Abstract
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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Andersson M, Alvarez-Cermeño J, Bernardi G, Cogato I, Fredman P, Frederiksen J, Fredrikson S, Gallo P, Grimaldi LM, Grønning M, et al. (1994) Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 57:897–902
Bracco F, Gallo P, Menna R, Battistin L, Tavolato B (1987) Free light chains in the CSF in multiple sclerosis. J Neurol 234:303–307
Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ, Drayson MT, Drew R (2001) Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 47:673–680
Caudie C, Birouk AM, Bancel J, Claudy D, Gignoux L, Vukusic S, Confavreux C (2005) Cytoimmunological profile of cerebrospinal fluid in diagnosis of multiple sclerosis. Pathol Biol 53:68–74
Davies G, Keir G, Thompson EJ, Giovannoni G (2003) The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study. Neurology 60:1163–1166
DeCarli C, Menegus MA, Rudick RA (1987) Free light chains in multiple sclerosis and infections of the CNS. Neurology 37:1334–1338
Desplat-Jego S, Feuillet L, Pelletier J, Bernard D, Cherif AA, Boucraut J (2005) Quantification of immunoglobulin free light chains in cerebrospinal fluid by nephelometry. J Clin Immunol 25:338–345
Fagnart OC, Sindic CJ, Laterre C (1988) Free kappa and lambda light chain levels in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J Neuroimmunol 19:119–32
Falip M, Tintore M, Jardi R, Duran I, Link H, Montalban X (2001) Clinical usefulness of oligoclonal bands. Rev Neurol 32:1120–1124
Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G (2004) Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 364:1489–1496
Fischer C, Ameth B, Koehler J, Lotz J, Lackner KJ (2004) Kappa free light chains in cerebrospinal fluid as markers of intrathecal immunoglobulin synthesis. Clin Chem 50:1809–1813
Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ, Sellebjerg F, Tourtellotte WW (2005) Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 62:865–870
Goffette S, Schluep M, Henry H, Duprez T, Sindic CJ (2004) Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis. J Neurol Neurosurg Psychiatry 75:308–310
Grimaldi LM, Castagna A, Maimone D, Martino GV, Dolci A, Pristera R, Lazzarin A, Roos RP (1991) Kappa light chain predominance in serum and cerebrospinal fluid from human immunodeficiency virus type 1 (HIV-1)-infected patients. J Neuroimmunol 32:259–268
Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta- 1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898–904
Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, Kyle RA (2002) Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 48:1437–1444
Kinkel RP, Kollman C, O‘Conner P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman M, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M, CHAMPIONS Study Group (2006) IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 66:678–684
Kostulas VK, Link H, Lefvert AK (1987) Oligoclonal IgG bands in cerebrospinal fluid. Principles for demonstration and interpretation based on findings in 1114 neurological patients. Arch Neurol 44:1041–1044
Krakauer M, Schaldemose Nielsen H, Jensen J, Sellebjerg F (1998) Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis. Acta Neurol Scand 98:161–165
Lefvert AK, Link H (1985) IgG production within the central nervous system: a critical review of proposed formulae. Ann Neurol 17:13–20
Link H, Huang YM (2006) Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol 180:17–28
Masjuan J, Alvarez-Cermeño JC, García-Barragán N, Díaz-Sánchez M, Espiño M, Sádaba MC, González- Porqué P, Martínez San Millán J, Villar LM (2006) Clinically isolated syndromes: a new oligoclonal band test accurately predicts conversion to MS. Neurology 66:576–578
Mata S, Galli E, Amantini A, Pinto F, Sorbi S, Lolli F (2006) Anti-ganglioside antibodies and elevated CSF IgG levels in Guillain-Barré syndrome. Eur J Neurol 13:153–160
McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127
McLean BN, Luxton RW, Thompson EJ (1990) A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications. Brain 113:1269–1289
Nielsen JM, Korteweg T, Barkhof F, Uitdehaag BM, Polman CH (2005) Overdiagnosis of multiple sclerosis and magnetic resonance imaging criteria. Ann Neurol 58:781–783
Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846
Rinker JR 2nd, Trinkaus K, Cross AH (2006) Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology 67:1288–1290
Rudick RA, Cookfair DL, Simonian NA, Ransohoff RM, Richert JR, Jacobs LD, Herndon RM, Salazar AM, Fischer JS, Granger CV, Goodkin DE, Simon JH, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munchsauer FE, O’Reilly K, Priore RL, Whitham RH, et al. (1999) Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. J Neuroimmunol 93:8–14
Rudick RA, French CA, Breton D, Williams GW (1989) Relative diagnostic value of cerebrospinal fluid kappa chains in MS: comparison with other immunoglobulin tests. Neurology 39:964–968
Rudick RA, Medendorp SV, Namey M, Boyle S, Fischer J (1995) Multiple sclerosis progression in a natural history study: predictive value of cerebrospinal fluid free kappa light chains. Mult Scler 1:150–155
Rudick RA, Pallant A, Bidlack JM, Herndon RM (1986) Free kappa light chains in multiple sclerosis spinal fluid. Ann Neurol 20:63–69
Rudick RA, Peter DR, Bidlack JM, Knutson DW (1985) Multiple sclerosis: free light chains in cerebrospinal fluid. Neurology 35:1443–1449
Van der Heijden M, Kraneveld A, Redegeld F (2006) Free immunoglobulin light chains as target in the treatment of chronic inflammatory diseases. Eur J Pharmacol 533:319–326
Villar LM, Masjuan J, Sádaba MC, González-Porqué P, Plaza J, Bootello A, Alvarez-Cermeño JC (2005) Early differential diagnosis of multiple sclerosis using a new oligoclonal band test. Arch Neurol 62:574–577
Zeman AZ, Kidd D, McLean BN, Kelly MA, Francis DA, Miller DH, Kendall BE, Rudge P, Thompson EJ, McDonald WI (1996) A study of oligoclonal band negative multiple sclerosis. J Neurol Neurosurg Psychiatry 60:27–30
Author information
Authors and Affiliations
Corresponding author
Additional information
The study was performed in accordance with the ethical standards.
An erratum to this article can be found at http://dx.doi.org/10.1007/s00415-009-5354-5
Rights and permissions
About this article
Cite this article
Presslauer, S., Milosavljevic, D., Brücke, T. et al. Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis. J Neurol 255, 1508–1514 (2008). https://doi.org/10.1007/s00415-008-0954-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-008-0954-z