treatment with 2 CDA and in 25 patients before and after therapy with high doses of prednisone. The high variations in the level of free kappa chains indicate a limited diagnostic value, and only for cases with very high level. We have found effect of 2 CDA therapy in chronic progressive MS group on free kappa light chain value. A significant effect of prednisone treatment was observed in early onset cases of multiple sclerosis and in cases with clinical improvement after therapy. In conclusion, the study suggests that urinary free light chains level may be considered as one of markers for monitoring of the effect of therapy on the activity of the immunological processes in multiple sclerosis.     

Erratum to: Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis

Journal of Neurology -     

Clinical and CSF findings in multiple sclerosis patients with or without IgG oligoclonal bands at isoelectric focusing examination of CSF and serum proteins

The IgG oligoclonal bands in CSF can be found in high percentage of MS patients but the existence of a limited number of cases with CSF normal IgG profile is known as well. In the present study 63 out of 70 patients with definite MS and 24 out of 35 with probable MS had oligoclonal bands in the CSF at the isoelectric focusing examination. The 18 patients with normal CSF IgG pattern did not show any statistically significant difference as concerns the age at onset and the duration of the disease, the functional disability, the course of the disease and the quantitative CSF parameters (IgG index, IgG synthesis and serum/CSF albumin quotient). The oligoclonal pattern does not seem of value to discriminate different groups of MS patients but it remains essentially of great diagnostic importance in this disease.     

Light chain composition of CSF oligoclonal IgG bands in multiple sclerosis and subacute sclerosing penecephalitis

The light chain composition of MS and SSPE CSF oligoclonal IgG bands was examined using isoelectric focusing and sensitive peroxidase-anteperoxidase (PAP) staining technique specific for gamma heavy chains (γ), kappa light chains (κ), or lambda light chains (λ) and a radioimmunoassay (RIA) for γ, κ, or λ. Many bands in the 7 MS and 4 SSPE CSF examined were monoclonal, staining for either IgG-κ or IgG-λ. By staining, all MS CSF were κ predominant; SSPE CSF were variously κ orλ predominant. RIA confirmed the κ predominance of MS CSF. Three MS and 2 SSPE CSF contained bands staining for λ alone, i.e. free light chains. Analysis of RIA data confirmed these findings in 2 MS cases. The difference in light chain predominance of MS and SSPE CSF may reflect differences in the antigenic target, or the age of patient at the time when band-synthesizing clones are triggered. Six of 7 MS and all 4 SSPE CSF contained oligoclonal bands staining for γ and for both κ and λ, probably representing artifacts of IEF. No predominant immunochemical differences between bands in MS and SSPE were detected.     

Absence of oligoclonal IgA in CSF and serum of multiple sclerosis patients

CSF and serum from patients with MS and other neurologic diseases were analyzed by isoelectric focusing (IEF) in polyacrylamide gel and immunofixation with specific anti human IgA sera. The IgA band patterns seen in pH 4.5-6.0 region were rather diffuse and lacked oligoclonal feature.     

Cerebrospinal fluid IgG profiles and oligoclonal bands in Chinese patients with multiple sclerosis

OBJECTIVES: To investigate the significance of oligoclonal bands (OCBs) and intrathecal IgG fractions (IgGIF) for the diagnosis of multiple sclerosis (MS) in northern China. MATERIALS AND METHODS: OCBs in cerebrospinal fluid from 30 patients with MS, 34 with other inflammatory neurological diseases (IND) and 22 with non-inflammatory neurological diseases (NIND) were detected using isoelectric focusing. IgGIF was calculated based on corresponding formula. RESULTS: There was no significant difference in the frequencies of positive OCBs and elevated IgGIF between the MS group and the IND group. Compared with NIND, the MS and IND groups had a significantly higher incidence of OCBs and elevated IgGIF. The sensitivity, specificity and positive result likelihood ratio of OCBs for the diagnosis of MS were 63.3%, 74.2% and 2.5 respectively; those of IgGIF were 36.7%, 84.5% and 2.4. CONCLUSIONS: The two parameters, OCBs and IgGIF are of less diagnostic value for MS in China.     

MR peri‐CSF lesions and CSF oligoclonal bands in Italian multiple sclerosis patients

Objectives – We investigated the association between brain lesion distribution and the presence of oligoclonal IgG bands (OCBs) in Italian multiple sclerosis (MS) patients. Materials and methods – We retrospectively selected brain magnetic resonance imaging (MRI) uniformly performed in 56 relapsing patients (41 patients OCB positive). Results – Brain lesions in periventricular areas occurred in 92.86% of the patients (100% OCB+ and 73.33% OCB?) (P = 0.004), but we did not find a significant difference for their median volume (P = 0.553) and median number (P = 0.606) between the two groups. Parenchymal lesions occurred in 76.8% of the patients with a similar distribution (P = 1.00) and no significant difference in the median volume (P = 0.818) and number (P = 0.643) between the two groups. Conclusions – The present study on cohort of Italian MS patients demonstrated a lack of correlation between lesion distribution and OCBs, suggesting that B cells producing them could be localized both in meningeal niches and cerebral parenchyma.     

Genetic basis of multiple sclerosis: HLA antigens, disease progression, and oligoclonal IgG in CSF

The HLA antigens B7 and Dw2 occurred at elevated frequencies in 105 multiple sclerosis (MS) patients (49 and 47%, respectively), compared to healthy controls (29 and 30%), especially in MS patients with oligoclonal CSF-IgG (51 and 50%), in cases with CSF-IgG index values above 1.5 (64 and 64%), and in those with the most malignant course of the disease (47 and 59%). Normal or only slightly elevated frequencies of B7 and Dw2 were found in MS patients without oligoclonal CSF IgG (35 and 29%), normal CSF-IgG index (43 and 39%), and the most benign course (42 and 37%). No correlation was found between the HLA type and measles virus antibody titers in serum or a measles virus antibody response within the CNS.     

A comparative study of Japanese multiple sclerosis patients with and without oligoclonal IgG bands

The cerebrospinal fluid oligodonal IgG bands (OB) are less frequently observed in Japanese multiple sclerosis (MS) patients compared with Caucasian patients. We studied 40 consecutive Japanese MS patients to investigate the differences in the clinical and magnetic resonance imaging (MRI) features of MS between OB-positive patients and OB-negative ones. Among the 40 patients, 22 (55%) patients were OB-positive by either agarose gel electrophoresis (AGE) or isoelectric focusing (IEF), and 18 (45%) patients were OB-negative by both AGE and IEF. There were differences between the two groups only in the clincal forms of MS, but not in terms of gender, onset age, disease duration, or disease severity. In the OB-negative group, nine (50%) of the patients had the optic-spinal form of MS (OS-MS), but only one patient (4.5%) in the OB-positive group had OS-MS. Although most OB-positive patients showed brain MRI lesions typical of MS, 13 (72%) of the OB-negative patients showed no or few brain MRI lesions and the rest of the OB-negative patients showed atypical MS lesions, such as diffuse white matter lesions or large ring-enhanced lesions. Our results suggest that the majority of OB-negative Japanese MS patents show either no or few brain MRI lesions or atypical brain MRI lesions.     

Discontinuos distribution of IgG oligoclonal bands in cerebrospinal fluid from multiple sclerosis patients

To test the effect of sampling on the detection of immunoglobulin (Ig) cerebrospinal fluid (CSF) abnormalities, we analyzed the first and last 1 ml fraction of 10 ml obtained during a single CSF removal from 27 multiple sclerosis (MS) patients and six patients with other neurological diseases. IgG index, hyperbolic function, and IgG synthesis rate decreased between the first and the last CSF aliquot. Discordant results were found in (15%) MS patients. In (7.5%) clinically definite MS patients, the number of CSF oligoclonal bands (OCB) decreased between the first and the last fraction. In one of the two patients, the three OCB visualized in the first fraction were not found in the last. We conclude that fractionated sampling may partially account for the absence of OCB in the CSF of some definite MS patients.     

Free light chains in the CSF in multiple sclerosis

Summary The presence of free light chains (FLC) was investigated in 32 patients with clinically definite or laboratory supported definite multiple sclerosis (MS), 2 patients with neurosyphilis and 10 normal controls. The detection of FLC in unconcentrated cerebrospinal fluid (CSF) was performed by means of agarose isoelectric focusing, followed by transfer of proteins to nitrocellulose membranes, double immunofixation, avidin-biotin amplification and peroxidase staining. Bands due to FLC were clearly demonstrated in the CSF of 28 MS patients; 3 of them showed only kappa FLC, 10 only lambda FLC, while 15 had both kappa and lambda FLC. The CSF of 4 MS patients was FLC negative. In both cases of neurosyphilis FLC bands were observed. FLC were never found in normal CSF. Among the indexes of intrathecal immunological activity (IgG oligoclonal bands, FLC, IgG index, intra-blood-brain barrier IgG synthesis rate, pleocytosis) the FLC proved to be the second most frequent abnormality in MS CSF, the presence of IgG oligoclonal bands being the first. In one MS case an FLC band was found, while all the other indexes of intrathecal IgG production were negative. A high correlation was found between an elevated number of FLC and pleocytosis. The presence of FLC in MS CSF seems to indicate a recent immunological stimulation leading to increased synthesis of FLC within the CNS.     

IgG ratios and oligoclonal IgG in multiple sclerosis and other neurological disorders

The findings are reported of various CSF abnormalities, including IgG indices and oligoclonal IgG, in 160 patients with multiple sclerosis of differing diagnostic certainty and 146 patients with other neurological disorders.

An abnormal IgG index, defined as the ratio of IgG/albumin in CSF to that in serum, has been found in 77.7% of definite MS cases, falling to a figure of 32.1% in the single lesion group. A tendency, reported previously, for IgG levels to be higher in disabled patients, particularly those with a short history or early onset, has been confirmed.

Oligoclonal IgG, on the other hand, has been found in 56% of definite MS cases, less frequently than in most other reported series. Analysis of the literature suggests considerable variability in the finding of oligoclonal IgG in other than definite MS, and in other neurological disorders. The possibility that subjective factors are partly responsible for this variability, rather than discrepancies in patient selection requires consideration, and suggests that CSF electrophoresis and IgG estimations are complementary aids in the diagnosis of multiple sclerosis.

Differences have been expressed regarding the relationship of oligoclonal IgG to clinical parameters of the disease. Further sequential analysis of the development and variability of the oligoclonal pattern in MS is required.     

Discontinuous distribution of IgG oligoclonal bands in cerebrospinal fluid from multiple sclerosis patients

To test the effect of sampling on the detection of immunoglobulin (Ig) cerebrospinal fluid (CSF) abnormalities, we analyzed the first and last 1 ml fraction of 10 ml obtained during a single CSF removal from 27 multiple sclerosis (MS) patients and six patients with other neurological diseases. IgG index, hyperbolic function, and IgG synthesis rate decreased between the first and the last CSF aliquot. Discordant results were found in 4/27 (15%) MS patients. In 2/27 (7.5%) clinically definite MS patients, the number of CSF oligoclonal bands (OCB) decreased between the first and the last fraction. In one of the two patients, the three OCB visualized in the first fraction were not found in the last. We conclude that fractionated sampling may partially account for the absence of OCB in the CSF of some definite MS patients.