Laboratory Diagnosis of Intrathecal Synthesis of Immunoglobulins: A Review about the Contribution of OCBs and K-index.

The diagnosis of MS relies on a combination of imaging, clinical examinations, and biological analyses, including blood and cerebrospinal fluid (CSF) assessments. G-Oligoclonal bands (OCBs) are considered a "gold standard" for MS diagnosis due to their high sensitivity and specificity. Recent advancements have involved the introduced of kappa free light chain (k-FLC) assay into cerebrospinal fluid (CSF) and serum (S), along with the albumin quotient, leading to the development of a novel biomarker known as the "K-index" or "k-FLC index". The use of the K-index has been recommended to decrease costs, increase laboratory efficiency, and to skip potential subjective operator-dependent risk that could happen during the identification of OCBs profiles. This review aims to provide a comprehensive overview and analysis of recent scientific articles, focusing on updated methods for MS diagnosis with an emphasis on the utility of the K-index. Numerous studies indicate that the K-index demonstrates high sensitivity and specificity, often comparable to or surpassing the diagnostic accuracy of OCBs evaluation. The integration of the measure of the K-index with OCBs assessment emerges as a more precise method for MS diagnosis. This combined approach not only enhances diagnostic accuracy, but also offers a more efficient and cost-effective alternative.

Saliva Free Light Chains in Patients with Neuro-Sjögren.

Background: Sjögren's syndrome (SS) is an autoimmune disease characterized by sicca symptoms and various extra-glandular manifestations. The diagnosis of SS requires sicca symptoms, anti-SSA(Ro)-antibody positivity, and/or pathological focus scores on a minor salivary gland biopsy. Previous studies have investigated different biomarkers in order to avoid invasive diagnostic procedures. It was found that kappa and lambda free light chains (KFLC and LFLC) in saliva are specific for SS. Methods: FLC concentrations in saliva and serum were determined in 130 patients-50 with SS and neurological involvement (Neuro-Sjögren) and 80 neurological controls. The EULAR SS disease activity index and patient reported index (ESSPRI) were determined in patients with SS. Results: Patients with SS revealed increased pain and decreased saliva production according to the ESSPRI and Saxon test, respectively, with increasing FLC concentrations in the saliva. No significant differences in serum and salivary protein concentrations were observed between patients with SS and controls. Conclusion: KFLC and LFLC concentrations in saliva are not suitable to distinguish patients with Neuro-Sjögren and neurological control subjects, thus a diagnostic biopsy is still required. The association of salivary KFLC and LFLC concentrations with saliva production and ESSPRI pain score suggests a complex relationship between dryness and pain in patients with SS.

Biological Markers in Early Multiple Sclerosis: the Paved Way for Radiologically Isolated Syndrome.

Radiologically Isolated Syndrome (RIS) is characterized by MRI-typical brain lesions fulfilling the 2009 Okuda criteria, detected in patients without clinical conditions suggestive of MS. Half of all RIS patients convert to MS within 10 years. The individual course of the disease, however, is highly variable with 12% of RIS converting directly to progressive MS. Demographic and imaging markers have been associated with the risk of clinical MS in RIS: male sex, younger age, infra-tentorial, and spinal cord lesions on the index scan and gadolinium-enhancing lesions on index or follow-up scans. Although not considered as a distinct MS phenotype, RIS certainly shares common pathological features with early active and progressive MS. In this review, we specifically focus on biological markers that may help refine the risk stratification of clinical MS and disability for early treatment. Intrathecal B-cell activation with cerebrospinal fluid (CSF) oligoclonal bands, elevated kappa free light chains, and cytokine production is specific to MS, whereas neurofilament light chain (NfL) levels reflect disease activity associated with neuroaxonal injury. Specific microRNA profiles have been identified in RIS converters in both CSF and blood. CSF levels of chitinases and glial acidic fibrillary protein (GFAP) reflecting astrogliosis might help predict the evolution of RIS to progressive MS. Innovative genomic, proteomic, and metabolomic approaches have provided several new candidate biomarkers to be explored in RIS. Leveraging data from randomized controlled trials and large prospective RIS cohorts with extended follow-up to identify, as early as possible, biomarkers for predicting greater disease severity would be invaluable for counseling patients, managing treatment, and monitoring.

Kappa Free Light Chains in Cerebrospinal Fluid in Inflammatory and Non-Inflammatory Neurological Diseases.

BACKGROUND: Oligoclonal bands represent intrathecal immunoglobulin G (IgG) synthesis and play an important role in the diagnosis of multiple sclerosis (MS). Kappa free light chains (KFLC) are increasingly recognized as an additional biomarker for intrathecal Ig synthesis. However, there are limited data on KFLC in neurological diseases other than MS. METHODS: This study, conducted at two centers, retrospectively enrolled 346 non-MS patients. A total of 182 patients were diagnosed with non-inflammatory and 84 with inflammatory neurological diseases other than MS. A further 80 patients were classified as symptomatic controls. Intrathecal KFLC production was determined using different approaches: KFLC index, Reiber's diagram, Presslauer's exponential curve, and Senel's linear curve. RESULTS: Matching results of oligoclonal bands and KFLC (Reiber's diagram) were frequently observed (93%). The Reiber's diagram for KFLC detected intrathecal KFLC synthesis in an additional 7% of the patient samples investigated (4% non-inflammatory; 3% inflammatory), which was not found by oligoclonal band detection. CONCLUSIONS: The determination of both biomarkers (KFLC and oligoclonal bands) is recommended for routine diagnosis and differentiation of non-inflammatory and inflammatory neurological diseases. Due to the high sensitivity and physiological considerations, the assessment of KFLC in the Reiber's diagram should be preferred to other evaluation methods.

The contribute of cerebrospinal fluid free light-chain assay in the diagnosis of multiple sclerosis and other neurological diseases in an Italian multicenter study.

BACKGROUND: Cerebrospinal fluid (CSF) free light chains (FLCs) can be an alternative assay to oligoclonal bands (OCBs) in inflammatory neurological disorders, but threshold has no consensus. OBJECTIVE: To assess the diagnostic accuracy of CSF FLCs in multiple sclerosis (MS) and other neurological diseases. METHODS: A total of 406 patients from five Italian centers. FLCs were measured in CSF and serum using Freelite MX assays on Optilite. RESULTS: A total of 171 patients were diagnosed as MS, 154 non-inflammatory neurological diseases, 48 inflammatory central nervous system (CNS) diseases, and 33 peripheral neurological diseases. Both kFLC and λFLC indices were significantly higher in patients with MS compared to other groups (p < 0.0001). The kFLC index ⩾ 6.4 is comparable to OCB for MS diagnosis (area under the receiver operating characteristic curve (AUC) = 0.876; sensitivity 83.6% vs 84.2%; specificity 88.5% vs 90.6%). λFLC index ⩾ 5 showed an AUC of 0.616, sensitivity of 33.3% and specificity of 90.6%. In all, 12/27 (44.4%) MS patients with negative OCB had kFLC index ⩾ 6.4. Interestingly, 37.5% of 24 patients with a single CSF IgG band showed high kFLC index and 12.5% positive λFLC index. CONCLUSION: Our findings support the diagnostic utility of FLC indices in MS and other CNS inflammatory disorders, suggesting a combined use of FLC and OCB to help clinicians with complementary information.

The Influence of Renal Function Impairment on Kappa Free Light Chains in Cerebrospinal Fluid.

BACKGROUND: The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters. METHODS: In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with "physiological" (n = 139), "non-inflammatory" (n = 146), and "inflammatory" (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF). RESULTS: All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function (P-values between <.0001 and .0209). In "inflammatory" CSF profile samples, 15% of the patients presented a KFLC index <5.9 while 10% showed an intrathecal KFLC fraction below QKappa(lim), suggesting possible false negative KFLC results. CONCLUSIONS: The influence of renal function should be considered while interpreting KFLC results in patients with neuroinflammatory diseases. The interpretation of KFLC in quotient diagrams is less susceptible to renal function impairment than the KFLC index and should be preferentially used.

Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

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.

KFLC Index utility in multiple sclerosis diagnosis: Further confirmation.

The Multiple Sclerosis (MS) diagnosis is based on dissemination of focal lesions in time and space. The free light chains (FLCs) determination might be a sensitive alternative to oligoclonal bands assay. The study aim was to redefine sensitivity, specificity of the kFLC Index cut-off. We analyzed serum and cerebrospinal fluid of 176 patients, with different neurological disorders. We obtained a cut off of 12,3 for kFLC Index with a sensitivity and specificity of 93% and 100% respectively. Our data confirm that the kFLC Index is a valid tool in the diagnosis of MS.

Determination of κFLC and κ Index in cerebrospinal fluid: a valid alternative to assess intrathecal immunoglobulin synthesis.

Intrathecal immunoglobulin synthesis is observed in several disorders of the central nervous system, but its detection by current laboratory tests is relatively insensitive and operator depending. We assessed the diagnostic accuracy of a nephelometric assay for k free light chain determination in cerebrospinal fluid and serum. The patients were grouped according to clinical and laboratory criteria. ROC curves for all methods were performed to find the best cut-off value. kFLC Index seems to be more accurate than other parameters. Our data indicate that nephelometric assay for kFLCs in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate multiple sclerosis patients.