What is the diagnostic and treatment approach for a patient with suspected or confirmed tuberculosis (TB) infection, particularly with neurological involvement, and abnormal cerebrospinal fluid (CSF) findings?

CSF Findings in Tuberculous Meningitis

Tuberculous meningitis presents with characteristic CSF findings: lymphocytic pleocytosis (typically 100-500 cells/μL), markedly elevated protein (>1 g/L), and low glucose (<2.2 mmol/L or CSF:serum glucose ratio <0.5). 1, 2, 3

Diagnostic CSF Profile

Cell Count and Differential

• Lymphocytic predominance is the hallmark, though early disease may show neutrophil predominance that shifts to lymphocytes over 24-48 hours 2, 3
• Total white cell count typically ranges from 100-500 cells/μL, though can be lower in immunocompromised patients 4, 5
• The lymphocytic pattern distinguishes TB meningitis from acute bacterial meningitis (which shows ≥1,180 neutrophils/μL) 5

Glucose

• CSF glucose <2.2 mmol/L has 96% specificity for TB meningitis but only 68% sensitivity 6
• CSF:serum glucose ratio <0.5 is more sensitive (90%) and should be used preferentially over absolute values 6
• This low glucose distinguishes TB meningitis from typical viral encephalitis (which maintains CSF:plasma glucose ratio >0.36) 1
• The combination of lymphocytic pleocytosis with low glucose strongly suggests TB meningitis over viral causes 7, 3

Protein

• CSF protein >1 g/L diagnoses TB meningitis with 94% specificity and 78% sensitivity 6
• Markedly elevated protein (often 1-5 g/L) is characteristic and helps differentiate from viral meningitis 2, 3
• Protein >100 mg/dL with subacute onset should trigger mycobacterial testing 5

Microbiological Confirmation

Acid-Fast Bacillus (AFB) Smear and Culture

• AFB smear has low sensitivity (10-20%) but culture remains the gold standard with >97% specificity 4, 2
• Diagnostic yield increases dramatically with large volume samples (≥6 mL) and multiple specimens 4, 5
• Repeat lumbar puncture at 24-48 hours if initial studies are non-diagnostic but clinical suspicion remains high 5, 3
• Culture provides isolates for drug susceptibility testing, which is critical for guiding therapy and preventing treatment failure 4

Nucleic Acid Amplification Testing (NAAT/PCR)

• CSF PCR has 62% sensitivity but 98% specificity - a positive result confirms TB meningitis, but a negative result cannot exclude it 4
• PCR on CSF filtrates (not sediments) increases sensitivity to 87.6% versus 53.1% for sediments 8
• Nested PCR techniques can detect as little as 0.1 fg of M. tuberculosis DNA with 98% sensitivity and 92% specificity 9
• A negative NAAT should never delay treatment when clinical suspicion is high 4, 2

Critical Management Principles

Immediate Treatment Imperative

• TB meningitis is a medical emergency - start empiric therapy immediately when clinical suspicion is supported by initial CSF findings 1, 2, 3
• Do not wait for microbiological confirmation, as treatment delay is strongly associated with death and permanent neurologic sequelae 1, 3
• Treatment outcomes depend critically on early initiation before neurologic deterioration 1

Standard Treatment Regimen

• Four-drug regimen: isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 7-10 months (total 9-12 months) 1, 3
• Adjunctive dexamethasone 0.4 mg/kg/day for 3 weeks, then taper over 3 weeks, reduces mortality in all patients 1, 3
• Corticosteroids are particularly critical in patients with decreased level of consciousness 1

Drug-Resistant TB Considerations

• Patients with drug-resistant TB meningitis require at least 5 effective drugs, including a fluoroquinolone and injectable agent 1
• Treatment must be individualized based on drug susceptibility testing results 1

Special Populations

HIV-Infected Patients

• Maintain high suspicion regardless of CSF cell count, as immunocompromised patients may have atypical presentations 5
• Monitor for drug interactions and immune reconstitution inflammatory syndrome 1, 3
• May require longer treatment courses 1
• Management should involve specialists with expertise in both HIV and tuberculosis 3

Children

• Dosing adjusted by weight, with same 9-12 month treatment duration 1
• Children often have history of recent TB contact or family from high-incidence areas 4
• Should be managed by pediatricians with TB expertise 3

Common Pitfalls to Avoid

• Never delay treatment while awaiting culture results - the mortality benefit is time-dependent 1, 3
• Do not rely on single CSF sample - submit large volumes (≥6 mL) and repeat LP if initial non-diagnostic 4, 3
• Do not exclude TB meningitis based on negative PCR alone - sensitivity is only 62% 4
• Do not withhold corticosteroids - they reduce mortality regardless of disease severity 1, 3
• Consider partially treated bacterial meningitis in the differential, which can mimic TB with lymphocytic predominance and low glucose 7