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%).     

Free kappa light chains in multiple sclerosis spinal fluid

Based on prior reports of free light chains of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), we quantitated free kappa and lambda chains and whole IgG concentrations using sensitive and specific radioimmunoassays (RIAs). The RIA for free kappa chains had a sensitivity of 0.25 micrograms/ml and was capable of specifically measuring free kappa chains in whole CSF or serum even in the presence of a 4-log excess of whole IgG. By RIA, free kappa chains were detected in CSF samples from 33 (84%) of 39 MS patients but in only 1 (2.4%) of 42 controls. The control patients included 10 with noninfectious inflammatory diseases and 9 with central nervous system infections. The concentration of free kappa chains in the CSF of the MS patients was 1.40 +/- 1.21 micrograms/ml. Free kappa chains were concentrated in the CSF 71- to 120-fold relative to reference proteins. In contrast, increased levels of free lambda chains or of whole IgG were nonspecific; abnormalities were seen in controls with infections or inflammatory diseases as often as in MS patients. These studies suggest that the measurement of free kappa light chains may have important diagnostic usefulness, since the specificity of the finding for MS appears to be high.     

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     

Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis

Objective – The detection of oligoclonal immunoglobulin free light chains (FLC) in the diagnosis of multiple sclerosis (MS) was compared to IgG isoelectric focusing. Material and methods – Cerebrospinal fluid and serum samples from 69 patients with possible first attacks of MS, 50 patients with clinically definite MS (CDMS), and 118 patients with other neurological diseases (OND) were analyzed. IgG and FLC oligoclonal bands were detected by isoelectric focusing and immunoperoxidase staining. Results – Intrathecal synthesis of IgG, kappa FLC, and lambda FLC oligoclonal bands, respectively, was seen in 92%, 92%, and 86% of MS patients; in 61%, 62%, and 64% of patients with possible first attacks of MS; and in 3%, 3%, and 8% of the patients with OND. In control patients without IgG synthesis intrathecal lambda FLC synthesis was more common than kappa FLC synthesis ( P =0.03). Conclusion – Kappa FLC detection proved as useful as IgG analysis for the laboratory diagnosis of MS whereas the presence of intrathecal lambda FLC synthesis was less specific.     

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

Journal of Neurology -     

Increased free light chains in the urine from patients with multiple sclerosis

We quantitated free kappa (kappa) and lambda light (L) chains in coded urine specimens from subjects with clinically definite multiple sclerosis (MS) (N = 56), other neurologic diseases (OND) (N = 30), and age-matched normal controls (N = 28). Urine from MS patients showed statistically significant increases in free L chains compared with the other groups, although there was overlap between MS patients and OND patients. The ratio of kappa/creatinine was significantly greater in the relapsing-remitting MS group than in patients with clinically stable MS, OND, and normal controls. Elevated free L chains were usually independent of urinary albumin and beta 2-microglobulin levels. Serial studies showed that urinary free kappa/creatinine ratios were elevated during periods of clinical worsening in seven of eight MS patients and subsequently decreased during clinical recovery. The measurement of free L chains in urine obtained at intervals from MS patients may be useful as a marker to monitor disease activity.     

Intrathecal synthesis of free immunoglobulin light chains and IgM in initial multiple sclerosis

We studied the intrathecal synthesis of free kappa, free lambda immunoglobulin light chains and of IgM in 33 consecutive patients with possible or probable MS at the time of their first diagnosis. Nineteen patients presented free kappa or lambda light chain bands in CSF after agarose isoelectric focusing, protein transfer to nitrocellulose and immunostaining with specific antisera. Nineteen patients had increased CSF levels of free kappa light chains as measured with a competitive ELISA. Fourteen had an increased IgM index, as evaluated with a sandwich ELISA. Twenty-six patients displayed CSF oligoclonal IgG bands in CSF and 25 had cerebral magnetic resonance imaging lesions suggestive of MS. The local production of free immunoglobulin light chains and IgM is often detected in the CSF of patients with early MS.     

Multiple sclerosis: free light chains in cerebrospinal fluid

We found free light chains in the CSF of 18 MS patients, but not in any of 14 patients with other neurologic disease. CSF from all MS patients contained kappa and lambda chain dimers, less frequently contained light chain monomers, and never contained free gamma heavy chains. Light chains were not detected in matched serum samples. CSF from MS patients did not release free light chains from whole IgG in CSF of controls. The findings suggest that these free light chains originate in plasma cells, not from degradation of whole IgG.     

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.     

Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis

BACKGROUND: Oligoclonal free kappa bands are present as frequently as oligoclonal IgG bands in the cerebrospinal fluid (CSF) from patients with definite multiple sclerosis (MS) and can even occur in the absence of oligoclonal IgG. As such, they too are markers of an ongoing intrathecal immune process. OBJECTIVES: To determine how frequently oligoclonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted oligoclonal IgG. METHODS: An immunoaffinity mediated immunoblotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF oligoclonal IgG. CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al. RESULTS: Eighteen CSF samples contained oligoclonal free kappa bands (54%), mainly from patients with motor dysfunction (83%) and optic neuritis (64%). All patients with a positive MRI according to Barkhof's criteria (n = 6) had free kappa bands in their CSF. CONCLUSIONS: (1) Oligoclonal free kappa bands in the CSF are related to the dissemination of MS lesions; (2) such bands should be looked for in oligoclonal IgG negative CSF, and (3) the presence of free kappa bands in the CSF may be a substitute for oligoclonal IgG in the McDonald's criteria for diagnosis of MS.     

Free light chains in multiple sclerosis and infections of the CNS

The intrathecal humoral immune response was analyzed in 83 patients with MS and 35 patients with acute CNS infections. CSF free kappa chains and CSF free lambda chains were quantified by radioimmunoassay; CSF IgG and albumin were measured by electroimmunodiffusion. The MS patients were characterized by higher levels of free kappa chains; free kappa:free lambda chain ratio; free kappa chain:albumin ratio; and IgG:albumin ratio. There were no differences in the level of free lambda chains or absolute concentration of IgG. A significant correlation was observed between free kappa chains and total IgG in MS and between free lambda chains and total IgG in infections, suggesting that the immune response was predominantly IgG-kappa in MS and IgG-lambda in infections.     

Evidence of cerebrospinal fluid free kappa light chains in AIDS patients with Toxoplasma gondii encephalitis

Cerebrospinal fluid (CSF) free light chains of kappa or lambda (FLC kappa/lambda) type were investigated by affinity mediated blotting technique (AMI) and ELISA in 28 patients of which nine with AIDS and Toxoplasma gondii encephalitis (AIDS, TE), 11 with AIDS with or without other CNS AIDS-related opportunistic infections (non-TE AIDS) and eight control patients with or without inflammatory neurological disorders (control group). CSF restricted oligoclonal FLC bands either of k or lambda isotype or both were found by AMI in 18 (90%) out of 20 AIDS patients, while a CSF pattern predominantly characterized by FkappaLC rather than FlambdaLC was observed in eight (88.8%) out of nine TE patients. No FLC components were detected in the matched sera of TE or non-TE AIDS patients or in the CSF and sera from control group. The anti-parasite-specific FkappaLC CSF/serum mean levels and the T. gondii-specific FkappaLC index values were found by ELISA to be significantly more elevated in TE patients when compared to non-TE AIDS or control group. These findings suggest that the increased production of T. gondii-specific FkappaLC could provide insights into pathogenesis of reactivated TE in immunocompromised patients and may have important diagnostic usefulness.     

High sensitivity of free lambda and free kappa light chains for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid

Background – So far, an inflammation of the central nervous system (CNS) is diagnosed by immunoglobulin measurement in cerebrospinal fluid (CSF) and serum as well as by determination of the oligoclonal bands. With the free kappa and lambda light chains, new markers to diagnose intrathecal synthesis are available. Methods – In addition to routine diagnostic tests and the assessment of standard parameters, free immunoglobulin light chains were measured in the CSF of patients with neurological disorders. Results – A significant agreement was found between an increase in free kappa light chain CSF serum quotients and results of the currently widely applied method of oligoclonal band measurement for the detection of intrathecal immunoglobulin synthesis. A sensitivity of 95% and 100% specificity for free kappa light chain concentrations at a cut‐off of 0.41 mg/l was determined for free kappa light chains compared with oligoclonal bands. However, the free lambda light chains in 20 out of the 110 investigated samples were characterized by inconsistent behaviour. These otherwise unremarkable samples yielded increased CSF quotients, leading to the assumption that free lambda light chains represent a highly sensitive measure of intrathecal immunologlobulin synthesis. Thirteen of the 20 samples described above were obtained from patients with cerebral infarction, 4 samples derived from patients with cerebral paresis (primarily facial paresis), one sample was from a patient with multisystem atrophy and two were obtained from patients with migraine and neuralgia. Conclusion – These findings suggest that the high sensitivity of lambda light chains for the detection intrathecal immunoglobulin synthesis may be of benefit in establishing clinical diagnoses.     

Oligoclonal bands staining for IgG, IgA, IgM, and kappa and lambda light chains in cerebrospinal fluid of patients with multiple sclerosis

We investigated the oligoclonal bands (OB) in CSF of patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and aseptic meningitis (AS) using polyacryamide or agarose isoelectric focusing following electroblotting and immunostaining for IgG, IgA, IgM and light chains. OB staining for IgG was detected in 80% of patients with MS, 25% with GBS and 13% with AS. OB staining for IgA and IgM was not detected in any disease. In MS, OB were stained only for the kappa or lambda light chains, which was compatible with OB staining for IgG. These results suggest that in MS, OB are monoclonal because they can be stained for gamma heavy chains and for only one light chains.     

Cerebrospinal fluid free kappa light chains versus IgG findings in neurological disorders: qualitative and quantitative measurements

In this study free kappa light chains in cerebrospinal fluid (CSF) were determined both by an affinity mediated capillary blotting technique after isoelectric focusing (IEF) in agarose gel and by a quantitative enzyme linked immunosorbent assay (ELISA). The free kappa results were compared with the IgG findings in 4 neurological patient groups with a distinct CSF IgG pattern: (1) CSF without oligoclonal IgG bands, (2) CSF with serum derived IgG bands, (3) CSF restricted IgG bands and (4) CSF restricted and serum derived IgG bands. Oligoclonal free kappa bands are nearly absent in CSF of groups 1 + 2, and present in 88% of group 3 and 84% of group 4 patients. We could also establish free kappa indices from specimens in the 4 groups in analogy to IgG indices. Group 1 had a median free kappa index of 1.1, group 2: 1.0 and groups 3 + 4: 10.0. The correspondence between immunoblot and index findings for free kappa is better than for IgG. Free kappa index is more sensitive but somewhat less specific than IgG index for establishing intrathecal immune production.     

Dystonia in multiple sclerosis]

Two cases of involuntary movements of the type of segmental dystonia were observed in patients with a history of multiple sclerosis since many years. The reports on dystonic involuntary movements in multiple sclerosis are scant but, together with the present cases, they suggest that dystonia may be a sign of multiple sclerosis, although a rare one.     

Oligoclonal IgG and free chains in multiple sclerosis demonstrated by thin-layer polyacrylamide gel isoelectric focusing and immunofixation

A modified technique of isoelectric focusing on thin-layer polyacrylamide gel followed by immunofixation with monospecific antisera was used to identify individual cerebrospinal fluid (CSF) and serum proteins and to define the oligoclonal reaction observed in multiple sclerosis (MS). "Normal" IgG gave about 20 to 30 bands at pH 3.5 to 9.5, IgA about 10 bands at pH 3.5 to 6.4, beta-trace protein a smear at pH 3.5 to 8.5, and gamma-trace protein 1 or 2 bands at pH 8.0, 9.5 or both. Up to 11 oligoclonal IgG bands migrating between pH 6.5 and 9.5 were found in CSF from 26 of 27 consecutive patients with MS and also in 20 of the corresponding sera, although at lower numbers and concentrations. In 26 patients, 1 or more of the bands corresponding to normal polyclonal IgG were stronger in CSF than in serum. These data support the hypothesis that two colonies of lymphocytes are activated intrathecally, one of them synthesizing oligoclonal and the other polyclonal IgG. Up to 11 mostly faint bands of free light chains, predominantly of lambda type and migrating between pH 3.5 and 9.5, were found in 8 of 9 CSF specimens from patients with MS.