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Advances in the Diagnosis and Management of Tubercular Meningitis in Children

  • Review Article
  • Published:
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Abstract

Tubercular meningitis (TBM) continues to be a common cause of neuromorbidity in children. There is no single diagnostic method that can rapidly detect Mycobacterium tuberculosis (M.tb) in TBM patients with high sensitivity and specificity. Newer diagnostic modalities like Xpert/RIF assay and Loop mediated isothermal amplification assay (LAMP) have gained an essential stand in molecular diagnostics due to their high specificity, modest sensitivity in cerebrospinal fluid (CSF) and quick availability of results. Intensified drug regimens using high dose rifampicin, fluoroquinolone and aspirin appear to be useful adjunct therapy but more pediatric clinical trials on large scale are needed to determine their appropriate place in pediatric TBM. The emergence of multi and extreme drug resistant M.tb strains further challenges the standard therapy. In this review authors summarize challenges of the currently used diagnostic methods and treatment for TBM and discuss the recent advances.

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References

  1. Yaramis A, Bükte Y, Katar S, Ozbek MN, et al. Chest computerized tomography scans findings in 74 children with tuberculous meningitis in southeastern Turkey. Turk J Pediatr. 2007;49:365–9.

    PubMed  Google Scholar 

  2. Iseman MD. A Clinician's Guide to Tuberculosis. Baltimore: Lippincott Williams & Wilkins; 1999.

    Google Scholar 

  3. Huang TY, Zhang XX, Wu QL, et al. Antibody detection tests for early diagnosis in tuberculous meningitis. Int J Infect Dis. 2016;48:64–9.

    CAS  PubMed  Google Scholar 

  4. Jorstad MD, Marijani M, Dyrhol-Riise AM, Sviland L, Mustafa T. MPT64 antigen detection test improves routine diagnosis of extrapulmonary tuberculosis in a low-resource setting: a study from the tertiary care hospital in Zanzibar. PLoS One. 2018;13:e0196723.

    PubMed  PubMed Central  Google Scholar 

  5. Garg RH. Tuberculous meningitis. Acta Neurol Scand. 2010;122:75–90.

    CAS  PubMed  Google Scholar 

  6. Chen P, Shi M, Feng GD, et al. A highly efficient Ziehl- Neelsen stain: identifying de novo intracellular mycobacterium tuberculosis and improving detection of extracellular M. tuberculosis in cerebrospinal fluid. J Clin Microbiol. 2012;50:1166–70.

    PubMed  PubMed Central  Google Scholar 

  7. Ho J, Marais BJ, Gilbert GL, Ralph AP. Diagnosing tuberculous meningitis – have we made any progress? Tropical Med Int Health. 2013;18:783–93.

    Google Scholar 

  8. Thwaites G. Tuberculous meningitis. Medicine. 2013;41:683–5.

    Google Scholar 

  9. Tuon FF, Higashino HR, Lopes MI, et al. Adenosine deaminase and tuberculous meningitis--a systematic review with meta-analysis. Scand J Infect Dis. 2010;42:198–207.

    CAS  PubMed  Google Scholar 

  10. Rufai SB, Singh A, Singh J, Kumar P, Sankar MM, Singh S; TB Research Team. Diagnostic usefulness of Xpert MTB/RIF assay for detection of tuberculous meningitis using cerebrospinal fluid. J Inf Secur. 2017;75:125–31.

    Google Scholar 

  11. Gupta R, Talwar P, Talwar P, et al. Diagnostic accuracy of nucleic acid amplification based assays for tuberculous meningitis: a meta-analysis. J Inf Secur. 2018;77:302–13.

    Google Scholar 

  12. Kumar P, Benny P, Jain M, Singh S. Comparison of an in-house multiplex PCR with two commercial immuno-chromatographic tests for rapid identification and differentiation of MTB from NTM isolates. Int J Mycobacteriol. 2014;3:51–6.

    Google Scholar 

  13. Pham TH, Peter J, Mello FCQ, et al. Performance of the TB-LAMP diagnostic assay in reference laboratories: results from a multicentre study. Int J Infect Dis. 2018;68:44–9.

    PubMed  PubMed Central  Google Scholar 

  14. WHO. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. WHO/CDS/TB/2018.4; 2018.

  15. Ajbani K, Kazi M, Naik S, Soman R, Shetty A, Rodrigues C. Utility of pyrosequencing for rapid detection of tubercular meningitis (TBM) and associated susceptibility directly from CSF specimens. Tuberculosis (Edinb). 2018;111:54–6.

    CAS  Google Scholar 

  16. Andronikou S, Smith B, Hatherhill M, Douis H, Wilmshurst J. Definitive neuroradiological diagnostic features of tuberculous meningitis in children. Pediatr Radiol. 2004;34:876–85.

    PubMed  Google Scholar 

  17. Splendiani A, Puglielli E, De Amicis R, Necozione S, Masciocchi C, Gallucci M. Contrast-enhanced FLAIR in the early diagnosis of infectious meningitis. Neuroradiology. 2005;47:591–8.

    PubMed  Google Scholar 

  18. Kremer S, Abu Eid M, Bierry G, et al. Accuracy of delayed post-contrast FLAIR MR imaging for the diagnosis of leptomeningeal infectious or tumoral diseases. J Neuroradiol. 2006;33:285–91.

    CAS  PubMed  Google Scholar 

  19. Kalita J, Singh RK, Misra UK. Evaluation of cerebral arterial and venous system in tuberculous meningitis. J Neuroradiol. 2018;45:130–5.

    PubMed  Google Scholar 

  20. Kalita J, Prasad S, Maurya PK. MR angiography in tuberculous meningitis. Acta Radiol. 2012;53:324–9.

    PubMed  Google Scholar 

  21. Bansod A, Garg RK, Rizvi I, et al. Magnetic resonance venographic findings in patients with tuberculous meningitis: predictors and outcome. Magn Reson Imaging. 2018;54:8–14.

    PubMed  Google Scholar 

  22. Dhawan SR, Chatterjee D, Radotra BD, et al. A child with tuberculous meningitis complicated by cortical venous and cerebral sino-venous thrombosis. Indian J Pediatr. 2019;86:371–8.

    PubMed  Google Scholar 

  23. Sharawat IK, Soni V, Dhawan SR. Comments on ‘magnetic resonance venographic findings in patients with tuberculous meningitis’. Magn Reson Imaging. 2019;61:231–2.

    PubMed  Google Scholar 

  24. van Loenhout-Rooyackers JH, Keyser A, Laheij RJ, Verbeek AL, van der Meer JW. Tuberculous meningitis: is a 6-month treatment regimen sufficient? Int J Tuberc Lung Dis. 2001;5:1028–35.

    PubMed  Google Scholar 

  25. 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;33:248–52.

    PubMed  Google Scholar 

  26. Donald PR, Schoeman JF, van Zyl LE. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis. 1998;2:704–11.

    CAS  PubMed  Google Scholar 

  27. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb). 2010;90:279–92.

    CAS  Google Scholar 

  28. 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;13:27–35.

    PubMed  Google Scholar 

  29. Heemskerk D, Day J, Chau TT, et al. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kalita J, Misra UK, Prasad S. Safety and efficacy of levofloxacin versus rifampicin in tuberculous meningitis: an open-label randomized controlled trial. J Antimicrob Chemother. 2014;69:2246–51.

    CAS  PubMed  Google Scholar 

  31. Rizvi I, Malhotra HS, Garg RK, Kumar N, Uniyal R, Pandey S. Fluoroquinolones in the management of tuberculous meningitis: systematic review and meta-analysis. J Inf Secur. 2018;77:261–75.

    Google Scholar 

  32. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2008;1:CD002244. https://doi.org/10.1002/14651858.CD002244.pub3.

    Article  Google Scholar 

  33. Rock RB, Hu S, Gekker G, et al. Mycobacterium tuberculosis- induced cytokine and chemokine expression by human microglia and astrocytes: effects of dexamethasone. J Infect Dis. 2005;192:2054–8.

    CAS  PubMed  Google Scholar 

  34. Thuong NTT, Heemskerk D, Tram TTB. Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis. J Infect Dis. 2017;215:1020–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mai NT, Dobbs N, Phu NH. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife. 2018;7.

  36. Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial. J Neurol Sci. 2010;293:12–7.

    CAS  PubMed  Google Scholar 

  37. Schoeman JF, Janse van Rensburg A, Laubscher JA. The role of aspirin in childhood tuberculous meningitis. J Child Neurol. 2011;26:956–62.

    PubMed  Google Scholar 

  38. Rajshekhar V. Surgery for brain tuberculosis: a review. Acta Neurochir. 2015;157:1665–78.

    PubMed  Google Scholar 

  39. Rajshekhar V. Management of hydrocephalous in patients with tubercular meningitis. Neurol India. 2009;57:368–74.

    PubMed  Google Scholar 

  40. Chugh A, Husain M, Gupta RK, Ojha BK, Chandra A, Rastogi M. Surgical outcome of tuberculous meningitis hydrocephalus treated by endoscopic third ventriculostomy: prognostic factors and postoperative neuroimaging for functional assessment of ventriculostomy. J Neurosurg Pediatr. 2009;3:371–7.

    PubMed  Google Scholar 

  41. Husain M, Jha DK, Rastogi M, Husain N, Gupta RK. Role of neuroendoscopy in the management of patients with tuberculous meningitis hydrocephalus. Neurosurg Rev. 2005;28:278–83.

    PubMed  Google Scholar 

  42. Nagarathna S, Rafi W, Veenakumari HB, Mani R, Satishchandra P, Chandramuki A. Drug susceptibility profiling of tuberculous meningitis. Int J Tuberc Lung Dis. 2008;12:105–7.

    CAS  PubMed  Google Scholar 

  43. Molton JS, Huggan PJ, Archuleta S. Infliximab therapy in two cases of severe neurotuberculosis paradoxical reaction. Med J Aust. 2015;202:156–7.

    PubMed  Google Scholar 

  44. Lee JY, Yim JJ, Yoon BW. Adjuvant interferon-gamma treatment in two cases of refractory tuberculosis of the brain. Clin Neurol Neurosurg. 2012;114:732–4.

    PubMed  Google Scholar 

  45. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodefciency virus (HIV) associated tuberculous meningitis. Clin Infect Dis. 2011;52:1374–83.

    PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pediatrics, North Delhi Municipal Corporation (NDMC) Medical College and Associated Hindu Rao Hospital, Delhi, India

    Himani Bhasin

  2. Department of Neonatology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India

    Medha Goyal

  3. Division of Pediatric Neurology, Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India

    Suvasini Sharma

Authors
  1. Himani Bhasin
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  2. Medha Goyal
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  3. Suvasini Sharma
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Contributions

SS conceived the idea of writing the review article on Tubercular meningitis- recent advances in diagnosis and treatment. HB and MG wrote the first draft of the manuscript. SS critically revised the manuscript. All the authors approve the final draft of the manuscript. SS is the guarantor for this paper.

Corresponding author

Correspondence to Himani Bhasin.

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Additional information

Key Messages

• Triton processing (Modified ZN stain) prior to conventional ZN staining detects intracellular bacilli in immune cells and improves the detection of extracellular M.tb from small volume of CSF specimen (0.5–1 ml).

• Microscopic observation drug susceptibility (MODS) assay detects early stage of cord formation of M.tb in liquid culture with the advantage of shorter detection time (median 6 d) and better sensitivity (around 65%).

• NAATs, involving amplification of bacillary nucleic acid has a high specificity (around 100%) but low sensitivity (50%). It can detect tubercular DNA even after starting treatment for up to one month.

• Xpert MTB/RIF assay is a rapid fully automated NAAT endorsed by WHO as a preferred modality for diagnosis of TBM.

• Pyrosequencing seems to be a promising emerging tool to aid in early diagnosis of MDR and XDR TBM.

• Line probe assay and LAMP are other useful NAAT based tests.

• At present there is not much evidence to suggest the role of antigen and antibody detection for diagnosing TBM.

• Few previous studies have shown improved outcome with short duration therapy but more pediatric trials are needed to substantiate their mortality benefit and recurrence risk. Intensified drug regimens using high dose Rifampicin have better CSF penetration and improved mortality benefit.

• Preliminary studies in adults have shown improved survival and disability outcome with addition of fluoroquinolones but more pediatric trials are needed before recommending their routine use.

• Addition of aspirin has been shown to decrease the occurrence of new brain infarction on MRI without increasing risk of significant side effects.

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Bhasin, H., Goyal, M. & Sharma, S. Advances in the Diagnosis and Management of Tubercular Meningitis in Children. Indian J Pediatr 87, 26–33 (2020). https://doi.org/10.1007/s12098-019-03089-x

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  • DOI: https://doi.org/10.1007/s12098-019-03089-x

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