Tuberculous Encephalitis

  • Jean Paul StahlEmail author


Mycobacterium tuberculosis is one of the most frequent aetiologies of infectious encephalitis, the most frequent remaining HSV. Its pathophysiology doesn’t differ from other non-pulmonary tuberculosis: it results from bacteremia and then locates in the brain. Microbiological diagnosis is not easy to obtain, as bacterial inoculum is low. PCR tests are not highly sensitive, so far. Remarkable feature in CSF biology is high protein level, significatively different from other aetiologies. Clinical presentation doesn’t differ from other encephalitis except the delay between the onset and diagnosis (10 days vs 2). The treatment drugs are the same than in other tuberculous localization, with a longer duration (12 months). Despite an adequate treatment, case fatality rate reaches 33% (9% in other encephalitis cases).


Mycobacterium tuberculosis Encephalitis Mycobacterium tuberculosis PCR CSF adenosine deaminase Isoniazid Rifampicin Fluoroquinolone Pyrazinamide Ethambutol Brain MRI 


  1. 1.
    Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl J-P, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57(8):1114–28.CrossRefGoogle Scholar
  2. 2.
    Sotgiu G, Falzon D, Hollo V, KoÈdmoÈn C, Lefebvre N, Dadu A, van der Werf M. Determinants of site of tuberculosis disease: An analysis of European surveillance data from 2003 to 2014. Plos One. 2017; Scholar
  3. 3.
    Honnorat E, De Broucker T, Mailles A, Stahl JP. Encephalitis due to Mycobacterium tuberculosis in France. Med Mal Infect. 2013;43(6):230–8.CrossRefGoogle Scholar
  4. 4.
    Cobo F, Salas-Coronas J, Cabezas-Fernandez MT, Vazquez-Villegas J, Cabeza-Barrera MI, Soriano-Perez MJ. Infectious diseases in immigrant population related to the time of residence in Spain. J Immigr Minor Health. 2016;18:8–15.CrossRefGoogle Scholar
  5. 5.
    Mailles A, Stahl J-P. Infectious encephalitis in France in 2007: a national prospective study. Clin Infect Dis. 2009;49:1838–47.CrossRefGoogle Scholar
  6. 6.
    Granerod J, Ambrose HE, Davies NWS, Clewley JP, Walsh AL, Morgan D, et al. Causes of encephalitis and 5 differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835–44.CrossRefGoogle Scholar
  7. 7.
    Christie LJ, Loeffler AM, Honarmand S, Flood JM, Baxter R, Jacobson S, Alexander R, Glaser CA. Diagnostic challenges of central nervous system tuberculosis. Emerg Infect Dis. 2008;14(9):1473–5.CrossRefGoogle Scholar
  8. 8.
    Algood HM, Lin PL, Flynn JL. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis. 2005;41(Suppl 3):S189–93.CrossRefGoogle Scholar
  9. 9.
    Edwards D, et al. The immunology of mycobacterial diseases. Am Rev Respir Dis. 1986;134:1062–71.CrossRefGoogle Scholar
  10. 10.
    Friedland JS. Cytokines, phagocytosis, and mycobacterium tuberculosis. Lymphokine Cytokine Res. 1993;12:127–33.PubMedGoogle Scholar
  11. 11.
    Fillatre P, Crabol Y, Morand P, Piroth L, Honnorat J, Stahl JP, Lecuit M. Infectious encephalitis: Management without etiological diagnosis 48 hours after onset. Med Mal Infect. 2017;47:236–51.CrossRefGoogle Scholar
  12. 12.
    Thwaites GE, Chau TTH, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol. 2004;42(1):378–9.CrossRefGoogle Scholar
  13. 13.
    Erdem H, OzturkEngin D, Elaldi N, Gulsun S, Sengoz G, Crisan A, et al. The microbiological diagnosis of tuberculous meningitis: results of Haydarpasa1 study. Clin Microbiol Infect. 2014;20(10):O600–8.CrossRefGoogle Scholar
  14. 14.
    Xu HB, Jiang RH, Li L, Sha W, Xiao HP. Diagnostic value of adenosine deaminase in cerebrospinal fluid for tuberculous meningitis: a meta-analysis. Int J Tuberc Lung Dis. 2010;14(11):1382–7.PubMedGoogle Scholar
  15. 15.
    Solari L, Soto A, Agapito JC, Acurio V, Vargas D, Battaglioli T, et al. The validity of cerebrospinal fluid parameters for the diagnosis of tuberculous meningitis. Int J Infect Dis. 2013;17(12):e1111–5.CrossRefGoogle Scholar
  16. 16.
    Stahl JP, Azouvi P, Bruneel F, De Broucker T, Duval X, Fantin B, Girard N, Herrmann JL, Honnorat J, et al. Guidelines on the management of infectious encephalitis in adults. Med Mal Infect. 2017;47(3):179–94.CrossRefGoogle Scholar
  17. 17.
    Patel VB, Theron G, Lenders L, Matinyena B, Connolly C, Singh R, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med. 2013;10(10):e1001536.CrossRefGoogle Scholar
  18. 18.
    Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2014;44(2):435–46.CrossRefGoogle Scholar
  19. 19.
    Goulenok T, Buzelé R, Duval X, Bruneel F, Stahl JP, Fantin B. Management of adult infectious encephalitis in metropolitan France. Med Mal Infect. 2017;47:206–20.CrossRefGoogle Scholar
  20. 20.
    Chiang SS, Khan FA, Milstein MB, Tolman AW, Benedetti A, Starke JR, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(10):947–57.CrossRefGoogle Scholar
  21. 21.
    Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013;12(10):999–1010.CrossRefGoogle Scholar
  22. 22.
    Donald PR, Schoeman JF, Van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis. 1998;2(9):704–11.PubMedGoogle Scholar
  23. 23.
    Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009;59(3):167–87.CrossRefGoogle Scholar
  24. 24.
    American Thoracic Society, Center for Disease Control and Prevention, Infectious Disease Society of America. Treatment of tuberculosis. MMWR Morb Mortal Wkly Rep. 2003;52(RR–11):1–77.Google Scholar
  25. 25.
    Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med. 2016;374(2):124–34.CrossRefGoogle Scholar
  26. 26.
    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. N Engl J Med. 2004;351(17):1741–51.CrossRefGoogle Scholar
  27. 27.
    Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis. 1993;148(3):650–5.CrossRefGoogle Scholar
  28. 28.
    Kaojarern S, Supmonchai K, Phuapradit P, Mokkhavesa C. Clin Pharmacol Ther. 1991;49(1):6–12.CrossRefGoogle Scholar
  29. 29.
    Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis. 2005;192(1):79–88.CrossRefGoogle Scholar
  30. 30.
    Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013;13(1):27–35.CrossRefGoogle Scholar
  31. 31.
    Ellard GA, Humphries MJ, Gabriel M, Teoh R. Penetration of pyrazinamide into the cerebrospinal fluid in tuberculous meningitis. Br Med J (Clin Res Ed). 1987;294(6567):284–5.CrossRefGoogle Scholar
  32. 32.
    Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007;41(11):1859–66.CrossRefGoogle Scholar
  33. 33.
    Thwaites GE, Bhavnani SM, Chau TT, Hammel JP, Torok ME, Van Wart SA, et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother. 2011;55(7):3244–53.CrossRefGoogle Scholar
  34. 34.
    Alffenaar JW, van Altena R, Bokkerink HJ, Luijckx GJ, van Soolingen D, Aarnoutse RE, et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis. 2009;49(7):1080–2.CrossRefGoogle Scholar
  35. 35.
    Heemskerk AD. Intensified treatment with high-dose Rifampicin and Levofloxacin compared to standard treatment for adult patients with Tuberculous Meningitis (TBM-IT): protocol for a randomized controlled trial. Trials. 2011;12:25.CrossRefGoogle Scholar
  36. 36.
    Yu HY, Hu FS, Xiang DR, Sheng JF. Clinical management of tuberculous meningitis: experiences of 42 cases and literature review. Neurol Sci. 2014;35(2):303–5.CrossRefGoogle Scholar
  37. 37.
    Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2008;(1):CD002244.Google Scholar
  38. 38.
    Coulter JB, Baretto RL, Mallucci CL, Romano MI, Abernethy LJ, Isherwood DM, et al. Tuberculous meningitis: protracted course and clinical response to interferon gamma. Lancet Infect Dis. 2007;7(3):225–32.CrossRefGoogle Scholar
  39. 39.
    Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis. 2008;47(10):e83–5.CrossRefGoogle Scholar
  40. 40.
    Roberts MT, Mendelson M, Meyer P, Carmichael A, Lever AM. The use of thalidomide in the treatment of intracranial tuberculomas in adults: two case reports. J Infect. 2003;47(3):251–5.CrossRefGoogle Scholar
  41. 41.
    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.CrossRefGoogle Scholar
  42. 42.
    Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: a randomized open-label placebo-controlled trial. J Neurol Sci. 2010;293(1–2):12–7.CrossRefGoogle Scholar
  43. 43.
    Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. J Child Neurol. 2011;26(8):956–62.CrossRefGoogle Scholar
  44. 44.
    Cardenas G, Soto-Hernandez JL, Orozco RV, Silva EG, Revuelta R, Amador JL. Tuberculous brain abscesses in immunocompetent patients: management and outcome. Neurosurgery. 2010;67(4):1081–7.CrossRefGoogle Scholar
  45. 45.
    Erdem H, Ozturk-Engin D, Tireli H, Kilicoglu G, Defres S, Gulsun S, Sengoz G, Crisan A, Johansen IS, et al. Hamsi scoring in the prediction of unfavorable outcomes from tuberculous meningitis: results of Haydarpasa-II study. J Neurol. 2015;262(4):890–8.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Infectious Diseases department. CHU and University Grenoble AlpesGrenobleFrance
  2. 2.ESGIB (European Study Group for the Infections of the Brain)DakarSenegal

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