What is the role of dexamethasone in the treatment of Tuberculosis (TB) meningitis, particularly in patients with severe disease or compromised immune systems?

Dexamethasone in TB Meningitis

Adjunctive dexamethasone is strongly recommended for all patients with tuberculous meningitis, as it significantly reduces mortality and should be initiated before or concurrently with the first dose of anti-tuberculosis therapy. 1, 2

Dosing Regimen

Adults and children ≥25 kg:

• 12 mg/day for 3 weeks, then taper over the following 3 weeks 2

Children <25 kg:

• 8 mg/day for 3 weeks, then taper over the following 3 weeks 2

Critical Timing

Dexamethasone must be started before or with the first dose of anti-tuberculosis medication to maximize benefit by attenuating the inflammatory cascade before it fully develops. 2 This timing is essential because the drug prevents the inflammatory response resulting from bacteriolysis by antibiotics. 1

Evidence for Mortality Benefit

The strongest evidence comes from a landmark randomized controlled trial of 545 patients in Vietnam, which demonstrated:

• 31% reduction in mortality risk (relative risk 0.69; 95% CI 0.52-0.92; P=0.01) 3
• Significantly fewer serious adverse events in the dexamethasone group (26/274 vs. 45/271 patients, P=0.02) 3
• The greatest mortality benefit was observed in patients with Stage II disease (15% mortality with dexamethasone vs. 40% in controls, p<0.02) 2

Six of eight controlled trials demonstrated benefit in terms of survival, frequency of sequelae, or both. 2

Mechanism of Action

Dexamethasone likely improves outcomes by:

• Reducing hydrocephalus (fewer patients had hydrocephalus after 60 days with dexamethasone, p=0.217) 4
• Preventing cerebral infarction (27% vs 58% had infarction after 60 days, p=0.130) 4
• Modulating acute cerebrospinal fluid protein concentrations 5

Notably, the clinical benefit does not appear to result from measurable attenuation of peripheral or local immune responses, challenging previously held theories of corticosteroid action. 5

Long-Term Outcomes

At five-year follow-up:

• Two-year survival probabilities tended to be higher with dexamethasone (0.63 vs. 0.55; p=0.07) 6
• Five-year survival rates were similar overall (0.54 vs. 0.51, p=0.51) 6
• In patients with grade 1 TBM specifically, the benefit tended to persist (five-year survival 0.69 vs. 0.55, p=0.07) 6
• No difference in severe disability among survivors at five years (13.2% vs. 14.7%) 6

Special Population: HIV-Infected Patients

The evidence for dexamethasone benefit in HIV-infected patients with TB meningitis is limited and uncertain. 7 The 2016 ATS/CDC/IDSA guidelines note there are no large, prospective, randomized controlled trials using rifampin-based regimens in HIV-positive populations. 7

Key considerations for HIV-infected patients:

• Delay ART initiation for 8 weeks due to concerns about immune reconstitution inflammatory syndrome (IRIS) 7
• Monitor closely for IRIS development after ART initiation, particularly in patients with CD4 counts <50 cells/mm³ 7
• HIV-infected patients represent an exception to standard treatment approaches, and dexamethasone may not be beneficial in this population 7

Concurrent Anti-Tuberculosis Therapy

Initial 2-month intensive phase:

• INH, RIF, PZA, and EMB 1, 2

Continuation phase (7-10 months):

• INH and RIF after discontinuing PZA and EMB (for susceptible strains) 1, 2
• Total treatment duration: 9-12 months 2

Monitoring Requirements

Repeated lumbar punctures should be performed to monitor:

• CSF cell count 2
• Glucose 2
• Protein 2

This is especially important early in therapy to assess treatment response. 2

Critical Pitfalls to Avoid

Do not delay dexamethasone initiation. The drug must be given before or with the first anti-tuberculosis dose to prevent the inflammatory cascade. 2 Waiting even hours may reduce efficacy.

Do not confuse TB meningitis protocols with bacterial meningitis protocols. While dexamethasone is used in both, the dosing (12 mg/day for 3 weeks in TB meningitis vs. 10 mg every 6 hours for 4 days in bacterial meningitis) and duration differ substantially. 1, 2

Do not use dexamethasone as monotherapy. It must always be combined with appropriate anti-tuberculosis chemotherapy. 1, 8

Exercise extreme caution in HIV-infected patients. The benefit-risk ratio is unclear in this population, and IRIS risk must be carefully managed. 7