What is the recommended treatment regimen for disseminated tuberculosis with central nervous system (CNS) involvement in India, according to Indian guidelines?

Treatment of Disseminated Tuberculosis with CNS Involvement: Indian Guidelines

Critical Limitation for Newer Regimens

The BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) should NOT be used for disseminated tuberculosis with CNS involvement, as no efficacy data are available for patients with CNS, osteoarticular, or disseminated (miliary) TB. 1

Recommended Treatment Regimen

Standard First-Line Therapy

For disseminated TB with CNS involvement in India, use a 12-month regimen of rifampicin, isoniazid, pyrazinamide, and ethambutol (or streptomycin) for the initial 2 months, followed by rifampicin and isoniazid for 10 additional months. 2, 3, 4

Initial Intensive Phase (First 2 Months)

• Rifampicin: 10 mg/kg daily (maximum 600 mg/day) 2
• Isoniazid: 5 mg/kg daily (maximum 300 mg/day) 2
• Pyrazinamide: 35 mg/kg daily (maximum 2 g/day) 2
• Fourth drug options: 2, 3
  • Ethambutol 15 mg/kg daily (preferred), OR
  • Streptomycin (alternative)

Continuation Phase (10 Additional Months)

• Rifampicin: 10 mg/kg daily (maximum 600 mg/day) 2, 3
• Isoniazid: 5 mg/kg daily (maximum 300 mg/day) 2, 3

Total treatment duration: 12 months minimum 2, 3, 4

Drug Selection Rationale for CNS Disease

CSF Penetration Considerations

• Good CSF penetration: Isoniazid, pyrazinamide, and prothionamide/ethionamide achieve therapeutic concentrations in cerebrospinal fluid 2, 3
• Moderate CSF penetration: Rifampicin penetrates less well but remains critical for treatment efficacy 2, 3
• Limited CSF penetration: Streptomycin and ethambutol only achieve adequate concentrations when meninges are inflamed in early treatment stages 2
• Intrathecal streptomycin is NOT necessary 2

Corticosteroid Therapy

Add high-dose corticosteroids for severe disease (stages II and III CNS involvement): 2, 3

• Prednisolone: 60 mg/day initially 2, 3
• Taper gradually over several weeks 2, 3
• Clear mortality and morbidity benefit demonstrated in severe CNS TB 2, 3

Treatment Modifications

If Pyrazinamide Cannot Be Used

Extend total treatment duration to 18 months if pyrazinamide is omitted or not tolerated 2, 3

Special Precautions

• Ethambutol caution: Use carefully in unconscious patients as visual acuity cannot be monitored 2, 4
• Pyridoxine supplementation: 10-25 mg/day recommended to prevent peripheral neuropathy, especially important in CNS disease 4

Indian-Specific Considerations

API TB Consensus Guidelines (India)

The Association of Physicians of India recommends the same regimen for extrapulmonary and disseminated TB: 4

• 2EHRZ + 4HR (2 months of ethambutol, isoniazid, rifampicin, pyrazinamide followed by 4 months of isoniazid and rifampicin) for most extrapulmonary TB
• However, for CNS TB specifically, extend to 12 months total duration 4
• Thrice-weekly intermittent therapy (2E₃H₃R₃Z₃ + 4H₃R₃) is advocated by WHO and implemented by India's Revised National TB Control Programme for pulmonary TB, but daily therapy is preferred for CNS involvement 4

DOTS Implementation

• Directly Observed Therapy Short Course (DOTS) should be implemented where the patient takes drugs under direct observation of a health worker 4
• Fixed-dose combinations (FDCs) minimize opportunity for selective medication adherence 4

Monitoring Requirements

Clinical and neuroimaging monitoring is essential: 2, 3

• Serial neurological examinations
• Repeat neuroimaging to assess treatment response 2, 3
• Monitor for paradoxical worsening, especially in HIV co-infection 4

Drug-Resistant TB with CNS Involvement

If multidrug-resistant TB (MDR-TB) is suspected or confirmed: 1, 4

• Immediate consultation with TB expert is mandatory 1
• Molecular drug susceptibility testing should be obtained urgently 1
• Treatment must be individualized based on susceptibility patterns 4
• BPaLM regimen remains contraindicated for CNS TB even in MDR cases 1
• Consider longer individualized regimens with second-line agents based on DST results 4

Common Pitfalls to Avoid

• Do not use 6-month regimens for CNS TB - minimum 12 months required 2, 3, 4
• Do not use BPaLM/BPaL regimens for CNS involvement - no safety or efficacy data 1
• Do not omit corticosteroids in severe disease - clear mortality benefit 2, 3
• Do not use intrathecal streptomycin - unnecessary and potentially harmful 2
• Do not delay treatment initiation while awaiting DST results in new cases 4