Knowledge-base for interpretation of cerebrospinal fluid data patterns. Essentials in neurology and psychiatry

Reiber, Hansotto

doi:10.1590/0004-282X20160066

Hansotto Reiber

CSF and Complexity Studies, Sao Paulo SP, Brasil;

University Goettingen, Former Neurochemistry Laboratory, Goettingen, Germany.

Correspondence: Hansotto Reiber; CSF and Complexity Studies; Rua Piaui, 163; 01241-001, Sao Paulo SP, Brasil. E-mail: ho@horeiber.de

Conflict of interest: There in no conflict of interest to declare.

Figures (5)
Tables (5)

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Figure 1
Idealized cross section through the subarachnoidal lumbar space with associated blood vessels. F = bulk flow of CSF with all contents (proteins, cells). The turnover rate F is about 500 ml/day, in the cisterns divided into lumbar and cortical subarachnoidal space. The local CSF flow rate, r, depends on the local cross section , A, of the CSF space. J = molecular flux (molecular diffusion) according to Fick’s 1st law of diffusion depending on the local concentration gradient dc/dx and the molecular size dependent diffusion coefficient, D. The overall concentration gradient between blood (Cser) and CSF(CCSF) is not relevant for the calculation of the molecular flux J. Under pathological conditions with changing CSF flow rate the steady state condition changes into a nonlinear function for J with dc/dxdt corresponding to Ficks 2nd law8.

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Figure 2
The idealized model of the diffusion between blood and CSF. In blood the mean concentration of a single protein is defined as C(ser) =1. In CSF the concentration is given as the CSF/serum quotient (Q), a dimensionless concentration of CSF (normalized for the serum concentration). X = the effective diffusion pathlength in the inhomogeneous tissue between blood and CSF. This must not be characterized for the relation of diffusion between two molecules (e.g., albumin and IgM) as this local diffusion path is the same for all serum proteins (e.g., albumin and IgM). The example shows the subsequent changes of the local gradient dc/dx with an increasing CSF concentration (e.g. QIgM) increasing from the initial normal QA via QB , QC etc. This time dependent dynamic is the change to Fick’s 2nd law with dc/dxdt. The local gradient increases nonlinearly up to a maximum for QAlb = 500 x 10-3 = 0.5 and subsequently decreases to reach a value dc/dx = 0 for a flow rate = 0 (e.g. in a corpse). The curve of the nonlinear concentration gradient in the tissue is part of a Gaussian distribution curve8.

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Figure 3
Biological variation of serum proteins in CSF. The reference range of Qmean ± 3 SD (includes 99% of the cases) is used for diagnostics and the reference range Qmean ± 2 SD (includes 96 % of the cases) is used for statistics (s text). The biological coefficient of variation CV = SD/Qmean x 100 [%], in this case for IgG in CSF, is constant, i.e. independent of the albumin quotient, QAlb. This indicates a diffusion controlled transfer from blood (no “leakage”). The symmetrical distribution of the values around Qmean support this statement, i.e., the CSF flow rate is the modulator for the barrier function (see Figure 4).

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Figure 4
Data distribution of patients with an albumin quotient, QAlb, between 20x10-3 and 150 x 10-3 (Part of the data set with 4300 patients)8. The upper and lower curve of the reference ranges as well as the curves for the mean (Qmean) are hyperbolic functions. The data of the three representative patients are either all (QIgG, QIgA, QIgM) at the upper or lower range or all in a middle range. That means: if one quotient is relatively higher then the other both, this indicates very sensitive an increasing intrathecal synthesis already before the quotient is above the reference range (Q > Qlim, IF > 0). The ratio ΔQ/ Qmean (corresp. to CV) is constant for all QAlb values, but molecular size dependent.

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Figure 5
QIgG , QIgA and QIgM values of an individual patient in ventricular (open circle), cisternal (filled circle) and lumbar(square) CSF. The values are in all diagrams on the Qlim curve. Ventricular, cisternal as well as lumbar CSF data can be evaluated in the same quotient diagrams. The shown values of QAlb (v) = 3,0 x 10-3, QAlb (c) = 4,8 x 10-3 and QAlb (l) = 7,5 x 10-3 are normal for an age of 75 y. The age-related reference range limits are 3,6 / 6,0 / 9,0 x 10-3 correspondingly (bold vertical bars for the lumbar CSF). This diagram was created with the software from Albaum21.

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Table 1
Serum proteins in normal serum and normal CSF. The concentration gradient CSF: serum (CSF:S) depends on the mean molecular radius, R, corresponding only roughly with molecular weight, MW. Mean concentration values given for IgG, IgA and IgM for the mean QAlb = 5 x 10-3 are calculated from Qmean in Ref8. The biological variation (CV) of CSF concentration values, analysed in a group of N= 300 control patients, are critically dependent on molecular size (diffusion). Serum concentration ranges are the 5th and 95th percentiles3.

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Table 2
Reference ranges of the albumin quotient of newborns and young children3. QAlb is decreasing with increasing CSF flow due to the maturation of the arachnoid villi in the first 4 months.

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Table 3
Frequencies of polyspecific antibodies in CSF of multiple sclerosis patients (IgG class). The frequency is different for the different Epstein Barr virus (EBV) antigens(*) or depends on different prevalence of systemic borrelia infections in different countries, here the different frequencies in Germany and Czech republic (**)21. The values depend on the use of a corrected Antibody Index22 which leads to higher frequencies in particular in MS with a usually high intrathecal total IgG22,23,24,25.

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Table 4
Differences between IgG class antibodies (AB) from an acute infection with persisting causative antigen and from a polyspecific immune response in the absence of an antigen.

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Table 5
Frequencies of diagnostic relevant concentrations of IgA and IgM in CSF. Data from 8500 consecutively received samples analysed in the Neurochemistry Laboratory, University Göttingen, in 2005–2006.

Variable	MW (kD)	R (nm)	CSF: S	Serum	CSF

			Mean	Range (g/l)	median (mg/l)	CV (%)
Alb	69	3.58	1:200	35–55	250	45
IgG	150	5.34	1:429	7–16	26	68
IgA	160	5.68	1:775	0,7–4,5	3,3	70
IgM	971	12.1	1:3300	0,4–2,6	0,44	105

Age	Birth	1. Mon	2. Mon	3. Mon	4.Mon to 4 y
Q_Alb•10³	8 to 28	5 to 15	3 to 10	2 to 5	0,5 to 3,5

Antibody specificity	Frequencies in %
Measles (M)	78
Rubella (R)	60
Varicella Zoster (Z)	55
Herpes simplex (H)	28
Chlamydia	30
HHV-6	20
EBV	10(30)*
Borrelia b.	10–26**
toxoplasmosis	10
ds-DNA	19
MRZ reaction (2–3 param.)	75
MRZ reaction (1–3 param.)	96

Variable	AB in acute infection	Polyspecific AB-Reaction
Avidity/Affinity maturation	Low	High
Fraction of total CSF IgG	10–20%	0.1–0.5 %
Cell count	High	Low (< 20/μl)
QAlb	High	Low (< 15 x 10^-3)
AB concentration	Decaying	Locally Stable
Antigen	Present/persisting	Not present
Cumulative CSF report	Disease related pattern

	IgM		IgA

Conc	Frequencies		Conc	Frequencies

mg/L	N/8467	%	mg/L	N/ 8470	%
< 0.2	2,642	31.2	< 0.3	155	1.8
0.2–0.8	3,533	41.7	0.3–2.0	2,311	27.3
0.8–5.0	1,543	18.2	2.0–8.0	4,107	48.5
5.0–20	515	6.1	8.0–20	1,111	13.1
20–100	207	2.4	20–100	649	7.7
> 100	23	0.27	> 100	137	1.6

[1] Correspondence: Hansotto Reiber; CSF and Complexity Studies; Rua Piaui, 163; 01241-001, Sao Paulo SP, Brasil. E-mail: ho@horeiber.de

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ABSTRACT