Most cases of meningitis are caused by an infectious agent that has colonized or established a localized infection elsewhere in the host. Potential sites of colonization or infection include the skin, the nasopharynx, the respiratory tract, the gastrointestinal (GI) tract, and the genitourinary tract. The organism invades the submucosa at these sites by circumventing host defenses (eg, physical barriers, local immunity, and phagocytes or macrophages).An infectious agent (ie, a bacterium, virus, fungus, or parasite) can gain access to the CNS and cause meningeal disease via any of the 3 following major pathways:
- Invasion of the bloodstream (ie, bacteremia, viremia, fungemia, or parasitemia) and subsequent hematogenous seeding of the CNS
- A retrograde neuronal (eg, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri or Gnathostoma spinigerum)
- Direct contiguous spread (eg, sinusitis, otitis media, congenital malformations, trauma, or direct inoculation during intracranial manipulation)
Invasion of the bloodstream and subsequent seeding is the most common mode of spread for most agents. This pathway is characteristic of meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis.
Rarely, meningitis arises from invasion via septic thrombi or osteomyelitic erosion from infected contiguous structures. Meningeal seeding may also occur with a direct bacterial inoculate during trauma, neurosurgery, or instrumentation. Meningitis in the newborn may be transmitted vertically, involving pathogens that have colonized the maternal intestinal or genital tract, or horizontally, from nursery personnel or caregivers at home.
Local extension from contiguous extra-cerebral infection (eg, otitis media, mastoiditis, or sinusitis) is a common cause. Possible pathways for the migration of pathogens from the middle ear to the meninges include the following:
- The bloodstream
- Preformed tissue planes (eg, posterior fossa)
- Temporal bone fractures
- The oval or round window membranes of the labyrinths
The brain is naturally protected from the body’s immune system by the barrier that the meninges create between the bloodstream and the brain. Normally, this protection is an advantage because the barrier prevents the immune system from attacking the brain. However, in meningitis, the blood brain barrier can become disrupted; once bacteria or other organisms have found their way to the brain, they are somewhat isolated from the immune system and can spread.When the body tries to fight the infection, the problem can worsen; blood vessels become leaky and allow fluid, WBCs, and other infection-fighting particles to enter the meninges and brain. This process, in turn, causes brain swelling and can eventually result in decreasing blood flow to parts of the brain, worsening the symptoms of infection.
Depending on the severity of bacterial meningitis, the inflammatory process may remain confined to the subarachnoid space. In less severe forms, the pial barrier is not penetrated, and the underlying parenchyma remains intact. However, in more severe forms of bacterial meningitis, the pial barrier is breached, and the underlying parenchyma is invaded by the inflammatory process. Thus, bacterial meningitis may lead to widespread cortical destruction, particularly when left untreated.
Replicating bacteria, increasing numbers of inflammatory cells, cytokine-induced disruptions in membrane transport, and increased vascular and membrane permeability perpetuate the infectious process in bacterial meningitis. These processes account for the characteristic changes in CSF cell count, pH, lactate, protein, and glucose in patients with this disease. Exudates extend throughout the CSF, particularly to the basal cisterns, resulting in the following:
- Damage to cranial nerves (eg, cranial nerve VIII, with resultant hearing loss)
- Obliteration of CSF pathways (causing obstructive hydrocephalus)
- Induction of vasculitis and thrombophlebitis (causing local brain ischemia)
Intracranial pressure and cerebral fluid
One complication of meningitis is the development of increased intracranial pressure (ICP). The pathophysiology of this complication is complex and may involve many pro-inflammatory molecules as well as mechanical elements. Interstitial edema (secondary to obstruction of CSF flow, as in hydrocephalus), cytotoxic edema (swelling of cellular elements of the brain through the release of toxic factors from the bacteria and neutrophils), and vasogenic edema (increased blood brain barrier permeability) are all thought to play a role.
Without medical intervention, the cycle of decreasing CSF, worsening cerebral edema, and increasing ICP proceeds unchecked. Ongoing endothelial injury may result in vasospasm and thrombosis, further compromising CSF, and may lead to stenosis of large and small vessels. Systemic hypotension (septic shock) also may impair CSF, and the patient soon dies as a consequence of systemic complications or diffuse CNS ischemic injury.
The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid space and diminished venous outflow lead to interstitial edema. The accumulation of the products of bacterial degradation, neutrophils, and other cellular activation leads to cytotoxic edema. The ensuing cerebral edema (ie, vasogenic, cytotoxic, and interstitial) significantly contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition, hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment. Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.
Cytokines and secondary mediators in bacterial meningitis
Key advances in understanding the pathophysiology of meningitis include insight into the pivotal roles of cytokines (eg, tumor necrosis factor alpha [TNFα] and interleukin [IL]1), chemokines (IL 8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage during occurrences of bacterial meningitis.
Increased CSF concentrations of TNFα, IL1, IL6, and IL8 are characteristic findings in patients with bacterial meningitis. Cytokine levels, including those of IL6, TNFα, and interferon gamma, have been found to be elevated in patients with aseptic meningitis.
The proposed events involving these inflammation mediators in bacterial meningitis begin with the exposure of cells (eg, endothelial cells, leukocytes, microglia, astrocytes, and meningeal macrophages) to bacterial products released during replication and death; this exposure incites the synthesis of cytokines and proinflammatory mediators. This process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan and lipopolysaccharide) to patternrecognition receptors, such as the Tolllike receptors (TLRs).
TNFα and IL1 are most prominent among the cytokines that mediate this inflammatory cascade. TNFα is a glycoprotein derived from activated monocytemacrophages, lymphocytes, astrocytes, and microglial cells.
IL1, previously known as endogenous pyrogen, is also produced primarily by activated mononuclear phagocytes and is responsible for the induction of fever during bacterial infections. Both IL1 and TNFα have been detected in the CSF of individuals with bacterial meningitis. In experimental models of meningitis, they appear early during the course of disease and have been detected within 3045 minutes of intracisternal endotoxin inoculation.
Many secondary mediators, such as IL6, IL8, nitric oxide, prostaglandins (eg, prostaglandin E2 [PGE2]), and platelet activation factor (PAF), are presumed to amplify this inflammatory event, either synergistically or independently. IL6 induces acutephase reactants in response to bacterial infection. The chemokine IL8 mediates neutrophil chemoattractant responses induced by TNFα and IL1.
Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts. PGE2, a product of cyclo-oxygenase (COX), appears to participate in the induction of increased bloodbrain barrier permeability. PAF, with its myriad biologic activities, is believed to mediate the formation of thrombi and the activation of clotting factors within the vasculature. However, the precise roles of all these secondary mediators in meningeal inflammation remain unclear.
The net result of the above processes is vascular endothelial injury and increased blood-brain barrier permeability, leading to the entry of many blood components into the subarachnoid space. In many cases, this contributes to vasogenic edema and elevated CSF protein levels. In response to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and penetrate the damaged blood-brain barrier, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis.
Genetic predisposition to inflammatory response
The inflammatory response and the release of pro-inflammatory mediators are critical to the recruitment of excess neutrophils to the subarachnoid space. These activated neutrophils release cytotoxic agents, including oxidants and metallo-proteins that cause collateral damage to brain tissue.
Pattern recognition receptors, of which TLR A4 (TLRA4) is the best studied, lead to increase in the myeloid differentiation 88 (MyD88)dependent pathway and excess production of pro-inflammatory mediators. At present, dexamethasone is used to decrease the effects of cellular toxicity by neutrophils after they are present. Researchers are actively seeking ways of inhibiting TLRA4 and other pro-inflammatory recognition receptors through genetically engineered suppressors.
Bacterial seeding of the meninges usually occurs through hematogenous spread. In patients without an identifiable source of infection, local tissue and bloodstream invasion by bacteria that have colonized the nasopharynx may be a common source. Many meningitiscausing bacteria are carried in the nose and throat, often asymptomatically. Most meningeal pathogens are transmitted through the respiratory route, including Neisseria meningitidis (meningococcus) and S pneumoniae (pneumococcus).
Certain respiratory viruses are thought to enhance the entry of bacterial agents into the intravascular compartment, presumably by damaging mucosal defenses. Once in the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, and neutrophil phagocytosis).
Subsequently, hematogenous seeding into distant sites, including the CNS, occurs. The specific pathophysiologic mechanisms by which the infectious agents gain access to the subarachnoid space remain unclear. Once inside the CNS, the infectious agents likely survive because host defenses (eg, immunoglobulins, neutrophils, and complement components) appear to be limited in this body compartment. The presence and replication of infectious agents remain uncontrolled and incite the cascade of meningeal inflammation described above.