Pathophysiology Pathogenesis mechanism comprises the following steps: nasopharyngeal colonization, invasion of nasopharyngeal epithelial cells, invasion of blood

flow, blood brain barrier crossing and replication inside the subarachnoid space. Neisseria meningitidis and Streptococcus pneumoniae are part of the normal flora of the nasal epithelium and does not produce any disease only when the host immune system is compromised and the bacteria enter the bloodstream. Invasion involves shunting epithelial secretory immunoglobulin A ciliary mechanisms and avoid cleaning. Venous Sinuses of the dura mater and choroid plexus is the major route of invasion of the central nervous system. Once the bacteria have entered the subarachnoid space, they find a favorable environment for development, with small resources subarachnoid space defense. Humoral host defense mechanisms (activity-dependent immunoglobulin and complement activation) are almost nonexistent in the subarachnoid space. Phagocytosis of pathogenic bacteria in cerebrospinal fluid is ineffective. With the multiplication of bacteria in the subarachnoid space will produce meninges inflammation, inflammation that is responsible for the clinical syndrome of bacterial meningitis. Inflammation of the subarachnoid space is induced by constituents of bacteria. Effects of inflammation meningiene and enter the bacterial multiplication resulting in increased permeability of blood brain barrier, cerebral edema vasogen, darkening the normal flow of cerebrospinal fluid, cerebral vasculitis, increased intracranial pressure, decreased cerebral blood flow, hypoxia and acidosis cortical cerebrospinal fluid. Pathologically speaking exudate in subarachnoid space is one that has a typical appearance, yellow-gray or yellowish, more abundant in tanks at the base of the brain and the external surface of the cerebral hemispheres. Exudate tends to accumulate in the basal cisterns and extends along the spinal cord and along the spinal and cranial nerve sheaths. Microscopic examination of the exudate reveals a large number of neutrophils and bacteria. After several days of infection subarahnoid vessel walls become inflamed, meningeene veins dilate and focal necrosis may complicate the vascular wall. Sometimes it can cause a hemorrhagic stroke caused by cortical trombozarea cortical veins and dural sinuses. One week after infection, neutrophils leave the place of the component exudate macrophages. Nuclei of neurons and glial cells nuclei shrink perivascular space infiltrates with neutrophils and lymphocytes. Increased intracranial pressure is the result of blocking the opening of Magendie, and intracranial pressure too high increases the risk of cerebral edema combined with cerebellar tonsils hernierii life-threatening.

Bacterial Virulence Factors

Bacteria express or secrete virulence factors in order to achieve host colonization, cell entry and exit, immunoevasion, immunosuppresion, and nutrition acquisition. Virulence factors are a pathogen's tools of invasion and a cause of disease. 1. Fimbriae Fimbriae, also known as pili, are bacterial organelles that mediate adhesion of bacteria to host cell. Although fimbriae often play a role in initial adherence within the nasopharynx, their presence is not necessary for the organism to cause meningitis. 2. Polysaccharide Capsule The polysaccharide capsule of Streptococcus pneumoniae acts as a virulence factor because it prevents phagocytosis. Because the capsule surface is slippery, the bacterium slips away from the phagocyte during phagocytosis. 3. IgA1 Proteases IgA, a natural antibody type found in mucosal secretion, inhibits the adherence of microorganisms to mucosal surfaces. Bacterial pathogens (e.g. Neisseria, Haemophilus, and Streptococcus species) produce IgA1 proteases which cleave IgA in the hinge region of the immunoglobulin and facilitate bacterial adherence to mucosal surfaces. [1] 4. Bacteriocins Bacteriocins are toxins produced by bacteria that inhibit the growth of other bacterial strains. The pathogen expresses bacteriocins to clear the area of any competitors for nutrients and space needed for colonization. Hemocin is a bacteriocin produced by H. influenzae.

Mucosal colonization and systemic invasion

Most cases of bacterial meningitis originate from the host obtaining an infectious agent by nasopharyngeal colonization. In vitro infection of human nasopharyngeal cells in organ culture with meningococci or H. influenzae type b results in: Breakdown of epithelial cell tight junctions, sloughing of ciliated cells, and ciliostasis via cytotoxicity. This is significant because the cilia are critical in beating infectious agents upwards and away from the lungs in the respiratory tract. Selective attachment to nonciliated epithelial cells and microcolony formation. Note that normal flora (commensals) reduce suitable areas of attachment. Invasion of the epithelium by intracellular or intercellular routes. Passage of organisms to the submucosa. Various infectious agents utilize different mechanisms to invade nasopharyngeal mucosa. Meningococci utilize parasite-directed endocytosis (e.g. intracellular mechanism) while H. influenzae type b adheres to cells, causing a breakdown in tight junctions between epithelial cells and leading to invasion by an intercellular mechanism. [1]

Bacteremia

Invading bacteria gain access to the bloodstream after crossing the mucosal barrier. Blood, like CSF, is normally a sterile environment; the presence of bacteria in blood is known as bacteremia. In this environment, the bacterial capsule is a virulence factor that enhances bloodstream survival and replication of the pathogen. Not only does the capsule inhibit phagocytosis by neutrophils and other professional phagocytes, but it also resists classical complement activation (triggered by antigen-antibody complexes). It is no surprise that the most common meningeal pathogens are encapsulated. Host defense mechanisms can counteract the antiphagocytic bacterial capsule. Unlike classical complement pathway, the alternative complement pathway is not antibody-mediated and can easily overwhelm encapsulated bacteria. It is triggered by the cleavage of C3 into C3a and C3b and the attachment of C3b to MAMPs (Microbe Associated Molecular Patterns), such as the capsular polysaccharides. The C3b molecules osponsize the pathogen, facilitating its phagocytosis and intravascular clearance. Furthermore, the complement cascade leads to the formation of proteolytic C3and C5 convertases and the terminal membrane attack complex, which lyses the pathogen. However, a potentially fatal drawback from lysing the pathogen is the release of endotoxic lipopolysaccharides, which elicit an out-of-control immune response.

Meningeal Invasion
Currently, the mechanism by which bacterial pathogens access the central nervous system (CNS) is unknown. However, three factors that determine whether or not the pathogen can access the CNS are the size of the inoculum (e.g. number of invading organisms), the immune competence of the host, and the invasive ability of the infectious agent. Sustained bacteremia, not transient bacteremia, is observed in those who develop meningitis. The site of CNS invasion by meningeal pathogens is unclear. Current research suggests that initial bacterial entry into CSF occurs in the lateral ventricles via the choroid plexi. The choroid plexus has a high rate of blood flow (~200 ml/g/min). During an infection, more bacteria are delivered to the choroid plexus than to other anatomic locations in the CNS per unit of time. In addition, sampling CSF compartments early during bacterial meningitis demonstrates higher bacterial densities in the lateral ventricles than in the cisterna magna, lumbar subarchnoid space, or supracortical subarachnoid space. [1] In addition, the mechanism by which the meningeal pathogen accesses the CNS is unclear. A possible explanation for bacterial CNS invasion is the Trojan horse hypothesis. A study that attempted to explore this hypothesis discovered that circulating monocytes containing phagocytized bacterium-sized particles migrated into the CSF via the choroid plexus. Thus, bacteria may gain access to CSF by accompanying monocytes migrating along normal pathways. Bacterial meningitis increases the permeability of the blood brain barrier by increasing the permeability of the tight junctions sealing the endothelial cells that line the brain capillaries. Anatomically, the increased permeability occurs at the level of the choroid plexus epithelium and/or the cerebral microvascular endothelium. It is induced by the presence of lipopolysaccharides and cytokines IL-1 and TNF-, which act in a synergistic manner. [1]

Bacterial Survival in Subarachnoid Space

Once the pathogens infiltrate the subarachnoid space, they cannot be stopped by host defense mechanisms. Complement proteins are almost absent in CSF, so opsonic and bactericidal activities are also nearly absent in patients with meningitis. Some of the explanations for the state of complement in CSF during meningitis include: Insufficient traversal across the blood brain barrier Inflammation of the subarachnoid space Enhanced clearance from the subarachnoid space Low production rates in CNS

Degradation at the site of infection by leukocyte proteases. Normal CSF also has very low immunoglobulin (i.e. IgG, IgM, IgD, etc) concentrations, which increase during bacterial meningitis but remain low compared to concentrations in serum and IgG does not appear in CSF until late in the disease course. In addition, systemic administration of type-specific antibody is ineffective because of the blood brain barrier. Unlike complement and immunoglobulin, neutrophils are capable of traversing the blood brain barrier through mechanisms that are undefined. Complement component C5a is a chemotactic substance that appears before neutrophil influx into CSF. Although neutrophils can access CSF, the host defense mechanism in CFS remains compromised because of the lack of opsonic and bactericidal activity. As a result, huge concentrations of bacteria develop in CSF unhindered. The recruited neutrophils are thought to prevent the travel of bacteria from CSF to blood (i.e. secondary bacteremia) or enhance neutrophil-mediated bacterial elimination from the bloodstream at extraneural sites. [1]

Subarachnoid Space Inflammation

Many of the pathophysiologic consequences of bacterial meningitis result from virulence factor induced inflammation of the subarachnoid space.

Cell Wall: The cell walls of gram positive bacteria such as S. pneumoniae trigger inflammation. More specifically, cell wall components such as teichoic acid and peptidoglycan induce severe inflammation. It is worth mentioning that the bacterial capsule that allowed for pathogen survival in the blood and subarachnoid space by hindering phagocytosis is non-inflammatory. Lipopolysaccharide (LPS): Lipid A region of LPS induces severe inflammation. On the other hand, the oligosaccharide portion of LPS is non-inflammatory. Inflammatory mediators: Specific mediators are IL-1, TNF, and prostaglandins. IL-1 production is induced by pneumococcal cell wall (namely, lipoteichoic acid). [3]

Increased Intracranial Pressure

The increase in intracranial pressure is primarily due to the development of cerebral edema, which may be vasogenic, cytotoxic, and/or interstitial in origin. Vasogenic cerebral edema is due to increased blood brain barrier permeability. Cytotoxic cerebral edema results from swelling of the cellular elements of the brain, most likely due to release of toxic factors from neutrophils and/or bacteria. Interstitial edema results from obstruction of flow in normal CSF pathways as in hydrocephalus. Increase in outflow resistance to CSF movement may cause interstitial brain edema and/or hydrocephalus. [3]

Cerebral Vasculitis and Altered Cerebral Blood Flow

Bacterial meningitis affects the blood vessels that course through the subarachnoid space. This results in vasculitis which leads to narrowing and/or thrombosis of cerebral blood vessels, ischemia, and/or infarction of the brain. Severe neurological problems such as hemiparesis and quadriparesis (i.e. paralysis of 2 and 4 limbs respectively) may result from large cranial arterial abnormalities. These abnormalities may include vasospasms, vasodilation, or stenosis that my lead to brain infarction, focal neurologic deficits, and seizure. Vasculitis leads to altered cerebral blood flow, which is passively dependent on systemic blood pressure. In other words, the cerebral blood flow increases when the systemic blood pressure increases, and vice versa. Since this relationship is passive, the brain may loses cerebrovascular autoregulation, and the intracranial pressure is easily fluctuated. A study showed that patients with bacterial meningitis also have altered cerebral blood flow, which could further lead to other fatal complications, such as hypoxia (insufficient oxygen supply) due to lowered blood flow and subsequently cranial lactic acidosis, or elevated intracranial pressure due to elevated blood flow.

Reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC358273/pdf/cmr000350040.pdf http://medicaldb.blogspot.com/2011/01/acute-bacterial-meningitis_28.html http://bacterial-meningitis.weebly.com/pathophysiology.html