An Updated Evaluation of Intrathecal IgG Synthesis Markers in Relation to Oligoclonal Bands

The aim was to evaluate the performance of the latest quantitative marker for intrathecal IgG synthesis and to compare it with other established markers used for the same purpose. We retrospectively applied Auer’s and Reiber’s intrathecal IgG synthesis formulae in a cohort of 372 patients under investigation for central nervous system demyelination who had undergone lumbar puncture and oligoclonal bands (OCBs) detection for demonstrating intrathecal IgG synthesis. A ROC analysis revealed Auer’s formula had lower sensitivity (68%) compared to Reiber’s formula (83%) and IgG index (89%), in our cohort of patients that exhibited normal to mildly elevated albumin quotients (4.48 ± 3.93). By excluding possible sources of errors, we assume that Auer’s formula is less sensitive than other established tools for the “prediction” of the detection of OCBs in routine cerebrospinal fluid (CSF) analyses due to the mathematical model used. Given the ability of Reiber’s hyperbolic formula to describe the blood–CSF IgG distribution across a wide range of blood–brain barrier functionality, its use and the use of similar formulae are recommended for the discrimination between CNS-derived and blood-derived molecules in clinical laboratories.

[1]  A. Petersmann,et al.  A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis , 2022, Biomolecules.

[2]  T. Berger,et al.  Cerebrospinal Fluid Findings in 541 Patients With Clinically Isolated Syndrome and Multiple Sclerosis: A Monocentric Study , 2021, Frontiers in Immunology.

[3]  D. Chicco,et al.  The Matthews Correlation Coefficient (MCC) is More Informative Than Cohen’s Kappa and Brier Score in Binary Classification Assessment , 2021, IEEE Access.

[4]  H. Reiber Non-linear ventriculo - lumbar protein gradients validate the diffusion-flow model for the blood-CSF barrier. , 2020, Clinica chimica acta; international journal of clinical chemistry.

[5]  H. Reiber,et al.  Diagnostic relevance of free light chains in cerebrospinal fluid - The hyperbolic reference range for reliable data interpretation in quotient diagrams. , 2019, Clinica chimica acta; international journal of clinical chemistry.

[6]  X. Montalban,et al.  Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study , 2019, Multiple sclerosis.

[7]  A. Ludolph,et al.  CSF Free Light Chains as a Marker of Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis: A Blood-CSF Barrier Related Evaluation in a Large Cohort , 2019, Front. Immunol..

[8]  David H. Miller,et al.  Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria , 2017, The Lancet Neurology.

[9]  C. Enzinger,et al.  Prognostic value of free light chains lambda and kappa in early multiple sclerosis , 2017, Multiple sclerosis.

[10]  M. Zaffaroni,et al.  Cerebrospinal fluid analysis and the determination of oligoclonal bands , 2017, Neurological Sciences.

[11]  A. Zeileis,et al.  Quantitation of intrathecal immunoglobulin synthesis – a new empirical formula , 2016, European journal of neurology.

[12]  S. Rauch,et al.  Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study , 2015, Multiple sclerosis.

[13]  H. Tumani,et al.  Cerebrospinal Fluid Immunoglobulin Kappa Light Chain in Clinically Isolated Syndrome and Multiple Sclerosis , 2014, PloS one.

[14]  S. Presslauer,et al.  Kappa Free Light Chains: Diagnostic and Prognostic Relevance in MS and CIS , 2014, PloS one.

[15]  D. Centonze,et al.  Determination of kFLC and K Index in cerebrospinal fluid: A valid alternative to assessintrathecal immunoglobulin synthesis , 2013, Journal of Neuroimmunology.

[16]  G. Csako Isoelectric focusing in agarose gel for detection of oligoclonal bands in cerebrospinal and other biological fluids. , 2012, Methods in molecular biology.

[17]  Jeffrey A. Cohen,et al.  Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria , 2011, Annals of neurology.

[18]  Jeffrey A. Cohen,et al.  Differential diagnosis of suspected multiple sclerosis: a consensus approach , 2008, Multiple sclerosis.

[19]  T. Brücke,et al.  Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis , 2008, Journal of Neurology.

[20]  A. Rovira,et al.  Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? , 2008, Neurology.

[21]  H. Link,et al.  Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness , 2006, Journal of Neuroimmunology.

[22]  N. Gilhus,et al.  Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force , 2006, European journal of neurology.

[23]  G. Giovannonid,et al.  Guidelines on routine cerebrospinal fluid analysis . Report from an EFNS task force , 2006 .

[24]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[25]  D. Bernard,et al.  Quantification of Immunoglobulin Free Light Chains in CerebroSpinal Fluid by Nephelometry , 2005, Journal of Clinical Immunology.

[26]  Gavin Giovannoni,et al.  Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. , 2005, Archives of neurology.

[27]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[28]  G. Bernardi,et al.  Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[29]  H. Reiber Flow rate of cerebrospinal fluid (CSF) — A concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases , 1994, Journal of the Neurological Sciences.

[30]  J. Ernerudh,et al.  Comparison of Seven Formulae and Isoelectrofocusing for Determination of Intrathecally Produced IgG in Neurological Diseases , 1992, Annals of clinical biochemistry.

[31]  E. Thompson,et al.  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. , 1990, Brain : a journal of neurology.

[32]  E. Thompson,et al.  Isoelectric Focusing of Cerebrospinal Fluid Immunoglobulin G: An Annotated Update , 1990, Annals of clinical biochemistry.

[33]  E. Thompson,et al.  Isoelectric focusing versus quantitative measurements in the detection of intrathecal local synthesis of IgG. , 1990, Clinica chimica acta; international journal of clinical chemistry.

[34]  P. Forsberg,et al.  An improved formula for the judgement of intrathecally produced IgG in the presence of blood brain barrier damage. , 1989, Clinica chimica acta; international journal of clinical chemistry.

[35]  E. Schuller,et al.  IgG synthesis within the central nervous system. Comparison of three formulas. , 1987, Archives of neurology.

[36]  H. Reiber,et al.  Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. , 1987, Clinica chimica acta; international journal of clinical chemistry.

[37]  J. E. Hopper,et al.  Evidence by radioimmunoassay that mitogen-activated human blood mononuclear cells secrete significant amounts of light chain Ig unassociated with heavy chain. , 1986, Cellular immunology.

[38]  H. Reiber Evaluation of IgG Synthesis in the Central Nervous System , 1980 .

[39]  S. Poser,et al.  Progress in Multiple Sclerosis Research , 1980, Springer Berlin Heidelberg.

[40]  S. Ohman,et al.  Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. , 1977, Scandinavian journal of clinical and laboratory investigation.

[41]  G. Tibbling,et al.  Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. , 1977, Scandinavian journal of clinical and laboratory investigation.

[42]  B. Delpech,et al.  [Immunochemical estimation of IgG and albumin in cerebrospinal fluid]. , 1972, Clinica chimica acta; international journal of clinical chemistry.