Current Infectious Disease Reports

, Volume 12, Issue 4, pp 291–298

Approach to the Diagnosis and Management of Tuberculous Meningitis



Meningitis caused by Mycobacterium tuberculosis remains an important cause of morbidity and mortality worldwide, and presents particular challenges in terms of diagnosis and management. The nonspecific clinical presentation of tuberculous meningitis (TBM) has led researchers to develop newer molecular methods of making the diagnosis. Several of these methods have excellent sensitivity and specificity, although many are not yet available for clinical use. Successful treatment of TBM requires a combination of antimicrobial agents, with vigilance regarding the possibility of disease caused by resistant organisms. Adjunctive corticosteroids also have a role in treating this potentially devastating infection, as can neurosurgery. With proper therapy, morbidity and mortality can be minimized in patients with TBM.


Mycobacterium tuberculosis Tuberculous meningitis Extrapulmonary tuberculosis Hydrocephalus Polymerase chain reaction Corticosteroid therapy 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Zuger A: Tuberculosis. In Infections of the Central Nervous System, edn 3. Edited by Scheld WM, Whitley RJ, Marra CM. Philadelphia: Lippincott Williams & Wilkins; 2004:441–460.Google Scholar
  2. 2.
    Tunkel AR: Bacterial Meningitis. Philadelphia: Lippincott Williams & Wilkins; 2001.Google Scholar
  3. 3.
    Fitzgerald DW, Sterling TR, Haas DW: Mycobacterium tuberculosis. In Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, edn 7. Edited by Mandell GL, Bennett JE, Dolin R. Philadelphia: Churchill Livingstone; 2010:3129–3163.Google Scholar
  4. 4.
    Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD: The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000, 181:118–126.CrossRefPubMedGoogle Scholar
  5. 5.
    Torok ME, Chau TT, Mai PP, et al.: Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS ONE 2008, 3:e1772.CrossRefPubMedGoogle Scholar
  6. 6.
    Tan EK, Chee MWL, Chan LL, Lee YL: Culture positive tuberculous meningitis: clinical indicators of poor prognosis. Clin Neurol Neurosurg 1999, 101:157–160.CrossRefPubMedGoogle Scholar
  7. 7.
    Kumar R, Singh SN, Kohli N: A diagnostic rule for tuberculous meningitis. Arch Dis Child 1999, 81:221–224.CrossRefPubMedGoogle Scholar
  8. 8.
    Mihailescu R, Hristea A, Baicus C, et al.: Predictors of tuberculosis in acute aseptic meningitis syndrome. Rom J Intern Med 2007, 45:379–385.PubMedGoogle Scholar
  9. 9.
    • van Well GT, Paes BF, Terwee CB, et al.: Twenty years of pediatric tuberculous meningitis: a retrospective cohort study in the western cape of South Africa. Pediatrics 2009, 123:e1–e8. This paper reports on the largest pediatric cohort of TBM patients (554) yet published. Ethnicity, stage of disease, headache, convulsions, motor function, brainstem dysfunction, and cerebral infarctions were independently associated with poor clinical outcome. Stage II and III disease were very common, as were poor weight gain (or frank weight loss), loss of consciousness, and hydrocephalus. At 6 months, mortality was 13%, and only 16% of children were clinically normal at follow-up.CrossRefPubMedGoogle Scholar
  10. 10.
    Hosoglu S, Geyik MF, Balik I, et al.: Predictors of outcome in patients with tuberculous meningitis. Int J Tubercul Lung Dis 2002, 6:64–70.Google Scholar
  11. 11.
    Chan KH, Cheung RT, Fong CY, et al.: Clinical relevance of hydrocephalus as a presenting feature of tuberculous meningitis. Q J Med 2003, 96:643–648.Google Scholar
  12. 12.
    Kalita J, Misra UK, Nair PP: Predictors of stroke and its significance in the outcome of tuberculous meningitis. J Stroke Cerebrovasc Dis 2009, 18:251–258.CrossRefPubMedGoogle Scholar
  13. 13.
    Yaramis A, Bukte Y, Katar S, Ozbek MN: Chest computerized tomography scan findings in 74 children with tuberculous meningitis in southeastern Turkey. Turk J Pediatr 2007, 49:365–369.PubMedGoogle Scholar
  14. 14.
    Piepaar M, Andronikou S, van Toorn R: MRI to demonstrate diagnostic features and complications of TBM not seen with CT. Childs Nerv Syst 2009, 25:941–947.CrossRefGoogle Scholar
  15. 15.
    Pinto VL Jr., Lima MA, Rolla VC, et al.: Atypical cerebrospinal fluid profile in tuberculous meningitis. Trop Doct 2009, 39:76–78.CrossRefPubMedGoogle Scholar
  16. 16.
    • Patel VB, Burger I, Connolly C: Temporal evolution of cerebrospinal fluid following initiation of treatment for tuberculous meningitis. S Afr Med J 2008, 98:610–613. Prior to this publication, changes in CSF following the initiation of antituberculous treatment had not been well described. The rapid changes in neutrophil count and glucose concentration on repeat CSF samples of 99 patients with TBM seemed to assist clinicians in making decisions about patient care in the early phase of treatment, in contrast to the slow changes in lymphocyte count and protein concentration. It was believed to be very atypical for TBM for a repeat lumbar puncture (at 4–8 weeks) not to show definite improvement in neutrophil count and glucose concentration.PubMedGoogle Scholar
  17. 17.
    Venkataswamy MM, Rafi W, Nagarathna S, et al.: Comparative evaluation of BACTEC 460TB system and Lowenstein-Jensen medium for the isolation of M. tuberculosis from cerebrospinal fluid samples of tuberculous meningitis patients. Indian J Med Microbiol 2007, 25:236–240.CrossRefPubMedGoogle Scholar
  18. 18.
    •• Caws M, Dang TM, Torok E, et al.: Evaluation of the MODS culture technique for the diagnosis of tuberculous meningitis. PLoS ONE 2007, 2:e1173. These investigators showed the MODS culture technique to be nearly as sensitive as mycobacterial growth indicator tube (MGIT) and Lowenstein-Jensen (LJ) cultures for the diagnosis of TBM (65% sensitivity for MODS vs 70% sensitivity for the other two methods, using clinical diagnosis as the gold standard). The great advantages to the MODS technique were a mean time to positive culture of 6 days (vs 15.5 days for MGIT and 24 days for LJ cultures), a very low cost per sample (once an inverted microscope is purchased), and the ability to have susceptibility results as soon as cultures are positive.CrossRefPubMedGoogle Scholar
  19. 19.
    Corral I, Quereda C, Navas E, et al.: Adenosine deaminase activity in cerebrospinal fluid of HIV-infected patients: limited value for diagnosis of tuberculous meningitis. Eur J Clin Microbiol Infect Dis 2004, 23:471–476.CrossRefPubMedGoogle Scholar
  20. 20.
    Rafi W, Venkataswamy MM, Nagarathna S, et al.: Role of IS6110 uniplex PCR in the diagnosis of tuberculous meningitis: experience at a tertiary neurocentre. Int J Tubercul Lung Dis 2007, 11:209–214.Google Scholar
  21. 21.
    • Takahashi T, Tamura M, Asami Y, et al.: Novel wide-range quantitative nested real-time PCR assay for Mycobacterium tuberculosis DNA: clinical application for diagnosis of tuberculous meningitis. J Clin Microbiol 2008, 46:1698–1707. The use of PCR in the diagnosis of TBM has had much promise, but not nearly as much clinical success up to this point. However, advances are constantly being made. This paper describes a new PCR technique that combines the high sensitivity of nested PCR, the accurate quantification of real-time PCR, and a wide detection range for number of copies of DNA in CSF samples. The clinical usefulness of this exciting technique remains to be determined.CrossRefPubMedGoogle Scholar
  22. 22.
    Huang HJ, Xiang DR, Sheng JF, et al.: rpoB nested PCR and sequencing for the early diagnosis of tuberculous meningitis and rifampicin resistance. Int J Tubercul Lung Dis 2009, 13:749–754.Google Scholar
  23. 23.
    Haldar S, Sharma N, Gupta VK, Tyagi JS: Efficient diagnosis of tuberculous meningitis by detection of Mycobacterium tuberculosis DNA in cerebrospinal fluid filtrates using PCR. J Med Microbiol 2009, 58(Pt 5):616–624.CrossRefPubMedGoogle Scholar
  24. 24.
    Thwaites GE, Caws M, Chau TT, et al.: Comparison of conventional bacteriology with nucleic acid amplification (amplified mycobacterium direct test) for diagnosis of tuberculous meningitis before and after inception of antituberculosis chemotherapy. J Clin Microbiol 2004, 42:996–1002.CrossRefPubMedGoogle Scholar
  25. 25.
    Chandramuki A, Lyashchenko K, Kumari HB, et al.: Detection of antibody to Mycobacterium tuberculosis protein antigens in the cerebrospinal fluid of patients with tuberculous meningitis. J Infect Dis 2002, 186:678–683.CrossRefPubMedGoogle Scholar
  26. 26.
    Kashyap RS, Agarwal NP, Chandak NH, et al.: The application of the Mancini technique as a diagnostic test in the CSF of tuberculous meningitis patients. Med Sci Monit 2002, 8:MT95–MT98.PubMedGoogle Scholar
  27. 27.
    Kashyap RS, Kainthla RP, Biswas SK, et al.: Rapid diagnosis of tuberculous meningitis using the Simple Dot ELISA method. Med Sci Monit 2003, 9:MT123–MT126.PubMedGoogle Scholar
  28. 28.
    Mathai A, Radhakrishnan VV, Sarada C, George SM: Detection of heat stable mycobacterial antigen in cerebrospinal fluid by Dot-Immunobinding assay. Neurol India 2003, 51:52–54.PubMedGoogle Scholar
  29. 29.
    Quan C, Lu CZ, Qiao J, et al.: Comparative evaluation of early diagnosis of tuberculous meningitis by different assays. J Clin Microbiol 2006, 44:3160–3166.CrossRefPubMedGoogle Scholar
  30. 30.
    • Alffenaar JW, van Altena R, Bokkerink HJ, et al.: Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis 2009, 49:1080–1082. It has been almost 50 years since the introduction of a new first-line antimicrobial agent for the treatment of tuberculosis. Of currently available drugs, the new fluoroquinolones have the most promise. Moxifloxacin has the greatest in vitro activity against M. tuberculosis, and though published clinical data on its use in TBM are limited, this report is encouraging with regard to thinking about moxifloxacin as a reasonable second-line agent for TBM.CrossRefPubMedGoogle Scholar
  31. 31.
    American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003, 167:603–662.CrossRefGoogle Scholar
  32. 32.
    Berning SE, Cherry TA, Iseman MD: Novel treatment of meningitis caused by multidrug-resistant Mycobacterium tuberculosis with intrathecal levofloxacin and amikacin: case report. Clin Infect Dis 2001, 32:643–646.CrossRefPubMedGoogle Scholar
  33. 33.
    Takahashi T. Ogawa K. Sawada S, et al.: A case of refractory tuberculous meningitis markedly improved by intrathecal administration of isoniazid (INH) [Japanese]. Rinsho Shinkeigaku Clin Neurol 2003, 43:20–25.Google Scholar
  34. 34.
    Kumar R, Prakash M, Jha S: Paradoxical response to chemotherapy in neurotuberculosis. Pediatr Neurosurg 2006, 42:214–222.CrossRefPubMedGoogle Scholar
  35. 35.
    Ashby M, Grant H: Tuberculous meningitis treated with cortisone. Lancet 1955, 1:65–66.CrossRefGoogle Scholar
  36. 36.
    Voljavec BF, Corpe RF: The influence of corticosteroid hormones in the treatment of tuberculous meningitis in Negroes. Am Rev Respir Dis 1960, 81:539–545.Google Scholar
  37. 37.
    Lepper MH, Spies HW: The present status of the treatment of tuberculosis of the central nervous system. Ann NY Acad Sci 1963, 106:106–123.CrossRefPubMedGoogle Scholar
  38. 38.
    O’Toole RD, Thornton GF, Mukherjee MK, Nath RL: Dexamethasone in tuberculous meningitis: relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969, 70:39–48.PubMedGoogle Scholar
  39. 39.
    Escobar JA, Belsey MA, Duenes A, Medina P: Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975, 56:1050–1055.PubMedGoogle Scholar
  40. 40.
    Girgis NI, Farid Z, Hanna LS, et al.: The use of dexamethasone in preventing ocular complications in tuberculous meningitis. Trans R Soc Trop Med Hyg 1983, 77:658–659.CrossRefPubMedGoogle Scholar
  41. 41.
    Girgis NI, Farid Z, Kilpatrick ME, et al.: Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991, 10:179–183.CrossRefPubMedGoogle Scholar
  42. 42.
    Kumarvelu S, Prasad K, Khosla A, et al.: Randomized controlled trial of dexamethasone in tuberculous meningitis. Tubercle Lung Dis 1994, 75:302–307.CrossRefGoogle Scholar
  43. 43.
    Chotmongkol V, Jitpimolmard S, Thavornpitak Y: Corticosteroid in tuberculous meningitis. J Med Assoc Thai 1996, 79:83–90.PubMedGoogle Scholar
  44. 44.
    Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR: Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcomes in young children with tuberculous meningitis. Pediatrics 1997, 99:226–231.CrossRefPubMedGoogle Scholar
  45. 45.
    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. Philipp J Neurol 1998, 4:4–10.Google Scholar
  46. 46.
    Thwaites GE, Nguyen DB, Nguyen HD, et al.: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. New Engl J Med 2004, 351:1741–1751.CrossRefPubMedGoogle Scholar
  47. 47.
    •• Prasad K, Singh MB: Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008, 1:CD002244. This systematic review examined seven randomized controlled trials (1140 patients) of adjunctive corticosteroids in TBM, and noted a significant improvement in mortality rate with steroid therapy. In the three trials that studied the composite endpoint of death or disabling residual neurologic deficit, a significant improvement was noted. The authors recommended dexamethasone or prednisolone for HIV-negative children (3–6 weeks of therapy) and adults (6 weeks of therapy) to reduce death and disabling residual neurologic deficit among survivors.PubMedGoogle Scholar
  48. 48.
    Singh D, Sachdev V, Singh AK, Sinha S: Endoscopic third ventriculostomy in post-tubercular meningitic hydrocephalus: a preliminary report. Minim Invasive Neurosurg 2005, 48:47–52.CrossRefPubMedGoogle Scholar
  49. 49.
    Das SK, Ghosh D, Singhi A, et al.: Dural biopsy—an important prognostic indicator in tuberculous meningitis with hydrocephalus following shunt surgery. J Indian Med Assoc 2007, 105:12–15.PubMedGoogle Scholar
  50. 50.
    Kelly JJ, Horowitz EA, Destache CJ, et al.: Diagnosis and treatment of complicated tubercular meningitis. Pharmacotherapy 1999, 19:1167–1172.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Robert Wood Johnson Medical SchoolUniversity of Medicine and Dentistry of New JerseyNew BrunswickUSA
  2. 2.ID CareHillsboroughUSA

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