How is tuberculosis (TB) meningitis diagnosed in high-risk individuals, such as those from endemic regions or with compromised immune systems?

Diagnosis of Tuberculous Meningitis

TB meningitis diagnosis requires CSF analysis with large volume sampling (≥5 mL) for acid-fast bacilli (AFB) smear, culture, nucleic acid amplification testing (NAAT/CBNAAT), and adenosine deaminase (ADA), combined with clinical assessment and neuroimaging, though culture remains the gold standard despite its low sensitivity of 25-70%. 1

Clinical Recognition and Risk Stratification

TB meningitis should be suspected in patients presenting with:

• Fever lasting more than 7 days, headache, or neck stiffness 2
• Altered mental status with a subacute course (symptoms persisting for weeks) 3
• History of recent tuberculosis contact or family originating from high TB incidence areas 4

High-risk populations requiring heightened suspicion include: 4

• HIV-positive individuals at all CD4 counts 4
• Immunocompromised patients (those on corticosteroids, TNF-α antagonists, chemotherapy) 4
• Travelers from or residents of TB-endemic regions (Africa, Central America, South and Southeast Asia, Middle East, former Soviet states, parts of South America) 4
• Young children, particularly those under 4 years of age 4

Critical pitfall: TB meningitis can occur in immunocompetent hosts, so do not exclude the diagnosis based solely on immune status 5. Even patients with normal physical examination and chest radiograph findings may have TB meningitis, especially when immunocompromised 4.

Cerebrospinal Fluid Analysis

Characteristic CSF findings include: 3, 2

• Lymphocytic-predominant pleocytosis
• Elevated protein
• Low glucose (CSF:plasma glucose ratio <50%) 2

Optimal diagnostic approach requires sending all tests simultaneously: 1

• AFB smear and culture: Culture is the gold standard with 25-70% sensitivity; highest yields occur with large volumes (≥5 mL) of CSF 1
• NAAT/CBNAAT (GeneXpert MTB/RIF or Xpert Ultra): Highly specific but suboptimal sensitivity; a negative result does not rule out TB meningitis 1, 6
• Adenosine deaminase (ADA): Should be sent alongside other tests 1

Key diagnostic principle: Despite advances in molecular technology, CBNAAT/PCR should always be accompanied by culture requests due to suboptimal sensitivity 1. Multiple large-volume CSF samples increase diagnostic yield 3.

Neuroimaging

MRI should be performed as soon as possible in all patients with suspected TB meningitis 4. Characteristic findings include:

• Basal meningeal enhancement 3, 2
• Hydrocephalus 6, 2
• Tuberculomas 2
• Evidence of vasculitis and infarction 2

CT scan should be considered before lumbar puncture in patients with known severe immunocompromise 4.

Additional Diagnostic Considerations

For immunocompromised patients, the diagnostic workup should also include: 4

• Indian ink staining and/or cryptococcal antigen (CRAG) testing for Cryptococcus neoformans
• CSF PCR for EBV and CMV
• Blood and CSF culture for Listeria monocytogenes
• Toxoplasma gondii antibody testing

For travelers from endemic regions: 4

• Rapid blood malaria antigen tests and thick/thin blood films (thrombocytopenia or malaria pigment may provide clues even if films are negative)
• Consider other endemic infections based on travel history

Screening for Latent TB in High-Risk Populations

For patients from endemic regions or with prolonged exposure risk: 4

• Interferon-gamma release assays (IGRAs) such as QuantiFERON TB-Gold or T-SPOT are preferred over tuberculin skin test (TST), particularly in immunosuppressed patients 4
• TST has high false-negative rates in immunosuppressed patients (83% anergic on steroids/immunomodulators vs 43% not on these therapies) 4
• Chest radiograph should be performed in all cases 4

For travelers returning from endemic areas: 4

• Screen before departure if no prior testing or negative screening >1 year ago
• Repeat testing 8-10 weeks after return if initial test was negative 4

Treatment Initiation

If clinical suspicion is high and ADA is elevated, empiric treatment should not be delayed while waiting for culture or CBNAAT results 1. Treatment delay is strongly associated with death, and empirical anti-tuberculosis therapy should be started promptly in all patients in whom TB meningitis is suspected 2. Empiric treatment should include at least four first-line drugs: isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol 3.

Critical caveat: Whenever possible, collect CSF specimens prior to initiating antimicrobial therapy 7, but do not delay treatment if TB meningitis is strongly suspected based on clinical presentation and initial CSF parameters 1.