Laboratory Diagnosis in Neurology, 1 Ed.

21 Reference Ranges of Analytes in CSF and Serum

H. Reiber

Electrolytes and Substrates

The concentrations of electrolytes and substrates in CSF are similar to those in serum (Table 21.1), except for Mg2+, of which the concentration in CSF is characteristically higher than that expected of a plasma dialysate (Davson et al., 1996). The osmolalities in human CSF and plasma are reported by several authors to be equal, but the absolute values vary (Davson et al., 1996; Thomas 2008).

Proteins

Serum Proteins in CSF and Serum

The CSF reference values in Table 21.2 are provided for orientation in the laboratory analysis, not as a basis for the clinical evaluation of CSF results. Concentrations of plasma or serum proteins in CSF are better represented as barrier-related quotients than as absolute values. The relationship between QAlb and total protein in CSF is shown in Table 21.3.

Age-Dependent Reference Ranges of QAlb

For reasons of physiology presented in Chap. 5, “CSF/Serum Albumin Q uotient” and Fig. 1.2, the albumin concentration in CSF is age-dependent. The ranges and upper limit values are provided in Table 21.4 and in the function given below.

Reference range for QAlb: calculation of the upper limit. The following equation is valid for age > 5 years (Trendelenburg, 1994):

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From this can be calculated for various age groups:

• Up to 15 years of age: QAlb (ref) = 5 × 10−3.

• Up to 40 years of age: QAlb (ref) = 6.5 × 10−3.

• Up to 60 years of age: QAlb (ref) = 8 × 10−3.

Blood–CSF barrier dysfunction. Due to strong individual variations, like body size of the patient, or due to preanalytical influences, like volume of extraction, a blood–CSF barrier dysfunction QAlb > QAlb(ref) should be diagnosed with higher significance (+10% or +20% level) if

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as proposed for statistics with an example in Table 5.8.

Albumin quotient in ventricular and cisternal CSF. Corresponding to the rostrocaudal concentration gradient, the CSF concentration of serum proteins increases from the ventricles (V) to the cisterns (C) and lumbar spaces (L); accordingly, the age-related reference ranges for QAlb change as well. The reference ranges for ventricular and cisternal CSF are thus calculated as follows from those valid for lumbar CSF:

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Reference Ranges for Immunoglobulins in CSF

The reference ranges of blood-derived immunoglobulin fractions in CSF are used for analytical orientation but not for diagnostic purposes (Table 21.5).

Brain Proteins

Table 21.6 shows the mean concentrations of primarily brain-derived proteins, arranged according to their concentrations in CSF (Thompson, 2005; Zettl et al., 2005).

Amino Acids, Lipids, and Vitamins

Table 21.7 shows the mean concentrations of free amino acids in CSF and serum and Table 21.8 that of the lipids in CSF. The concentrations of vitamin C and vitamin E in CSF and serum (Table 21.9) are important for the understanding of the reduction-oxidation balance in the brain cells (see also Chap. 6, “Special Serum Analysis”). Vitamin C (ascorbic acid) is actively transported from blood to brain, ten-fold increased in intercellular fluid and CSF, with subsequent active uptake into brain cells. Due to CSF outflow into venous blood, the serum concentration of vitamin C depends on QAlb (Reiber et al., 1993).

Vitamin E is a mixture of 75–87% α-tocopherol, about 10% γ-tocopherol, and others. About 70% of α- and γ-tocopherol are associated with HDL-LDL in the serum. α-Tocopherol and γ-tocopherol pass the blood–CSF barrier in association with a protein larger than 100 kDa. As a consequence, the CSF/serum tocopherol quotient correlates strongly with QAlbQα-T = 0.83 × QAlbQγ-T = 0.76 × QAlb (Uhr, 1995).

Cells

Cell Counts in CSF

CSF cell counts (see also Chap. 5, “Cytology”) up to 4 cells/μL are normal. Counts above 20 cells/μL are interpreted as showing definite inflammation. The differential cell count is normal when 70–100% lymphocytes and up to 30% monocytes are present. Occasionally, the following cells are also found in normal CSF without having pathognomonic significance:

• Ependymal cells, choroid plexus cells, or cartilage cells.

• Very rarely also a mitotic monocyte.

The following cell types in CSF should always be characterized as abnormal cytological findings:

• Granulocytes.

• Plasma cells.

• Macrophages.

• Erythrocytes (unless artificially introduced by puncture).

• Cells in mitosis, such as tumor cells.

In bacterial meningitis, microorganisms are often directly visible in the CSF (Kölmel, 2005).

Correction of Cell Count and Protein Concentration when Artificial Blood Contamination Has Occurred

Artificial blood contamination of CSF may falsify the CSF data significantly. To some extent, it is possible to correct the data. As shown in Table 21.10, the error of the IgG value in CSF is below 20%, even with a contamination of 2000 erythrocytes/μL. Considering the large range of biological variation, minor artificial contamination with blood (< 1000 erythrocytes/μL) is negligible in respect of protein values.

CSF in which artificial blood contamination exceeds 7000 erythrocytes/μL should not be used for interpretation in the quotient diagram—mathematical correction is no longer reliable.

The reference to the erythrocyte count does not take into account the individual hematocrit, because the underlying cell numbers counted in CSF are generally too low.

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Correction of leukocyte counts. For every 1000 erythrocytes/μL, 1 leukocyte/μL should be subtracted from the leukocyte count (see Chap. 12).

Correction of CSF protein values. The empirical protein concentration in CSF (y) is mathematically corrected (y) on the basis of the erythrocyte count (z) in CSF according the following equation (Reiber et al., 2001):

y′ = y – x × z/v

where

x = Protein concentration in serum in mg/L (e. g., total protein, albumin, or IgG)

y = Measured protein concentration in CSF in mg/L, matching x

v = Erythrocyte count in blood

z = Erythrocyte count in CSF

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Table 21.5 Relationship between albumin quotient and reference ranges for immunoglobulins in CSF

 

CSF/serum quotient, Q × 103

 

Mean (QMean)

Range (QLow−QLim)

Albumin

4.5*

IgG

2.05

1.26–3.06

IgA

1.13

0.35–2.02

IgM

0.26

0.03–0.83

* Set value as an example of the mean (QMean) and the QLow–QLim range calculated according to Table 5.3.

† QMean ± 3SD.

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Table 21.8 Lipids in CSF (Tourtelotte and Haerer, 1969; Seidel, 1986; Fishman, 1992)

Lipids

Concentration, mg/L

Total cholesterol

5.4

Free cholesterol

1.9

Cholesteryl ester

3.5

Lecithin

2.0

Sphingomyelin

1.0

Cephaline

1.3

Cerebrosides

0.4

Total lipids

19

Table 21.9 Concentrations of vitamin C and vitamin E in CSF and serum (Reiber et al., 1994; Uhr, 1995)

 

CSF, μmol/L

Serum, μmol/L

Vitamin C

160 ± 34

42 ± 18*

α-Tocopherol

(0.53 × CSer)

42 ± 15

γ-Tocopherol

(0.67 × CSer)

3.1 ± 1.8

* The serum concentration of vitamin C (CSer) depends on QAlb (Reiber et al., 1993).

† Vitamin E is a mixture of 75–87% α-tocopherol, about 10% γ-tocopherol, and others.

‡ The tocopherol CSF/serum quotient correlates strongly with the albumin quotient: Qα-T = 0.83 × QAlbQγ-T = 0.76 × QAlb (Uhr, 1995).

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If no serum values are available, an approximation can be arrived at by using the following mean values from a healthy cohort: v= 4.5 × 106/μL; total protein = 69 200 mg/L; albumin = 40 600 mg/L; IgG = 11400 mg/L. The corresponding correction values for the protein concentrations and the error percentages are shown in Table 21.10.

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