What is the recommended antitubercular regimen, dosage, duration, and adjunctive therapy for central nervous system tuberculosis (tuberculous meningitis) in a patient without documented drug resistance?

Treatment of Central Nervous System Tuberculosis

For CNS tuberculosis without documented drug resistance, treat with a 12-month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol for the first 2 months, followed by isoniazid and rifampicin for 10 additional months, plus adjunctive dexamethasone or prednisolone tapered over 6–8 weeks starting immediately. 1, 2, 3

Anti-Tuberculosis Drug Regimen

Intensive Phase (First 2 Months)

• Isoniazid: 5 mg/kg daily (maximum 300 mg) 3, 4
• Rifampicin: 10 mg/kg daily (maximum 600 mg) 3, 4
• Pyrazinamide: 35 mg/kg daily (maximum 2 g) 3, 4
• Ethambutol: 15 mg/kg daily as the preferred fourth drug in adults 3, 5
  • Streptomycin 15 mg/kg daily IM may substitute when ethambutol cannot be used (e.g., unconscious patients who cannot report visual changes) 4, 6

Continuation Phase (Months 3–12)

• Isoniazid and rifampicin only, continuing for 10 additional months to complete a total of 12 months of therapy 1, 3, 6
• Daily dosing is strongly preferred over intermittent regimens for CNS tuberculosis 2, 3

Rationale for Drug Selection

• Isoniazid and pyrazinamide penetrate well into cerebrospinal fluid 3, 4
• Rifampicin has moderate CSF penetration but remains essential 3, 4
• Ethambutol and streptomycin penetrate adequately only when meninges are inflamed during early treatment 3, 4

Adjunctive Corticosteroid Therapy

Corticosteroids reduce mortality by approximately 25% (relative risk 0.75) and are strongly recommended for all patients with CNS tuberculosis, regardless of disease severity or HIV status. 1, 2, 6

Dexamethasone Regimen (Preferred)

Adults and Children ≥25 kg

• Initial dose: 12 mg IV daily (or 0.4 mg/kg/day, maximum 12 mg) for 3 weeks 2
• Tapering: Gradually decrease over the following 3 weeks (total 6-week course) 2

Children <25 kg

• Initial dose: 8 mg IV daily for 3 weeks 2
• Tapering: Gradually decrease over the following 3 weeks 2

Prednisolone Regimen (Alternative)

• Initial dose: 60 mg oral daily for 4 weeks 2, 3
• Tapering schedule: 30 mg/day for 4 weeks, then 15 mg/day for 2 weeks, then 5 mg/day for the final week 2
• Oral prednisolone is acceptable when IV access is problematic 2

Greatest Benefit

• Patients with Stage II (lethargic) disease show the most dramatic mortality reduction—from approximately 40% to 15% with dexamethasone 2
• Even comatose (Stage III) patients should receive the full corticosteroid course 2

Critical Pitfalls and How to Avoid Them

Duration Error (Most Common and Dangerous)

• Never use a 6-month regimen for CNS tuberculosis—this is adequate only for pulmonary disease and leads to treatment failure and relapse in meningitis 2, 3, 6
• The minimum duration is 9 months; 12 months is strongly preferred 1, 3, 6

Corticosteroid Management

• Never stop corticosteroids abruptly, even if the patient improves clinically 2
• Complete the full 6–8 week tapered course to prevent adrenal crisis from HPA axis suppression 2
• Abrupt discontinuation after prolonged high-dose therapy can cause life-threatening adrenal insufficiency 2

Paradoxical Reactions

• Development of new tuberculomas or enhancing lesions during therapy represents a paradoxical inflammatory response, not treatment failure 2, 7
• Do not discontinue steroids or anti-TB drugs when paradoxical reactions occur 2
• For isolated CNS tuberculomas (without meningitis), prolonged corticosteroid therapy beyond 6–8 weeks may be required—up to 18 months in some cases 8

Drug Selection

• Avoid using ethambutol in unconscious patients because visual acuity cannot be monitored 4, 6
• In such cases, substitute streptomycin or ethionamide as the fourth drug 4, 6

Monitoring Requirements

Early Treatment Phase

• Perform repeated lumbar punctures to track CSF cell count, glucose, and protein trends, especially during the first weeks of therapy 2, 3

Hepatotoxicity Surveillance

• Monitor liver function regularly given the hepatotoxic potential of isoniazid, rifampicin, and pyrazinamide 3

Neurological Assessment

• Regular clinical neurological examination and neuroimaging to assess response 4, 6

Neurosurgical Referral Indications

Immediate neurosurgical consultation is warranted for: 2

• Hydrocephalus requiring shunt placement
• Tuberculous cerebral abscess
• Paraparesis or spinal cord compression
• Progressive neurological deficits despite optimal medical therapy

Special Populations

Pediatric Considerations

• Use the same 12-month regimen with weight-based dosing 3, 6
• For children, consider ethionamide or an aminoglycoside instead of ethambutol to avoid visual acuity monitoring challenges 2, 3
• Pyridoxine supplementation is recommended for HIV-infected, malnourished, or breast-fed children 3

HIV-Positive Patients

• The same treatment principles apply, but manage in consultation with HIV specialists due to drug interactions and immune reconstitution inflammatory syndrome risk 6, 9
• For moderate-to-severe paradoxical TB-IRIS after antiretroviral initiation, prednisone ≈1.25 mg/kg/day significantly reduces hospitalization and surgical intervention needs 2