Treatment of Tuberculosis Meningitis
TB meningitis requires 12 months of treatment with rifampicin and isoniazid, supplemented by pyrazinamide and a fourth drug (ethambutol or streptomycin) for the first 2 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 ensure adequate bacterial killing and prevent resistance development:
- Rifampicin: 10 mg/kg daily (maximum 600 mg) 2, 3
- Isoniazid: 5 mg/kg daily (maximum 300 mg) 1, 3, 4
- Pyrazinamide: 35 mg/kg daily 3
- Fourth drug: Either ethambutol 15 mg/kg daily OR streptomycin 15 mg/kg daily 1, 2, 3
Ethambutol is generally preferred over streptomycin in adults because it can be given orally and has fewer adverse effects, though both penetrate adequately into cerebrospinal fluid only when meninges are inflamed during early treatment. 1, 3, 5
The fourth drug should be included even in previously untreated patients unless local isoniazid resistance is documented to be less than 4%. 1, 4, 6
Continuation Phase (10 Additional Months)
After completing 2 months of four-drug therapy:
- Rifampicin and isoniazid should be continued daily for 10 additional months 1, 2, 3
- Total treatment duration: 12 months (not the 6 months used for pulmonary TB—this is a critical distinction) 1, 2, 3, 5
The British Thoracic Society explicitly recommends the full 12-month duration based on extensive clinical experience, even though some older data suggested 9 months might be adequate. 1, 2, 3
Adjunctive Corticosteroid Therapy
Corticosteroids should be given to all patients with stage II (confused or with focal neurological signs) or stage III (comatose/stuporous) disease. 1, 2, 3, 5, 6
Dosing options:
Taper gradually over 6-8 weeks; avoid tapering too quickly as this can cause recurrence of CNS inflammation. 2, 3, 6
The evidence for corticosteroids is strong, showing reduced mortality and decreased neurological sequelae, particularly when started early in the disease course. 1, 3, 5
Drug Penetration Considerations
Understanding cerebrospinal fluid penetration is essential for treatment success:
- Good CSF penetration: Isoniazid, pyrazinamide, ethionamide 1, 3, 5
- Moderate CSF penetration: Rifampicin (still essential despite lower penetration) 1, 3, 5
- Poor CSF penetration: Streptomycin and ethambutol (adequate only when meninges are inflamed early in treatment) 1, 3, 5
This is why intrathecal streptomycin is unnecessary—adequate concentrations are achieved systemically during the critical early inflammatory phase. 1
Pediatric Considerations
Children require the same 12-month duration with weight-based dosing:
- Isoniazid: 10-15 mg/kg daily (maximum 300 mg) 4
- Rifampicin: 10 mg/kg daily 2
- Pyrazinamide: 35 mg/kg daily 3
- Fourth drug: Ethambutol 15 mg/kg daily OR streptomycin 15 mg/kg daily 1, 2
Ethambutol can be used safely in children aged 5 years and older at 15 mg/kg/day; for younger children, it can also be used without undue fear of side effects, though visual acuity monitoring may be challenging. 1
Doses should be recalculated as the child gains weight during treatment. 2
Monitoring Requirements
Essential monitoring includes:
- Neurological assessment: Regular evaluation for improvement or deterioration 2, 3, 5
- Hepatotoxicity monitoring: Baseline and regular liver function tests, especially in the first 2 months, given the hepatotoxic potential of isoniazid, rifampicin, and pyrazinamide 1, 3, 5
- CSF monitoring: Repeated lumbar punctures to assess cell count, glucose, and protein, particularly early in therapy 3, 5
For patients with chronic liver disease, weekly liver function tests for the first 2 weeks, then every 2 weeks during the intensive phase. 1
Special Populations
Pregnancy
Standard treatment should be given to pregnant women with TB meningitis. 1
- Rifampicin, isoniazid, pyrazinamide, and ethambutol are safe in pregnancy 1, 4
- Avoid streptomycin (causes congenital deafness) 1, 4
- Patients can breastfeed normally while taking antituberculosis drugs 1
Renal Disease
Rifampicin, isoniazid, and pyrazinamide can be given in standard doses. 1
If streptomycin or ethambutol are used, reduced doses are required with serum concentration monitoring. 1
HIV Co-infection
HIV-positive patients may require longer treatment courses and have higher rates of drug-resistant TB. 6, 7
Screening of antimycobacterial drug levels may be necessary due to malabsorption, especially in advanced HIV disease. 4
Drug interactions between rifampicin and antiretroviral therapy must be carefully managed. 7
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, 5
Omitting the fourth drug: When local isoniazid resistance exceeds 4% or is unknown, a fourth drug is essential 1, 3, 4, 6
Failing to use corticosteroids: In stage II and III disease, corticosteroids significantly reduce mortality and neurological sequelae 1, 2, 3, 5
Premature corticosteroid taper: Tapering too quickly can cause recurrence of CNS inflammation 6
Inadequate monitoring: Regular hepatotoxicity monitoring is essential given the hepatotoxic potential of multiple first-line drugs 1, 3, 5
Drug-Resistant TB Meningitis
If drug resistance is suspected or confirmed, treatment must be modified based on susceptibility testing:
- Isoniazid mono-resistance: Rifampicin, pyrazinamide, ethambutol, and a fluoroquinolone for 12-15 months 3
- Rifampicin mono-resistance: Isoniazid, pyrazinamide, ethambutol, fluoroquinolone, and an injectable agent for 18 months 3
- Multidrug-resistant TB (MDR-TB): Injectable drug for 4-6 months with total treatment duration of 18-24 months 3
Consultation with a TB expert is strongly recommended for all drug-resistant cases. 4, 6
Neurosurgical Considerations
Immediate neurosurgical consultation is warranted for: