Adult CSF total protein upper reference limits should be age-partitioned and significantly higher than 0.45 g/L: a systematic review

  • Ari BreinerEmail author
  • David Moher
  • John Brooks
  • Wei Cheng
  • Harald Hegen
  • Florian Deisenhammer
  • Christopher R. McCudden
  • Pierre R. Bourque
Original Communication



Cerebrospinal fluid total protein (CSF-TP) is measured in the diagnosis of a range of immune or infectious disorders of the nervous system. Most laboratories and the medical literature use an antiquated, age-independent upper limit of 0.45 g/L. Therefore, we performed a systematic review of reference studies in the medical literature, with the primary objective of determining the CSF total protein upper reference limit (URL). Secondary objectives were to assess the effects of age, gender, laboratory methods, and methodological quality.


A pre-planned and peer-reviewed electronic search strategy was used to search Ovid Medline and EMBASE for 1960–2017. All records underwent title/abstract review, and potentially relevant records underwent independent full-text review by two researchers. The remaining studies underwent quality assessment using a modification of the QUADAS2 revised tool. CSF-TP upper reference limits extracted from these studies were used to compute weighted means.


Twenty-two articles were retained for qualitative analysis and 20 for quantitative analysis. The weighted average of CSF-TP URL was 0.55 g/L, in studies with high methodological quality. Studies that examined the effect of age reported consistent correlations with advancing age, and CSF-TP URL values incrementally exceeded 0.60 g/L after age 50. There were no meaningful differences according to gender, laboratory method, or quality assessment score.


There is concordance in available literature to recommend increasing CSF total protein upper reference limits, and to consider implementing age-adjusted values above 0.60 g/L starting at age 50. This information merits worldwide dissemination, to reduce the risk of over-diagnosis.


Cerebrospinal fluid CSF CSF total protein Upper reference limits Systematic review 


Author contributions

AB, PB: conception of the work, data acquisition, data interpretation, drafting of manuscript. DM, WC: data analysis, revision of manuscript for critically important intellectual content. JB, HH, FD, CM: contributions to study design, data interpretation, and revisions for critically important intellectual content.

Compliance with ethical standards

Conflicts of interest

No relevant conflicts or competing interests.

Supplementary material

415_2018_9174_MOESM1_ESM.doc (57 kb)
Supplementary material 1 (DOC 57 KB)
415_2018_9174_MOESM2_ESM.docx (18 kb)
Supplementary material 2 (DOCX 17 KB)
415_2018_9174_MOESM3_ESM.doc (64 kb)
Supplementary material 3 (DOC 63 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Neurology, Department of MedicineThe Ottawa Hospital and University of OttawaOttawaCanada
  2. 2.Ottawa Hospital Research InstituteOttawaCanada
  3. 3.Ottawa Methods CentreOttawa Hospital Research InstituteOttawaCanada
  4. 4.Neuroimmunology Laboratory, Department of NeurologyMedical University of InnsbruckInnsbruckAustria
  5. 5.Department of Pathology and Laboratory MedicineThe Ottawa Hospital and University of OttawaOttawaCanada

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