Acute And Chronic Meningitis Health Article

Specific bacterial virulence factors for meningeal pathogens include specialized surface components (e.g. the polysaccharide capsule with specific epitopes and fimbriae or pili). These factors are crucial for adherence to the nasopharyngeal epithelium, the evasion of local host defense mechanisms and subsequent invasion of the bloodstream. Hydrogen peroxide produced by Strep. pneumoniae has a bactericidal effect on the microbial flora in the respiratory tract, suggesting that the ability to produce hydrogen peroxide might provide the organism with a competitive advantage for colonization. The invasion of pneumococci needs the activation of nasopharyngeal epithelial cells and the presentation of receptors suitable for pneumococci. The presence of the polymeric immunoglobulin A receptor on human mucosa, which binds to a major pneumococcal adhesin, CbpA, correlates with the ability of pneumococci to invade the mucosal barrier. Lack of specific mucosal antibodies correlates with an increased risk of invasive disease. Viral infection of the respiratory tract may also promote invasive disease. From the nasopharyngeal surface, encapsulated organisms cross the epithelial cell layer and invade the small subepithelial blood vessels. ³⁹

In the bloodstream, bacteria must survive host defenses, including circulating antibodies, complement-mediated bactericidal mechanisms and neutrophil phagocytosis. Encapsulation is a shared feature of the principal hematogenous meningeal pathogens ( H. influenzae, N. meningitidis, Strep. pneumoniae, E. coli K1 and group B streptococci). The capsule is instrumental in inhibiting neutrophil phagocytosis and complement-mediated bactericidal activity.

Several defense mechanisms counteract the antiphagocytic activity of the bacterial capsule. Activation of the alternative complement pathway results in cleavage of C3 with subsequent deposition of C3b on the bacterial surface, thereby facilitating opsonization, phagocytosis and intravascular clearance of the organism.

Impairment of the alternative complement pathway occurs in patients with sickle-cell disease and those who have undergone splenectomy, and these groups of patients are predisposed to the development of pneumococcal meningitis. Recently, functional deficiencies of several components involved in the activation and function of complement-mediated defenses have been identified (i.e. mannose-binding lectin, properdin, lack of terminal comple-ment components), which increase the susceptibility for invasive meningococcal infections. ¹³

Studies on the pathogenesis of experimental bacterial meningitis show that cells in the choroid plexus and cerebral capillaries possess receptors for adherence of meningeal pathogens. For E. coli , a complex interplay between endothelial factors and microbial genes orchestrates the crossing of the blood-brain barrier by bacteria. ⁴⁰ Experimental evidence has identified the choroid plexus as a potential site for the invasion of meningeal pathogens, and this may be facilitated by its exceptionally high rate of bloodflow (200ml/g per minute) and the presence of pathogen-specific receptors.

Pneumococci are thought to enter the CNS by crossing the blood-brain barrier or the blood-CSF barrier either by local tissue damage or by transcytosis through microvascular endothelial cells. ⁴¹ Pneumolysin, a major pneumococcal virulence factor, was shown to damage endothelial cells and to be an important component for compromising the blood-brain barrier. ⁴²

Nonhematogenous invasion of the CSF by bacteria occurs in situations of compromised integrity of the barriers surrounding the brain (e.g. in otitis media, mastoiditis, sinusitis). Direct communication between the subarachnoid space and the skin or mucosal surfaces as a result of malformation or trauma give rise to meningeal infection with bacterial species that vary with the site of the abnormal communication. Bacteria can also reach the CSF as a complication of neurosurgery, spinal anesthesia or ventriculostomy placement. ⁴³

Pathogens reaching the CSF are likely to survive because of a paucity of resident macrophages and deficient opsonization due to low concentrations of capsule-specific immunoglobulins and complement in the CSF. Lack of opsonization greatly reduces the effectiveness of incoming granulocytes and allows largely unrestricted multiplication of the meningeal pathogens. Bacterial multiplication is associated with the release of bacterial products (fragments of cell wall, lipopolysaccharide) that:

• trigger the inflammatory response in the subarachnoid space by inducing the production and release of inflammatory cytokines (e.g. TNF-α, IL-1 and IL-6) and chemokines (e.g. IL-8, the growth-related oncogene α [GRO-α], the CC chemokine monocyte chemoattractant protein-1 [MCP-1] and others), and lipid inflammatory mediators such as platelet activation factor;

• upregulate adhesion molecules on brain vascular endothelial cells; and

• promote the recruitment of granulocytes into the CSF.

The blood-brain barrier separates the brain from the intravascular compartment and maintains homeostasis within the CNS. The permeability of the blood-brain barrier increases in meningitis at the level of the choroid plexus epithelium and the cerebral microvascular endothelium. Separation of intercellular tight junctions and increased pinocytosis contribute to the increased permeability. Matrix metalloproteinases (MMP), zinc-dependent enzymes produced as part of the immune response to bacteria that degrade extracellular matrix proteins, also contribute to the increased permeability of the blood-brain barrier. ⁴⁶ The resulting increased extravasation of serum components, including antibiotics leads to higher concentrations in the CSF during meningitis, with an approximately fivefold increase over the uninfected state for most antibiotics. ^{47, 48}

The major element leading to increased intracranial pressure in bacterial meningitis is the development of cerebral edema, which may be vasogenic, cytotoxic or interstitial in origin. Vasogenic cerebral edema is primarily a consequence of increased blood-brain barrier permeability.

Cytotoxic edema results from an increase in intracellular water following alterations of the cell membrane and loss of cellular homeostasis. Cytotoxic mechanisms include ischemia and the effect of excitatory amino acids. Secretion of antidiuretic hormone also contributes to cytotoxic edema by making the extracellular fluid hypotonic and increasing the permeability of the brain to water.

Interstitial edema occurs by an increase in CSF volume, either through increased CSF production via increased bloodflow in the choroid plexus, or decreased resorption secondary to increased CSF outflow resistance. ^{49, 50}

Bacterial meningitis is associated with marked changes in cerebral bloodflow. In the early phase of the disease, an increase in bloodflow is observed, and this appears to be mediated by nitric oxide and oxidative radicals. Formation of oxidative radicals in meningitis has been documented to occur together with the presence of inflammatory cells in the subarachnoid space and along penetrating cortical blood vessels, and leads to oxidative alterations of the cerebral vasculature, which may contribute to the cerebral bloodflow reduction observed in advanced meningitis. ^{51, 52, 53, 54}

Other factors involved in bloodflow reduction in advanced meningitis include the vasoconstrictor peptide family of endothelins, the levels of which are greatly increased in the CSF during bacterial meningitis. An antagonist of endothelin receptors normalized cerebral bloodflow and prevent cortical injury in experimental meningitis. ^{52, 55}

Several clinical studies have found an association between severe cerebral bloodflow reduction and adverse outcomes in children and adults with meningitis, suggesting that ischemia is an important mediator of brain damage in meningitis. Cerebral bloodflow reduction during meningitis can be global, as a result of reduced cerebral perfusion pressure (resulting from increased intracranial pressure, systemic hypotension, or both), or focal, as a result of the vascular involvement of cerebral arteries and veins by the subarachnoid space inflammation (Fig 22.2. ⁵¹

The exact mechanisms that lead to permanent brain injury are incompletely understood. There is converging evidence, however, that cerebral ischemic necrosis contributes to this process, particularly regarding damage to the cerebral cortex. Acute breakdown of the blood-brain barrier, intrathecal production of cytokines, and accumulation of blood-derived leukocytes in the CSF are key events leading to brain edema, cerebral vasculitis and ultimately neuronal injury. These events are in part mediated by MMPs (see 'Blood-brain barrier', above). CSF levels of specific MMPs (i.e. MMP-9) were significantly higher in patients who developed neurological sequelae than in those who recovered fully. The metalloproteinase TNF-α converting enzyme (TACE), a close relative of the MMPs, may contribute to the pathophysiology of bacterial meningitis by its ability to release cytokines and their receptors, thus increasing stimuli that trigger further MMP release. ⁴⁶ Given as adjuvant therapy in addition to antibiotics, combined inhibition of MMP and TACE reduced the extent of cortical and hippocampal damage and protected from learning disability resulting from meningitis. ⁵⁶

While the mechanisms of necrosis in the cortex have only partially been explored, even less is known regarding the causes of neuronal injury in the dentate gyrus of the hippocampus. In patients dying from bacterial meningitis and in corresponding animal models, neuronal cell death in the hippocampal dentate gyrus fulfils criteria for apoptosis that appears to be induced by activation of the effector caspase-3 and other caspase-independent mechanisms. ^{57, 58, 59}

Important pathologic findings in patients with meningitis include:

• subarachnoid space inflammation;

• inflammatory involvement of the cerebral vasculature; and

• parenchymal brain damage.

Inflammation also involves the inner ear, to which it gains access via the cochlear aqueduct connecting the subarachnoid space with the endolymphatic space. Toxic effects of the inflammation on hair cells of the inner ear appear to be responsible for the hearing impairment associated with bacterial meningitis (Table 22.5).

Damage to the brain parenchyma is evidenced by the presence of brain edema (including signs of cerebral herniation), by areas of cerebral infarction resulting from ischemia and by histologic changes. Loss of neurons is associated with a marked reaction of astrocytes and microglia. Apart from the damage to the cortex, neuronal injury is evident in the dentate gyrus of the hippocampus in patients dying from meningitis, and damage to the hippocampus is further suggested by a decreased hippocampal volume in patients surviving meningitis. ^{60, 61} Given the function of the hippocampus, injury to this structure may represent the substrate for the learning and memory deficits in survivors of meningitis. The extent and localization of neuronal loss probably determines the type of neurologic sequelae resulting from meningitis (see Table 22.5). ^{40, 52}