Management of Tuberculous Meningitis
Treat tuberculous meningitis with a 12-month regimen consisting of rifampicin, isoniazid, pyrazinamide, and a fourth drug (ethambutol or streptomycin) for the initial 2 months, followed by rifampicin and isoniazid for 10 additional months, plus adjunctive corticosteroids for moderate to severe disease (stages II and III). 1, 2, 3
Initial Intensive Phase (First 2 Months)
The intensive phase must include four drugs to maximize bacterial kill and prevent resistance:
- Rifampicin 10 mg/kg daily (maximum 600 mg) 2, 3
- Isoniazid 5 mg/kg daily (maximum 300 mg) 1, 3
- Pyrazinamide 35 mg/kg daily 3
- Fourth drug: Either ethambutol 15 mg/kg daily OR streptomycin 15 mg/kg daily 1, 2, 3
Critical consideration for the fourth drug: Ethambutol should be used with caution in unconscious patients (stage III disease) because visual acuity cannot be monitored, making streptomycin the preferred fourth agent in this setting. 1 However, streptomycin and ethambutol only penetrate adequately into cerebrospinal fluid when meninges are inflamed during early treatment. 1, 2, 3
Continuation Phase (Months 3-12)
After completing the 2-month intensive phase, continue with:
Duration: Total treatment must be 12 months, not the 6 months used for pulmonary tuberculosis. 1, 2, 3 This extended duration is essential because CNS tuberculosis has slower bacterial clearance and higher relapse risk.
Adjunctive Corticosteroid Therapy
Corticosteroids are mandatory for moderate to severe disease (stages II and III) and improve survival and neurological outcomes. 1, 2, 3, 4, 5
Disease Staging (British Medical Research Council):
- Stage I: Fully conscious, rational, no neurologic signs
- Stage II: Confused or has neurologic signs (cranial nerve palsy, hemiparesis)
- Stage III: Comatose or stuporous with severe neurologic signs 5
Corticosteroid Regimen:
- Dexamethasone 6-12 mg/day OR Prednisone/Prednisolone 60-80 mg/day 2, 3, 5
- Taper gradually over 6-8 weeks 2, 3, 5
- Warning: Symptoms of CNS inflammation may recur if tapering is too rapid or premature. 5
Corticosteroids are recommended for stages II and III disease based on evidence showing reduced mortality and decreased neurological sequelae. 1, 2, 3
Special Populations
Children
- Same 12-month regimen as adults: rifampicin, isoniazid, pyrazinamide, and fourth drug (ethambutol or streptomycin) for 2 months, then rifampicin and isoniazid for 10 months 1, 2
- Use weight-based dosing and recalculate doses as weight increases 1
- Pyridoxine supplementation for breast-fed infants and malnourished children 1
- Emerging evidence: A 6-month intensive regimen (6HRZEto) using higher-dose isoniazid and rifampicin with ethionamide instead of ethambutol showed 94.6% treatment success vs 75.4% with the 12-month regimen in children, though this requires further validation. 6
Pregnancy
- Standard treatment should be given; first-line drugs are not teratogenic 1
- Avoid streptomycin due to fetal ototoxicity risk 1
- Patients can breastfeed normally while on treatment 1
HIV-Positive Patients
- Use the same standard four-drug regimen 1
- Treatment duration remains 12 months for fully sensitive organisms 1
- Monitor for drug interactions with antiretroviral therapy 1
Unconscious Patients
- Administer medications via nasogastric tube (isoniazid and rifampicin as syrup, pyrazinamide crushed) 1
- Alternatively, use intravenous rifampicin and isoniazid 1
- Prefer streptomycin over ethambutol as the fourth drug since visual monitoring is impossible 1
Drug Penetration into CSF
Understanding CSF penetration explains drug selection:
- Good penetration: Isoniazid, pyrazinamide, ethionamide 1, 2, 3
- Moderate penetration: Rifampicin (less than ideal but essential) 1, 2, 3
- Poor penetration: Streptomycin and ethambutol (adequate only when meninges inflamed early in treatment) 1, 2, 3
Recent pharmacokinetic data: Higher-dose rifampicin (15 mg/kg) increases CSF concentrations substantially, though a trial using this dose with levofloxacin showed no survival benefit. 7, 8 Importantly, isoniazid exposure was associated with survival, with low exposure predicting death, particularly in fast metabolizers. 8
Monitoring Requirements
Clinical Assessment
- Regular neurological examination for improvement or deterioration 2
- Repeated lumbar punctures to monitor CSF parameters (cell count, glucose, protein) 3
Laboratory Monitoring
- Baseline liver function tests required 1
- Frequent monitoring in first 2 months for patients with chronic liver disease: weekly for first 2 weeks, then every 2 weeks 1
- Stop rifampicin, isoniazid, and pyrazinamide immediately if AST/ALT rises to 5× normal or bilirubin rises 9
Visual Monitoring
- If using ethambutol, monitor visual acuity regularly (baseline and monthly) 1
- Cannot be done in unconscious patients—use streptomycin instead 1
Critical Pitfalls to Avoid
Inadequate treatment duration: TB meningitis requires 12 months, not 6 months. This is the most common and dangerous error. 2, 3
Omitting corticosteroids in stages II and III disease: This reduces survival and increases neurological sequelae. 1, 2, 3
Omitting the fourth drug: When local isoniazid resistance exceeds 4% or is unknown, a fourth drug is mandatory. 3, 5
Using ethambutol in unconscious patients: Visual monitoring is impossible; use streptomycin instead. 1
Premature corticosteroid taper: CNS inflammation may recur if steroids are tapered too quickly. 5
Inadequate monitoring in liver disease: Rifampicin, isoniazid, and pyrazinamide are all hepatotoxic; frequent monitoring is essential. 1
Drug interactions: Rifampicin reduces efficacy of oral contraceptives and sulphonylureas, and doubles corticosteroid requirements for other conditions. 1
Alternative Regimen Consideration
If pyrazinamide cannot be tolerated or is contraindicated, extend treatment to 18 months with rifampicin, isoniazid, and ethambutol. 1 However, pyrazinamide is highly effective in TB meningitis due to excellent CSF penetration and should be used whenever possible. 1