Corticosteroids in Tuberculous Meningitis

Abstract & Commentary

Synopsis: Adjunctive dexamethasone therapy of adolescents and adults with tuberculous meningitis was associated with improved survival, but not with reduced severe disability among those who did survive.

Source: Thwaites GE, et al. Dexamethasone For the Treatment of Tuberculous Meningitis in Adolescents and Adults. N Engl J Med. 2004;351:1741-1751.

Thwaites and colleagues randomized 545 adults and adolescents with tuberculous meningitis to receive, in addition to standard antituberculous therapy for 9 months, either dexamethasone (4 weeks for mild disease, 8 weeks for more severe illness) or placebo. HIV coinfection was present in 16.1% of the placebo and 19.9% of the dexamethasone group. Of the 170 M. tuberculous isolates tested, 58.2% were susceptible to all first line drugs, and 5.9% were resistant to at least isoniazid and rifampin; resistant isolates were approximately equally distributed between the treatment groups.

Adjunctive dexamethasone administration was associated with a significantly reduced risk of death (31.8% vs 41.3%) RR, 0.69; 95% CI, 0.52-0.92; P = 0.01). There was, however, no significant intergroup difference with regard to the development of severe disability among survivors, which was observed in 18.2% in the corticosteroid and 13.8% in the placebo arms. Relapse occurred in 15% of dexamethasone recipients and 17.7% of placebo recipients (P = 0.42). The 98 patients who were HIV infected had higher mortality than the rest of the study participants, but without a significant difference between treatment groups.

Adverse events occurred more frequently among placebo recipients than those assigned dexamethasone (79% vs 68%; P = 0.005), but with similar rates of discontinuation. Eight placebo recipients, one of whom died, developed severe hepatitis, while no dexamethasone recipient did so (P = 0.004).

Comment by Stan Deresinski, MD, FACP

The results of this study present a mixed bag—adjunctive dexamethasone was associated with improved survival in this study of adolescents and adults, but no reduction in the proportion of survivors with severe disability. A metaanalysis of previous randomized, controlled trials had found evidence of improved survival in children but not adults given adjunctive corticosteroids, and also pointed out the many limitations of those studies.1 The reduction in severe adverse events seen with corticosteroid administration has been previously observed in patients with pulmonary tuberculosis.

The lack of benefit observed in the HIV-infected patients is confounded by the small number enrolled and the fact that, in contrast to the rest of the study population, deaths were spread throughout the 9 months of observation. The latter suggests that many of the deaths were not directly related to the tuberculous infection. It is likely that few of these patients in Vietnam had access to effective antiretroviral therapy.

The relapse rate of approximately 16% in this study was quite high, raising questions about the therapy, including compliance. In a recently reported study, none of 591 patients who received more than 6 months of treatment relapsed, although 2 of 131 (1.5%) of those treated for only 6 months did so.2

The unequivocal diagnosis of tuberculous meningitis remains difficult. In this study, at study entry, only approximately one-sixth had definite (positive acid fast smear) or probable tuberculosis (one or more of: compatible chest X-ray, positive smear at site other than CSF, or clinical evidence of other extrapulmonary tuberculosis). When culture is also taken into account, however, 34% had microbiologic evidence of tuberculous meningitis. Furthermore, in a high prevalence setting such as Vietnam, it is likely that most of the rest also had M. tuberculosis as the etiology of their meningitis. While nucleic acid amplifications tests such as PCR were not used for diagnosis in this study, their use would likely have been only of somewhat marginal benefit, given their reported overall sensitivity with CSF of only 56%.3

At least one other agent with putative anti-inflammatory properties has been evaluated in patients with tuberculous meningitis. A placebo-controlled, randomized trial in children was aborted because of excess toxicity and mortality in those given thalidomide.4

This study provides clear evidence of survival benefit in adolescents and adults with tuberculous meningitis, as well as for a reduction in antituberculous drug related adverse events. The lack of benefit with regard to severe disability among survivors, however, gives one pause. Nonetheless, adjunctive corticosteroids will remain part of the therapeutic recommendations for treatment of tuberculous meningitis in children, adolescents, and adults.

References

1. Prasad K, et al. Steroids For Treating Tuberculous Meningitis. Cochrane Database Syst Rev. 2000;3: CD00224.

2. van Loenhout-Rooyackers JH, et al. Tuberculous Meningitis: Is A 6-Month Treatment Regimen Sufficient? Int J Tuberc Lung Dis. 2001;5:1028-1035.

3. Pai M, et al. Diagnostic Accuracy of Nucleic Acid Amplification Tests For Tuberculous Meningitis: A Systematic Review and Meta-Analysis. Lancet Infect Dis. 2003;31:387-391.

4. Schoeman JF, et al. Adjunctive Thalidomide Therapy For Childhood Tuberculous Meningitis: Results of a Randomized Study. J Child Neurol. 2004;19:250-257.

Stan Deresinski, MD, FACP Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.