The Global Neurological Burden of Tuberculosis

 

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Abstract

Central nervous system (CNS) involvement of tuberculosis (TB) is the most severe manifestation of TB and accounts for approximately 5 to 10% of all extrapulmonary TB (EPTB) cases and approximately 1% of all TB cases. TB meningitis (TBM) is the most common form of CNS TB, though other forms occur, often in conjunction with TBM, including intracranial tuberculomas, tuberculous brain abscesses, and spinal tubercular arachnoiditis. CNS TB often presents with nonspecific clinical features that mimic symptoms of other neurological conditions, often making diagnosis difficult. Defining neuroimaging characteristics of TBM include thick basal meningeal enhancement, hydrocephalus, and parenchymal infarctions most commonly involving the basal ganglia and internal capsule. Traditional cerebrospinal fluid sample analysis frequently requires lengthy times-to-result and have low sensitivity. Given the pitfalls of conventional CNS TB diagnostic methods, various molecular-based methods, including immunoassays and polymerase chain reaction (PCR)-based assays have emerged as alternative diagnostic tools due to their rapidity, sensitivity, and specificity. Expert panels on TBM have recently emphasized the need for standard research procedures with updated case definitions and standardized study methods, which will hopefully pave the way for more robust multicenter international studies. In this article, we review the epidemiology, diagnosis, molecular factors associated with disease presentation and outcome, and treatment of CNS TB.

• References

• 1 World Health Organization. Global Tuberculosis Report 2016. Geneva, Switzerland: 2016
  Google Scholar
• 2 Cherian A, Thomas SV. Central nervous system tuberculosis. Afr Health Sci 2011; 11 (01) 116-127
  PubMedGoogle Scholar
• 3 Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev 2008; 21 (02) 243-261
  CrossrefPubMedGoogle Scholar
• 4 Changal KH, Raina AH. Central nervous system manifestations of tuberculosis: a review article. J Mycobac Dis 2014; 4 (02) 146-150
  PubMedGoogle Scholar
• 5 Lee JY. Diagnosis and treatment of extrapulmonary tuberculosis. Tuberc Respir Dis (Seoul) 2015; 78 (02) 47-55
  CrossrefPubMedGoogle Scholar
• 6 Leonard JM. Central nervous system tuberculosis. Microbiol Spectr 2017; 5 (02) 1-10
  PubMedGoogle Scholar
• 7 Ramachandran TS. Tuberculosis meningitis. Medscape. Available at: http://emedicine.medscape.com/article/1166190-overview#a5 . Accessed August 2, 2017
  PubMedGoogle Scholar
• 8 Rali P, Arshad H, Bihler E. A case of tuberculous meningitis with tuberculoma in nonimmunocompromised immigrant. Case Rep Pulmonol 2016; 2016: 9016142 . Doi: 10.1155/2016/9016142
  PubMedGoogle Scholar
• 9 Chou PS, Liu CK, Lin RT, Lai CL, Chao AC. Central nervous system tuberculosis: a forgotten diagnosis. Neurologist 2012; 18 (04) 219-222
  CrossrefPubMedGoogle Scholar
• 10 Christie LJ, Loeffler AM, Honarmand S. , et al. Diagnostic challenges of central nervous system tuberculosis. Emerg Infect Dis 2008; 14 (09) 1473-1475
  CrossrefPubMedGoogle Scholar
• 11 Thwaites GE, Nguyen DB, Nguyen HD. , et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351 (17) 1741-1751
  CrossrefPubMedGoogle Scholar
• 12 Török ME, Yen NTB, Chau TTH. , et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011; 52 (11) 1374-1383
  CrossrefPubMedGoogle Scholar
• 13 Nelson CA, Zunt JR. Tuberculosis of the central nervous system in immunocompromised patients: HIV infection and solid organ transplant recipients. Clin Infect Dis 2011; 53 (09) 915-926
  CrossrefPubMedGoogle Scholar
• 14 Oommen TT, Mallesh P, Ramaiah M, Thayyil AA, Narayanagowda L. Choroidal tubercles in isolated tuberculous meningitis. J Evolution Med Dent Sci 2016; 5 (33) 1858-1859
  PubMedGoogle Scholar
• 15 Furqan M, Butler J. Miliary pattern on chest radiography: TB or not TB?. Mayo Clin Proc 2010; 85 (02) 108
  CrossrefPubMedGoogle Scholar
• 16 Miftode EG, Dorneanu OS, Leca DA. , et al. Tuberculous meningitis in children and adults: A 10-year retrospective comparative analysis. PLoS One 2015; 10 (07) 1-10
  CrossrefPubMedGoogle Scholar
• 17 Torok ME, Chau TTH, Mai PP. , et al. Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS One 2008; 3 (03) e1772
  CrossrefPubMedGoogle Scholar
• 18 Sütlaş PN, Unal A, Forta H, Senol S, Kirbaş D. Tuberculous meningitis in adults: review of 61 cases. Infection 2003; 31 (06) 387-391
  PubMedGoogle Scholar
• 19 Corr PD. Imaging in CNS tuberculosis. Medscape. Available at: http://emedicine.medscape.com/article/344862-overview . Accessed August 2, 2017
  PubMedGoogle Scholar
• 20 Andronikou S, Smith B, Hatherhill M, Douis H, Wilmshurst J. Definitive neuroradiological diagnostic features of tuberculous meningitis in children. Pediatr Radiol 2004; 34 (11) 876-885
  CrossrefPubMedGoogle Scholar
• 21 Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous system tuberculosis. Indian J Radiol Imaging 2009; 19 (04) 256-265
  Article in Thieme ConnectPubMedGoogle Scholar
• 22 Sanei Taheri M, Karimi MA, Haghighatkhah H, Pourghorban R, Samadian M, Delavar Kasmaei H. Central nervous system tuberculosis: an imaging-focused review of a reemerging disease. Radiol Res Pract 2015; 2015: 202806 . Doi: 10.1155/2015/202806
  PubMedGoogle Scholar
• 23 Nhu NTQ, Heemskerk D, Thu DA. , et al. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol 2014; 52 (01) 226-233
  CrossrefPubMedGoogle Scholar
• 24 Brancusi F, Farrar J, Heemskerk D. Tuberculous meningitis in adults: a review of a decade of developments focusing on prognostic factors for outcome. Future Microbiol 2012; 7 (09) 1101-1116
  CrossrefPubMedGoogle Scholar
• 25 Takahashi T, Tamura M, Takasu T. The PCR-based diagnosis of central nervous system tuberculosis: up to date. Tuberc Res Treat 2012; 2012: 831292 . Doi: 10.1155/2012/831292
  PubMedGoogle Scholar
• 26 Lawn SD, Nicol MP. Xpert® MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance. Future Microbiol 2011; 6 (09) 1067-1082
  CrossrefPubMedGoogle Scholar
• 27 Wilkinson RJ, Rohlwink U, Misra UK. , et al; Tuberculous Meningitis International Research Consortium. Tuberculous meningitis. Nat Rev Neurol 2017; 13 (10) 581-598
  CrossrefPubMedGoogle Scholar
• 28 Patel VB, Theron G, Lenders L. , 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
  CrossrefPubMedGoogle Scholar
• 29 Bahr NC, Tugume L, Rajasingham R. , et al. Improved diagnostic sensitivity for tuberculous meningitis with Xpert(®) MTB/RIF of centrifuged CSF. Int J Tuberc Lung Dis 2015; 19 (10) 1209-1215
  CrossrefPubMedGoogle Scholar
• 30 Making publicly funded medical technologies accessible in developing countries: Tuberculosis. PublicCitizen. Available at: https://www.citizen.org/sites/default/files/genexpert-tb-fact-sheet.pdf . Accessed August 23, 2017
  PubMed
• 31 World Health Organization. Xpert MTB/RIF Implementation Manual: Technical and Operational “How-To”: Practical Considerations. Geneva, Switzerland: 2014
  Google Scholar
• 32 2017 launch of new TB test Ultra backed by WHO recommendation. Cepheid; 2017. Available at: http://www.cepheid.com/us/about-us/news-events/press-releases/216-2017-launch-of-new-tb-test-ultra-backed-by-who-recommendation . Accessed September 4, 2017
  PubMed
• 33 Bahr NC, Nuwagira E, Evans EE. , et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2018; 18 (01) 68-75
  CrossrefPubMedGoogle Scholar
• 34 World Health Organization. Non-Inferiority Analysis of Xpert MTB/RIF Ultra Compared to Xpert MTB/RIF. Geneva, Switzerland: 2017
  Google Scholar
• 35 Pai M, Behr MA, Dowdy D. , et al. Tuberculosis. Nat Rev Dis Primers 2016; 2: 16076 . doi: 10.1038/nrdp.2016.76
  CrossrefPubMedGoogle Scholar
• 36 Philip N, William T, John DV. Diagnosis of tuberculous meningitis: challenges and promises. Malays J Pathol 2015; 37 (01) 1-9
  PubMedGoogle Scholar
• 37 Salzberg SL, Breitwieser FP, Kumar A. , et al. Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system. Neurol Neuroimmunol Neuroinflamm 2016; 3 (04) e251
  CrossrefPubMedGoogle Scholar
• 38 Marais S, Thwaites G, Schoeman JF. , et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 2010; 10 (11) 803-812
  CrossrefPubMedGoogle Scholar
• 39 Marais BJ, Heemskerk AD, Marais SS. , et al; Tuberculous Meningitis International Research Consortium. Standardized methods for enhanced quality and comparability of tuberculous meningitis studies. Clin Infect Dis 2017; 64 (04) 501-509
  PubMedGoogle Scholar
• 40 Simmons CP, Thwaites GE, Quyen NT. , et al. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. J Immunol 2005; 175 (01) 579-590
  CrossrefPubMedGoogle Scholar
• 41 Simmons CP, Thwaites GE, Quyen NT. , et al. Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome. J Immunol 2006; 176 (03) 2007-2014
  CrossrefPubMedGoogle Scholar
• 42 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 (03) (Suppl. 03) S189-S193
  CrossrefPubMedGoogle Scholar
• 43 Tsenova L, Bergtold A, Freedman VH, Young RA, Kaplan G. Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Proc Natl Acad Sci U S A 1999; 96 (10) 5657-5662
  CrossrefPubMedGoogle Scholar
• 44 Hashimoto M, Ishikawa Y, Yokota S. , et al. Action site of circulating interleukin-1 on the rabbit brain. Brain Res 1991; 540 (1-2): 217-223
  CrossrefPubMedGoogle Scholar
• 45 de Vries HE, Kuiper J, de Boer AG, Van Berkel TJ, Breimer DD. The blood-brain barrier in neuroinflammatory diseases. Pharmacol Rev 1997; 49 (02) 143-155
  PubMedGoogle Scholar
• 46 Rohlwink UK, Mauff K, Wilkinson KA. , et al. Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis. Clin Infect Dis 2017; 65 (08) 1298-1307
  CrossrefPubMedGoogle Scholar
• 47 Rohlwink UK, Figaji AA. Biomarkers of brain injury in cerebral infections. Clin Chem 2014; 60 (06) 823-834
  CrossrefPubMedGoogle Scholar
• 48 Tobin DM, Roca FJ, Oh SF. , et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 2012; 148 (03) 434-446
  CrossrefPubMedGoogle Scholar
• 49 van Laarhoven A, Dian S, Ruesen C. , et al. Clinical parameters, routine inflammatory markers, and LTA4H genotype as predictors of mortality among 608 patients with tuberculous meningitis in Indonesia. J Infect Dis 2017; 215 (07) 1029-1039
  CrossrefPubMedGoogle Scholar
• 50 Tsenova L, Mangaliso B, Muller G. , et al. Use of IMiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrob Agents Chemother 2002; 46 (06) 1887-1895
  CrossrefPubMedGoogle Scholar
• 51 van Toorn R, Schaaf HS, Laubscher JA, van Elsland SL, Donald PR, Schoeman JF. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J 2014; 33 (03) 248-252
  CrossrefPubMedGoogle Scholar
• 52 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. J Infect 2009; 59 (03) 167-187
  CrossrefPubMedGoogle Scholar
• 53 Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb) 2010; 90 (05) 279-292
  CrossrefPubMedGoogle Scholar
• 54 Ruslami R, Ganiem AR, Dian S. , et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13 (01) 27-35
  CrossrefPubMedGoogle Scholar
• 55 Te Brake L, Dian S, Ganiem AR. , et al. Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. Int J Antimicrob Agents 2015; 45 (05) 496-503
  CrossrefPubMedGoogle Scholar
• 56 Heemskerk AD, Bang ND, Mai NTH. , et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med 2016; 374 (02) 124-134
  CrossrefPubMedGoogle Scholar
• 57 Crevel RV, Ruslami R, Aarnoutse R. Therapy for tuberculous meningitis. N Engl J Med 2016; 374(22): 2187-2189
  CrossrefPubMedGoogle Scholar
• 58 Dooley K. Optimizing treatment to improve TBM outcomes in children (TBM-KIDS). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT02958709 . Accessed September 4, 2017
  PubMedGoogle Scholar
• 59 Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2016; 4: CD002244 . Doi: 10.1002/14651858.CD002244.pub4
  CrossrefPubMedGoogle Scholar
• 60 Sorrells SF, Sapolsky RM. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 2007; 21 (03) 259-272
  CrossrefPubMedGoogle Scholar
• 61 Török ME. Tuberculous meningitis: advances in diagnosis and treatment. Br Med Bull 2015; 113 (01) 117-131
  CrossrefPubMedGoogle Scholar
• 62 Aspirin to prevent a first heart attack or stroke. National Institute of Health. Available at: https://www.nhlbi.nih.gov/health/health-topics/topics/aspirin-prevent-first-heart-attack-or-stroke . Accessed September 3, 2017
  PubMedGoogle Scholar
• 63 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): 12-17
  CrossrefPubMedGoogle Scholar
• 64 A pilot-study of adjunctive aspirin for the treatment of HIV negative adults with tuberculous meningitis (Aspirin TBM). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT02237365 . Accessed September 4, 2017
  PubMedGoogle Scholar
• 65 Bahr N, Boulware DR, Marais S, Scriven J, Wilkinson RJ, Meintjes G. Central nervous system immune reconstitution inflammatory syndrome. Curr Infect Dis Rep 2013; 15 (06) 583-593
  CrossrefPubMedGoogle Scholar
• 66 Murdoch DM, Venter WDF, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther 2007; 4 (09) 9 . Doi: 10.1186/1742-6405-4-9
  CrossrefPubMedGoogle Scholar
• 67 Socías ME, Sued O, Laufer N. , et al; Grupo Argentino de Seroconversión Study Group. Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters. J Int AIDS Soc 2011; 14 (40) 40 . Doi: 10.1186/1758-2652-14-40
  CrossrefPubMedGoogle Scholar
• 68 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 (04) 643-646
  CrossrefPubMedGoogle Scholar
• 69 Patel VB, Padayatchi N, Bhigjee AI. , et al. Multidrug-resistant tuberculous meningitis in KwaZulu-Natal, South Africa. Clin Infect Dis 2004; 38 (06) 851-856
  CrossrefPubMedGoogle Scholar
• 70 Padayatchi N, Bamber S, Dawood H, Bobat R. Multidrug-resistant tuberculous meningitis in children in Durban, South Africa. Pediatr Infect Dis J 2006; 25 (02) 147-150
  CrossrefPubMedGoogle Scholar
• 71 Vinnard C, Winston CA, Wileyto EP, MacGregor RR, Bisson GP. Multidrug resistant tuberculous meningitis in the United States, 1993-2005. J Infect 2011; 63 (03) 240-242
  CrossrefPubMedGoogle Scholar
• 72 World Health Organization. Guidelines for Treatment of Tuberculosis. Geneva, Switzerland: 2010
  Google Scholar
• 73 Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010; 10 (09) 621-629
  CrossrefPubMedGoogle Scholar
• 74 Gualano G, Capone S, Matteelli A, Palmieri F. New antituberculosis drugs: from clinical trial to programmatic use. Infect Dis Rep 2016; 8 (02) 6569
  PubMedGoogle Scholar
• 75 Akkerman OW, Odish OF, Bolhuis MS. , et al. Pharmacokinetics of bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis. Clin Infect Dis 2016; 62 (04) 523-524
  PubMedGoogle Scholar
• 76 Shibata M, Shimokawa Y, Sasahara K. , et al. Absorption, distribution and excretion of the anti-tuberculosis drug delamanid in rats: extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis. Biopharm Drug Dispos 2017; 38 (04) 301-312
  CrossrefPubMedGoogle Scholar
• 77 Verdon R, Chevret S, Laissy JP, Wolff M. Tuberculous meningitis in adults: review of 48 cases. Clin Infect Dis 1996; 22 (06) 982-988
  CrossrefPubMedGoogle Scholar
• 78 Merkler AE, Reynolds AS, Gialdini G. , et al. Neurological complications after tuberculous meningitis in a multi-state cohort in the United States. J Neurol Sci 2017; 375: 460-463
  CrossrefPubMedGoogle Scholar
• 79 Chiang SS, Khan FA, Milstein MB. , et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14 (10) 947-957
  CrossrefPubMedGoogle Scholar
• 80 Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007; 14 (01) 33-37
  CrossrefPubMedGoogle Scholar
• 81 Steingart KR, Ramsay A, Pai M. Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis. Expert Rev Anti Infect Ther 2007; 5 (03) 327-331
  CrossrefPubMedGoogle Scholar
• 82 Boulware DR. TBM Diagnostics: Xpert Ultra. University of Minnesota; 2017
  Google Scholar
• 83 Ghosh GC, Sharma B, Gupta BB. CSF ADA determination in early diagnosis of tuberculous meningitis in HIV-infected patients. Scientifica (Cairo) 2016; 2016: 5820823 . Doi: 10.1155/2016/5820823
  PubMedGoogle Scholar
• 84 Chakravorty S, Simmons AM, Rowneki M. , et al. The New Xpert MTB/RIF Ultra: improving detection of Myobacterium tuberculosis and resistance to rifampin in an assay suitable for point-of-care testing. MBio 2017; 8 (04) e00812-e00817
  PubMedGoogle Scholar