What is the recommended treatment regimen for a patient with central nervous system (CNS) tuberculosis (TB)?

Treatment of Central Nervous System Tuberculosis

For CNS tuberculosis (TB meningitis or tuberculoma), treat with rifampin, isoniazid, pyrazinamide, and a fourth drug (ethambutol, streptomycin, or ethionamide) for 2 months, followed by rifampin and isoniazid for 10 additional months, for a total duration of 12 months. 1

Initial Intensive Phase (2 Months)

Four-drug regimen is mandatory:

• Rifampin 10 mg/kg (maximum 600 mg) daily 2, 3
• Isoniazid 5 mg/kg (maximum 300 mg) daily 2, 4
• Pyrazinamide 35 mg/kg daily for patients <50 kg or 2.0 g daily for patients >50 kg 2, 5
• Fourth drug options include:
  • Ethambutol 15 mg/kg daily (use with caution in unconscious patients as visual acuity cannot be monitored) 1
  • Streptomycin 1
  • Ethionamide 1

Drug Penetration Rationale

The British Thoracic Society guidelines specifically note that isoniazid, pyrazinamide, and prothionamide/ethionamide penetrate well into cerebrospinal fluid, while rifampin penetrates less well. 1 Streptomycin and ethambutol only achieve adequate CSF concentrations when meninges are inflamed during the early treatment phase. 1 Intrathecal streptomycin administration is unnecessary. 1

Critical Caveat for Ethambutol

Although ethambutol is an acceptable fourth drug, it should be used with extreme caution in unconscious patients (stage III disease) because visual acuity cannot be tested to monitor for optic neuritis. 1 In such cases, streptomycin or ethionamide are safer alternatives.

Continuation Phase (10 Months)

Two-drug regimen:

• Rifampin 10 mg/kg (maximum 600 mg) daily 2, 3
• Isoniazid 5 mg/kg (maximum 300 mg) daily 2, 4

The continuation phase extends to 10 months (rather than the standard 4 months for pulmonary TB) because CNS disease requires prolonged therapy to prevent relapse. 1

Exception for Pyrazinamide Intolerance

If pyrazinamide cannot be tolerated or must be omitted, treatment duration must be extended to 18 months total. 1

Adjunctive Corticosteroid Therapy

Corticosteroids are strongly recommended for more severe CNS tuberculosis (stages II and III disease):

• Prednisolone 60 mg/day initially (or equivalent dexamethasone dose), tapering over several weeks 1, 2
• Corticosteroids decrease neurologic sequelae and improve outcomes, especially when administered early in the disease course 1, 2

The British Thoracic Society guidelines emphasize that corticosteroids have demonstrated clear benefit in preventing neurologic complications in TB meningitis. 1

Cerebral Tuberculoma Without Meningitis

For isolated cerebral tuberculoma(s) without meningitis, the 12-month regimen is still recommended (2 months of four drugs followed by 10 months of rifampin and isoniazid). 1

Essential Supportive Care

Pyridoxine (vitamin B6) supplementation:

• 25-50 mg daily should be administered to all patients receiving isoniazid to prevent peripheral and central nervous system side effects 1, 2
• This is particularly important in CNS disease where neurologic complications must be minimized 1

Administration Schedule

Daily dosing is mandatory for CNS tuberculosis. 2 Intermittent (twice or thrice weekly) dosing should never be used for CNS disease due to the severity and potential for permanent neurologic sequelae. 2

Directly observed therapy (DOT) is strongly recommended for all CNS TB patients to ensure treatment adherence and prevent treatment failure. 2, 4

Special Populations

HIV Co-infection

• Use the same 12-month regimen (2HRZE followed by 10HR) 6
• Be aware of significant drug interactions between rifampin and protease inhibitors/NNRTIs 1
• Consider rifabutin as an alternative to rifampin if antiretroviral therapy cannot be interrupted, with dose adjustments: 150 mg daily when used with indinavir, nelfinavir, or amprenavir 1

Pediatric CNS TB

• Children with TB meningitis should receive a minimum of 12 months of therapy 4, 7
• Dosing: Isoniazid 10-15 mg/kg (max 300 mg), Rifampin 10-15 mg/kg (max 600 mg), Pyrazinamide 35 mg/kg, Ethambutol 15-25 mg/kg 4
• Ethambutol can be used in children ≥5 years at 15 mg/kg/day; use with caution in younger children 1

Pregnancy

• All first-line drugs (rifampin, isoniazid, pyrazinamide, ethambutol) can be used during pregnancy 8
• Streptomycin is contraindicated due to fetal ototoxicity 4, 8
• Prophylactic pyridoxine 10 mg/day is mandatory 8

Monitoring Treatment Response

• Baseline hepatic function tests (AST/ALT, bilirubin) are essential, especially in HIV-infected patients, pregnant women, and those with liver disease or alcohol use 2
• Clinical and radiographic response must be monitored closely, as bacteriologic evaluation of CNS disease is limited 4
• Drug susceptibility testing should be performed on all initial isolates 4, 3

Common Pitfalls to Avoid

1. Never use a 6-month regimen for CNS tuberculosis - this is the most critical error. CNS disease requires 12 months minimum. 1

2. Never use intermittent dosing (twice or thrice weekly) for CNS TB - daily administration is mandatory. 2

3. Do not omit the fourth drug in the initial phase, even in low-resistance settings, as CNS disease is too severe to risk inadequate treatment. 1

4. Do not use ethambutol as the fourth drug in unconscious patients without considering alternatives, as visual monitoring is impossible. 1

5. Do not forget corticosteroids in stages II and III disease - they significantly reduce mortality and neurologic sequelae. 1, 2

6. Never use three-drug regimens (without rifamycin or aminoglycoside) - if such regimens must be used, minimum duration is 18 months. 1