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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult CSF total protein: Higher upper reference limits should be considered worldwide. A web-based survey.

BACKGROUND: The cerebrospinal fluid total protein level (CSF-TP) is commonly used as a potential marker of infectious or immune disease of the CNS and PNS. Recent laboratory reference studies indicate that the antiquated single upper reference limit of 0.45 g/L commonly used by hospital laboratories and widely quoted in medical literature is a significant underestimation. METHODS: We distributed worldwide a web-based survey comprised of three questions: 1. What is the CSF-TP upper limit used at your institution? 2. What is the source of this upper limit? 3. Do you adjust your upper limit according to age? RESULTS: A total of 473 unique responses were obtained from North America (37.5%), South America (5.5%), Europe (29.4%), Africa (4%), Asia (21.6%) and Oceania (1.7%). A strong preponderance (86.8%) of institutions reported an upper limit of 0.45 g/L or less. Only 4% reported making age-partitioned adjustments. CONCLUSIONS: Worldwide, a strong majority of hospital laboratories presently use an underestimation of CSF-TP upper reference value, particularly for older adults. Recent well powered laboratory reference studies support higher values with age adjustment.

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

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.

Is standardization more important than methodology for assay of total protein in cerebrospinal fluid?

Four manual micromethods for protein determination, two turbidimetric (trichloroacetic and sulfosalicylic acid-sodium sulfate) and two colorimetric (Lowry and Coomassie Brilliant Blue--sodium dodecyl sulfate, CBB-SDS) were used to compare the standard curves for total protein (0.30 to 3 g/L) produced with three reference materials: bovine serum albumin, human serum albumin, and diluted human serum. We measured the apparent protein content of a sample of pooled human cerebrospinal fluid by all four methods and with use of all three standards. The only reference material that gave similar results with all four methods was diluted human serum; the CBB-SDS was the only method that gave identical results with all three reference materials. We then measured the protein concentration of 28 individual cerebrospinal fluid samples by the four methods, with diluted human serum as standard. Results by all methods correlated well, but only the sulfosalicylic acid and the CBB-SDS methods gave equivalent results. We conclude that the choice of standard is more important than the method used. However, the CBB-SDS method may be the preferred method because it produced identical standard curves with all three protein standards.

[Bidimensional electrophoresis in the study of cerebrospinal fluid protein (author's transl)]. / Apports de l'immuno-électrophorèse bidimensionnelle dans l'étude des protéines du liquide céphalo-rachidien

The authors report 650 bidimensional electrophoreses of the cerebrospinal fluid (CSF). All examinations were carried out after prior concentration of CSF protein. The technic used is that described by Rebeyrotte in 1970. Four types of tracing were noted: -- Two tracings were unusual by the presence of a large peak in the alpha-2 region. -- One tracing was of the hypergamma type. -- One tracing was comparable to serum by the richness of the precipitations. A change in the first migration permitted us to obtain electrophoretic separations from 100 microlitres of pure CSF. The bidimensional immunoelectrophoresis tracings are comparable to those described previously.