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MENINGITIS

A Comprehensive Seminar Reference — In the Context of Pyrexia of Unknown Origin (PUO)

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MENINGITIS AND PUO — THE CLINICAL LINK

"Persistent fever with headache demands CSF examination." — Harrison's Principles of Internal Medicine 22E

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1. DEFINITION

Types of Meningitis by Aetiology:

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2. EPIDEMIOLOGY

Bacterial Meningitis

• Annual incidence in developed countries: ~1.4 cases/100,000 population (United States), and 0.5–1.5/100,000 in other developed nations — Harrison's 22E; Goldman-Cecil
• The incidence has dropped dramatically following vaccine introduction (Hib conjugate, pneumococcal, meningococcal vaccines)
• Since introduction of the Hib vaccine, S. pneumoniae has become the most common pathogen, accounting for ~70% of adult cases — Goldman-Cecil
• The disease is now more common in older adults than in children — Goldman-Cecil
• Mortality rate remains ~15–20% despite antibiotic therapy — Goldman-Cecil; Harrison's
• Worldwide, incidence is related to poverty and remains a major cause of mortality and morbidity
• Nosocomial meningitis accounts for an increasing proportion of cases in tertiary hospitals (~40% in some series)
• N. meningitidis causes recurring epidemics every 8–12 years — Harrison's 22E

Age Distribution of Causative Organisms:

Viral Meningitis

• Enteroviruses are the dominant cause worldwide, responsible for ~50% of all cases of meningitis and encephalitis in the United States — Goldman-Cecil
• Viral meningitis is far more common than bacterial meningitis but carries a much better prognosis

Fungal/Cryptococcal Meningitis

• Cryptococcal meningitis is predominantly seen in HIV/AIDS patients with CD4 count <100 cells/μL
• In the early 1990s, there were >1,000 cases/year in New York City alone — a figure exceeding all cases of bacterial meningitis — Harrison's 22E
• Mortality: 10–25% in developed countries, up to 43% in resource-poor settings — Bradley and Daroff's

Malaysia/Southeast Asia Context

• TB meningitis is particularly relevant in Malaysia given the high burden of tuberculosis in Southeast Asia
• Angiostrongylus cantonensis (rat lungworm) is the most common global cause of eosinophilic meningitis, with high endemicity in Southeast Asia and the Pacific — Adams and Victor's 12E
• Gnathostoma spinigerum causes severe eosinophilic meningoencephalitis in Southeast Asia, including Malaysia — Adams and Victor's
• Melioidosis (Burkholderia pseudomallei) is an important endemic cause of meningitis in Southeast Asia — Adams and Victor's

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3. AETIOLOGY

Bacterial Causes

Non-Bacterial Causes

• Viral: Enteroviruses (most common overall), HSV-2 (recurrent meningitis), VZV, EBV, CMV, HIV (acute seroconversion), West Nile virus, mumps
• Fungal: Cryptococcus neoformans/gattii (HIV/AIDS, organ transplant, haematological malignancy); Candida, Aspergillus (nosocomial/immunocompromised)
• Parasitic: Angiostrongylus cantonensis (eosinophilic meningitis), Gnathostoma spinigerum (SE Asia)
• Non-infectious: Sarcoidosis, systemic lupus erythematosus (SLE), Behçet disease, neoplastic/carcinomatous meningitis, drug-induced (NSAIDs, TMP-SMX, IVIG)

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4. PATHOPHYSIOLOGY

Step 1 — Colonisation and Invasion

Step 2 — Bacteraemia

Step 3 — Replication in CSF

• Normal CSF contains few WBCs
• Relatively small amounts of complement proteins and immunoglobulins — insufficient for effective opsonisation
• Fluid nature of CSF is less conducive to phagocytosis than solid tissue

Step 4 — Inflammatory Cascade (Critical Step)

"Many of the neurologic manifestations and complications of bacterial meningitis result from the immune response to the invading pathogen rather than from direct bacteria-induced tissue injury." — Harrison's 22E

• Lysis of bacteria → release of cell-wall components (LPS from Gram-negatives; teichoic acid and peptidoglycans from S. pneumoniae) into the SAS
• These stimulate microglia, astrocytes, monocytes, endothelial cells, and CSF leukocytes to produce TNF-α and IL-1β within 1–2 hours
• This is followed by: ↑ CSF protein concentration + leukocytosis
• Chemokines and proinflammatory cytokines → leukocyte migration into CSF
• Bacteraemia and cytokines → excitatory amino acids, reactive oxygen species (ROS), nitric oxide, peroxynitrite → neuronal death (especially hippocampal dentate gyrus)

Step 5 — Blood-Brain Barrier Disruption and Oedema

• TNF-α + IL-1β act synergistically to increase BBB permeability → vasogenic oedema + leakage of serum proteins into SAS
• Subarachnoid exudate obstructs CSF flow through the ventricular system and impairs arachnoid granulation resorption → obstructive and communicating hydrocephalus + interstitial oedema
• Inflammatory cytokines upregulate selectins on cerebral endothelium → leukocyte adherence → further BBB disruption
• Neutrophil degranulation → toxic metabolites → cytotoxic oedema, cell injury and death

Step 6 — Vascular Injury and Raised ICP

• Early: ↑ cerebral blood flow; later: ↓ CBF with loss of cerebrovascular autoregulation
• Vasculitis (endothelial swelling, intimal thickening) → narrowing of arteries at the base of the brain, ischaemia and infarction
• Thrombosis of middle cerebral artery branches, major cerebral venous sinuses, and cortical veins
• The combination of interstitial + vasogenic + cytotoxic oedema → raised ICP → coma
• Cerebral herniation results from focal or generalised cerebral oedema; hydrocephalus and dural sinus/cortical vein thrombosis contribute

Vascular Histopathology (Adams and Victor's)

• Within 48–72 hours: endothelial cells swell and multiply, adventitia infiltrated by neutrophils
• Focal necrosis of arterial wall, subintimal fibrosis
• Veins more susceptible to thrombosis due to thinner walls and slower flow
• Cortical thrombophlebitis does not usually develop before the end of the second week
• In TB and syphilitic meningitis: Heubner arteritis is a prominent vascular feature

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5. CLINICAL FEATURES

Classic Presentation

1. Fever
2. Headache (severe, generalised)
3. Neck stiffness (nuchal rigidity)

Other Key Symptoms and Signs

Meningeal Signs

Rash in Meningococcal Disease

• Petechial or purpuric skin lesions are a critical diagnostic clue for meningococcal disease
• The rash results from dermal seeding of organisms with vascular endothelial damage
• In some patients the disease is fulminant, progressing to death within hours of symptom onset
• Skin biopsy of petechial lesions may reveal organisms on Gram stain — Harrison's 22E
• Rash begins as non-specific erythematous maculopapular → petechial → purpuric (non-blanching)

Raised ICP Signs

• Papilloedema (may be absent in acute setting)
• Cushing's triad (hypertension, bradycardia, irregular breathing) — late sign
• Pupillary changes, posturing (decorticate/decerebrate)
• Sixth nerve palsy (false localising sign)

Viral Meningitis (Aseptic Meningitis)

• Headache (almost invariably present, often frontal or retroorbital)
• Photophobia, pain on moving the eyes
• Nuchal rigidity (usually mild, present only near the limit of anteflexion)
• Malaise, myalgia, anorexia, nausea, vomiting, diarrhoea
• Mild lethargy or drowsiness
• No profound alteration in consciousness (distinguishes from encephalitis)
• No focal neurological signs or seizures (if present, suspect encephalitis)
• Harrison's 22E, Chapter 143

TB Meningitis — Subacute/Chronic Features (PUO Relevance)

• Insidious onset over weeks with low-grade fever, malaise, anorexia, weight loss
• Headache and meningism develop gradually
• Cranial nerve palsies (especially CN III, IV, VI, VII) — from basilar meningitis
• Altered consciousness and focal deficits develop later
• Choroidal tubercles on fundoscopy (pathognomonic when present)
• Hyponatraemia (SIADH) is common

Cryptococcal Meningitis (PUO Relevance)

• Insidious onset over weeks; often in HIV/AIDS (CD4 <100) or organ transplant recipients
• Fever, headache, altered mental status
• Meningism may be minimal or absent
• Elevated ICP is a key feature (>25 cmH₂O) — can cause papilloedema and visual loss

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6. INVESTIGATIONS

A. Imaging Before Lumbar Puncture

• Immunocompromised state
• History of CNS disease (mass lesion, stroke, focal infection)
• New-onset seizures
• Papilloedema
• Altered level of consciousness
• Focal neurological deficit

Do not delay antibiotics for CT or LP — in suspected bacterial meningitis, blood cultures should be drawn and empirical antibiotics started immediately if CT or LP cannot be performed without delay.

B. Lumbar Puncture and CSF Analysis

• Opening pressure
• Appearance (clear/turbid/xanthochromic)
• Cell count with differential
• Protein
• Glucose (simultaneous serum glucose)
• Gram stain
• Culture and sensitivity
• PCR (bacterial multiplex, viral PCR, TB PCR/GeneXpert)
• India ink (for Cryptococcus)
• Cryptococcal antigen (CrAg) — sensitivity >90%
• AFB smear and culture (if TB suspected)
• Adenosine deaminase (ADA) — elevated in TB meningitis

CSF Interpretation Table

C. Blood Investigations

• Blood cultures (2 sets before antibiotics if LP can be delayed; do not delay antibiotics)
• FBC — leucocytosis (bacterial); lymphocytosis (viral/TB/fungal)
• CRP and ESR — markedly elevated in bacterial
• Procalcitonin — elevated in bacterial meningitis; helps distinguish bacterial from viral
• Electrolytes — hyponatraemia (SIADH, especially TB meningitis)
• Serum glucose (simultaneous with CSF)
• Coagulation profile — DIC may complicate bacterial meningitis
• HIV test — if cryptococcal/TB meningitis suspected
• Blood glucose for CSF:serum ratio

D. Microbiology

• Gram stain: Positive in >60% of bacterial meningitis cases — Harrison's 22E
• Culture: Positive in >80%
• PCR multiplex panel (FilmArray Meningitis/Encephalitis Panel): HSV-1, HSV-2, enteroviruses, VZV, HHV-6, human parechovirus, bacterial targets — Harrison's 22E
• India ink: Identifies Cryptococcus (large capsule)
• Cryptococcal antigen (CrAg): Sensitivity >90%, specificity >90%
• AFB smear + culture + GeneXpert MTB/RIF: TB meningitis
• Petechial skin biopsy: Gram stain may reveal N. meningitidis

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7. MANAGEMENT

PRINCIPLE: Bacterial Meningitis is a Medical Emergency

"The goal is to begin antibiotic therapy within 60 minutes of a patient's arrival in the emergency room." — Harrison's 22E

Step 1 — Empirical Therapy (Before Culture Results)

Step 2 — Specific (Targeted) Therapy by Organism

Duration of Antibiotic Therapy

Step 3 — TB Meningitis Management

• Isoniazid (H) 5 mg/kg/day + Rifampicin (R) 10 mg/kg/day + Pyrazinamide (Z) 25 mg/kg/day + Ethambutol (E) 15 mg/kg/day for 2 months, then
• Isoniazid + Rifampicin for 7–10 months (total duration: 9–12 months)
• Corticosteroids (Dexamethasone): Reduces mortality and morbidity in TB meningitis (WHO-recommended)
• Pyridoxine (Vitamin B6) 10 mg/day to prevent INH-related neuropathy

Step 4 — Cryptococcal Meningitis Management (3-Phase Approach)

• ICP management is critical in cryptococcal meningitis — serial therapeutic LPs (remove 20–30 mL CSF) or lumbar drain/ventriculostomy if refractory
• Lipid formulations of AmB (L-AmB) preferred in resource-rich settings to reduce nephrotoxicity

Step 5 — Viral Meningitis Management

• Largely supportive — analgesia, antipyretics, antiemetics, IV fluids
• Acyclovir 10 mg/kg IV q8h for HSV meningitis/encephalitis (empirically given if HSV suspected)
• Enteroviruses: no specific antiviral; Pleconaril (investigational)
• Recovery usually within 7–14 days

Step 6 — Supportive Care and ICP Management

• Elevation of head to 30–45°
• Intubation and hyperventilation (PaCO₂ 25–30 mmHg) — temporary ICP reduction
• Mannitol 0.25–0.5 g/kg IV — osmotic diuresis
• ICP monitoring device in patients with raised ICP — Harrison's 22E
• Seizure management: Benzodiazepines acutely; phenytoin/levetiracetam for prophylaxis
• Fluid management: Avoid hypovolaemia; treat SIADH with fluid restriction
• ICU care for patients with altered consciousness, need for ventilation, or haemodynamic instability

Step 7 — Chemoprophylaxis (Close Contacts of Meningococcal Disease)

Step 8 — Vaccination (Prevention)

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8. COMPLICATIONS

• Transtentorial (uncal) herniation: Third nerve compression → unilateral dilated pupil
• Central herniation: Bilateral cortical dysfunction
• Cerebellar/tonsillar herniation: Cervical cord compression → quadriplegia, cardiorespiratory arrest

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9. PROGNOSIS AND OUTCOMES

• Decreased intellectual function and memory impairment
• Sensorineural hearing loss and dizziness (most common sequela — highest with pneumococcal meningitis)
• Seizures
• Gait disturbances
• Hydrocephalus (communicating or obstructive)
• Visual impairment / optic atrophy

Poor Prognostic Factors (Harrison's 22E):

1. Decreased level of consciousness on admission
2. Onset of seizures within 24 hours of admission
3. Signs of raised ICP
4. Young age (infancy) and age >50
5. Comorbidities including shock and/or need for mechanical ventilation
6. Delay in initiation of treatment
7. CSF glucose <2.2 mmol/L (<40 mg/dL)
8. CSF protein >3 g/L (>300 mg/dL)

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SUMMARY TABLE: Key Differentiating Features

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KEY REFERENCES

• Harrison's Principles of Internal Medicine 22E (2025, McGraw-Hill) — Chapter 143: Meningitis, Encephalitis, Brain Abscess, and Empyema; Chapter 22: Fever of Unknown Origin
• Goldman-Cecil Medicine International Edition — Chapter 381: Meningitis
• Adams and Victor's Principles of Neurology, 12th Edition — Chapter 31: Bacterial and Fungal Infections of the Nervous System
• Bradley and Daroff's Neurology in Clinical Practice — Cryptococcal Meningitis and HIV-related Neurological Infections
• Malaysian National TB Programme (NTP) Guidelines — TB Meningitis Management

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What's Included