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Meningitis — Seminar Notes

Context: Pyrexia of Unknown Origin

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1. DEFINITION

• Acute pyogenic (usually bacterial) — polymorphonuclear (neutrophilic) CSF response
• Aseptic (usually viral) — lymphocytic CSF response
• Chronic (usually tuberculous, spirochetal, or fungal) — subacute onset over weeks to months

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2. EPIDEMIOLOGY

Global Burden

• Incidence of bacterial meningitis in developed countries: 0.5–1.5 per 100,000 adults — dramatically reduced by vaccination campaigns against H. influenzae type b (Hib), S. pneumoniae, and N. meningitidis
• Worldwide, incidence is closely tied to poverty; it remains a major cause of morbidity and mortality in low-income countries
• Despite improved diagnostics and antibiotics, mortality remains approximately 15% for bacterial meningitis
• Survivors carry significant neurological sequelae — highest rates in pneumococcal meningitis

Post-vaccination Epidemiology

• Since the Hib vaccine (1990s), S. pneumoniae has become the leading cause of bacterial meningitis, accounting for ~70% of adult cases
• The disease has shifted demographically — now more common in older adults than children
• Viral meningitis is now the most common overall due to the decline in bacterial causes

Meningococcal Disease

• N. meningitidis is most common in children and young adults in close-contact settings (military barracks, university dormitories)
• Serogroups A, C, Y, W-135 covered by conjugate vaccine; serogroup B requires a separate vaccine
• Group B prevalent in Europe; Group C in USA; Group A in sub-Saharan Africa (meningitis belt)

Malaysian Context

• PCV-13 (pneumococcal) as part of the National Immunisation Programme
• Meningococcal vaccine for high-risk groups and travellers
• Hib vaccine as part of the pentavalent vaccine in the primary series

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3. AETIOLOGY

Age-Based Causative Organisms

Viral Causes (Aseptic Meningitis)

• Enteroviruses (Enterovirus B species) — dominant cause of viral meningitis across all ages; account for ~50% of all meningitis/encephalitis in the USA
• Herpesviruses (HSV-1, HSV-2, VZV, CMV, EBV)
• Mumps virus (in unvaccinated populations)
• HIV (acute seroconversion illness)
• Arboviruses (e.g., Japanese Encephalitis Virus — endemic in Southeast Asia including Malaysia)

Fungal Causes (usually in immunocompromised)

• Cryptococcus neoformans — especially in HIV/AIDS, organ transplant recipients
• Histoplasma, Coccidioides, Candida — less common

Mycobacterial / Chronic Causes

• Mycobacterium tuberculosis — subacute/chronic meningitis; particularly relevant in Malaysia (high TB burden)
• Treponema pallidum (neurosyphilis)
• Borrelia burgdorferi (Lyme meningitis)

Risk Factors Predisposing to Meningitis

• Otitis media (most common predisposing condition)
• Sinusitis, mastoiditis
• CSF leak (post-traumatic or post-surgical)
• Alcoholism, asplenia, immunocompromised state (HIV, organ transplant, malignancy)
• Unvaccinated status
• Close-contact settings (military, dormitories, pilgrims — Hajj relevant to Malaysian Muslim population)
• Dural breach (neurosurgery, lumbar puncture)

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4. PATHOPHYSIOLOGY

Step 1 — Nasopharyngeal Colonisation & Mucosal Invasion

Step 2 — Bacteraemia & Blood-Brain Barrier (BBB) Penetration

• Bacteria enter the bloodstream → bacteraemia
• Cross the BBB via transcytosis through cerebral capillary endothelial cells, via infected monocytes ("Trojan horse"), or through choroid plexus epithelium
• The capsular polysaccharides of key pathogens resist phagocytosis and complement-mediated killing

Step 3 — Subarachnoid Space Proliferation

• Once within the CSF and subarachnoid space, host defence is severely limited — low immunoglobulin levels, poor complement activity, and minimal phagocytic capacity in normal CSF
• Bacteria proliferate rapidly

Step 4 — Inflammatory Cascade

• Bacterial cell wall components (lipopolysaccharide, teichoic acid, peptidoglycan) trigger release of pro-inflammatory cytokines — TNF-α, IL-1β, IL-6
• Leukocytes (predominantly neutrophils) are recruited into the CSF — pleocytosis
• This cascade produces:
  • Increased BBB permeability → vasogenic oedema
  • Cerebral vasculitis → cytotoxic oedema and cerebral ischaemia
  • Interstitial oedema due to impaired CSF reabsorption
  • Elevated intracranial pressure (ICP) from all three oedema types combined
  • Decreased cerebral blood flow → cerebral hypoxia and infarction
  • Venous sinus thrombosis (~1% of cases) → seizures and focal deficits

Step 5 — Systemic Complications

• Waterhouse-Friderichsen syndrome (meningococcemia): bilateral adrenal haemorrhage, DIC, purpura fulminans
• Endotoxic shock and cardiovascular collapse in fulminant disease

Viral Meningitis Pathophysiology

• Virus gains access via haematogenous spread or along neural pathways
• Triggers a lymphocytic/mononuclear inflammatory response in the meninges
• Less robust inflammatory cascade → less oedema, lower ICP → milder clinical course

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5. CLINICAL MANIFESTATIONS

Classic Triad

Fever + Headache + Neck Stiffness — present in ~85% of adult bacterial meningitis patients

Full Symptom Profile

Meningeal Signs

• Kernig's sign: Inability to fully extend the knee when the hip is flexed to 90°
• Brudzinski's sign: Passive neck flexion causes involuntary flexion of hips and knees
• Sensitivity: <12% (low) | Specificity: high — if present, strongly suggests meningitis
• Unreliable in infants <1 year

Age-Specific Presentations

Meningococcal-Specific Features

• Petechial → purpuric rash on extremities (anywhere on body)
• Rapid progression to endotoxic shock, DIC, purpura fulminans
• Waterhouse-Friderichsen syndrome: bilateral adrenal haemorrhage
• Cerebral venous thrombosis: new seizures, focal deficits

Fungal Meningitis (Cryptococcal)

• Subtle presentation even in healthy adults
• Low-grade fever, headache, malaise, weight loss
• Often not considered initially due to mild symptoms

Tuberculous Meningitis

• Subacute to chronic onset (weeks to months)
• May present with cranial nerve palsies (especially CN VI, III)
• Basal meningitis pattern — thick exudates at base of brain
• Relevant in Malaysia given high TB burden

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6. INVESTIGATIONS & EXPECTED OUTCOMES

A. Lumbar Puncture (LP) — CORNERSTONE of Diagnosis

• Papilledema
• Optic nerve sheath diameter >5 mm on bedside USS
• New-onset seizures
• Altered consciousness/focal neurological deficits
• Signs of mass lesion
• Coagulopathy (platelets <40,000, INR >1.4 on warfarin)
• Skin infection overlying puncture site

⚠️ Do NOT delay antibiotics while awaiting CT or LP — CSF can be sterilised within 1 hour of antibiotics but empirical treatment must not be withheld in high clinical suspicion cases.

B. CSF Analysis — Expected Findings

• India ink stain → Cryptococcus (low sensitivity ~30%; replaced by antigen test)
• Cryptococcal antigen → gold standard for cryptococcal meningitis (serum + CSF)
• AFB stain and TB culture → TB meningitis (AFB stain sensitivity <60%)
• PCR (multiplex): sensitivity 67–100% for H. influenzae, S. pneumoniae, N. meningitidis; remains positive up to 1 week post-antibiotics
• Viral PCR: HSV (96% sensitivity, 99% specificity), enterovirus, VZV

C. Blood Investigations

• Full blood count: Leukocytosis with neutrophilia in bacterial meningitis
• Blood cultures (×2 sets before antibiotics) — positive in up to 50% of bacterial meningitis
• CRP, procalcitonin — elevated in bacterial; helps differentiate from viral
• Serum glucose — required to calculate CSF:serum glucose ratio (<0.4 suggests bacterial)
• Serum electrolytes, renal function — SIADH may develop (hyponatraemia)
• Coagulation profile (PT, APTT, platelet) — assess for DIC in meningococcal disease
• LFTs — baseline before medications
• HIV serology — if cryptococcal or TB meningitis suspected

D. Imaging

• CT brain (contrast): Required before LP if contraindications exist
  • May show meningeal enhancement, hydrocephalus, cerebritis, abscess
  • MRI is superior for detecting leptomeningeal enhancement and complications
• MRI brain with gadolinium: Shows diffuse leptomeningeal/pachymeningeal enhancement, basilar enhancement (TB), temporal lobe involvement (HSV encephalitis)
• Chest X-ray: TB meningitis workup (primary focus, miliary pattern)

E. Other Investigations

• Optic nerve sheath ultrasound (bedside): >5 mm diameter suggests raised ICP; helps decide need for CT before LP
• EEG — if seizures or encephalitis suspected
• Mantoux/IGRA (interferon-gamma release assay) — TB meningitis workup

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7. MANAGEMENT PLAN

A. Immediate Stabilisation (First 30–60 Minutes)

1. ABCs: Secure airway; supplemental oxygen; IV access
2. Vital signs monitoring: BP, HR, SpO₂, GCS
3. Blood cultures ×2 — before antibiotics
4. Empirical antibiotics IMMEDIATELY — do not delay for LP/CT if clinical suspicion is high
5. IV dexamethasone — first dose before or with first antibiotic dose
6. CT brain only if indicated (papilledema, focal deficits, seizures, altered GCS)
7. LP as soon as safe

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B. Empirical Antibiotic Therapy

Vancomycin is added in areas with >2% incidence of highly drug-resistant S. pneumoniae (DRSP) — relevant in Malaysia.

• Ceftriaxone 2g IV q12h + Vancomycin 15–20 mg/kg IV q8–12h (targeting trough 15–20 µg/mL)
• Add Ampicillin 2g IV q4h if Listeria suspected (age >50, alcoholic, immunocompromised)
• Add Acyclovir 10 mg/kg IV q8h if HSV encephalitis cannot be excluded

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C. Adjunctive Corticosteroids

• Start before or with the first dose of antibiotics
• Reduces mortality and neurological sequelae, especially hearing loss
• Grade A evidence in:
  • Adults with suspected/proven pneumococcal meningitis (IDSA Grade A recommendation)
  • Children with Hib meningitis

⚠️ If not S. pneumoniae on culture, consider discontinuing dexamethasone — it may blunt penetration of vancomycin into CSF.

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D. Specific Targeted Therapy (after culture/sensitivity)

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E. Supportive Care

• Head elevation 30°, neutral neck position — reduce ICP
• IV fluids: Maintain euvolaemia — avoid hypovolaemia (worsens ischaemia) and overhydration (worsens oedema)
• Treat hyponatraemia carefully — SIADH is common; restrict fluids if Na <130 mEq/L
• Seizure management: Benzodiazepines acutely; prophylactic AEDs in selected cases
• Analgesia: Opioid analgesia for severe headache
• Antipyretics: Paracetamol for fever control
• Monitor for complications: DIC, septic shock, SIADH, cerebral herniation

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F. Raised ICP Management

• Dexamethasone (see above)
• Mannitol 0.25–1 g/kg IV for acute ICP elevation
• Hyperventilation (target PaCO₂ 30–35 mmHg) — temporising measure
• Consider external ventricular drain (EVD) if obstructive hydrocephalus develops

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G. Chemoprophylaxis for Close Contacts (Meningococcal Meningitis)

• Rifampicin 600 mg PO q12h × 2 days (adults) — first-line
• Ciprofloxacin 500 mg PO single dose (non-pregnant adults) — alternative
• Ceftriaxone 250 mg IM single dose (pregnant women)
• Also administer meningococcal vaccine to close contacts

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H. Vaccination (Prevention)

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8. COMPLICATIONS

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9. MENINGITIS IN THE CONTEXT OF PUO

• Fever is accompanied by headache, neck stiffness, or altered consciousness
• Fever persists despite treatment of other identified foci
• Immunocompromised patients with unexplained fever (lower threshold for LP)
• Subacute/chronic fever with cranial nerve palsies (TB meningitis — highly relevant in Malaysia)
• HIV-positive patients with fever and any CNS symptoms (cryptococcal meningitis)

• Bacterial: Acute onset, rapidly progressive, neutrophilic CSF
• Viral: Acute onset, self-limiting, lymphocytic CSF
• TB: Subacute (days to weeks), lymphocytic CSF with very low glucose, basal cistern involvement on MRI
• Fungal: Subacute to chronic, lymphocytic CSF, elevated opening pressure, India ink / cryptococcal antigen positive

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SUMMARY TABLE: CSF Profiles at a Glance

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• Goldman-Cecil Medicine International Edition (26th Ed.) — Bacterial Meningitis Chapter
• Rosen's Emergency Medicine: Concepts and Clinical Practice (9th Ed.) — Chapter 95
• Robbins & Kumar Basic Pathology (10th Ed.) — Chapter 21
• Textbook of Family Medicine (9th Ed.) — Chapter 41
• IDSA Clinical Practice Guidelines for Bacterial Meningitis (Tunkel et al., 2004; updated 2023)
• Malaysian Ministry of Health Clinical Practice Guidelines: Management of Meningitis
• WHO Guidelines on the management of endemic meningitisHere is your comprehensive seminar resource on Meningitis within the context of Pyrexia of Unknown Origin, drawn from Goldman-Cecil Medicine, Rosen's Emergency Medicine, Robbins & Kumar Pathology, and Textbook of Family Medicine.

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Meningitis — Seminar Notes

Context: Pyrexia of Unknown Origin

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1. DEFINITION

• Acute pyogenic (usually bacterial) — polymorphonuclear (neutrophilic) CSF response
• Aseptic (usually viral) — lymphocytic CSF response
• Chronic (tuberculous, fungal, spirochetal) — subacute, developing over weeks to months

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2. EPIDEMIOLOGY

Global Burden

• Incidence of bacterial meningitis in developed countries: 0.5–1.5 per 100,000 adults — dramatically reduced by vaccination
• Despite diagnostic advances, mortality remains ~15%; survivors carry significant neurological sequelae (highest in pneumococcal meningitis)
• Post-Hib vaccine era: S. pneumoniae now accounts for ~70% of adult bacterial meningitis; disease has shifted toward older adults
• Viral meningitis is now the most common overall form owing to the decline in bacterial disease

Meningococcal Epidemiology

• N. meningitidis predominates in children and young adults in close-contact settings (dormitories, military barracks)
• Serogroup distribution: Group B — Europe; Group C — USA; Group A — sub-Saharan Africa (meningitis belt)
• Malaysian relevance: Meningococcal vaccine (MenACWY) is mandatory for Hajj/Umrah pilgrims per Ministry of Health Malaysia

Malaysian Context

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3. AETIOLOGY

By Age Group

Viral Causes (Aseptic Meningitis)

• Enteroviruses (Enterovirus B species) — dominant; account for ~50% of all meningitis/encephalitis; fever, headache, meningism; usually self-limiting
• Herpesviruses: HSV-1/2, VZV, CMV, EBV
• HIV (acute seroconversion)
• Arboviruses: Japanese Encephalitis Virus — endemic in Southeast Asia including Malaysia
• Mumps — in unvaccinated populations

Fungal (Immunocompromised)

• Cryptococcus neoformans — HIV/AIDS, organ transplant; subacute presentation
• Candida, Histoplasma, Coccidioides — less common

Chronic / TB

• Mycobacterium tuberculosis — highly relevant in Malaysia (high TB burden); subacute/chronic onset; basal meningitis
• Treponema pallidum (neurosyphilis)
• Borrelia burgdorferi (Lyme — also causes facial palsy, radiculopathy)

Predisposing Risk Factors

• Otitis media (most common)
• Sinusitis, mastoiditis, CSF leak (post-traumatic/surgical)
• Alcoholism, asplenia, immunocompromised state
• Unvaccinated status
• Close-contact settings; pilgrims (Hajj/Umrah)
• Dural breach (neurosurgery, lumbar puncture)

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4. PATHOPHYSIOLOGY

Step 1 — Nasopharyngeal Colonisation & Mucosal Invasion

Step 2 — Bacteraemia & BBB Penetration

• Transcytosis through cerebral capillary endothelial cells
• Infected monocytes ("Trojan horse")
• Choroid plexus epithelium

Step 3 — Subarachnoid Proliferation

Step 4 — Inflammatory Cascade

Step 5 — Systemic Complications

• Waterhouse-Friderichsen syndrome (meningococcal): bilateral adrenal haemorrhage + DIC + purpura fulminans
• Endotoxic shock → cardiovascular collapse in fulminant disease
• SIADH → hyponatraemia

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5. CLINICAL MANIFESTATIONS

Classic Triad

Fever + Severe Headache + Neck Stiffness — present in ~85% of adults

Key Signs & Symptoms

Meningeal Signs

• Kernig's sign: Inability to fully extend the knee when hip is flexed to 90°
• Brudzinski's sign: Passive neck flexion causes involuntary hip/knee flexion
• Sensitivity <12% (low) but high specificity — presence strongly confirms meningitis
• Unreliable in infants <1 year

Age-Specific Presentations

Meningococcal-Specific

• Petechial/purpuric rash on extremities (anywhere)
• Rapid progression → endotoxic shock, DIC
• Waterhouse-Friderichsen syndrome: bilateral adrenal haemorrhage

TB Meningitis (Subacute–Chronic)

• Cranial nerve palsies (CN VI most common, then CN III)
• Symptoms over weeks to months
• Basal meningitis pattern; CSF with markedly low glucose

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6. INVESTIGATIONS & EXPECTED OUTCOMES

A. Pre-LP Assessment

• Bedside optic nerve sheath USS: diameter >5 mm → raised ICP
• If any of the following → CT brain first:
  • Papilledema
  • New seizures / focal neurological deficit
  • Altered GCS
  • Signs of mass lesion

⚠️ Never delay empirical antibiotics pending CT/LP if high clinical suspicion exists. CSF can be sterilised within 1 hour of antibiotics, so LP should be as expeditious as possible.

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B. CSF Analysis — Expected Findings

• PCR (multiplex): H. influenzae (67–100%), S. pneumoniae (79–100%), N. meningitidis (91–100%); sensitivity 70% even after 1 week of antibiotics
• HSV PCR: 96% sensitivity, 99% specificity — avoids need for brain biopsy
• Cryptococcal antigen: gold standard for cryptococcal meningitis (serum + CSF)
• India ink stain: quick but low sensitivity (~30%) for Cryptococcus
• AFB stain/TB culture + adenosine deaminase (ADA): for TB meningitis (AFB sensitivity <60%)

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C. Blood Investigations

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D. Imaging

• Diffuse leptomeningeal/pachymeningeal enhancement along cerebral convexities and basal cisterns
• Basilar cisternal exudates → TB meningitis
• Temporal lobe signal changes → HSV encephalitis

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7. MANAGEMENT

A. Immediate Stabilisation (First Hour)

1. ABCs: Airway, breathing, circulation; O₂, IV access
2. Blood cultures ×2 — before antibiotics, without delaying treatment
3. Empirical IV antibiotics IMMEDIATELY
4. Dexamethasone IV — first dose given before or with first antibiotic dose
5. CT brain only if LP is contraindicated (avoid delaying treatment)
6. LP as soon as it is safe

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B. Empirical Antibiotic Therapy

Add Vancomycin where drug-resistant S. pneumoniae (DRSP) incidence is >2% — relevant in Malaysia.

Add Ampicillin 2g IV q4h if Listeria suspected (age >50, alcoholism, immunosuppression).

Add Acyclovir 10 mg/kg IV q8h if HSV encephalitis cannot be excluded.

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C. Adjunctive Corticosteroids — Grade A Recommendation

• Start before or with the first antibiotic dose
• Reduces mortality and neurological sequelae (especially sensorineural hearing loss)
• Grade A evidence in:
  • Adults with suspected/proven pneumococcal meningitis (IDSA)
  • Children with Hib meningitis (IDSA)

⚠️ If S. pneumoniae not confirmed on culture, consider stopping dexamethasone — it may reduce CSF penetration of vancomycin.

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D. Targeted Therapy (After Culture/Sensitivity)

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E. Supportive Care

• Head of bed elevated 30°, neutral neck position (reduce ICP)
• Maintain euvolaemia (avoid both hypovolaemia and fluid overload)
• Treat SIADH/hyponatraemia (fluid restrict if Na <130 mEq/L)
• Seizure management: benzodiazepines acutely; AEDs in recurrent seizures
• Analgesia (opioids for severe headache), antipyretics (paracetamol)
• Monitor for complications: DIC, septic shock, herniation

F. Raised ICP Management

• Dexamethasone (see above)
• Mannitol 0.25–1 g/kg IV for acute ICP elevation
• Controlled hyperventilation (PaCO₂ 30–35 mmHg) as temporising measure
• EVD (external ventricular drain) if obstructive hydrocephalus develops

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G. Chemoprophylaxis (Meningococcal Close Contacts)

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H. Vaccination (Prevention)

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8. COMPLICATIONS

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9. MENINGITIS IN THE CONTEXT OF PUO

• Fever + headache/neck stiffness/altered consciousness — classical presentation
• Subacute fever + cranial nerve palsy → TB meningitis (especially in Malaysia)
• HIV+ patient with unexplained fever and any CNS symptom → cryptococcal meningitis
• Prolonged fever in immunocompromised patient without obvious source → low threshold for LP
• Fever + purpuric rash → meningococcal disease — a medical emergency

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