Bacterial meningitis/Immunopathogenesis and pathophysiology
Once the organism has invaded into the CSF, a number of bacterial components, particularly lipo-polysaccharide (LPS) or lipo-oligosaccharide (LOS) and peptidoglycan are the major determinants of the meningeal inflammation [1]. The techoic-acid of gram-positive organisms [2], and peptidoglycan components of both gram-positive and gram-negative organisms have been shown to be potent inducers of inflammation in the CSF and to impair blood brain barrier function on direct intracisternal inoculation in experimental animals [1, 3]. Similarly, direct inoculation of LPS from H. influenzae or the LOS of N. meningitidis into the CSF of experimental animals causes an intense inflammatory reaction with influx of leukocytes, increase in protein and lactate and a decline in CSF glucose concentration [3, 4, 5, 6]. These studies have provided overwhelming evidence that bacterial endo-toxins and other bacterial cell wall constituents are important in the initiation of the inflammatory changes within the CSF, and the disturbance of function of the blood-brain barrier.
The inflammatory changes in the CSF occur several hours following the inoculation of bacteria or cell wall constituents into the meningeal space of experimental animals. This has led to the hypothesis that elaboration and release of host mediators are instrumental in the development of the inflammatory changes. Animal models have established that tumour necrosis factor alpha (TNF) and interleukin 1 beta (ILI) are important mediators of the initial meningeal inflammation [7]. Levels of TNF and IL1 together with interleukin 6 (IL6) increase in the CSF of animals following intracisternal inoculation of meningococcal LOS, and this rise in cytokine levels precedes cellular influx and protein exudation [7, 8, 9, 10]. These cytokine mediators have been shown to stimulate the release of other factors in the inflammatory cascade, including platelet activating factor (PAF), interleukin 8 (IL8) and interferon gamma (IFN). Release of these pro-inflammatory mediators causes up-regulation of cellular adhesion molecules, which include molecules such as the integrins, selectins and the IgG superfamily, on the surface of peripheral blood leukocytes and vascular endothelial cells of the blood-brain barrier, resulting in attraction, attachment and migration of leukocytes into the CSF [1, 11]. Once present in the CSF, polymorphonuclear neutrophils (PMN) are activated and undergo degranu-lation and release of proteolytic enzymes, cationic proteins and reactive oxygen species [1, 8]. These products further alter the integrity of the blood-brain barrier, thus interrupting its primary functions: active transport and facilitated diffusion of nutrients (including glucose and other metabolites) and secretion of CSF. Increased permeability of the blood-brain barrier results in leakage of albumin and other macro-molecules into the CSF, causing vasogenic oedema. The presence of anaphylotoxins (C3a, C5a) in the CSF due to the protein leak also encourages passage of PMN into the CSF, further accentuating the inflammatory process. Toxic products of neutrophil activation and other inflammatory cells cause cytotoxic oedema and damage to surrounding cells.
The importance of the cytokines, TNF and IL1 have been confirmed in studies which have shown that the inflammatory response to LPS in the CSF of experimental animals can be reduced by the simultaneous inoculation of antibodies to TNF, IL1 or both [9, 10]. However, the use of antibodies against these cytokines does not completely abrogate the inflammatory response, suggesting that other mediators also have an important role. Furthermore, direct inoculation of TNF, ILl and IFN induces inflammatory changes which closely resemble those which are seen with LPS inoculation. In addition to the development of vasogenic and cytotoxic oedema, interstitial oedema may be caused by impaired reabsorption of CSF by the arachnoid villi, a phenomenon which has been demonstrated in experimental models of meningitis [12].
The consequences of increased secretion of CSF, diminished reabsorption and breakdown of the blood-brain barrier are an increase in brain water content and CSF volume, and the development of severe brain oedema. This leads to an increase in intracranial pressure, which, if severe will lead to a reduction in cerebral blood flow (CBF). In experimental models of meningitis, CBF at first increases due to local vasodilatation induced by inflammation, and then decreases as a consequence of raised intracranial pressure [13]. These changes are paralleled by an increase in CSF lactate levels indicating tissue hypoxia [14]. Changes in CBF may also be a consequence of a loss of cerebrovascular autoregulation, which has been demonstrated to occur in severe bacterial meningitis [14]. Cerebral blood flow is normallymaintained at constant levels irrespective of systemic arterial pressure. Once autoregulation has been lost, CBF is totally dependent on systemic pressure. Inadequate blood flow may occur if systemic hypotension occurs. The rise in intracranial pressure, together with systemic hypotension which is common in meningococcal sepsis, may readily result in cerebral hypoperfusion. Together with the vasculitis and thrombosis of cerebral vessels, ischaemia of areas of the brain may result, leading to neuronal injury and focal or diffuse brain damage.
Understanding of the pathophysiological and immu-nological events leading to cerebral injury, as outlined above, has allowed more rational approaches to therapy, and the introduction of new forms of therapy designed to reduce the intracranial inflammatory process [15]
