What is the treatment and prognosis of Tuberculosis (TB) meningitis?

Tuberculous Meningitis: Clinical Presentation, Diagnosis, Treatment and Prognosis

Clinical Presentation

TB meningitis presents as a subacute meningitis with symptoms persisting for weeks, and patients with more severe neurologic impairment (drowsiness, obtundation, or coma) have significantly higher mortality and risk of permanent neurologic sequelae. 1, 2

Key Clinical Features

• Fever lasting more than 7 days, headache, and neck stiffness are the cardinal symptoms 3
• Subacute onset with symptoms evolving over 2-3 weeks before diagnosis, distinguishing it from acute bacterial meningitis 2
• Neurologic signs including cranial nerve palsies (especially VI and VII), altered mental status, and focal deficits 1, 4

Disease Staging (British Medical Research Council Classification)

• Stage I (alert): Fully conscious, rational, no neurologic signs 4
• Stage II (lethargic): Confused or neurologic signs such as cranial nerve palsy or hemiparesis 1, 4
• Stage III (comatose): Stuporous or comatose with severe neurologic signs 1, 4

Special Populations

• HIV-infected patients have increased risk of developing TB meningitis, though clinical features are similar to HIV-negative patients 1, 3
• Infants and children under 3 years have the shortest incubation period (4-6 weeks) and highest risk for rapid progression to severe disease 5

Diagnosis

Cerebrospinal Fluid Analysis

Characteristic CSF findings include lymphocytic-predominant pleiocytosis, elevated protein (often >100 mg/dL), and low glucose (<50% of plasma glucose). 2, 3

• CSF glucose-to-plasma ratio <0.5 is highly suggestive 3
• Elevated CSF protein is nearly universal 2
• Lymphocytic pleocytosis typically 100-500 cells/μL 2

Microbiological Diagnosis

• CSF acid-fast bacilli (AFB) smear has low sensitivity (10-20%) but high specificity 2
• CSF mycobacterial culture remains the gold standard but takes 2-8 weeks; sensitivity increases with multiple large-volume samples (≥6 mL) 2
• PCR/nucleic acid amplification is highly specific (>95%) but sensitivity is suboptimal (50-60%), so a negative test does not rule out TB meningitis 2

Neuroimaging

• Basal meningeal enhancement, hydrocephalus, tuberculomas, and infarcts are characteristic findings on MRI 3, 6

Critical Diagnostic Principle

Empiric treatment should be initiated immediately when clinical suspicion is supported by initial CSF studies, without waiting for microbiological confirmation, as treatment delay is strongly associated with death. 3, 6

Treatment

Antimicrobial Therapy

Initiate treatment with a four-drug regimen: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for an initial 2-month intensive phase, followed by INH and RIF for an additional 7-10 months (total duration 9-12 months). 1

Initial Phase (First 2 Months)

• INH: 5 mg/kg up to 300 mg daily (or 15 mg/kg up to 900 mg twice weekly) 7
• RIF: 10 mg/kg up to 600 mg daily 8
• PZA: 35 mg/kg up to 2 g daily 9
• EMB: 15 mg/kg daily 1, 9

Continuation Phase (Months 3-12)

• INH and RIF continued for 7-10 additional months 1
• Total treatment duration: 9-12 months minimum 1, 4

Parenteral Options

For patients with altered mental status unable to take oral medications, INH, RIF, aminoglycosides, capreomycin, and fluoroquinolones are available in parenteral forms. 1

Pediatric Considerations

• Children: INH 10-15 mg/kg up to 300 mg daily, with consideration of aminoglycoside or ethionamide instead of EMB as the fourth drug 1

Adjunctive Corticosteroid Therapy

Adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks is strongly recommended for all patients with TB meningitis, particularly those with decreased level of consciousness, as it reduces mortality. 1, 10

Adult Dosing

• Dexamethasone: 0.4 mg/kg/day (maximum 12 mg/day) intravenously for 3 weeks, then gradually tapered over the following 3 weeks 10
• Alternative prednisolone regimen: 60 mg/day for 4 weeks, then 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and 5 mg/day for the final week 10

Pediatric Dosing

• Children <25 kg: Dexamethasone 8 mg/day 1, 10
• Children ≥25 kg: Dexamethasone 12 mg/day 1, 10
• Duration: Initial dose for 3 weeks, then gradually decreased over following 3 weeks 10

Evidence for Corticosteroids

The greatest mortality benefit is seen in Stage II disease (lethargic patients), where dexamethasone reduced mortality from 40% to 15%. 1 For Stage III (comatose) patients, the benefit is less clear but corticosteroids are still recommended 1

Monitoring

Repeated lumbar punctures should be considered to monitor CSF cell count, glucose, and protein changes, especially early in therapy. 1, 10

Special Situations

Drug-Resistant TB

• Isoniazid-resistant TB: Add a fluoroquinolone (moxifloxacin or levofloxacin) to 6-month regimen of RIF, EMB, and PZA 9
• Multidrug-resistant TB: Consultation with TB expert is mandatory; use at least 5 effective drugs including a fluoroquinolone and injectable agent 9

HIV Co-infection

HIV-positive patients require careful attention to drug interactions, immune reconstitution inflammatory syndrome (IRIS), and may need longer treatment courses. 4, 2

Complications Requiring Neurosurgical Referral

• Hydrocephalus (may require ventriculoperitoneal shunting) 1, 4
• Tuberculous cerebral abscess 1
• Paraparesis from spinal involvement 1

Common Pitfalls

Development of tuberculomas during therapy represents a paradoxical reaction and does not necessarily indicate treatment failure; continue therapy without modification. 1

Symptoms of CNS inflammation may recur if corticosteroid taper is implemented too rapidly; extend taper if symptoms return. 4

Prognosis

TB meningitis remains a potentially devastating disease with high morbidity and mortality despite prompt adequate chemotherapy, with more than half of patients experiencing death or permanent disability. 1, 6

Mortality and Morbidity Factors

• Stage at presentation is the strongest predictor of outcome 1, 4
• Stage I patients: Best prognosis with early treatment 4
• Stage II patients: 15-40% mortality depending on corticosteroid use 1
• Stage III patients: 64-76% mortality even with optimal therapy 1

HIV Co-infection Impact

HIV-infected patients have similar short-term outcomes but significantly decreased 9-month survival compared to HIV-negative patients. 1

Neurologic Sequelae

Patients presenting with drowsiness, obtundation, or coma have greater risk of permanent neurologic sequelae including cognitive impairment, seizures, cranial nerve deficits, and motor deficits. 1