Cerebral edema and thrombosis

In addition to the development of vasogenic and cytotoxic edema as described above, interstitial edema may be caused by impaired reabsorption of cerebrospinal fluid by the arachnoid villi, a phenomenon which has been demonstrated in experimental models of meningitis. The consequences of increased secretion and diminished reabsorption of cerebrospinal fluid, and breakdown of the blood-brain barrier, are an increase in brain water content and cerebrospinal fluid volume, with the development of severe brain edema, relative hydrocephalus, and therefore increased intracranial pressure. If this increase in intracranial pressure is severe, it will lead to a reduction in cerebral blood flow. In experimental models of meningitis, cerebral blood flow first increases due to local vasodilatation, probably induced by oxygen-free radicals and local NO production from leukocytes, vascular smooth muscle, vascular endothelium, and glial cells. This suggests that cerebral blood volume is increased, at least early in the disease, and this probably contributes to raised intracranial pressure. These changes are paralleled by an increase in cerebrospinal fluid lactate levels, possibly indicating tissue hypoxia. However, the origin of the increased cerebrospinal fluid lactate is unclear. Increased lactate may contribute to the increase in cerebral blood flow, as acidosis is a vasodilator. Following this initial hyperemic stage, cerebral blood flow then decreases, presumably as a consequence of raised intracranial pressure, but again the reduction in cerebral blood flow is likely to be multifactorial. Reduction in cerebral blood flow has been correlated with levels of tumor necrosis factor-a and cerebrospinal fluid endothelin Changes in cerebral blood flow may also be a consequence of a loss of cerebrovascular autoregulation, which has been demonstrated to occur in bacterial meningitis. Cerebral blood flow is normally maintained at constant levels irrespective of systemic arterial pressure. Once autoregulation has been lost, cerebral blood flow is totally dependent on systemic pressure. Blood flow may become inadequate if systemic hypotension occurs. Thus the rise in intracranial pressure, together with systemic hypotension which is common in bacterial sepsis, may result in cerebral hypoperfusion.

All patients with bacterial meningitis are likely to have raised intracranial pressure as part of their disease process. In a recent study the mean opening pressure at the time of lumbar puncture was 180 ± 70 mmH2O.

Intracranial pressure is an important determinant of the cerebral perfusion pressure, and its level appears to be correlated with outcome of bacterial meningitis. Several studies have demonstrated that morbidity and mortality are highest in those individuals with a cerebral perfusion pressure below 30 mmHg. It is likely that the reduction of cerebral perfusion pressure is more a consequence of increased intracranial pressure than of systemic hypotension.

Vasculitis, vascular spasm, and thrombosis have been demonstrated to occur in large intracerebral arteries and veins in children and adults with bacterial meningitis. As these blood vessels lie over the surface of the brain and are bathed in infected cerebrospinal fluid containing cytokines and other mediators, bacterial products, and leukocytes, they are particularly susceptible to vascular damage. These findings are often associated with the presence of neurological deficits on clinical examination, secondary to cerebral infarction.

Another aspect of central nervous system disturbance is alteration in cerebral metabolism. The increased cerebrospinal fluid lactate has already been referred to. Another universal finding in bacterial meningitis is the reduction in cerebrospinal fluid glucose concentration. The etiology of this is unclear, but is believed to involve increased metabolism of glucose by leukocytes and bacteria, and disturbance of glucose transport into the cerebrospinal fluid ( Pfister.etal 1994).

Excitatory amino acids, such as glutamate, which interact with neuronal N-methyl-D-aspartate receptors are believed to play a significant role in other models of neuronal injury, and several reports have documented a rise in glutamate concentrations in brain interstitium and cerebrospinal fluid of experimental animals with pneumococcal and Escherichia coli meningitis. Animal models of bacterial meningitis treated with the glutamate antagonist kynurenic acid showed reduced neuronal injury compared with untreated control animals.

All these recent advances in our understanding of the pathophysiology and molecular mechanisms leading to the clinical consequences of bacterial meningitis will improve the delivery of rational therapies for this life-threatening infection.

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