Meningitis - etiology pathogenesis

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Meningitis - Etiology and Pathogenesis

Definition

Meningitis is an inflammatory process involving the leptomeninges (pia mater and arachnoid) within the subarachnoid space. When infection extends into the underlying brain parenchyma, the condition is termed meningoencephalitis. The term also applies to non-infectious settings (chemical meningitis from ruptured epidermoid cyst debris, carcinomatous meningitis from metastatic cancer).

Robbins & Kumar Basic Pathology, p. 833

Classification and Etiology

By Acuity and Cause

Type	Usual Cause	Key Organisms
Acute pyogenic	Bacterial	See age-stratified table below
Aseptic (acute)	Viral	Enteroviruses, herpesviruses, HIV, LCM virus
Chronic	Tuberculosis, spirochetes, fungi	M. tuberculosis, Treponema pallidum, Cryptococcus
Non-infectious	Chemical, neoplastic	Epidermoid cysts, metastatic cancer

Bacterial Etiology: Age-Stratified

Age Group	Most Common Organisms
Neonates (< 6 weeks)	Escherichia coli, Group B streptococci
Infants and young children	Neisseria meningitidis, S. pneumoniae
Adolescents and young adults	Neisseria meningitidis (predominant)
Adults	Streptococcus pneumoniae (> 50% of adult cases)
Elderly and immunocompromised	S. pneumoniae, Listeria monocytogenes
Post-neurosurgery / CSF leak	Coagulase-negative staphylococci, S. aureus, Cutibacterium acnes, Pseudomonas aeruginosa

Robbins & Kumar Basic Pathology, p. 833; Rosen's Emergency Medicine, p. 2268

Important epidemiologic note: Haemophilus influenzae type b was previously a major cause in children but its incidence has sharply declined since the HiB vaccine. Meningococcal disease is most common in those living in close proximity (military barracks, college dormitories); serogroup B predominates in Europe, serogroup C in the United States. - Rosen's Emergency Medicine, p. 2268

Viral Etiology

Enteroviruses are now the most common cause of meningitis overall (given bacterial decline from vaccination)
Herpesviruses (HSV-1, HSV-2, CMV, EBV, VZV) - often in immunocompromised
HIV, mumps, influenza, measles, LCM virus
Prognosis for most viral meningitis is excellent

Pathogenesis

Step 1: Acquisition and Nasopharyngeal Colonization

Bacterial meningitis generally begins with nasopharyngeal colonization. Organisms like N. meningitidis and S. pneumoniae are carried asymptomatically in the nasopharynx of many individuals. Invasion occurs when bacteria penetrate the mucosal surface. Bacterial capsular polysaccharides are a key virulence factor that resist phagocytosis and allow the organism to survive in the bloodstream (bacteremia).

Step 2: Bacteremia and Blood-Brain Barrier (BBB) Crossing

Once in the bloodstream, bacteria must cross the BBB to enter the CSF. The subarachnoid space, once breached, supports rapid bacterial proliferation because it lacks adequate local immune defenses (low complement, low immunoglobulin levels in CSF). Bacteria multiply freely.

Step 3: Inflammatory Cascade in the Subarachnoid Space

This is the heart of pathogenesis. The immediate effect of bacteria (or their toxins, e.g., LPS, teichoic acid) in the subarachnoid space triggers a cascade:

Hyperemia of meningeal venules and capillaries, with increased vascular permeability
Exudation of protein and migration of neutrophils into the pia and subarachnoid space
Cytokine release into CSF (IL-1, IL-6, TNF-alpha) - this inflammatory cascade promotes:
- Further increased permeability of the BBB
- Cerebral vasculitis
- Cerebral edema
- Increased intracranial pressure (ICP)
Decreased cerebral blood flow → cerebral hypoxia

Because the subarachnoid space is continuous around the brain, spinal cord, and optic nerves, an organism gaining entry spreads rapidly throughout. Meningitis is therefore always cerebrospinal in extent. Infection also reaches the ventricles - either directly through the choroid plexuses or by reflux through the foramina of Magendie and Luschka.

Adams and Victor's Principles of Neurology, 12th Ed., p. 708; Rosen's Emergency Medicine, p. 2268

Temporal Sequence of Inflammatory Events (Adams & Victor's)

This temporal understanding explains the clinical state and its sequelae:

Timeframe	Pathological Event
Early (hours)	Hyperemia, increased vascular permeability, protein exudation; neutrophils migrate into pia and subarachnoid space
First few days	Subarachnoid exudate forms over brain base, into cranial and spinal nerve sheaths, and into cortical perivascular spaces. Neutrophils (mature and immature) predominate; many contain phagocytosed bacteria. Fibrinogen exudes and begins converting to fibrin
Days 3-5	Lymphocytes and histiocytes increase in number
End of week 1 - week 2	Plasma cells appear; exudate organizes into outer layer (neutrophils + fibrin, sub-arachnoid) and inner layer (lymphocytes, plasma cells, macrophages, next to pia). Fibroblasts proliferate. Thrombophlebitis of larger cortical veins may begin
Resolution	Inflammatory cells disappear in reverse order. Neutrophils disintegrate by days 4-5 with treatment. Lymphocytes/plasma cells/macrophages disappear slowly (may persist months)

Adams and Victor's Principles of Neurology, 12th Ed.

Vascular Changes

A striking feature of meningitis - appearing within 48-72 hours:

Endothelial cells of subarachnoid arteries swell, multiply, and crowd the lumen
Adventitial connective tissue sheath infiltrated by neutrophils
Foci of arterial wall necrosis may occur
Neutrophils and lymphocytes migrate from adventitia to sub-intimal region (subintimal fibrosis later)
In veins: endothelial swelling, adventitial infiltration, diffuse wall infiltration; mural thrombi and focal wall necrosis in affected veins
Thrombophlebitis of larger cortical veins may develop (usually not before end of second week)

This vascular reaction is most notably prominent in tuberculous and syphilitic meningitis (Heubner arteritis). It is anatomically explained by the fact that the adventitia of subarachnoid vessels is formed by an investment of the arachnoid membrane - which is invariably involved by the infectious process.

Adams and Victor's Principles of Neurology, 12th Ed., p. 709

Gross and Histologic Pathology

Gross appearance:

Gross section of brain showing areas of dark discoloration (hemorrhage/infarction) in meningitis

The brain surface shows cloudy, opaque arachnoid with purulent exudate filling the sulci; this exudate accumulates over the base of the brain particularly.

Histology:

Histological section showing dense neutrophilic infiltrate in subarachnoid space (pyogenic meningitis)

Dense neutrophilic infiltrate fills the subarachnoid space. The image shows neutrophils (blue-dark) concentrated in the meninges with relative sparing of the cortex (left).

Pathologic-Clinical Correlations

Acute Meningeal Inflammation

Pathological Event	Clinical Manifestation
Pure pia-arachnoiditis	Headache, stiff neck, Kernig and Brudzinski signs
Subpial encephalopathy	Confusion, stupor, coma, convulsions
Cranial nerve root inflammation	Ocular palsies, facial weakness, deafness (also caused by middle ear infection, inner ear extension, or aminoglycoside toxicity)
Meningeal vein thrombosis	Focal seizures, hemiparesis, aphasia
Obstructed CSF outflow	Raised ICP: papilledema, CN VI palsy, altered consciousness
Cerebellar/cerebral herniation	Upper cervical cord compression, quadriplegia, midbrain-third nerve compression

Subacute/Chronic Forms

Complication	Mechanism
Hydrocephalus	Purulent exudate at base of brain blocking CSF flow; later meningeal fibrosis
Subdural effusion	Impaired meningeal drainage
Venous or arterial infarction	Infectious vasculitis at brain base; cortical vein thrombosis

Late Sequelae

Meningeal fibrosis around optic nerves → blindness, optic atrophy
Spinal cord/root fibrosis → spastic paraparesis, sensory loss
Chronic meningoencephalitis with hydrocephalus → dementia, paralysis
Adams and Victor's Principles of Neurology, 12th Ed., pp. 708-710

Meningitis in Specific Contexts

Neonatal Meningitis

The most significant factor in the pathogenesis of neonatal meningitis is maternal infection (usually UTI or puerperal fever). In E. coli neonatal meningitis, pathogenesis involves colonization of the infant with maternal E. coli, with the K1 capsular antigen facilitating invasion.

Adams and Victor's Principles of Neurology, 12th Ed.

Tuberculous Meningitis

A form of chronic meningitis with especially prominent vascular changes (Heubner arteritis). The granulomatous exudate is concentrated at the base of the brain. Results in a particularly high rate of cranial nerve palsies, hydrocephalus, and deep infarctions due to involvement of perforating arteries.

Viral (Aseptic) Meningitis

Enteroviruses and herpesviruses are most common. The inflammatory response is predominantly lymphocytic rather than neutrophilic. CSF shows lymphocytic pleocytosis, mildly elevated protein, and normal or only mildly reduced glucose. Prognosis is generally excellent.

CSF Summary

Feature	Bacterial	Viral	TB/Fungal
Pressure	Elevated	Normal/mildly elevated	Elevated
Cells	Neutrophils (>1000/µL)	Lymphocytes (<500/µL)	Lymphocytes
Protein	Markedly elevated	Mildly elevated	Elevated
Glucose	Low (<45 mg/dL)	Normal	Very low
Appearance	Turbid/purulent	Clear	Clear/viscous

Key Sources:

Adams and Victor's Principles of Neurology, 12th Edition, Chapter 31 (Bacterial Meningitis section, pp. 708-710)
Robbins & Kumar Basic Pathology, Chapter 21 (CNS Infections, p. 833)
Rosen's Emergency Medicine, Chapter on Bacterial Meningitis (p. 2268)

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