Pathophysiology of Bacterial Meningitis
Bacterial meningitis in a 15-year-old male follows a sequential pathogenic cascade beginning with nasopharyngeal colonization, progressing to bacteremia, CNS invasion, and culminating in intense subarachnoid inflammation that drives the majority of neurological damage.
Initial Colonization and Systemic Invasion
Nasopharyngeal colonization is the first step, where bacteria such as Neisseria meningitidis (most common in adolescents) or Streptococcus pneumoniae establish residence in the upper respiratory tract 1, 2.
Bacterial encapsulation allows pathogens to evade neutrophil phagocytosis and resist complement-mediated killing, facilitating development of high-grade bacteremia 1.
Systemic invasion occurs when bacteria traverse mucosal barriers and survive in the bloodstream, a prerequisite for CNS entry 2.
Central Nervous System Invasion
Blood-brain barrier (BBB) penetration occurs through mechanisms that remain incompletely understood, but bacteria cross either the blood-brain barrier or blood-cerebrospinal fluid barrier to enter the subarachnoid space 2.
In adolescents, N. meningitidis represents the second peak of meningococcal disease (ages 16-25), making it a critical pathogen in this age group 3.
Inflammatory Cascade Initiation
Pattern recognition receptors (PRRs), particularly Toll-like receptors (TLRs), recognize bacterial pathogen-associated molecular patterns (PAMPs) and initiate the inflammatory response 4, 5.
TLR signaling leads to MyD88-dependent production of proinflammatory cytokines, particularly the interleukin-1 family 4.
Positive feedback amplification occurs as secreted IL-1 family cytokines create a self-perpetuating loop that dramatically increases production of proinflammatory mediators 4.
NLRP3 inflammasome activation results in maturation and release of IL-1β and IL-18, further potentiating neuroinflammation 5.
Subarachnoid Space Inflammation
Massive cytokine release includes TNF-α, IL-6, IL-8, CXCL1, and other mediators that drive the intense inflammatory response 5.
Neutrophil recruitment occurs in massive numbers to the subarachnoid space, representing the hallmark cellular response 4, 1.
CSF pleocytosis develops with predominantly polymorphonuclear leukocytes, typically with white blood cell counts in the thousands with neutrophil predominance 6.
Blood-brain barrier disruption increases permeability, allowing protein and additional inflammatory cells to enter the subarachnoid space 1.
Direct Tissue Damage Mechanisms
Neutrophil-mediated injury occurs as activated neutrophils release oxidants, matrix metalloproteinases, proteases, and excitatory amino acids that cause collateral damage to brain tissue 4, 7.
Direct bacterial cytotoxicity contributes independently to neuronal damage, particularly through toxins like pneumolysin (a cholesterol-binding hemolysin) that has direct toxic effects on neuronal cells 4, 7.
Microglial activation by bacterial products increases phagocytic capacity but can also lead to destruction of neurons through release of free radicals and cytokines 7.
Pathophysiologic Consequences
Cerebral edema develops through three mechanisms: vasogenic (BBB breakdown), cytotoxic (cellular swelling from energy failure), and interstitial (impaired CSF resorption) 1, 7.
Increased intracranial pressure results from cerebral edema, increased CSF outflow resistance, and swelling of necrotic cells 7.
Vasculitis and focal ischemia occur as inflammation affects cerebral vessels, leading to secondary brain damage 7.
Hydrocephalus develops in 40-85% of patients with chronic meningitis due to impaired CSF circulation, though less common in acute bacterial meningitis in adolescents 8.
Meningococcal Sepsis-Specific Pathophysiology
Capillary leak syndrome causes profound hypovolemia as vascular permeability increases dramatically 3.
Myocardial dysfunction contributes to shock independent of volume status 3.
Altered vasomotor tone and potential adrenal insufficiency compound cardiovascular collapse 3.
Compensatory mechanisms in healthy adolescents maintain cerebral perfusion until late stages, potentially masking the severity of cardiovascular collapse—a critical pitfall where alert mental status may cause underestimation of shock severity 3.
Cryptic shock can occur without hypotension but is indicated by elevated lactate >4 mmol/L, representing tissue hypoperfusion despite normal blood pressure 3.
Clinical Correlation
Rapidly progressing rash, coma, hypotension, lactate >4 mmol/L, low peripheral white blood cell count, and absence of meningitis are risk factors for fatal outcome in meningococcal disease 3.
The pathophysiology explains why delay in antibiotic treatment is strongly associated with death and poor neurological outcomes, as the inflammatory cascade and tissue damage progress rapidly once initiated 9.