What is the pathophysiology of bacterial meningitis?

Pathophysiology of Bacterial Meningitis

Bacterial meningitis is a life-threatening infection characterized by a cascade of events beginning with nasopharyngeal colonization, followed by bacteremia, blood-brain barrier penetration, and culminating in an intense subarachnoid inflammatory response that drives cerebral edema, increased intracranial pressure, and neuronal injury. 1

Initial Pathogenic Sequence

Colonization and Systemic Invasion

• Most cases begin with nasopharyngeal colonization by the pathogen, followed by mucosal invasion and development of high-grade bacteremia 1
• Bacterial capsular polysaccharides are critical virulence factors that inhibit neutrophil phagocytosis and resist complement-mediated bactericidal activity, allowing bacteria to survive in the bloodstream 1
• The three most common pathogens—Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae—account for the majority of cases, with S. pneumoniae causing approximately two-thirds of meningitis in developed countries 2

Central Nervous System Invasion

• Bacteria traverse from the circulation across the blood-brain barrier (BBB) and choroid plexus to reach the CNS, though the exact anatomical site of bacterial entry remains incompletely understood 1, 2
• Once bacteria penetrate the BBB, they multiply freely in the cerebrospinal fluid, which lacks adequate immune defenses to contain the infection 3

Inflammatory Cascade and Cytokine Release

Pathogen Recognition and Immune Activation

• Bacterial components (PAMPs) trigger multiple inflammatory pathways including Toll-Like Receptor (TLR) signaling, NOD-like receptor pathways, and NF-κB activation 4
• Pneumococcal pneumolysin and other bacterial virulence factors directly stimulate inflammatory responses in the subarachnoid space 4
• The NLRP3 inflammasome complex is activated, leading to maturation and release of IL-1β and IL-18, which potentiate neuroinflammation 4

Pro-inflammatory Mediator Production

• The host response generates a complex array of inflammatory mediators including IL-1β, TNF-α, IL-6, IL-8, and CXCL1 4
• These cytokines, along with reactive oxygen intermediates and matrix metalloproteinases, contribute to progressive brain injury 5
• The subarachnoid space inflammatory response is the major factor driving morbidity and mortality in bacterial meningitis 6, 1

Blood-Brain Barrier Disruption

Mechanisms of BBB Breakdown

• Bacterial virulence factors and inflammatory cytokines increase permeability of the BBB, allowing protein and neutrophils to move into the subarachnoid space 1
• While the BBB normally protects the CNS by maintaining homeostasis and shielding against neurotoxic substances, its dysfunction is central to the pathophysiology of bacterial meningitis 2
• Inflammatory processes, including release of cytokines and free radicals, further increase vascular permeability and contribute to excessive neural damage 2

Pathophysiologic Consequences

Cerebral Edema and Increased Intracranial Pressure

• The intense inflammatory response leads to cerebral edema (vasogenic, cytotoxic, and interstitial), which is a primary mechanism of brain injury 1, 3
• Increased intracranial pressure results from cerebral edema and impaired CSF reabsorption 1
• S. pneumoniae causes the most severe intracranial hypertension among bacterial pathogens, with the highest rates of cerebral edema and mortality 7

Cerebrovascular Complications

• Alterations of cerebral vasculature include disruption of the BBB, global and focal ischemia, and loss of cerebral blood flow autoregulation 5, 2
• Cerebrovascular complications occur frequently and include cerebral infarctions, subarachnoid hemorrhage, intracerebral hemorrhage, and venous sinus thrombosis 6
• Injury to cerebral microvasculature and vascular occlusion may result from increased intracranial pressure 2
• Cerebral vasculitis contributes to altered cerebral blood flow and neuronal injury 6

Neuronal Damage

• Direct neuronal injury occurs through multiple mechanisms including inflammatory mediators, ischemia, and excitotoxicity 5
• Abnormal neuronal hyperexcitability manifests as seizures, which are common complications 2
• Damage to cochlear structures results in sensorineural hearing loss in 5-35% of survivors 6

Pathogen-Specific Differences

Pneumococcal Meningitis

• S. pneumoniae produces the most intense inflammatory response, leading to greater cerebral edema, altered cerebral blood flow, and cerebral vasculitis compared to other pathogens 7
• Pneumococcal meningitis has the highest mortality rates (14-34%) and worst neurological outcomes among bacterial meningitis types 7

Meningococcal Disease

• N. meningitidis more commonly presents with septicemia and shock rather than isolated meningitis with elevated intracranial pressure 7
• The event rate for mortality and neurological complications is substantially lower in meningococcal meningitis compared to pneumococcal disease 7

Listeria Monocytogenes

• Listeria causes less severe intracranial hypertension compared to pneumococcal disease 7
• This pathogen is particularly important in elderly, immunocompromised patients, those with cancer, and patients on immunosuppressive therapy, accounting for 20-40% of cases in these populations 6

Clinical Implications

Therapeutic Rationale for Adjunctive Therapy

• Dexamethasone attenuates the subarachnoid inflammatory response, decreasing cerebral edema, intracranial pressure, altered cerebral blood flow, cerebral vasculitis, and neuronal injury mediated by pro-inflammatory cytokines 6, 8
• The strongest benefit of dexamethasone is seen in pneumococcal meningitis, where it significantly reduces unfavorable outcomes (26% vs 52%) and mortality (14% vs 34%) 8

Complications and Sequelae

• Neurological deficits occur in approximately 50% of adults with bacterial meningitis during their clinical course 6, 9
• One-third of patients develop hemodynamic or respiratory insufficiency 6
• Long-term sequelae include hearing loss (5-35%), seizures (13%), motor deficits (12%), cognitive defects (9%), hydrocephalus (7%), and visual loss (6%) 6
• Despite effective bactericidal antibiotics, bacterial meningitis remains fatal in 5-40% of patients and causes neurological sequelae in up to 30% of survivors 5