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Light-microscopic demonstration of plasma proteins in the perivascular neuropil and astrocytes

Light-microscopic demonstration of potassium loss in astrocytes and neurons

Fig. 4.3a-d. Vasogenic and cytotoxic edema. Experimentally induced ischemia of the right hemisphere in gerbils results in a disruption of the blood-brain barrier (vasogenic edema: a, b) and a potassium loss (cytotoxic edema - see. Oehmichen et al. 2000: c); d human brain expresses extravasated albumin (brown

Fig. 4.3a-d. Vasogenic and cytotoxic edema. Experimentally induced ischemia of the right hemisphere in gerbils results in a disruption of the blood-brain barrier (vasogenic edema: a, b) and a potassium loss (cytotoxic edema - see. Oehmichen et al. 2000: c); d human brain expresses extravasated albumin (brown color) exclusively during the very early postmortem interval (see Oehmichen and Gencic 1980a) (a, b Evans blue fluorescence; magnification b X100; c histochemical demonstration of potassium; d albumin reactivity, magnification X300)

Fig. 4.4a, b. Vasogenic perifocal edema in a case of a traffic accident associated with liver failure and elevated bilirubin level. a Massive intracerebral hemorrhages and green-colored edema; b focal hemorrhage; perifocal as well as contralateral green-colored edema

copy (Fig. 4.3b). The demonstration of albumin in human brain using immunohistochemistry will only succeed during the very early postmortem interval (Fig. 4.3d) - before a general diffusion of blood serum occurs within the brain parenchyma - as a morphological marker of the diffuse postmortem BBB disturbance. Under experimental conditions an accumulation of plasma proteins in Purkinje cells (Oehmichen and Gencic 1980a, Ikegaya et al. 2004) takes place.

Anatomically the BBB consists of a capillary en-dothelium containing intercellular tight junctions and specialized enzymes, such as transpeptidases, dehydrogenases, decarboxylases, and monoamine oxidases (Reese and Karnowsky 1967; Brightman and Reese 1969; Lee 1982). The intercellular junctions are most conspicuous near the luminal surface where the cell membranes fuse. A basement membrane in contact with astrocytic foot processes surrounds the endothelial cells. Pericytes are enclosed by an envelope of the perivascular basement membrane, which splits to enclose the pericyte. Brain capillaries are almost totally invested by astrocytic processes. As-trocytes exert inductive actions during development and are thereby largely responsible for the special attributes exhibited by endothelial cells, such as the presence of tight junctions between the cells (Abbott et al. 1992). Astrocytes and microglia both contribute to the formation of the BBB (Prat et al. 2001).

There is an inverse hemodynamic relation between ICP and cerebral blood flow (CBF): the higher the ICP, the lower the CBF. If cerebral circulation and circulatory autoregulation are normal, a drop in ICP will induce only a slight increase in CBF until a threshold level of about 8 kPa is attained. CBF is regulated by mechanisms such as compensatory dilatation of small arteries and arterioles.

Patients suffering from acute MBI, intracranial hemorrhage, or hypoxic brain injury need a mean arterial blood pressure above 8 kPa to maintain perfusion. The brain damage in such circumstances is associated with a rise in cerebrovascular resistance due to the vessels' spastic reactivity. Baseline ICP levels may even need to be higher in order to drive sufficient blood through the brain tissue (Chan et al. 1992). Should CBF drop below 10 (ml/min)/100 g, potassium levels in the intercellular spaces rise, while intracellular sodium and calcium increase. Cellular edema causes the cells to swell and a calcium influx triggers a series of autodestructive processes.

The BBB can be compromised by the following three mechanisms (see Miller and Ironside 1997):

1. Enhanced vesicular transport and creation of transendothelial channels by perturbation of endothelial plasmalemma, increased pinocytic activity, the activity of free oxygen radicals, or an increase in superoxides. Subarachnoid application of hemoglobin and hemoglobin degradation are known to cause brain edema (Huang et al. 2002).

2. Disconnection of the interendothelial tight junctions, e.g., by substances of very high osmolarity.

3. Structural or biochemical modification of the endothelial membrane that intensifies its permeability.

It has also been known for a long time that the ability of certain substances to pass through the BBB depends on their specific properties:

— Their nature regarding the capacity of the BBB for active transport (Broman and Steinwall 1967)

— Their affinity for carrier molecules (Lajtha 1968).

— Their molecular radius (Thompson 1970).

— Their lipid solubility (Oldendorf 1977).

As shown in detail later, the permeability of the BBB also depends on age. A good example of this is bilirubin encephalopathy, which is caused by bilirubin crossing the BBB of certain nuclei during the perinatal period - a feat it is incapable of in later life -and inflicting damage on nerve cells and, to a lesser degree, on astrocytes (for further information see pp. 452 ff). Thus for bilirubin at least the BBB appears to be less efficient at birth than in children or adults (Haymaker et al. 1961). In MBI with intracerebral hemorrhages and associated elevation of the bilirubin level the perifocal edema can be marked by a green color demonstrating extravascular bilirubin as demonstrated in Fig. 4.4. In senile and mentally disturbed patients, the BBB has been found to have a lower rate of transport, a reduced uptake of glucose and other nutrients, plus a diminished outflow of metabolic wastes (Quadbeck 1967, 1968).

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