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Meta-Analysis
. 2016 Apr 28;4(4):CD002244.
doi: 10.1002/14651858.CD002244.pub4.

Corticosteroids for managing tuberculous meningitis

Kameshwar Prasad  1 , Mamta B Singh, Hannah Ryan
Affiliations
Meta-Analysis

Corticosteroids for managing tuberculous meningitis

Kameshwar Prasad et al. Cochrane Database Syst Rev. .

Abstract

Background: Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial.

Objectives: To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists.

Selection criteria: Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures.

Data collection and analysis: We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data.

Main results: Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction.One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial.

Authors' conclusions: Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality.The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients.

PubMed Disclaimer

Conflict of interest statement

KP is a co‐author of two of the included trials (Kumarvelu 1994; Prasad 2006). HR independently conducted 'Risk of bias' assessments and data entry and interpretation with the CIDG Co‐ordinating Editor, Paul Garner.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.
4
4
Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.1 Death.
5
5
Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.2 Disabling neurological deficit.
6
6
Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.4 Adverse events.
7
7
Forest plot of comparison: 2 Any corticosteroid versus control: stratified by severity of illness, outcome: 2.1 Death.
8
8
Forest plot of comparison: 3 Any corticosteroid versus control: stratified by HIV status, outcome: 3.1 Death.
9
9
Funnel plot of risk ratio (RR) from the included trials with the log of their standard error (SE) values.
1.1
1.1. Analysis
Comparison 1 Any corticosteroid versus control, Outcome 1 Death.
1.2
1.2. Analysis
Comparison 1 Any corticosteroid versus control, Outcome 2 Disabling neurological deficit.
1.3
1.3. Analysis
Comparison 1 Any corticosteroid versus control, Outcome 3 Death or disabling neurological deficit.
1.4
1.4. Analysis
Comparison 1 Any corticosteroid versus control, Outcome 4 Adverse events.
2.1
2.1. Analysis
Comparison 2 Any corticosteroid versus control: stratified by severity of illness, Outcome 1 Death.
3.1
3.1. Analysis
Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 1 Death.
3.2
3.2. Analysis
Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 2 Disabling neurological deficit.
3.3
3.3. Analysis
Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 3 Death or disabling residual neurological deficit.
4.1
4.1. Analysis
Comparison 4 Sensitivity analysis, Outcome 1 Worst case scenario analysis.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Chotmongkol 1996 {published data only}
    1. Chotmongkol V, Jitpimolmard S, Thavornpitak Y. Corticosteroid in tuberculous meningitis. Journal of the Medical Association of Thailand 1996;79(2):83‐90. - PubMed
Girgis 1991 {published data only}
    1. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatric Infectious Disease Journal 1991;10(3):179‐83. - PubMed
Kumarvelu 1994 {published and unpublished data}
    1. Kumarvelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Randomized controlled trial of dexamethasone in tuberculous meningitis. Tubercle and Lung Disease 1994;75(3):203‐7. - PubMed
Lardizabal 1998 {unpublished data only}
    1. Lardizabal DV, Roxas AA. Dexamethasone as adjunctive therapy in adult patients with probable TB meningitis stage II and stage III: An open randomised controlled trial. Philippines Journal of Neurology 1998;4:4‐10.
Malhotra 2009 {published data only}
    1. Malhotra HS, Garg RK, Singh MK, Agarwal A, Verma R. Corticosteroids (dexamethasone versus intravenous methylprednisolone) in patients with tuberculous meningitis. Annals of Tropical Medicine and Parasitology 2009;103(7):625‐34. - PubMed
O'Toole 1969 {published data only}
    1. O'Toole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis. Relationship of cerebrospinal fluid effects to therapeutic efficacy. Annals of Internal Medicine 1969;70(1):39‐48. - PubMed
Prasad 2006 {unpublished data only}
    1. Prasad K. A randomized controlled trial to study the effectiveness of dexamethasone as an adjunct to standard antituberculous treatment in patients with clinically presumed tuberculous meningitis: 10‐year follow‐up study (as supplied 7 June 2015). Data on file.
Schoeman 1997 {published data only}
    1. Schoeman JF, Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99(2):226‐31. - PubMed
Thwaites 2004 {published data only}
    1. Simmons CP, Thwaites GE, Quyen NT, Chau TT, Mai PP, Dung NT, et al. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. Journal of Immunology 2005;175(1):579‐90. - PubMed
    1. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. New England Journal of Medicine 2004;351(17):1741‐51. - PubMed
    1. Török ME, Nguyen DB, Tran TH, Nguyen TB, Thwaites GE, Hoang TQ, et al. Dexamethasone and long‐term outcome of tuberculous meningitis in Vietnamese adults and adolescents. PLoS One 2011;6(12):e27821. - PMC - PubMed

References to studies excluded from this review

Donald 2004 {published data only}
    1. Donald PR, Schoeman JF. Tuberculous meningitis. New England Journal of Medicine 2004;351(17):1719‐20. - PubMed
Escobar 1975 {published data only}
    1. Escobar JA, Belsey MA, Dueñas A, Medina P. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;56(6):1050‐5. - PubMed
Freiman 1970 {published data only}
    1. Frieman I, Geefhuysen J. Evaluation of intrathecal therapy with streptomycin and hydrocortisone in tuberculous meningitis. Journal of Pediatrics 1970;76(6):895‐901. - PubMed
Girgis 1983 {published data only}
    1. Girgis NI, Farid Z, Hanna LS, Yassin MW, Wallace CK. The use of dexamethasone in preventing ocular complications in tuberculous meningitis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1983;77(5):658‐9. - PubMed
Heemskerk 2016 {published data only}
    1. Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M, Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. New England Journal of Medicine 14th January 2016;374(2):124‐134. - PubMed
Hockaday 1966 {published data only}
    1. Hockaday JM, Smith HM. Corticosteroids as an adjuvant to the chemotherapy of tuberculous meningitis. Tubercle 1966;47(1):75‐91. - PubMed
Kalita 2001 {published data only}
    1. Kalita J, Misra UK. Effect of methyl prednisolone on sensory motor functions in tuberculous meningitis. Neurology India 2001;49(3):267‐71. - PubMed
Kapur 1969 {published data only}
    1. Kapur S. Evaluation of treatment of tuberculous meningitis since the use of steroids as an adjuvant. Indian Pediatrics 1969;6(3):166‐71. - PubMed
Karak 1998 {published data only}
    1. Karak B, Garg RK. Corticosteroids in tuberculous meningitis. Indian Pediatrics 1998;35(2):193‐4. - PubMed
Lepper 1963 {published data only}
    1. Lepper MH, Spies HW. The present status of the treatment of tuberculosis of the central nervous system. Annals of the New York Academy of Sciences 1963;106:106‐23. - PubMed
Marras 2005 {published data only}
    1. Marras TK. Dexamethasone for tuberculous meningitis. New England Journal of Medicine 2005;352(6):628‐30. - PubMed
Quagliarello 2004 {published data only}
    1. Quagliarello V. Adjunctive steroids for tuberculous meningitis ‐ more evidence, more questions. New England Journal of Medicine 2004;351(17):1792‐4. - PubMed
Seligman 2005 {published data only}
    1. Seligman SJ. Dexamethasone for tuberculous meningitis. New England Journal of Medicine 2005;352(6):628‐30. - PubMed
Shah 2014 {published data only}
    1. Shah I, Meshram L. High dose versus low dose steroids in children with tuberculous meningitis. Journal of Clinical Neuroscience 2014;21(5):761‐4. - PubMed
Vagenakis 2005 {published data only}
    1. Vagenakis AG, Kyriazopoulou V. Dexamethasone for tuberculous meningitis. New England Journal of Medicine 2005;352(6):628‐30. - PubMed
Voljavec 1960 {published data only}
    1. Volijavec BF, Corpe RF. The influence of corticosteroid hormones in the treatment of tuberculous meningitis in Negroes. American Review of Respiratory Disease 1960;81(4):539‐45.
Wasz‐Höckert 1963 {published data only}
    1. Wosz‐Höckert O. Modern treatment and late prognosis of tuberculous meningitis. Acta Paediatrica 1963;52 Suppl 141:93‐102.
Weiss 1965 {published data only}
    1. Weiss W, Flippin HF. The changing incidence of and prognosis of tuberculous meningitis. American Journal of the Medical Sciences 1965;250:46‐59. - PubMed

Additional references

Alarcón 1990
    1. Alarcón F, Escalante L, Pérez Y, Banda H, Chacón G, Dueñas G. Tuberculous meningitis. Short course of chemotherapy. Archives of Neurology 1990;47(12):1313‐7. - PubMed
Berenguer 1992
    1. Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A, et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. New England Journal of Medicine 1992;326(10):668‐72. - PubMed
Berger 1994
    1. Berger JR. Tuberculous meningitis. Current Opinion in Neurology 1994;7(3):191‐200. - PubMed
BSI 2009
    1. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J, British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Journal of Infection 2009;59(3):167‐87. - PubMed
CDC 2003
    1. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52(RR‐11):1‐77. - PubMed
D'Arcy‐Hart 1950
    1. D'Arcy‐Hart P, Rees RJ. Enhancing effect of cortisone on tuberculosis in the mouse. Lancet 1950;2(6630):391‐5. - PubMed
Feldman 1958
    1. Feldman S, Behar AJ, Weber D. Experimental tuberculous meningitis in rabbits. 1. Results of treatment with antituberculous drugs separately and in combination with cortisone. A. M. A. Archives of Pathology 1958;65(3):343‐54. - PubMed
Geiman 1992
    1. Geiman BJ, Smith AL. Dexamethasone and bacterial meningitis. A meta‐analysis of randomized controlled trials. Western Journal of Medicine 1992;157(1):27‐31. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Jacobs 1990
    1. Jacobs RF, Sunakorn P. Tuberculous meningitis in children: an evaluation of chemotherapeutic regimens. American Review of Respiratory Disease 1990;141 Suppl:A337.
Jacobs 1992
    1. Jacobs RF, Sunakorn P, Chotpitayasunonah T, Pope S, Kelleher K. Intensive short course chemotherapy for tuberculous meningitis. Pediatric Infectious Disease Journal 1992;11(3):194‐8. - PubMed
Jorge 2012
    1. Jorge JH, Graciela C, Pablo AP, Luis SH. A life‐threatening central nervous system‐tuberculosis inflammatory reaction nonresponsive to corticosteroids and successfully controlled by infliximab in a young patient with a variant of juvenile idiopathic arthritis. Journal of Clinical Rheumatology 2012;18(4):189‐91. - PubMed
Jüni 2001
    1. Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6. - PMC - PubMed
Lee 2012
    1. Lee HS, Lee Y, Lee SO, et al Choi SH, Kim YS, Woo JH, et al. Adalimumab treatment may replace or enhance the activity of steroids in steroid‐refractory tuberculous meningitis. Journal of Infection and Chemotherapy 2012;18(4):555–7. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Green S, Higgins JPT (editors). The Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org. The Cochrane Collaboration.
Molton 2015
    1. Molton JS, Huggan PJ, Archuleta S. Infliximab therapy in two cases of severe neurotuberculosis paradoxical reaction. Medical Journal of Australia 2015;202(3):156‐7. - PubMed
MRC 1948
    1. Medical Research Council Report. Streptomycin treatment of tuberculous meningitis. Lancet 1948;1(6503):582‐96. - PubMed
Naing 2013
    1. Naing C, Mak JW, Maung M, Wong SF, Kassim AI. Meta‐analysis: the association between HIV infection and extrapulmonary tuberculosis. Lung 2013;191(1):27‐34. - PubMed
NICE 2011
    1. National Institute for Health and Care Excellence (NICE). Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. NICE clinical guidelines 117. Manchester: NICE, March 2011. - PubMed
Parsons 1988
    1. Parsons M. Tuberculous Meningitis: Tuberculomas and Spinal Tuberculosis ‐ A Handbook for Clinicians (Oxford Medical Publications). 2nd Edition. Oxford: Oxford University Press, 1988:32‐62.
Ramchandran 1986
    1. Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R, Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986;67(1):17‐29. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Schoeman 2001
    1. Schoeman JF, Ravenscroft A, Hartzenberg HB. Possible role of adjunctive thalidomide therapy in the resolution of a massive intracranial tuberculous abscess. Child's Nervous System 2001;17(6):370‐2. - PubMed
Schoeman 2004
    1. Schoeman JF, Springer P, Rensburg AJ, Swanevelder S, Hanekom WA, Haslett PA, et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. Journal of Child Neurology 2004;19(4):250‐7. - PubMed
Schoeman 2010
    1. Schoeman JF, Andronikou S, Stefan DC, Freeman N, Toorn R. Tuberculous meningitis‐related optic neuritis: recovery of vision with thalidomide in four consecutive cases. Journal of Child Neurology 2010;25(7):822–8. - PubMed
SNHS 2010
    1. Working Group of the Clinical Practice Guideline on the Diagnosis, Treatment and Prevention of Tuberculosis. Centro Cochrane Iberoamericano (Iberoamerican Cochrane Centre), coordinator. Clinical Practice Guideline on the Diagnosis, Treatment and Prevention of Tuberculosis. Quality Plan for the Spanish National Healthcare System of the Spanish Ministry for Health, Social Policy and Equality; Agència d’Informació, Avaluació i Qualitat en Salut de Catalunya (AIAQS ‐ Agency for Information, Evaluation, and Quality in Health of Catalonia). Ministry of Science and Innovation, Spain, 2010.
Tandon 1988
    1. Tandon PN, Bhatia R, Bhargava S. Tuberculous meningitis. In: Harris AA editor(s). Handbook of Clinical Neurology. Vol. 8, Amsterdam: Elsevier Science Publishers, 1988:195‐226.
Thwaites 2002
    1. Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360(9342):1287‐92. - PubMed
Thwaites 2013
    1. Thwaites GE, Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurology 2013;12(10):999‐1010. - PubMed
Tobin 2010
    1. Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND, et al. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 2010;140(5):717‐30. - PMC - PubMed
Tobin 2012
    1. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, et al. Host genotype‐specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 2012;148(3):434‐46. - PMC - PubMed
Török 2011
    1. Török ME, Nguyen DB, Tran TH, Nguyen TB, Thwaites GE, Hoang TQ, et al. Dexamethasone and long‐term outcome of tuberculous meningitis in Vietnamese adults and adolescents. PLoS One 2011;6(12):e27821. - PMC - PubMed
WHO 2014
    1. World Health Organization. Global Tuberculosis Report 2014. Geneva: World Health Organization, 2014.

References to other published versions of this review

Prasad 2000
    1. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database of Systematic Reviews 2000, Issue 3. [DOI: 10.1002/14651858.CD002244] - DOI - PubMed
Prasad 2006
    1. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD002244.pub2] - DOI - PubMed
Prasad 2008
    1. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/14651858.CD002244.pub3] - DOI - PubMed

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