1. General aetiopathogenesis of meningitis
   • Routes of infection, inflammatory response in the meninges, cerebral edema, raised intracranial pressure, vasculitis, hydrocephalus, and complications.
2. Acute bacterial (pyogenic) meningitis
   • Common organisms by age and setting.
   • Pathogenesis.
   • Gross morphology: purulent leptomeningeal exudate.
   • Microscopy: neutrophilic exudate in subarachnoid space, vascular congestion, possible cerebritis and ventriculitis.
3. Viral (aseptic) meningitis
   • Common viruses and route of infection.
   • Usually milder meningeal inflammation.
   • Gross and microscopic features: clear or mildly cloudy CSF and predominantly lymphocytic meningeal infiltrate.
4. Tuberculous meningitis
   • Hematogenous spread from a primary focus and formation/rupture of a Rich focus.
   • Characteristic basal gelatinous exudate, tubercles, granulomatous inflammation, vasculitis, infarction, and hydrocephalus.
5. CSF examination for differential diagnosis
   • Opening pressure, appearance, cell type/count, protein, glucose, chloride, Gram stain, culture, acid-fast tests, nucleic-acid tests, and antigen testing.
   • Pattern-based distinction among pyogenic, viral, and tuberculous meningitis.

• Acute bacterial meningitis
• Viral meningitis
• Tuberculous meningitis
• CSF differential diagnosis

1. Acute bacterial (pyogenic) meningitis

Gross features

• Leptomeninges are congested, opaque, and thickened due to acute inflammation.
• A thick yellow-green, creamy purulent exudate fills the subarachnoid space and covers the brain surface.
• Exudate is most prominent over the cerebral convexities, within sulci, and at the base depending on the organism.
• Meningeal blood vessels are dilated, engorged, and prominent.
• Pus may track along leptomeningeal vessels.
• In severe disease, the brain may be swollen due to cerebral edema.
• Complications visible at autopsy can include ventriculitis, venous thrombosis, hemorrhagic infarction, cerebritis, and later leptomeningeal fibrosis with communicating hydrocephalus.

Microscopic features

• The subarachnoid space is filled with a dense neutrophilic exudate containing fibrin, necrotic debris, and variable numbers of bacteria.
• Neutrophils may diffusely occupy the entire subarachnoid space or cluster around leptomeningeal blood vessels.
• Meningeal vessels show congestion, and in severe disease there is:
  • Inflammation of vessel walls
  • Vasculitis
  • Thrombosis, especially venous thrombosis
• The inflammation can extend through the pia into superficial cerebral cortex, causing focal cerebritis.
• Gram stain may demonstrate the responsible organism, especially before antimicrobial treatment.
• During healing, organization of the exudate produces fibrosis and adhesions that impair CSF absorption, leading to hydrocephalus.

2. Viral (aseptic) meningitis

Gross features

• Gross changes are usually mild compared with bacterial meningitis.
• The brain may be normal or show slight cerebral edema and congestion.
• Leptomeninges may appear mildly opaque, hyperemic, or congested.
• There is no thick purulent exudate.
• The CSF is generally clear, rather than turbid or frankly purulent.
• If the viral disease also causes encephalitis, the brain may show edema and focal changes specific to the virus. These parenchymal changes are not a feature of uncomplicated viral meningitis.

Microscopic features

• The principal lesion is a lymphocytic and mononuclear inflammatory infiltrate in the leptomeninges and subarachnoid space.
• Cells include:
  • Lymphocytes
  • Monocytes/macrophages
  • Occasional plasma cells
• Inflammation is often most evident around small meningeal vessels, producing perivascular mononuclear cuffing.
• There is vascular congestion and variable edema, but neutrophil-rich suppuration is absent.
• The underlying cerebral cortex is usually unaffected in pure meningitis.
• When associated with meningoencephalitis, additional parenchymal features may occur:
  • Microglial proliferation
  • Perivascular lymphocytic cuffing
  • Neuronal degeneration or neuronophagia, depending on the virus

3. Tuberculous meningitis

Gross features

• The characteristic lesion is a thick, gelatinous, gray-white or yellowish basal exudate.
• The exudate is concentrated around the:
  • Interpeduncular and pontine cisterns
  • Optic chiasm
  • Circle of Willis
  • Floor of the third ventricle
  • Medulla and undersurface of temporal lobes
• It may envelop cranial nerves and major blood vessels at the base of the brain.
• Small, discrete gray-white tubercles are scattered over the basal meninges and, less commonly, over the cerebral convexities.
• Basal cisterns may become obliterated by exudate and fibrosis.
• The ependyma and choroid plexus may have minute tubercles.
• Associated findings include:
  • Hydrocephalus from obstruction of CSF pathways or impaired CSF resorption
  • Cerebral infarcts due to tuberculous vasculitis
  • Tuberculomas in brain parenchyma
  • Involvement of spinal meninges in some cases

Microscopic features

• There is granulomatous inflammation in the meninges.
• Typical tubercles show:
  • Central caseous necrosis
  • Surrounding epithelioid histiocytes
  • Langhans-type giant cells
  • Peripheral lymphocytes, plasma cells, and fibroblasts/connective tissue
• The meningeal exudate contains fibrin, lymphocytes, plasma cells, macrophages/other mononuclear cells, and sometimes a small number of polymorphs.
• Unlike ordinary pyogenic meningitis, the inflammation frequently extends beyond the subarachnoid space:
  • Through the pia into underlying cortex
  • Into the ependyma and ventricular system
    Thus, tuberculous meningitis may become a meningoencephalitis.
• Blood vessels, especially at the base, may show:
  • Endarteritis and vasculitis
  • Intimal proliferation
  • Thrombosis and luminal occlusion
  • Resulting ischemic infarcts
• Chronic healing causes dense arachnoid fibrosis and adhesions, especially at the base, producing communicating or obstructive hydrocephalus.

One-line pathology comparison

CSF findings in meningitis: comparison table

High-yield diagnostic pattern

• Bacterial meningitis: high opening pressure + turbid CSF + very high neutrophil count + high protein + low glucose.
• Viral meningitis: clear CSF + lymphocytic pleocytosis + normal glucose + only modest protein rise.
• Tuberculous meningitis: raised opening pressure + lymphocytic pleocytosis + markedly raised protein + low glucose. The chronic course and basal meningeal disease support the diagnosis.

Aetiopathogenesis of meningitis

Aetiology

Routes by which organisms reach the meninges

1. Hematogenous spread - commonest route
   • Organisms first colonize or infect a distant site, enter the bloodstream, and reach meningeal vessels or choroid plexus.
   • They cross the blood-brain or blood-CSF barrier and multiply in CSF.
   • Typical for meningococcal, pneumococcal, viral, and tuberculous meningitis.
2. Direct extension from a local septic focus
   • Otitis media, mastoiditis, sinusitis, skull osteomyelitis, or vertebral infection may extend into the cranial cavity.
   • This route is particularly relevant in pneumococcal and other bacterial meningitides.
3. Direct inoculation
   • Skull fracture, penetrating trauma, neurosurgery, cochlear implants, ventricular shunts, or CSF leak can permit entry of bacteria.
   • Common pathogens include staphylococci and gram-negative bacilli.
4. Neural spread
   • Some viruses, notably HSV and VZV, may reach the CNS by retrograde spread along peripheral nerves, particularly trigeminal or olfactory pathways.

General pathogenesis

1. Entry and survival in blood

2. Crossing into the CNS

• Cerebral capillary endothelium
• Choroid plexus epithelium
• Postcapillary venules of the meninges

3. Host inflammatory response

• Increased vascular permeability
• Breakdown of the blood-brain barrier
• Entry of inflammatory cells into CSF
• Protein-rich exudate in the subarachnoid space
• Cerebral edema and raised intracranial pressure
• Impaired CSF absorption and hydrocephalus
• Vasculitis, thrombosis, ischemia, and infarction

Pathogenesis by major type

A. Acute bacterial meningitis

Sequence

Key mechanisms

• Bacteria and their products, for example lipopolysaccharide of gram-negative organisms or cell-wall components of gram-positive organisms, stimulate cytokine release.
• Endothelial injury and increased permeability allow plasma proteins and neutrophils to enter the subarachnoid space.
• A fibrinopurulent exudate forms around the leptomeninges and vessels.
• Cytokines and leukocyte products cause cerebral edema, impaired autoregulation of cerebral blood flow, raised intracranial pressure, and reduced cerebral perfusion.
• Vasculitis and thrombosis may cause focal ischemia or hemorrhagic infarction.
• Exudate and subsequent fibrosis obstruct CSF circulation or resorption, causing hydrocephalus.

B. Viral meningitis

Sequence

Key mechanisms

• Enteroviruses most often enter through the gastrointestinal tract and cause viremia before reaching the meninges.
• Respiratory viruses, mumps, and VZV commonly begin in the respiratory tract.
• HSV may reach the CNS through mucosal infection, viremia, or retrograde neural spread.
• Viral replication in meningeal cells and immune activation causes vascular congestion, increased permeability, and lymphocytic infiltration.
• Since neutrophilic suppuration and severe vascular injury are usually absent, viral meningitis is generally less destructive and more often self-limiting than bacterial meningitis.
• If the virus invades brain parenchyma, the illness becomes meningoencephalitis, with neuronal injury and microglial activation.

C. Tuberculous meningitis

Sequence

Key mechanisms

• M. tuberculosis reaches the CNS hematogenously, often during primary infection or later reactivation.
• Small tuberculous foci form in meninges, subpial brain tissue, or adjacent structures.
• Rupture of one or more foci into the subarachnoid space releases bacilli and produces diffuse meningeal infection.
• A delayed-type, cell-mediated immune response causes granulomatous inflammation with epithelioid cells, Langhans giant cells, lymphocytes, and caseous necrosis.
• The inflammation is characteristically concentrated at the base of the brain.
• A thick basal exudate encases cranial nerves and cerebral vessels, leading to:
  • Cranial nerve palsies
  • Obliterative endarteritis and infarction
  • Obstruction of basal cisterns and communicating hydrocephalus
  • Extension into cortex, ependyma, or spinal meninges

Flowchart for recall

Practice viva questions: Meningitis

Basic concepts

1. Define meningitis. Which meninges are primarily affected?
2. Classify meningitis according to duration and aetiology.
3. What is meant by acute pyogenic meningitis?
4. What is aseptic meningitis? Is it always viral?
5. What is chronic meningitis? Name its common infective causes.
6. Name the common organisms causing bacterial meningitis in:
   • Neonates
   • Children and young adults
   • Older adults
   • Immunocompromised patients
7. What is the commonest cause of viral meningitis?
8. What organism causes tuberculous meningitis?

Aetiopathogenesis

1. List the routes by which organisms reach the meninges.
2. What is the commonest route of infection in meningitis?
3. How do organisms cross the blood-brain barrier or blood-CSF barrier?
4. Why can bacteria multiply rapidly in the subarachnoid space?
5. Describe the sequence of events in bacterial meningitis from nasopharyngeal colonization to meningeal inflammation.
6. What bacterial factors help meningococci and pneumococci produce bacteremia?
7. What role do bacterial cell-wall products and endotoxins play in meningitis?
8. Name important inflammatory mediators involved in bacterial meningitis.
9. Why can neurological injury continue after antibiotics have sterilized the CSF?
10. How does meningeal inflammation cause cerebral edema and raised intracranial pressure?
11. How does meningitis produce hydrocephalus?
12. How does vasculitis in meningitis cause cerebral infarction?
13. Describe the pathogenesis of viral meningitis.
14. How do enteroviruses reach the meninges?
15. What is the route of CNS spread in HSV infection?
16. Explain the formation of a Rich focus in tuberculous meningitis.
17. Describe the pathogenesis of tuberculous meningitis from primary infection to meningeal disease.
18. Why is the exudate in tuberculous meningitis predominantly basal?
19. How does tuberculous meningitis cause cranial nerve palsies?

Gross pathology

1. Describe the gross appearance of acute bacterial meningitis at autopsy.
2. Where is the purulent exudate found in bacterial meningitis?
3. What is the appearance of meningeal vessels in acute pyogenic meningitis?
4. What is the gross appearance of viral meningitis?
5. Why is thick purulent exudate absent in viral meningitis?
6. Describe the characteristic gross features of tuberculous meningitis.
7. What is the nature and site of the exudate in tuberculous meningitis?
8. Name the basal structures commonly involved by the exudate in tuberculous meningitis.
9. What are meningeal tubercles?
10. What gross complications may be found in chronic tuberculous meningitis?

Microscopic pathology

1. Describe the microscopic features of acute bacterial meningitis.
2. Which inflammatory cell predominates in pyogenic meningitis and why?
3. What is the composition of the exudate in bacterial meningitis?
4. What is cerebritis? How can it occur in pyogenic meningitis?
5. What vascular complications occur in bacterial meningitis?
6. What late microscopic change can cause hydrocephalus after bacterial meningitis?
7. Describe the microscopic features of viral meningitis.
8. Which inflammatory cells predominate in viral meningitis?
9. What is meant by perivascular mononuclear cuffing?
10. How does viral meningoencephalitis differ from isolated viral meningitis?
11. Describe a tubercle microscopically.
12. Describe the microscopic features of tuberculous meningitis.
13. What are the components of the tuberculous meningeal exudate?
14. What is caseous necrosis?
15. What type of vascular lesion occurs in tuberculous meningitis?
16. Why may tuberculous meningitis be called a meningoencephalitis?
17. What changes are seen in the ependyma and choroid plexus in tuberculous meningitis?

CSF examination

1. What are the normal opening pressure, cell count, protein, and glucose values in CSF?
2. What tests should be requested on CSF in a patient with suspected meningitis?
3. Why should blood glucose be measured simultaneously with CSF glucose?
4. Describe the typical CSF findings in acute bacterial meningitis.
5. Why is CSF turbid in bacterial meningitis?
6. What is the usual CSF cell type in bacterial meningitis?
7. Why is glucose reduced in bacterial meningitis?
8. Why is CSF protein elevated in bacterial meningitis?
9. What are the CSF findings in viral meningitis?
10. Why is CSF glucose usually normal in viral meningitis?
11. What are the classical CSF findings in tuberculous meningitis?
12. What is a cobweb clot? In which condition is it classically described?
13. Which cells predominate in tuberculous meningitis?
14. Can early tuberculous meningitis show neutrophilic pleocytosis?
15. Can early viral meningitis show neutrophils in CSF?
16. What is the role of Gram stain in suspected bacterial meningitis?
17. What is the role of CSF bacterial culture?
18. What is the role of PCR or nucleic-acid amplification tests in viral and tuberculous meningitis?
19. What is the role and limitation of acid-fast staining of CSF?
20. What is the role of CSF ADA in tuberculous meningitis?
21. What happens to culture and Gram-stain yield if antibiotics are given before lumbar puncture?

Differential diagnosis viva scenarios

1. A patient has turbid CSF, opening pressure is high, WBC count is 3,000/µL with 90% neutrophils, protein is 250 mg/dL, and glucose is 20 mg/dL. What is the likely diagnosis?
2. CSF is clear, contains 300 cells/µL with lymphocyte predominance, protein is mildly raised, and glucose is normal. What is the likely diagnosis?
3. CSF shows 200 cells/µL with lymphocytic predominance, very high protein, low glucose, and a cobweb clot on standing. What is the likely diagnosis?
4. A patient with basal meningeal enhancement, hydrocephalus, and cranial nerve palsies most likely has which type of meningitis?
5. A patient has a lymphocytic CSF but glucose is low and protein is markedly raised. What diagnoses must be considered besides viral meningitis?
6. Can a partially treated bacterial meningitis have a misleading CSF profile? Explain.
7. What conditions can mimic the CSF findings of bacterial meningitis?
8. What conditions can mimic lymphocytic meningitis with low CSF glucose?

Complications

1. List the major complications of acute bacterial meningitis.
2. Explain the mechanism of raised intracranial pressure in meningitis.
3. How does bacterial meningitis lead to seizures?
4. How can bacterial meningitis cause hearing loss?
5. What are the important complications of tuberculous meningitis?
6. Why are infarcts common in tuberculous meningitis?
7. Why is hydrocephalus particularly important in tuberculous meningitis?
8. Which cranial nerves are commonly affected in tuberculous meningitis, and why?
9. What are the possible long-term sequelae of meningitis?

Practical viva questions

1. When should neuroimaging be considered before lumbar puncture?
2. If bacterial meningitis is strongly suspected but lumbar puncture is delayed, what should be done first?
3. What are the contraindications or major precautions for lumbar puncture?
4. Why are blood cultures important in suspected bacterial meningitis?
5. Why must CSF findings be interpreted together rather than using a single parameter?
6. Give a one-minute comparison of bacterial, viral, and tuberculous meningitis based on:

• Type of inflammation
• Predominant cells
• CSF glucose
• CSF protein
• Major complications

Final rapid-fire questions

1. Which meningitis is suppurative?
2. Which meningitis is non-purulent and lymphocytic?
3. Which meningitis produces basal gelatinous exudate?
4. Which meningitis classically produces caseating granulomas?
5. Which meningitis most typically has low CSF glucose and neutrophils?
6. Which meningitis most typically has normal CSF glucose and lymphocytes?
7. Which meningitis most commonly causes basal arachnoid fibrosis and hydrocephalus?
8. What is the single most important laboratory specimen in suspected meningitis?
9. What is the gold-standard test for identifying a bacterial pathogen in CSF?
10. What is the key pathological reason for permanent neurological deficits in meningitis?