Diagnostic value of kappa free light chain index in patients with primary progressive multiple sclerosis – a multicentre study

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS

Cerebrospinal fluid immunoglobulin kappa light chain in clinically isolated syndrome and multiple sclerosis.

BACKGROUND: Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test. METHODS: KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS). RESULTS: CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS. CONCLUSIONS: Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS

Threshold line of KFLC; sd = standard deviation.

<p>Threshold line of KFLC; sd = standard deviation.</p

Demographic data and basic cerebrospinal fluid findings.

<p>Data are shown as the median and IQR. Abbreviations: B-CNS-I bacterial central nervous system infections, CIS clinically isolated syndrome, CSF cerebrospinal fluid, MS multiple sclerosis, NB neuroborreliosis, NIND non-inflammatory neurological diseases, OCB oligoclonal IgG bands, V-CNS-I viral central nervous system infections.</p

CSF-serum ratio of KFLC (Q KFLC) was elevated in patients with positive oligoclonal IgG (OCB). Q KFLC of 77 CIS patients are shown.

<p>Dashed line indicates the approximately upper reference value of Q KFLC, described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088680#pone-0088680-g002" target="_blank">figure 2</a>. Black rhomb indicate positive OCBs, white rhomb indicate negative OCBs.</p

Sensitivity, specificity, positive and negative predictive value for elevated KFLC, MRI parameters and OCB regarding conversion of clinically isolate syndrome to definite multiple sclerosis.

<p>Data are shown as percent and 95% confidence interval. Q KFLC = CSF-serum ratio of KFLC above the approximately upper reference value described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088680#pone-0088680-g002" target="_blank">figure 2</a>. OCB = cerebrospinal fluid oligoclonal bands of IgG class not detectable in serum. Intrathecal IgG- Synthesis according to Reiber quotients diagrams. IgG- Index = CSF/serum IgG:CSF/serum albumin >0.7. Barkhof = 3 of 4 Barkhof criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088680#pone.0088680-Barkhof1" target="_blank">[21]</a> fulfilled.</p

CSF-serum ratio of KFLC (Q KFLC) among different oligoclonal IgG band patterns.

<p>There are five classic patterns of oligoclonal bands <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088680#pone.0088680-Andersson1" target="_blank">[48]</a> (type 1, no bands in CSF and serum; type 2, oligoclonal IgG bands in CSF but not in serum, indicative of intrathecal IgG synthesis; type 3, oligoclonal bands in CSF plus identical oligoclonal bands in serum and CSF, indicative of intrathecal IgG synthesis; type 4, identical pattern of oligoclonal bands in CSF and serum. There was no patient with type 5 (identical patterns of monoclonal bands in CSF and serum) in the study. Horizontal solid line indicates median, Kruskal-Wallis test among groups revealed a significant difference (p<0.001), significant P-values for pairwise comparisons (Mann-Whitney U test) are displayed.</p

KFLC in CSF and serum.

<p>Immunoglobulin kappa free light chain (KFLC) in CSF and serum of patients with MS, CIS, pathogen-related diseases and NIND (for abbreviations see legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088680#pone-0088680-t001" target="_blank">table 1</a>). Q KFLC: CSF- serum ratio of KFLC. Data are shown as the median and IQR.</p

Cerebrospinal fluid – serum ratio of kappa free light chain (Q KFLC) is plotted against CSF-serum ratio of albumin.

<p>Dashed lines indicate the 99% confidence interval of the linear regression line (straight line). The upper 99% confidence interval (dark dashed line) indicate the approximately upper reference value of Q KFLC based on a control group of 77 non-inflammatory neurologic diseases and a range of Q Albumin from 1.9 to 28.2.</p