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Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity

  • Harald Hegen , Michael Auer , Achim Zeileis and Florian Deisenhammer EMAIL logo
Published/Copyright: June 16, 2015
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 54 Issue 2

Abstract

Background: Determination of cerebrospinal fluid (CSF) total protein (TP) as well as of CSF/serum albumin quotient (Qalb) is part of the routine CSF work-up. However, currently used upper reference limits (URL) are not well validated leading to over-reporting of blood-CSF barrier dysfunction in approximately 15% of patients without neurological disease. The objective of this study was to determine age-related URL for CSF TP and Qalb in a cohort of control patients.

Methods: A total of 332 paired CSF and serum samples of patients without objective clinical and paraclinical findings of a neurological disease were analyzed for CSF TP and Qalb. CSF TP was measured by spectrophotometry and albumin in CSF and serum by nephelometry.

Results: CSF TP concentration and Qalb significantly correlated with age. In subjects at the age of 18–70 years, median CSF TP ranged from 320 to 460 mg/L and URL defined as the 95th percentile were 530–690 mg/L. Median Qalb ranged from 4.1 to 6.1 and URL from 8.7 up to 11.0. For URL of Qalb we calculated the following formula: age/25+8.

Conclusions: Age-dependent URL for CSF TP and Qalb are presented here in a large cohort of control patients. They are higher than those currently recommended and this probably explains why isolated blood-CSF barrier dysfunction has been apparently over-reported. These new URL might be considered in a future revision of CSF guidelines.

Keywords: albumin quotient; cerebrospinal fluid; control patients; reference interval; total protein
Corresponding author: Florian Deisenhammer, MD, MSc, Professor of Neurology, Clinical Department of Neurology, Neuroimmunology Laboratory, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria, Phone: +43 512 504 24264, Fax: +43 512 504 24266, E-mail:
aHarald Hegen and Michael Auer contributed equally to this work.

References

1. Deisenhammer F, Bartos A, Egg R, Gilhus NE, Giovannoni G, Rauer S, et al. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 2006;13:913–22.10.1111/j.1468-1331.2006.01493.xSearch in Google Scholar

2. Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 2001;184:101–22.10.1016/S0022-510X(00)00501-3Search in Google Scholar

3. Tibbling G, Link H, Ohman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385–90.10.3109/00365517709091496Search in Google Scholar

4. Garton MJ, Keir G, Lakshmi MV, Thompson EJ. Age-related changes in cerebrospinal fluid protein concentrations. J Neurol Sci 1991;104:74–80.10.1016/0022-510X(91)90218-VSearch in Google Scholar

5. Blennow K, Fredman P, Wallin A, Gottfries CG, Karlsson I, Langstrom G, et al. Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol 1993;33:129–33.10.1159/000116919Search in Google Scholar

6. Eeg-Olofsson O, Link H, Wigertz A. Concentrations of CSF proteins as a measure of blood brain barrier function and synthesis of IgG within the CNS in ‘normal’ subjects from the age of 6 months to 30 years. Acta Paediatr Scand 1981;70:167–70.10.1111/j.1651-2227.1981.tb05536.xSearch in Google Scholar

7. Brettschneider J, Claus A, Kassubek J, Tumani H. Isolated blood-cerebrospinal fluid barrier dysfunction: prevalence and associated diseases. J Neurol 2005;252:1067–73.10.1007/s00415-005-0817-9Search in Google Scholar

8. Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L, Comabella M, et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 2009;73:1914–22.10.1212/WNL.0b013e3181c47cc2Search in Google Scholar

9. Reiber H. Flow rate of cerebrospinal fluid (CSF) – a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994;122:189–203.10.1016/0022-510X(94)90298-4Search in Google Scholar

10. Teunissen C, Menge T, Altintas A, Alvarez-Cermeno JC, Bertolotto A, Berven FS, et al. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Mult Scler 2013;19:1802–9.10.1177/1352458513488232Search in Google Scholar PubMed

11. Meulemans O. Determination of total protein in spinal fluid with sulphosalicylic acid and trichloroacetic acid. Clin Chim Acta 1960;5:757–61.10.1016/0009-8981(60)90020-6Search in Google Scholar

12. Keir G, Luxton RW, Thompson EJ. Isoelectric focusing of cerebrospinal fluid immunoglobulin G: an annotated update. Ann Clin Biochem 1990;27:436–43.10.1177/000456329002700504Search in Google Scholar PubMed

13. R-Core-Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, 2014.Search in Google Scholar

14. Koenker R. Quantile regression. Cambridge: Cambridge University Press, 2005.10.1017/CBO9780511754098Search in Google Scholar

15. Ahonen A, Myllyla VV, Hokkanen E. Cerebrospinal fluid protein findings in various lower back pain syndromes. Acta Neurol Scand 1979;60:93–9.10.1111/j.1600-0404.1979.tb02956.xSearch in Google Scholar PubMed

16. Brackenridge CJ. Cerebrospinal fluid protein fractions in health and disease. J Clin Pathol 1962;15:206–10.10.1136/jcp.15.3.206Search in Google Scholar PubMed PubMed Central

17. Breebaart K, Becker H, Jongebloed FA. Investigation of reference values of components of cerebrospinal fluid. J Clin Chem Clin Biochem 1978;16:561–5.10.1515/cclm.1978.16.10.561Search in Google Scholar PubMed

18. Dufour-Rainfray D, Beaufils E, Vourc’h P, Vierron E, Mereghetti L, Gendrot C, et al. Total protein level in cerebrospinal fluid is stable in elderly adults. J Am Geriatr Soc 2013;61:1819–21.10.1111/jgs.12489Search in Google Scholar PubMed

19. Ganrot K, Laurell CB. Measurement of IgG and albumin content of cerebrospinal fluid, and its interpretation. Clin Chem 1974;20:571–3.10.1093/clinchem/20.5.571Search in Google Scholar

20. Gilland O. Lumbar cerebrospinal fluid total protein in healthy subjects. Acta Neurol Scand 1967;43:526–9.10.1111/j.1600-0404.1967.tb05758.xSearch in Google Scholar PubMed

21. Jung P, Rieder H, Jeltsch C. Normalwerte des Totalproteins im Lumballiquor; Alters-, Geschlechts- und Umweltabhängigkeit. Klin Wochenschr 1973;51:810–6.10.1007/BF01468076Search in Google Scholar PubMed

22. Keir G, Thompson EJ. Proteins as parameters in the discrimination between different blood-CSF barriers. J Neurol Sci 1986;75:245–53.10.1016/0022-510X(86)90072-9Search in Google Scholar

23. Lott JA, Warren P. Estimation of reference intervals for total protein in cerebrospinal fluid. Clin Chem 1989;35:1766–70.10.1093/clinchem/35.8.1766Search in Google Scholar

24. Lush B, Crowley MF, Fletcher E, Buchan JF. Total and differential protein levels in the blood and cerebrospinal fluid in rheumatoid arthritis. Ann Rheum Dis 1951;10:153–62.10.1136/ard.10.2.153Search in Google Scholar PubMed PubMed Central

25. Mertin J, Wisser H, Doerr P. Studies on the normal concentration range of total protein and the total protein fractions of the cerebrospinal fluid by electrophoresis on cellulose acetate. J Clin Chem Clin Biochem 1971;9:337–40.Search in Google Scholar

26. Rieder HP, Wuthrich R. The Cu-Folin method for determination of the total protein content in the cerebrospinal fluid. Klin Wochenschr 1962;40:1070–5.Search in Google Scholar

27. May C, Kaye JA, Atack JR, Schapiro MB, Friedland RP, Rapoport SI. Cerebrospinal fluid production is reduced in healthy aging. Neurology 1990;40:500–3.10.1212/WNL.40.3_Part_1.500Search in Google Scholar

28. Blennow K, Fredman P, Wallin A, Gottfries CG, Langstrom G, Svennerholm L. Protein analyses in cerebrospinal fluid. I. Influence of concentration gradients for proteins on cerebrospinal fluid/serum albumin ratio. Eur Neurol 1993;33:126–8.10.1159/000116918Search in Google Scholar PubMed

Supplemental Material:

The online version of this article (DOI: 10.1515/cclm-2015-0253) offers supplementary material, available to authorized users.

Received: 2015-3-12
Accepted: 2015-5-18
Published Online: 2015-6-16
Published in Print: 2016-2-1

©2016 by De Gruyter

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https://doi.org/10.1515/cclm-2015-0253
Keywords for this article
albumin quotient; cerebrospinal fluid; control patients; reference interval; total protein

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  2. Editorial
  3. Total error vs. measurement uncertainty: the match continues
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  6. Mini Review
  7. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity
  8. Opinion Papers
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  11. Total error vs. measurement uncertainty: revolution or evolution?
  12. Genetics and Molecular Diagnostics
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