Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment
Abstract
:1. Introduction
2. Methodology
3. Results
3.1. Host-Immune Responses against Infection
3.2. Pathogenesis of TB Meningitis
3.3. Clinical Presentation of TB Meningitis
3.4. Diagnosis
3.5. Treatment
4. Discussion
Adjunctive Therapy
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Article Name | Author | Summary |
---|---|---|
1. Global TB Report [1]. | World Health Organization (WHO) | Report provided information on TB epidemiology, progression in prevention, diagnosis, and treatment. |
2. Extrapulmonary tuberculosis in the United States [2]. | Rieder | Extrapulmonary TB is largest in children and decreases with increasing age, commonly seen in females and blacks/Asians. |
3. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection [3]. | Shafer | HIV infected patients are more likely than control patients to have TB. Although, fever was seen in the patients infected w/TB, the diagnosis was difficult and delayed as there is co-infection w/HIV and other pathologies have to be ruled out. Acid-fast bacteria sputum results were not as accurate (+ in less than 50%). Most immediate diagnostic test is a biopsy. |
4. Use of ImiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrobial agents and chemotherapy [4]. | Tsenova | Treatment with TB drugs along with IMiD3 limited the changes in patients’ neurology and improved the survival by 73% |
5. Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting [5]. | Marais | Six month all because mortality is lower in patients who received antiretroviral therapy during their TB treatment course with the hazard ratio at 0.30 (95% CI = 0.08 to 0.82) |
6. Oxidative stress and antioxidants in tubercular meningitis [6]. | Sudha | The study found that the blood antioxidant levels of TB meningitis patients were low compared to controls, and the levels improved after treatment, suggesting a role of free radicals in TB meningitis |
7. Evaluation of free radical status in CSF in childhood meningitis [7]. | Ray | Their result suggested that natural and synthetic antioxidants might have a role in preventing disease progression and tissue damage in childhood meningitis |
8. Variations of the glutathione level in the cerebrospinal fluid in tuberculous meningitis treated with streptomycin [8]. | Mule | TBM is the most common and severe form of extra-pulmonary TB associated with significant mortality. It remains difficult to diagnose due to broad, non-specific clinical spectrum. Clinical features include the following: Cerebral infarct/lesion, fever, headache, neck stiffness, and basal ganglia stroke. |
9. Clinical use of anti-TNF therapy and increased risk of infections [9]. | Ali | Anti-TNF drugs have emerged as successful agents in the treatment of chronic inflammatory diseases but do possess the risk of opportunistic infections. Patients taking such drugs should be adequately vaccinated and monitored for signs of infection. |
10. Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development of Pulmonary Tuberculosis [10]. | Cavalcanti | Cellular immunity such as TH1 cytokines play key role in TB host immune response. TNF alpha and IFN gamma stimulate reactive nitrogen intermediates, mediating tuberculostatic function of macrophages and granuloma formation (disease progression). An increase in IL10 has been implicated with increased survival of mycobacteria. |
11. Immunomodulation by vitamin D: implications for TB [11]. | Chun | It has been found that Vitamin D deficiency may be linked to increased risk of TB and other immune disorders. This article details cellular and molecular mechanisms of Vitamin D and its potential role in normal and abnormal immune function. |
12. Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection [12]. | Drennan | One of the ways that the immune system combats Mycobacterium infection is by recognition of the immune system. Specifically, in this infection, macrophages use the TLR -2 to eliminate the antigen, it is proposed that mice TLR-2 levels may be associated with mycobacterium infection and improved prognosis in human patients. |
13. The Intracellular Environment of Human Macrophages That Produce Nitric Oxide Promotes Growth of Mycobacteria [13]. | Jung | NO has a protective role in allowing TB to remain within macrophages via reactive nitrogen intermediates, although the clear mechanism is unknown. Treatment with IFN gamma resulted in increase NOS2/3 isoforms (enzymes that increased NO). |
14. Pattern recognition receptors and cytokines in Mycobacterium tuberculosis infection--the double-edged sword [14]? | Hossain | This article studies the paradox of human innate immunity response during M.TB infection. The paradox is explained as Dendritic cells promoting the first step of the immune response by promoting TLRs and PRRs. These receptors and cells through a cascade of biochemical reactions lead to the activiation of IFN-y and TNF-a which regulate inflammation and granuloma formation. It has been noted however that these responses may provide survival to the infecting pathogen. |
15. Latent tuberculosis infection: An overview [15]. | Kiazyk | Latent TB infection (LTBI) is persistent immune response to TB antigens without evidence of clinical manifestations. People with LTBI can progress to active TB or reactivation, seen increasingly in immunocompromised. |
16. The Immune Response in Tuberculosis [16]. | O’Garra | CD4 T-cells, IL 12, IFN gamma, and TNF alpha are critical in control on TB infection, but the host factors that determine why some individuals are protected from infection are unclear. Genetic factors may be implicated in increased risk of patients developing active infection. |
17. Tuberculous meningitis [17]. | Wilkinson | The paper discusses the new understanding about the inflammatory process in TB meningitis |
18. Tuberculous meningitis [18]. | Thwaites | The paper discusses the current uncertainties with regards to TB meningitis, paying more attention to the diagnosis and treatment |
19. Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe [19]. | Mezochow | The paper states that delayed diagnosis and treatment of TB meningitis can lead to neurologic consequences, such as hydrocephalus, cranial nerve palsy, and seizure |
20. Intracerebral Tuberculomas: A Rare Cause of Seizure in an Immunocompetent Young Male [20]. | Vu | The paper presents a rare clinical presentation of CNS involvement of TB: intracerebral tuberculoma |
21. Pathogenesis of central nervous system tuberculosis [21]. | Be | The groups found that unlike other types of bacteria that also cause meningitis, M. tuberculosis do not traverse the blood CSF barrier at the choroid plexus, but instead at the BBB |
22. Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited [22]. | Donald | The authors suggest that miliary tuberculosis may be directly involved in pathogenesis of TB meningitis since the bacillemia serves to increase the chance that meningeal focus is established, giving rise to TB meningitis |
23. Tuberculous Meningitis: Diagnosis and Treatment Overview [23]. | Marx | The paper gives overall diagnosis and treatment review of TB meningitis |
24. Tuberculous meningitis in children: Clinical management and outcome [24]. | Daniel | The paper reports that children that have TB meningitis should be treated with medications against tuberculosis, as well as steroids. They also report that levels of TB medications achieve lower concentration in the CSF of children vs. than in adults. |
25. Tuberculous meningitis: advances in diagnosis and treatment [25]. | Torok | The paper states that human genetic polymorphism may explain the differences in response to anti-inflammatory therapies |
26. Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity [26]. | Rohlwink | The study shows that the disease processes of tuberculosis are different in the peripheral vs. the central nervous system |
27. Tuberculous meningitis in adults: a review of 160 cases [27]. | Pehlivanoglu | The frequency of altered mental status, change in personality, and coma were noted in 59, 28, and 21 percent of patients, respectively. |
28. Incidence, predictors and prognostic value of cranial nerve involvement in patients with tuberculous meningitis: a retrospective evaluation [28]. | Sharman | The frequency of cranial nerve palsy was observed in 33 percent of patients in a studying involving 158 patients. |
29. Tuberculous meningitis at Cleveland Metropolitan General Hospital 1959 to 1963 [29]. | Hinman | The paper states that the discovery of isoniazid in 1952 has decreased the mortality rate of TB meningitis from 100% to between 20% to 50%. |
30. Tuberculous meningitis [30]. | Kennedy | The paper states that in a study of 52 patients with TB meningitis, 85% recovered, 4% had residual disability, and 15. |
31. Tuberculosis of the central nervous system in children: a 20-year survey [31]. | Farinha | The paper examined 38 children with CNS tuberculosis and found that overall mortality was 13% and permanent neurological sequelae were seen in 47%. |
32. Tuberculous meningitis: a 30-year review [32]. | Kent | The paper examined 58 cases of TB meningitis, of which 7% died, 5% developed neurological sequelae. |
33. Tuberculous encephalopathy with and without meningitis [33]. | Udani | Patients present case in which tuberculosis infection presents as dementia and as encephalitis instead of the classic signs and symptoms of meningitis. |
34. Tuberculous meningitis in adults: review of 61 cases [34]. | Sutlas | Only 6 patients out of 61 reported that they were aware of previous TB infection. |
35. The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis [35]. | Solomons | CSF showing elevated protein is well-described in literature as bacterial meningitis, but diagnostic evidence for TBM is lacking. Research done showed a significant decrease in glucose in groups with TBM than groups without. CSF of glucose <2.2 diagnosed TBM w/sensitivity 0.68 specificity 0.96. Research done showed a significant increase in protein in groups with TBM than groups without. CSF of protein >1 diagnosed TBM w/sensitivity 0.78 specificity 0.94. |
36. Characterization of a glutathione metabolic mutant of Mycobacterium tuberculosis and its resistance to glutathione and nitrosoglutathione [36]. | Dayaram | Glutathione is synthesized during production of ROS and NO, and iis directly toxic to M. TB. Study showed that M. TB intracellular survival in macrophages with glutathione mutation. |
37. Treatment of Tuberculous Meningitis and Its Complications in Adults [37]. | Davis | This article discusses several drugs widely used to treat Tuberculosis Meningitis. It concludes that although many drugs have certain efficacy against the disease, many have not been adequately studied and strong evidence cannot be found as to their ability to cross the blood brain barrier |
38. A Case Report on Complicated Tuberculous Meningitis [38]. | Jawad | This case follows a 19 years old Asan Female with Tb Meningitis in an attempt to study the importance of early diagnosis and treatment. |
39. Tuberculous Meningitis Diagnosis and Treatment in Adults: A Series of 189 Suspected Cases [39]. | Luo | This study summarizes the clinical features including imaging diagnostics, treatment and outcomes of Tb Meningitis in a cohort of 189 patients. |
40. Glutathione levels and immune responses in tuberculosis patients [40]. | Venketaraman | Glutathione levels are significantly reduced in mononuclear cells and RBC isolated from TB patients. Treatment with n-acetyl cystine improves control by decreasing IL 1, IL 6, IL 10, and TNF alpha. |
41. Glutathione and nitrosglutathione in macrophage defense against Mycobacterium tuberculosis [41]. | Venketaraman | M. TB is sensitive to glutathione, as it controls macrophage replication. |
42. Control of Mycobacterium tuberculosis growth by activated natural killer cells [42]. | Guerra | Glutathione-enhanced NK cells (activated from n-acetyl cysteine, IL2, and IL 12) inhibit M. TB growth via neutralization of Fas and CD40L. |
43. Natural killer cells, glutathione, cytokines and innate immunity against Mycobacterium tuberculosis [43]. | Millman | The study found that glutathione in combination with IL-2 and IL-12 improve NK cell functions, helping to control TB infection |
44. Adaptive immune responses against Mycobacterium tuberculosis infection in healthy and HIV infected individuals [44]. | Guerra | T-lymphocytes that are derived from HIV-infected individuals are deficient in glutathione, leading to decreased levels of TH1 cytokines (IL2, IL 12, IFN gamma) and increased growth of M. TB. |
45. Glutathione supplementation improves macrophage functions in HIV. Journal of Interferon and cytokine research [45]. | Morris | Treatment with n-acetyl cystine or IGSH (glutathione in liposomal formulation) replenishes glutathione and is correlated with a decrease in intracellular growth of M. TB. |
46. Unveiling the mechanisms for decreased glutathione in individuals with HIV infection [46]. | Morris | Lack of antioxidant activity (oxidized glutathione) and increased free radicals (IL 1, IL 17, TGF beta)/proinflammatory cytokines lead to an increase in M. TB. |
47. Glutathione synthesis is compromised in erythrocytes from individuals with HIV [47]. | Morris | The study found that levels of enzymes involving in GSH synthesis, such as GSS, GCLC, and GSR were significantly reduced in RBCs isolated from patients with HIV infection, and this correlated with decreased levels of GSH |
48. Investigating the causes for decreased levels of glutathione in individuals with type II diabetes [48]. | Lagman | The group reports that patients with type 2 diabetes mellitus have lower levels of GSH due to compromised levels of GSH synthesis and metabolism enzymes |
49. Liposomal Glutathione Supplementation Restores Appropriate Cytokine Response to Intracellular Mycobacterium tuberculosis Infection in HIV Infected Individuals [49]. | Ly | The groups establish a correlation between low level of GSH and increased susceptibility to TB infection, which may be relieved with IGSH supplementation |
50. Restoring cytokine balance in HIV Positive Individuals with Low CD4 T Cell Counts [50]. | Valdivia | The group found that supplementation with L-GSH in HIV patients whose CD4 + <350 help correct cytokine balance |
51. Analysis of Glutathione levels in the Brain tissue samples from HIV-Positive Individuals and subject with Alzheimer’s disease and its implication in the pathophysiology of the disease process [51]. | Saing | The group found that the levels of many enzymes involving in the synthesis of GSH were decreased in brain tissue samples from HIV-1 patients |
52. Role of glutathione in macrophage control of mycobacteria [52]. | Venketaraman | Glutathione is a tripeptide and antioxidant, and it synthesizes high levels of reactive oxygen and nitrogen intermediates used in regulating antigen-processing and ultimately intracellular mycobacterial growth. |
53. Drug-resistant tuberculosis: past, present, future [53]. | Chiang | Genetic resistance from random chromosomal mutation to anti-TB drugs is rare. Such resistance results in mycobacterial mutants gradually outnumbering susceptible bacilli and emerge as dominant. The reliability of drug susceptibility testing of second-line anti- TB drugs is questionable. |
54. A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine [54]. | Dutta | Thioridazine targets different pathways and can be used as multi-target inhibitor for M. TB. |
55. Tuberculosis: Commentary on a reemergent killer [55]. | Bloom | TB is the leading cause of death in the world from single infectious disease and there is little knowledge on pathogenesis and protection. Changes in social structure and public treatment programs are implicated. |
56. Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy, and survival [56]. | Chaisson | Patients with TB and AIDS were more likely to be non-white and heterosexual IV drug users. It was found that 60% of AIDS group had at least 1 extrapulmonary site of disease compared to 28% in the non-AIDS group. |
57. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection [57]. | Jones | Extrapulmonary TB was found in 70% (30/43) of patients with CD4 counts less than or equal to 100, 50% (10/20) with counts 101–200, 44% (7/16) 201–300, and 28% (5/18) 300+ (p = 0.02). Acid-fast smears were more positive in patients with low CD4 counts. CD8 does not correlate with TB manifestations. |
58. Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis [58]. | Lanoix | The study found that while PZA is only beneficial in first 2 months in treatment of BALB/c mice, it is beneficial even beyond 2 months in C3HeB/FeJ mice |
59. TGFbeta1-induced suppression of glutathione antioxidant defenses in hepatocytes: Caspase-dependent post-translational and caspase-independent transcriptional regulatory mechanisms [59]. | Franklin | Their findings suggest that the suppression of GSH antioxidant defenses and the depletion of intracellular GSH may play role in enhancing TGFbeta-1 induced oxidative stress and potentiating apoptotic cell death |
60. Circulating markers of free radical activity in patients with pulmonary tuberculosis [60]. | CI | This study aims to measure circulating free radical markers in patients with TB. Their results showed markedly elevated levels of the three radical markers tested in all patients with TB. |
61. Characterization of dendritic cell and regulatory T cell functions against M. tb infection [61]. | Morris | It is hypothesized that GSH plays a vital role in enhancing the immune system. This study aims to investigate whether GSH plays a role in enhancing both the innate and adaptive immune system. The results found that GSH both inhibits M.Tb inside DCs and increases certain immune mediating molecules. |
62. Recent advances in the diagnosis and treatment of multidrug-resistant tuberculosis [62]. | Ahmad | This article discusses the advancement in treatment and diagnosis of multi-drug resistant tuberculosis, it also provides epidemiological information and statistics on Tb. |
63. Controlled Clinical Trial Of Five Short-Course (4-Month) Chemotherapy Regimens In Pulmonary Tuberculosis [63]. | The Lancet | This study was conducted on a group of 696 pulmonary tuberculosis patients who took antibiotic combinatiorifampin + isoniazid supplemented with ehtambutol or streptomycin followed with a treatment of chemotherapy. The results showed a 1% relapse in patients who received the chemotherapy treatment. |
64. Comparative whole-genome sequence analysis of Mycobacterium tuberculosis isolated from tuberculous meningitis and pulmonary tuberculosis patients [64]. | Faksri | This study focuses on isolated M.Tb sputum and CSF samples to seek genetic variants likely associated with underlying pathophysiology of the disease |
65. Tuberculosis diagnostics: Challenges and opportunities [65]. | Nema | This report discusses the limitations in diagnosis and treatments of tuberculosis meningitis. |
66. Cerebral hemorrhage due to tuberculosis meningitis: A rare case report and literature review [66]. | Zou | This case follows a report of a woman who presents with a walking instability, in trace reveal hemorrhage and leptomeningeal enhancement due to TB meningitis. Due to the patient’s complicated symptoms the article decides to report on the complexity and challenges of diagnosis TB. Meningitis using current methods. |
67. PCR could be a method of choice for identification of both pulmonary and extra-pulmonary tuberculosis [67]. | Amin | This Report focuses on the efficacy of PCR testing for M. Tb infections. It is found that PCR is a sensitive tool for the early diagnosis of MTb. |
68. Polymerase chain reaction in the diagnosis of tuberculosis [68]. | Jatana | This study evaluates the efficacy of PCR testing for detection of M.Tb infections. The study is conducted on hospitalized patients by examining a comparison of PCR body fluids. The study ultimately concludes that PCR may be a valuable tool for the diagnosis of CNS Tb. |
69. Comparison of PCR with the routine procedure for diagnosis of tuberculosis in a population with high prevalence of tuberculosis and human immunodeficiency virus [69]. | Kivihya-Ndugga | In low income countries ZN stain is the standard for diagnosis of TB due to its cheapness and simplicity. In this study AMPLICOR PCR System is tested in the diagnosis of Pulmonary TB. It was concluded that this system can be considered an alternative to the ZN stain and that sensitivity and specificity were increased and not affected regardless of HIV or Non-HIV status. |
70. A breakthrough for the diagnosis of tuberculous pericarditis and pleuritis in less than 2 h [70]. | Saeed | This study aims to evaluate GENEXPERT Assay and its validity for detection of M.TB. It was concluded that this assay is an innovative tool with high sensitivity and specificity, which may facilitate diagnosis and management of Tb Pleuritis and Pericarditis. |
71. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV [71]. | Bjerrum | This study assesses the accuracy of the LF-LAM Assay to determine active Tb in HIV positive patients. Conclusions yielded results which state that LF-LAM has a sensitivity of 42% in the diagnosis of Tb on individuals who show symptoms. |
72. Tuberculous meningitis: A uniform case definition for use in clinical research [72]. | Marais | In an attempt to standardize criteria for the diagnosis and management of Tb meningitis, 41 international participants along with a consensus committee bound together to discuss treatment, management, pathogenesis and future of clinical research in the topic. It is the hope that by unifying the clinical diagnosis and management, decreased mortality and morbidity in Tb Meningitis should be observed. |
73. Diagnostic standards and classification of tuberculosis in adults and children [73]. | American Thoracic Society | This set of standards and classifications for Tb are installed in an attempt to provide a complete framework and understanding of clinical tuberculosis etiology and management. |
74. Burden of tuberculosis at postmortem in inpatients at a tertiary referral center in sub-Saharan Africa: A prospective descriptive autopsy study [74]. | Bates | Asymptomatic tuberculosis presents a clinical problem in that diagnosis is difficult due to the absence of symptoms and signs. This article reports on an autopsy performed in Lusaka Zambia in hopes of yielding information explaining the true burden of asymptomatic tuberculosis on affected patients. |
75. The vitamin D-antimicrobial peptide pathway and its role in protection against infection [75]. | Gombart | This article provides information on Vitamin D deficiency and its association with increased rates of infection. Specifically, the report provides insight on the possibility of using sunlight (environmental) and dietary vitamin D in the treatment of TB. |
76. Real-Time Investigation of Tuberculosis Transmission: Developing the Respiratory Aerosol Sampling Chamber (RASC) [76]. | Wood | TB is transmitted primarily through aerosol droplets. However, the adaptations which enable pathogens such as TB to avoid to exit the infected host, survive the external environment, adopt a form to enter the respiratory tract, and avoid innate defenses to establish nascent infection is unclear. A respiratory aerosol sampling chamber (RASC) was created to recreate the aerosol transmission. |
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Arshad, A.; Dayal, S.; Gadhe, R.; Mawley, A.; Shin, K.; Tellez, D.; Phan, P.; Venketaraman, V. Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment. J. Clin. Med. 2020, 9, 2962. https://doi.org/10.3390/jcm9092962
Arshad A, Dayal S, Gadhe R, Mawley A, Shin K, Tellez D, Phan P, Venketaraman V. Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment. Journal of Clinical Medicine. 2020; 9(9):2962. https://doi.org/10.3390/jcm9092962
Chicago/Turabian StyleArshad, Aysha, Sujay Dayal, Raj Gadhe, Ajinkya Mawley, Kevin Shin, Daniel Tellez, Phong Phan, and Vishwanath Venketaraman. 2020. "Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment" Journal of Clinical Medicine 9, no. 9: 2962. https://doi.org/10.3390/jcm9092962
APA StyleArshad, A., Dayal, S., Gadhe, R., Mawley, A., Shin, K., Tellez, D., Phan, P., & Venketaraman, V. (2020). Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment. Journal of Clinical Medicine, 9(9), 2962. https://doi.org/10.3390/jcm9092962