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Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review

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Abstract

Background

Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1 month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids.

Methods

Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18 years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020.

Results

We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19–49 years old), developed a paradoxical manifestation within 4–14 weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response.

Conclusions

This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.

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Data availability

All the data supporting our findings are contained within the manuscript.

Code availability

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References

  1. Wilkinson RJ, Rohlwink U, Misra UK et al (2017) Tuberculous meningitis. Nat Rev Neurol 13:581–598. https://doi.org/10.1038/nrneurol.2017.120

    Article  PubMed  Google Scholar 

  2. Manyelo CM, Solomons RS, Walzl G, Chegou NN (2021) Tuberculous meningitis: pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches. J Clin Microbiol 59:e01771-e1820. https://doi.org/10.1128/JCM.01771-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. World Health Organization (2020) Global tuberculosis report 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf. Accessed 24 Feb 2021

  4. Wen L, Li M, Xu T et al (2019) Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: systematic review and meta-analysis. J Neurol 266:3009–3021. https://doi.org/10.1007/s00415-019-09523-6

    Article  PubMed  Google Scholar 

  5. García-Grimshaw M, Gutiérrez-Manjarrez FA, Navarro-Álvarez S, González-Duarte A (2020) Clinical, imaging, and laboratory characteristics of adult Mexican patients with tuberculous meningitis: a retrospective cohort study. J Epidemiol Glob Health 10:59–64. https://doi.org/10.2991/jegh.k.191023.001

    Article  PubMed  PubMed Central  Google Scholar 

  6. Thao LTP, Heemskerk AD, Geskus RB et al (2018) Prognostic models for 9-month mortality in tuberculous meningitis. Clin Infect Dis 66:523–532. https://doi.org/10.1093/cid/cix849

    Article  CAS  PubMed  Google Scholar 

  7. Singh AK, Malhotra HS, Garg RK et al (2016) Paradoxical reaction in tuberculous meningitis: presentation, predictors and impact on prognosis. BMC Infect Dis 16:306. https://doi.org/10.1186/s12879-016-1625-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Garg RK, Malhotra HS, Kumar N (2014) Paradoxical reaction in HIV negative tuberculous meningitis. J Neurol Sci 340:26–36. https://doi.org/10.1016/j.jns.2014.03.025

    Article  PubMed  Google Scholar 

  9. Liu Y, Wang Z, Yao G et al (2019) Paradoxical reaction in HIV-negative tuberculous meningitis patients with spinal involvement. Int J Infect Dis 79:104–108. https://doi.org/10.1016/j.ijid.2018.11.366

    Article  PubMed  Google Scholar 

  10. Lanzafame M, Vento S (2016) Tuberculosis-immune reconstitution inflammatory syndrome. J Clin Tuberc Mycobact Dis 3:6–9. https://doi.org/10.1016/j.jctube.2016.03.002

    Article  Google Scholar 

  11. Thuong NTT, Thwaites GE (2017) Treatment-associated inflammatory deterioration in tuberculous meningitis: unpicking the paradox. J Infect Dis 215:665–667. https://doi.org/10.1093/infdis/jiw565

    Article  PubMed  Google Scholar 

  12. Tai M-LS, Nor HM, Kadir KAA et al (2016) Paradoxical manifestation is common in HIV-negative tuberculous meningitis. Medicine (Baltimore) 95:e1997. https://doi.org/10.1097/MD.0000000000001997

    Article  Google Scholar 

  13. Anuradha HK, Garg RK, Sinha MK et al (2011) Intracranial tuberculomas in patients with tuberculous meningitis: predictors and prognostic significance. Int J Tuberc Lung Dis 15:234–239

    CAS  PubMed  Google Scholar 

  14. Gonzalez-Duarte A, Higuera-Calleja J, Flores F et al (2012) Cyclophosphamide treatment for unrelenting CNS vasculitis secondary to tuberculous meningitis. Neurology 78:1277–1278. https://doi.org/10.1212/WNL.0b013e318250d84a

    Article  CAS  PubMed  Google Scholar 

  15. Marais S, Thwaites G, Schoeman JF et al (2010) Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis 10:803–812. https://doi.org/10.1016/S1473-3099(10)70138-9

    Article  PubMed  Google Scholar 

  16. Rock RB, Olin M, Baker CA et al (2008) Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev 21:243–261. https://doi.org/10.1128/CMR.00042-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Banks JL, Marotta CA (2007) Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 38:1091–1096. https://doi.org/10.1161/01.STR.0000258355.23810.c6

    Article  PubMed  Google Scholar 

  18. Carvalho ACC, De Iaco G, Saleri N et al (2006) Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 42:893–895. https://doi.org/10.1086/500459

    Article  CAS  PubMed  Google Scholar 

  19. González-Duarte A, Ponce de Leon A, Sifuentes Osornio J (2011) Importance of differentiating Mycobaterium bovis in tuberculous meningitis. Neurol Int 3:9. https://doi.org/10.4081/ni.2011.e9

    Article  CAS  Google Scholar 

  20. Thrush DC, Barwick DD (1974) Three patients with intracranial tuberculomas with unusual features. J Neurol Neurosurg Psychiatry 37:566–569. https://doi.org/10.1136/jnnp.37.5.566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng VCC, Ho PL, Lee RA et al (2002) Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 21:803–809. https://doi.org/10.1007/s10096-002-0821-2

    Article  CAS  PubMed  Google Scholar 

  22. Watson JD, Shnier RC, Seale JP (1993) Central nervous system tuberculosis in Australia: a report of 22 cases. Med J Aust 158:408–413. https://doi.org/10.5694/j.1326-5377.1993.tb121837.x

    Article  CAS  PubMed  Google Scholar 

  23. Sütlaş PN, Unal A, Forta H et al (2003) Tuberculous meningitis in adults: review of 61 cases. Infection 31:387–391. https://doi.org/10.1007/s15010-003-3179-1

    Article  PubMed  Google Scholar 

  24. Unal A, Sütlaş PN (2005) Clinical and radiological features of symptomatic central nervous system tuberculomas. Eur J Neurol 12:797–804. https://doi.org/10.1111/j.1468-1331.2005.01067.x

    Article  CAS  PubMed  Google Scholar 

  25. Misra UK, Kalita J, Singh AP, Prasad S (2013) Vascular endothelial growth factor in tuberculous meningitis. Int J Neurosci 123:128–132. https://doi.org/10.3109/00207454.2012.743127

    Article  CAS  PubMed  Google Scholar 

  26. Kalita J, Prasad S, Misra UK (2014) Predictors of paradoxical tuberculoma in tuberculous meningitis. Int J Tuberc Lung Dis 18:486–491. https://doi.org/10.5588/ijtld.13.0556

    Article  CAS  PubMed  Google Scholar 

  27. Lu T-T, Lin X-Q, Zhang L et al (2015) Magnetic resonance angiography manifestations and prognostic significance in HIV-negative tuberculosis meningitis. Int J Tuberc Lung Dis 19:1448–1454. https://doi.org/10.5588/ijtld.15.0113

    Article  PubMed  Google Scholar 

  28. Kalita J, Misra UK, Bhoi SK et al (2017) Possible role of transforming growth factor β in tuberculous meningitis. Cytokine 90:124–129. https://doi.org/10.1016/j.cyto.2016.11.004

    Article  CAS  PubMed  Google Scholar 

  29. Ledingham D, El-Wahsh S, Sebire D et al (2019) Adjuvant immunosuppression for paradoxical deterioration in tuberculous meningitis including one case responsive to cyclosporine. A tertiary referral hospital experience. J Neurol Sci 404:58–62. https://doi.org/10.1016/j.jns.2019.07.002

    Article  CAS  PubMed  Google Scholar 

  30. DeLance AR, Safaee M, Oh MC et al (2013) Tuberculoma of the central nervous system. J Clin Neurosci 20:1333–1341. https://doi.org/10.1016/j.jocn.2013.01.008

    Article  PubMed  Google Scholar 

  31. Bekker LG, Maartens G, Steyn L, Kaplan G (1998) Selective increase in plasma tumor necrosis factor-alpha and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis. J Infect Dis 178:580–584. https://doi.org/10.1086/517479

    Article  CAS  PubMed  Google Scholar 

  32. Lammie GA, Hewlett RH, Schoeman JF, Donald PR (2009) Tuberculous cerebrovascular disease: a review. J Infect 59:156–166. https://doi.org/10.1016/j.jinf.2009.07.012

    Article  PubMed  Google Scholar 

  33. Tai M-LS, Viswanathan S, Rahmat K et al (2016) Cerebral infarction pattern in tuberculous meningitis. Sci Rep 6:38802. https://doi.org/10.1038/srep38802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Davis AG, Rohlwink UK, Proust A et al (2019) The pathogenesis of tuberculous meningitis. J Leukoc Biol 105:267–280. https://doi.org/10.1002/JLB.MR0318-102R

    Article  CAS  PubMed  Google Scholar 

  35. Donovan J, Figaji A, Imran D et al (2019) The neurocritical care of tuberculous meningitis. Lancet Neurol 18:771–783. https://doi.org/10.1016/S1474-4422(19)30154-1

    Article  PubMed  Google Scholar 

  36. Raut T, Garg RK, Jain A et al (2013) Hydrocephalus in tuberculous meningitis: incidence, its predictive factors and impact on the prognosis. J Infect 66:330–337. https://doi.org/10.1016/j.jinf.2012.12.009

    Article  PubMed  Google Scholar 

  37. Zunt JR (2018) Tuberculosis of the central nervous system. Continuum (Minneap Minn) 24:1422–1438. https://doi.org/10.1212/con.0000000000000648

  38. Obeid T, Mousali Y, Wali S et al (1999) Paradoxical enlargement of lymph nodes during therapy of central nervous system tuberculosis. Ann Saudi Med 19:530–532. https://doi.org/10.5144/0256-4947.1999.530

    Article  CAS  PubMed  Google Scholar 

  39. Gupta RK, Kumar S (2011) Central nervous system tuberculosis. Neuroimaging Clin N Am 21:795–814. https://doi.org/10.1016/j.nic.2011.07.004

    Article  PubMed  Google Scholar 

  40. Tai M-LS, Sharma VK (2016) Role of transcranial Doppler in the evaluation of vasculopathy in tuberculous meningitis. PLoS ONE 11:e0164266. https://doi.org/10.1371/journal.pone.0164266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ramesh AK, Hagler S, Beal JC, Moshé SL (2014) Pearls & Oy-sters: CSF analysis and the therapeutic paradox in tuberculous meningitis. Neurology 83:e145-146. https://doi.org/10.1212/WNL.0000000000000859

    Article  PubMed  PubMed Central  Google Scholar 

  42. Marais S, Meintjes G, Pepper DJ et al (2013) Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 56:450–460. https://doi.org/10.1093/cid/cis899

    Article  CAS  PubMed  Google Scholar 

  43. Thwaites GE, Macmullen-Price J, Tran THC et al (2007) Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol 6:230–236. https://doi.org/10.1016/S1474-4422(07)70034-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Narendran G, Kavitha D, Karunaianantham R et al (2016) Role of LTA4H polymorphism in tuberculosis-associated immune reconstitution inflammatory syndrome occurrence and clinical severity in patients infected with HIV. PLoS ONE 11:e0163298. https://doi.org/10.1371/journal.pone.0163298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tobin DM, Roca FJ, Oh SF et al (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434–446. https://doi.org/10.1016/j.cell.2011.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Thuong NTT, Heemskerk D, Tram TTB et al (2017) Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis. J Infect Dis 215:1020–1028. https://doi.org/10.1093/infdis/jix050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chin JH (2014) Tuberculous meningitis: diagnostic and therapeutic challenges. Neurol Clin Pract 4:199–205. https://doi.org/10.1212/CPJ.0000000000000023

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lewinsohn DM, Leonard MK, LoBue PA et al (2017) Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis 64:e1–e33. https://doi.org/10.1093/cid/ciw694

    Article  PubMed  Google Scholar 

  49. Thwaites G, Fisher M, Hemingway C et al (2009) British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 59:167–187. https://doi.org/10.1016/j.jinf.2009.06.011

    Article  PubMed  Google Scholar 

  50. Prasad K, Singh MB, Ryan H (2016) Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 4:CD002244. https://doi.org/10.1002/14651858.CD002244.pub4

    Article  PubMed  Google Scholar 

  51. Rohilla R, Shafiq N, Malhotra S (2021) Efficacy and safety of aspirin as an adjunctive therapy in tubercular meningitis: a systematic review and meta-analysis. EClinicalMedicine 34:100819. https://doi.org/10.1016/j.eclinm.2021.100819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Davis A, Meintjes G, Wilkinson RJ (2018) Treatment of tuberculous meningitis and its complications in adults. Curr Treat Options Neurol 20:5. https://doi.org/10.1007/s11940-018-0490-9

    Article  PubMed  PubMed Central  Google Scholar 

  53. Thwaites GE, Bang ND, Dung NH et al (2004) Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 351:1741–1751. https://doi.org/10.1056/NEJMoa040573

    Article  CAS  PubMed  Google Scholar 

  54. Marais S, Lai RPJ, Wilkinson KA et al (2017) Inflammasome ativation underlying central nervous system deterioration in HIV-associated tuberculosis. J Infect Dis 215:677–686. https://doi.org/10.1093/infdis/jiw561

    Article  CAS  PubMed  Google Scholar 

  55. Shah I, Meshram L (2014) High dose versus low dose steroids in children with tuberculous meningitis. J Clin Neurosci 21:761–764. https://doi.org/10.1016/j.jocn.2013.07.021

    Article  CAS  PubMed  Google Scholar 

  56. Schutz C, Davis AG, Sossen B et al (2018) Corticosteroids as an adjunct to tuberculosis therapy. Expert Rev Respir Med 12:881–891. https://doi.org/10.1080/17476348.2018.1515628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee H-S, Lee Y, Lee S-O et al (2012) Adalimumab treatment may replace or enhance the activity of steroids in steroid-refractory tuberculous meningitis. J Infect Chemother 18:555–557. https://doi.org/10.1007/s10156-011-0334-y

    Article  CAS  PubMed  Google Scholar 

  58. Santin M, Escrich C, Majòs C et al (2020) Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis: case report and review. Medicine (Baltimore) 99:e22626. https://doi.org/10.1097/MD.0000000000022626

    Article  Google Scholar 

  59. Marais BJ, Cheong E, Fernando S et al (2021) Use of infliximab to treat paradoxical tuberculous meningitis reactions. Open Forum Infect Dis 8:ofaa604. https://doi.org/10.1093/ofid/ofaa604

    Article  CAS  PubMed  Google Scholar 

  60. Schoeman JF, Springer P, van Rensburg AJ et al (2004) Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J Child Neurol 19:250–257. https://doi.org/10.1177/088307380401900402

    Article  PubMed  Google Scholar 

  61. Lee J-Y, Yim J-J, Yoon B-W (2012) Adjuvant interferon-γ treatment in two cases of refractory tuberculosis of the brain. Clin Neurol Neurosurg 114:732–734. https://doi.org/10.1016/j.clineuro.2011.12.013

    Article  PubMed  Google Scholar 

  62. Coulter JBS, Baretto RL, Mallucci CL et al (2007) Tuberculous meningitis: protracted course and clinical response to interferon-gamma. Lancet Infect Dis 7:225–232. https://doi.org/10.1016/S1473-3099(07)70054-3

    Article  PubMed  Google Scholar 

  63. Xie YL, Ita-Nagy F, Chen RY et al (2019) Neurotuberculosis: control of steroid-refractory paradoxical inflammatory reaction with ruxolitinib. Open Forum Infect Dis 6:ofz422. https://doi.org/10.1093/ofid/ofz422

    Article  PubMed  PubMed Central  Google Scholar 

  64. de Jonge ME, Huitema ADR, Rodenhuis S, Beijnen JH (2005) Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 44:1135–1164. https://doi.org/10.2165/00003088-200544110-00003

    Article  PubMed  Google Scholar 

  65. Celotti A, Vianello F, Sattin A et al (2018) Cyclophosphamide immunomodulation of TB-associated cerebral vasculitis. Infect Dis Lond Engl 50:779–782. https://doi.org/10.1080/23744235.2018.1467038

    Article  Google Scholar 

  66. Vilaplana C, Marzo E, Tapia G et al (2013) Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis. J Infect Dis 208:199–202. https://doi.org/10.1093/infdis/jit152

    Article  CAS  PubMed  Google Scholar 

  67. Tonby K, Wergeland I, Lieske NV et al (2016) The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection. BMC Infect Dis 16:599. https://doi.org/10.1186/s12879-016-1938-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kroesen VM, Gröschel MI, Martinson N et al (2017) Non-steroidal anti-inflammatory drugs as host-directed therapy for tuberculosis: a systematic review. Front Immunol 8:772. https://doi.org/10.3389/fimmu.2017.00772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Maitra A, Bates S, Shaik M et al (2016) Repurposing drugs for treatment of tuberculosis: a role for non-steroidal anti-inflammatory drugs. Br Med Bull 118:138–148. https://doi.org/10.1093/bmb/ldw019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Col. Sección XVI Belisario Domínguez, 14080, Tlalpan, Mexico City, Mexico

    Rogelio Domínguez-Moreno, Miguel García-Grimshaw, David Medina-Julio, Carlos Cantú-Brito & Alejandra González-Duarte

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  1. Rogelio Domínguez-Moreno
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  2. Miguel García-Grimshaw
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Correspondence to Rogelio Domínguez-Moreno or Miguel García-Grimshaw.

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The study was revised and approved by our institutional Ethics and Research Committees (Reference: NER-2706–18-18–1). Due to the nature of the study, both Committees waived the need for signed informed consent.

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Rogelio Domínguez-Moreno and Miguel García-Grimshaw contributed equally to this work as co-first authors. Carlos Cantú-Brito and Alejandra González-Duarte are senior co-authors

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Domínguez-Moreno, R., García-Grimshaw, M., Medina-Julio, D. et al. Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review. Neurol Sci 43, 2699–2708 (2022). https://doi.org/10.1007/s10072-021-05693-2

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