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Blood / CSF barrier function (oligoclonal bands)

The cerebrospinal fluid produced in the cerebral ventricle is to be understood as the primary filtrate of the choroid plexus (approx. 20 ml liquor per hour). On the way to the lumbar sac, the liquor is varied in its protein composition. Basically, the blood / liquor barrier is permeable to all proteins, the concentration gradient depends on the size of the molecule and also the flow of liquor. The assessment of the blood / liquor barrier requires the achievement of a steady-state equilibrium between the two fluids; for albumin it takes about 4 days, for IgG about 6 days. The concept of the blood / cerebrospinal fluid barrier function allows a statement to be made as to whether a certain protein entered the cerebrospinal fluid by diffusion alone or whether it was produced there by the immigration of corresponding synthesizing cells (intra-thecal synthesis).

Evaluation of the blood / liquor barrier function

The ratio of the albumin concentration in liquor to serum (referred to as the albumin-liquor / serum quotient) has proven to be an effective assessment measure, since albumin is only produced in the liver and can therefore only occur in the liquor via this barrier. There is a clear age dependency due to an increased permeability of the blood / CSF barrier in early life and a reduced CSF turnover in older age. The adjacent table summarizes the established limit values ​​for the individual age groups. Due to the variation coefficients in the analysis, a disturbance of the blood / liquor barrier function should only be assumed if this limit value is exceeded by more than 10%.

Albumin quotient
QAlbumin = n x 10-3
 
4th month of life up to 6 years

The level of the albumin quotient allows conclusions to be drawn about the causal disease (see the following table):

Albumin quotient
QAlbumin = n x 10-3
 
Possible illness 
up to 10 ≈
Barrier disruption is "easy"
-Multiple sclerosis
-Chronic HIV encephalitis
-Varicella zoster ganglionitis
-Alcoholic polyneuropathy
-Amyotrophic Lateral Sclerosis
up to 20 ≈
Barrier disorder is "moderate"
-Viral meningitis
-Opportunistic
-Meningoencephalitis
- Diabetic neuropathy
-Stroke
-Cortical atrophy of the cerebral cortex
10 to 50 ≈
Barrier disorder is "severe"
-Guillain-Barré polyneuritis
-Meningopolyneuritis
-Bannwarth (Borrelia)
- HSV encephalitis
> 20 ≈
Barrier disorder is "severe"
-Tuberculous meningitis
- Purulent meningitis
- "Stop Liquor" in the case of intervertebral disc prolapse or tumor

The information applies to the first diagnostic puncture; as the disease progresses, the albumin quotient can change accordingly. Particularly in the case of purulent meningitis, a very sharp increase in the albumin quotient can be measured within a few hours.

Basically different causes for the disturbance of the blood / liquor barrier function come into question: Increasing the permeability of the vessels in the boundary layer or a reduction in the liquor turnover due to the obstruction of the liquor flow in the case of meningeal adhesions, tumors or herniated discs as well as an overall enlarged one CSF space (brain atrophy).

Evidence of intrathecal immunoglobulin synthesis

The dysfunction of the blood / liquor barrier also leads to an increase in the concentration of immunoglobulins in the liquor; In the context of inflammatory processes, intrathecal immunoglobulin synthesis can also occur after the immigration of B cells from around the 2nd week of the disease. The differentiation between diffusion into the liquor space and intrathecal synthesis is possible with the Göttingen diagram ("Reiber scheme", see graphic). The presentation is based on the examination of several thousand CSF / serum pairs. After determining the immunoglobulin concentration in the CSF and serum, the CSF / serum quotient is calculated and then plotted in a diagram on the y-axis against the associated albumin quotient (x-axis). The borderline marks a mathematical function (specific for IgA, IgG and IgM) that differentiates a diffusion of Ig (below the line) from an intrathecal production (above the line).




Fig .: "Reiber-Scheme" for IgG (according to Ref. 1)

Fig .: "Reiber scheme" for IgG (based on lit. 1)
Empirically determined function: describes the boundary line between diffusion and intra-thecal synthesis of IgG

Intrathecal IgG synthesis with an intact blood / liquor barrier
slight disturbance of the blood / liquor barrier
Intrathecal IgG synthesis for mild blood / CSF barrier dysfunction
Disturbance of the blood / liquor barrier (severe)

The proportion of the respective Ig (intrathecal fraction) can be read from the 20% to 80% lines. A comparison between IgA, IgG and IgM is possible (weighting and determination of the dominance of a certain Ig). A 1-class, 2-class or 3-class reaction with IgG or IgA or IgM dominance is then spoken of. The following table shows an assignment of typical constellations of findings to individual diseases:

Overview of constellations of findings and associated diseases

(if the blood / liquor barrier function disorder is present at the same time)

strong dominance of IgG
(IgA> 20%, IgM> 50%)
-Multiple sclerosis
- HSV encephalitis
Chronic HIV encephalitis
1 class response
→ Immunoglobulin G
→ Immunoglobulin A
-HIV encephalitis, SSPE
-Meningitis tuberculosa
2-class response
→ IgG> IgM
→ IgG = IgM
→ IgG + IgA
→ IgG + IgM
-Multiple sclerosis
-Viral meningitis
-Purulent meningitis, neuro-tbc
-FSME, Progressive Paralysis
3-class response
→ IgG dominance
→ IgM dominance
→ IgA dominance
→ IgG + IgA + IgM
-Neurosyphilis
-Neuroborreliosis
-Adrenoleukodystrophy
-Mumps meningoencephalitis, opportunistic infections

It should be emphasized that there is NO possibility of differentiating between acute and past infections in the CSF based on the immunoglobulin classes. The antibody class switch from IgM or IgA to IgG, which is typically detected in the serum, is not observed in the CSF. Antibody production may also fail to occur if an infection is treated very early on.

The intrathecal synthesis of IgM or IgA WITHOUT further indications of the presence of an inflammation (increased QAlb) should always suggest the presence of an intracerebral myeloma. If a dominant intrathecal IgA synthesis is found during the first diagnostic puncture as part of an inflammation diagnosis, this can be interpreted as a typical indication of bacterial origin.

Detection of oligoclonal bands (IgG-specific):

In the case of chronic inflammation, IgG antibodies against numerous antigens are formed in the serum. The pattern of this polyclonal IgG synthesis is also found in the CSF; However, some IgG antibodies are also detected here in particularly high concentrations, which are visible as oligoclonal bands when comparing serum and liquor in the IgG range. The sensitivity of this method is better than the detection by determining IgG in the CSF / serum pair and displaying it in the quotient diagram. The following figure shows some examples from the daily routine:

Determination of oligoclonal IgG in the CSF / serum pair:



CSF / serum pair 1
negative result
CSF / serum pair 2
positive result with oligoclonal IgG