Definitive Diagnosis Of Tuberculous Meningitis Research Articles

Recent advances in microbiological and molecular biological detection techniques of tuberculous meningitis.

Tuberculous meningitis (TBM) is the most common type of central nervous system tuberculosis (TB) and has the highest mortality and disability rate. Early diagnosis is key to improving the prognosis and survival rate of patients. However, laboratory diagnosis of TBM is often difficult due to its paucibacillary nature and sub optimal sensitivity of conventional microbiology and molecular tools which often fails to detect the pathogen. The gold standard for TBM diagnosis is the presence of MTB in the CSF. The recognised methods for the identification of MTB are acid-fast bacilli (AFB) detected under CSF smear microscopy, MTB cultured in CSF, and MTB detected by polymerase chain reaction (PCR). Currently, many studies consider that all diagnostic techniques for TBM are not perfect, and no single technique is considered simple, fast, cheap, and efficient. A definite diagnosis of TBM is still difficult in current clinical practice. In this review, we summarise the current state of microbiological and molecular biological diagnostics for TBM, the latest advances in research, and discuss the advantages of these techniques, as well as the issues and challenges faced in terms of diagnostic effectiveness, laboratory infrastructure, testing costs, and clinical expertise, for clinicians to select appropriate testing methods.

Cerebrospinal fluid lactate as a predictive biomarker for tuberculous meningitis diagnosis.

The definitive diagnosis of tuberculous meningitis (TBM) is achieved by identifying Mycobacterium tuberculosis (MTb) in cerebrospinal fluid (CSF); however, diagnostic confirmation is difficult due to the inability ofcurrent tests for an effective diagnosis. Our objective was to retrospectively assess the characteristics of CSF lactate (CSF-LA) as an adjunct biomarker in the diagnosis of TBM. 608 CSF laboratory reports were assessed. Of these, 560 had clinically suspected TBM. These were classified as definite (n=36), probable (23), possible (278),or non-TBM (223) according to the international consensus TBM case definitions. An additional 48 CSF samples were negative controls with normal CSF. Against a reference standard of definite TBM, the cut-off value for CSF-LA was 4.0mmol/L, the area under the ROC curve was 0.88 (95% CI, 0.82-0.94; p=0.0001), sensitivity was 69%, specificity 90%, negative predictive value 98%. These diagnostic parameters decreased when calculated against those of the other categories of TBM. CSF-LA exhibited high specificity, efficiency, negative predictive value, and clinical utility index in all the groups studied. CSF-LA is a useful diagnostic marker to rule out TBM when associated with conventional microbiology tests, nucleic acid amplification assays, and clinical algorithms, particularly in endemic areas.

Tuberculous Meningitis in Which Inflammation Cannot Be Adequately Suppressed by Standard Therapy: How to Think and Treat

Tuberculous meningitis is the most severe form of tuberculosis and often causes critical illness with high mortality. Treatment should be initiated without waiting for a definitive diagnosis of tuberculous meningitis. Although we often experience treatment-resistant tuberculous meningitis, it is important to continue examination and treatment.

IgG response to Mycobacterium tuberculosis non-polar lipids and sonicated extracts among tuberculous meningitis patients.

Introduction The diagnosis of tuberculous meningitis (TBM) is a major global health concern due to its protean nature. There is a need to identify better biomarkers for the rapid and definitive diagnosis of TBM. Lipids have been poorly explored as diagnostic markers in TBM.Aim Non-polar lipids (NPL) and mycobacterial sonicate extract (MTSE) antigens were assessed for diagnosis of Mycobacterium tuberculosis .Methodology A total of 110 cerebrospinal fluid samples were categorized as confirmed, suspected and non-TBM cases according to clinical presentation and laboratory investigations, which were further analysed by NPL and MTSE ELISA.Results The sensitivity and specificity of the NPL ELISA were 39.6 and 96 %, respectively, whereas the MTSE ELISA was 17 % sensitive and 92 % specific. The combination of the NPL and MTSE ELISA test was superior to these tests alone, with sensitivity and specificity of 43 and 88 %, respectively.Conclusion This combination may be useful as an adjunct in the laboratory diagnosis of TBM. However, future studies in different settings among different populations, such as those with human immunodeficiency virus co-infection, are desirable to explore the full potential of biomarkers.

Feasibility and diagnostic benefit of increased cerebrospinal fluid volume and frequency in the diagnosis of tuberculous meningitis

Background: Definite diagnosis of tuberculous meningitis (TBM) requires demonstration of TB bacilli in the cerebrospinal fluid (CSF) on smear, culture, or nucleic acid amplification. However, the sensitivity of these tests is low. This study was done to see if smear and culture done on a larger volume and repeated samples of CSF increases the diagnostic yield of these tests. Methods: Adult patients with clinical features of meningitis for >5 days were prospectively and consecutively recruited. At admission, the usual 1 ml of CSF was taken for mycobacterial testing; another 4–8 ml was also taken for the same as the comparison. On the 3rd hospital day, 4–8 ml of CSF was taken for mycobacterial testing. Mycobacterial smear and culture were done by Auramine O stains and on modified Lowenstein–Jensen medium, respectively. The composite reference standard for TBM was considered the gold standard for the diagnosis of TBM. Definite and probable diagnosis was taken as positive, while a possible diagnosis and no TB were considered negative for TBM. In a subset, Xpert MTB/Rif assay was also performed on the CSF samples as per the routine diagnostic protocol. Results: 66/80 (82.5%) had the initial CSF examination in the emergency department, 80 (100%) had large-volume CSF on day 1, while 22/80 (27.5%) consented for the second large-volume CSF examination on day 3. There was a marginal increase in sensitivity from 22% to 26% with increasing CSF volume from 1 ml to 4–8 ml and 36% if another large-volume CSF was collected at 72 h. The specificity was 100% at all times. The negative likelihood ratios were 0.78, 0.74, and 0.64, respectively. The sensitivity of Xpert MTB/RI compared to the composite reference standard of TBM was 30.4%. Conclusions: Increasing the volume and frequency of CSF testing for Mycobacterium tuberculosis, marginally improves the sensitivity and negative likelihood ratios, but may not be adequate to rule out TBM with the certainty required to withhold antitubercular therapy. The feasibility of repeat CSF examinations needs to be considered while making guidelines.

KESAHIHAN PEMERIKSAAN COMPLEX SPECIFIC COCKTAIL ANTIGEN TB (ESAT-6, CFP-10, MPT-64) METODE CEPAT IMMUNOCHROMATOGRAPHY PADA CAIRAN SEREBROSPINAL PASIEN MENINGITIS TUBERKULOSIS {Validity of Rapid Immunochromatography Complex Specific Cocktail Antigen TB (Esat-6, Cfp-10, Mpt-64) Using Cerebrospinal Fluid of Tuberculous Meningitis Patient}

The early diagnosis of definite tuberculous meningitis (TBM) is very important in reducing its mortality. The current gold standard ofTBM relies on the isolation of M. tuberculosis from cerebrospinal fluid (CSF) either with direct staining or M. tuberculosis culture, but theseexamination have a low sensitivity due to the pausibasilary condition. Recently there is an assay using rapid Immunochromatography(ICT) cocktail antigen TB in CSF to diagnose TBM. This method can detect ESAT-6, CFP-10 and MPT-64 antigen as an important virulencefactor for the spreading of bacteria to extra pulmonary which is secreted by M. tuberculosis in CSF from TBM patient. The aim of thisstudy was to know the validity of rapid ICT cocktail antigen TB using CSF against MODS culture and acid-fast bacili as a gold standardto diagnose TBM by analyzing. This study iscarried out by a descriptive observational study using cross sectional study design. Thesubjects are patients who were diagnosed as suspected TBM based on Marais criteria and were obtained from the Department of NeurologyHospital Dr. Hasan Sadikin. The examination was done at the Clinical Microbiology Department of Clinical Pathology Dr. Hasan Sadikinhospital since January 2014 until May 2014. A total of 41 subjects which consisted of six (6) subjects with a definite diagnosis of TBM,26 with probable TBM and nine (9) with possible TBM were enrolled in this study. The result of this assay againts acid-fast bacili has the100% sensitivity, 64.1% specificity, 12.5% PPV, 100% NPV, LR(+) 2.78, LR(–)0 and 65.8% accuracy. The result of this assay againtsM. tuberculosis culture has the 83.3% sensitivity, 68.5% specificity, PPV 31.2%, NPV 96%, LR(+) 2.65, LR(–)0.24, accuracy 70.7% andprevalence ratio 7.8. Based on this study, it can be concluded that the validity of this assay againts acid-fast bacili has a high sensitivity,moderate specificity, low PPV, high NPV and moderate accuracy. The result of this assay againts M. tuberculosis culture has a moderatesensitivity and specificity, low PPV, high NPV and moderate accuracy.

Adenosine Deaminase (ADA) in Tuberculous Meningitis

Abstract not availableBangladesh J Medicine Jul 2014; 25 (2) : 61-71

Commercial nucleic acid amplification tests in tuberculous meningitis—a meta-analysis

Although nucleic acid amplification tests (NAATs) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation NAATs was suboptimal and variable. We conducted a meta-analysis of studies published between 2003 and 2013, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool to evaluate methodological quality. The diagnostic accuracy of newer commercial NAATs was assessed. Pooled estimates of diagnostic accuracy for commercial NAATs measured against a cerebrospinal fluid Mycobacterium tuberculosis culture-positive gold standard were sensitivity 0.64, specificity 0.98, and diagnostic odds ratio 64.0. Heterogeneity was limited; P value = 0.147 and I2 = 33.85%. The Xpert MTB/RIF® test was evaluated in 1 retrospective study and 4 prospective studies, with pooled sensitivity 0.70 and specificity 0.97. The QUADAS-2 tool revealed low risk of bias, as well as low concerns regarding applicability. Heterogeneity was pronounced among studies of in-house tests. Commercial NAATs proved to be highly specific with greatly reduced heterogeneity compared to in-house tests. Sub-optimal sensitivity remains a limitation.

English

INTRODUCTION: Tuberculosis remains one of the world’s deadliest diseases & tubercular meningitis is one of the most deadly complications due to missed diagnosis and delayed treatment result in significant morbidity and mortality. The signs and symptoms, results of routine analysis of CSF and radiographic findings for patients with CNS tuberculosis are often inadequate in making a definitive diagnosis. AIMS AND OBJECTIVES: 1. To study the levels of Adenosine deaminase in cases of meningitis, 2. To evaluate the sensitivity and specificity of CSF-ADA as a diagnostic test in tuberculosis meningitis. MATERIAL AND METHODS: In the cross sectional study, Adenosine deaminase activity (ADA) was studied in cerebrospinal fluid of 60 cases of tuberculous meningitis, 10 cases of pyogenic meningitis. 10 cases of aseptic meningitis and15 control. RESULTS: The mean CSF-ADA activity was 14.1±1.96 (tuberculous meningitis); 4.92±1.27 (pyogenic meningitis); 3.66±1.03 (aseptic meningitis) and 1.69±0.44 U/l (control) respectively. The sensitivity and specificity of this test for diagnosis of tuberculous meningitis was 100% and 97.44% respectively with ADA value of more than 10 U/L. CONCLUSION: The adenosine deaminase activity in tuberculous meningitis cases was significantly higher. So it can be of great value in the early and more definitive diagnosis of tuberculous meningitis, to help early diagnosis and treatment to prevent from deadly complications of tubercular meningitis.

Central nervous system tuberculosis.

Central nervous system (CNS) involvement, one of the most devastating clinical manifestations of tuberculosis (TB) is noted in 5 to 10% of extrapulmonary TB cases, and accounts for approximately 1% of all TB cases. Definitive diagnosis of tuberculous meningitis (TBM) depends upon the detection of the tubercle bacilli in the CSF. Every patient with TBM should preferably be evaluated by imaging with contrast enhanced CT either before or within the first 48 hours of treatment. An extra-neural focus of tuberculosis should be sought clinically and radiologically in all patients with CNS TB as it may indicate safer and more accessible sites for diagnostic samplings. A minimum of 10 months treatment is warranted, prompted by the uncertain influences of disease severity, CNS drug penetration, undetected drug resistance and patient compliance. All patients with TB meningitis may receive adjunctive corticosteroids at presentation regardless of disease severity even for those with HIV infection. Drug resistance is strongly associated with previous treatment. The key principle of managing drug-resistant TB is never to add a single drug to a failing regimen. Early ventriculo-peritoneal shunting should be considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the stage of tuberculous meningitis at which treatment has been started.

Detection of tubercule antigen in cerebrospinal fluids by ELISA for diagnosis of tuberculous meningitis

An Enzyme Linked Immunosorbent Assay (ELISA) was standardised to detect the presence of tubercule antigen in cerebrospinal fluids from patients with meningitis. CSF samples from clinically suspected cases of tuberculous meningitis, culture proven pyogenic meningitis and non-bacterial aseptic central nervous system (CNS) disorders were tested by ELISA to demonstrate its potential utility for routine diagnostic purpose. Tubercule antigen was detected in 73% cases of tuberculous meningitis and was absent in pyogenic and other non-bacterial CNS disorder cases. The test appears to be a promising approach for a definitive diagnosis of tuberculous meningitis.

Isotopic Cisternography in Tuberculous Meningitis of Childhood

The changes in the CSF circulation and absorption are valuable in the diagnosis and management of tuberculous meningitis. We describe the isotopic cisternographic analysis of 45 children with tuberculous meningitis and 30 children with purulent meningitis. The cisternographic patterns of tuberculous meningitis consist of (1) obliteration of CSF space at the level of basal cisterns or cisterna Sylvii and (2) ventricular entry of radiopharmaceutical without clearing by 24 hours (communicating hydrocephalus). None of the patients with a definite diagnosis of tuberculous meningitis demonstrated a normal CSF flow pattern. Thirty patients with purulent meningitis underwent isotopic cisternography. Sixteen of 30 patients demonstrated a normal CSF flow pattern, 3 had mild hydrocephalus, 6 had obliteration of the subarachnoid space at the level of cisterna Sylvii at either side, 3 had delay of CSF flow, and 2 had abnormal CSF collection due to a posttraumatic dura defect.