Severe Form Of Extrapulmonary Tuberculosis Research Articles

Diagnostic accuracy of GeneXpert in the diagnosis of spinal tuberculosis: A systematic review and meta-analysis.

Tuberculosis remains a significant global health issue, with spinal tuberculosis being a severe form of extrapulmonary tuberculosis. Despite the high morbidity associated with spinal tuberculosis, effective and rapid diagnostic methods are limited. The aim of this study was to evaluate the diagnostic accuracy of the GeneXpert compared to other microbiological methods in diagnosing spinal tuberculosis. A systematic review and meta-analysis were conducted following the PRISMA guidelines. Six databases (PubMed, Scopus, EBSCO, EMBASE, ScienceDirect, and Cochrane Central) were searched for relevant studies as of August 31, 2023. Studies were selected based on predefined inclusion criteria, focusing on patients diagnosed with spinal tuberculosis and comparing GeneXpert to microbiological culture, acid-fast bacilli (AFB) staining, and polymerase chain reaction (PCR). Two authors independently performed data extraction and quality assessment, and the meta-analysis was conducted using Meta-DiSc 2.0. Fourteen studies comprising retrospective cohort, prospective cohort, and cross-sectional designs were included. GeneXpert demonstrated a pooled sensitivity of 92% (85-96%) and specificity of 71% (51-86%) compared to culture. AFB smear had the highest specificity at 80% (70- 88%) but the lowest sensitivity at 27% (20-35%). The PCR had sensitivity and specificity of 83% (67-92%) and 58% (31-81%), respectively. Substantial heterogeneity was noted across the studies. This study highlighted that GeneXpert had high sensitivity and moderate specificity in diagnosing spinal tuberculosis, making it an alternative to conventional methods. However, further validation through larger, interventional studies is necessary to standardize its use in clinical practice.

Effective cerebral tuberculosis treatment via nose-to-brain transport of anti-TB drugs using mucoadhesive nano-aggregates.

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.

Cerebral meningitis due to tuberculoma and epstein barr: presentation of a clinical case

Neuroinfection is an inflammatory process that affects the meninges or brain parenchyma; it has various etiologies, including viral and non-viral, including autoimmune, bacterial and fungal; patients with this pathology represent a challenge for doctors; the severity varies, from benign, self-limiting to life-threatening. The Epstein-Barr virus (EBV) is a double-stranded DNA gamma herpesvirus that presents a latent infection and lytic replication; it can diffuse into the central nervous system and alter the integrity of the blood-brain barrier, being associated with neurocognitive impairment, neuronal damage and inflammation. In relation to tuberculosis, it became the second infectious disease that caused the most deaths in the world after COVID-19; tuberculous meningitis is considered the most severe form of extrapulmonary tuberculosis (TB) with a mortality of 70% in low-income countries. Below is the case of a 35-year-old man with a history of adrenal insufficiency and hyperthyroidism, who was receiving corticosteroids; he went to the emergency service with a 5-month history of clinical symptoms characterized by holocranial headache, focal retrograde amnesia, periods of altered state of consciousness, dizziness, nausea that led to vomiting on several occasions, with sudden loss of consciousness. , accompanied by involuntary tonic-clonic movements and hearing loss; after the diagnostic screening, EBV and TB are identified; receives specific treatment with good clinical evolution

Characteristics of Tuberculous Meningitis in HIV-Positive Patients from Northeast Romania.

One of the most severe forms of extrapulmonary tuberculosis (EPTB) is tuberculous meningitis (TBM), which is linked to significant morbidity and high mortality. It is well recognized that human immunodeficiency virus (HIV)-positive people are more likely to develop EPTB, including TBM, especially if they have severe immunodeficiencies. We aim to highlight the profile and the characteristics of TBM in HIV-infected patients. We conducted a retrospective clinical study based on hospital medical records of patients diagnosed with HIV/AIDS (acquired immunodeficiency syndrome) and TBM in Northeast Romania, hospitalized at "St. Parascheva" Clinical Hospital of Infectious Diseases of Iasi from 1 January 2010 to 1 December 2022. From a total number of 1692 patients on record in our center, 195 had a HIV-tuberculosis (TB) coinfection, and 19 cases were HIV-TBM coinfected. Six cases were newly HIV-diagnosed late presenters, and thirteen patients' names were already found in the center's records with deficient immunological viral status (median CD4 lymphocyte level 47/mm3). The average age in the study group was 27 years old. The clinical manifestations and cerebrospinal fluid (CSF) variables were typical in most cases, despite the severe immunodepression of the patients. The Thwaites scoring system correctly identified 89.5% of the patients. The median admission period was 18 days; the lethality rate was 31.6%, despite access to ART and anti-TB drugs, and was associated with a more severe immunosuppression. No rifampicin resistance was detected. TBM appeared in a minority of our HIV cohort and affected severely immunodepressed patients; the clinical and CSF variables had a typical aspect in most cases, and the Thwaites scoring system performed well for this type of patient. The lethality rate was high and was correlated with a more severe immunodepression.

Clinical features of the course of tuberculous meningitis in HIV-infected patients

Background. Central nervous system tuberculosis is one of the most severe forms of extrapulmonary tuberculosis, which is due to an unfavorable clinical course, a high incidence of neurological complications and deaths. Despite this, the problem of early diagnosis is still not solved.
 Aim. To study the clinical and laboratory-instrumental features of the early diagnosis of tuberculous meningitis in HIV-infected patients.
 Materials and methods. A retrospective analysis of 31 case histories of patients with tuberculous lesions of the meninges and central nervous system in the late stages of HIV infection who were treated at the Clinical Tuberculosis Dispensary of Krasnodar Territory in 20202022 was carried out. The data of clinical manifestations of the disease, the results of laboratory and instrumental methods of examination were analyzed. Statistical data processing was performed by Microsoft Office Excel 2021 with the calculation of averages, standard deviation.
 Results. Tuberculous lesions of the meninges and the central nervous system among HIV-infected people were more common in men of working age who were not previously registered in a tuberculosis dispensary. All HIV-infected patients had late stages of HIV infection with severe immunodeficiency: the content of CD4+ lymphocytes less than 100 cells was detected in 45.46%; from 100 to 200 cells/l of CD4+ lymphocytes were recorded in 36.36%, more than 200 cells/l in 18.18%. Also, in all the studied patients, the primary focus was established in the form of tuberculosis of the respiratory organs, represented in 56.52% of cases by disseminated pulmonary tuberculosis. More than 70% had generalized tuberculosis with damage to the kidneys, spleen, and peripheral lymph nodes. A feature of the manifestation of tuberculous meningitis in HIV-infected people can be considered a high frequency of acute increase in neurological symptoms. Of the cerebral manifestations, the most common were: headache, dizziness, photophobia. 13.04% of HIV-infected patients complained of nausea and vomiting. 91.30% showed signs of damage to the substance of the brain, represented by mono-, hemiparesis and damage to the cranial nerves, mainly IIIIV, VI, VII pairs. The composition of CSF in HIV-positive patients revealed the presence of mild pleocytosis (up to 100 cells/l) in 56.52% of cases. The nature of the change in the concentration of proteins, chlorides and glucose is nonspecific.
 Conclusions. The study revealed the features of medical and social characteristics, clinical and laboratory and instrumental picture of tuberculous meningitis in HIV-infected patients and without HIV infection.

Bilateral vocal cord palsy as complication of CNS tuberculosis

BackgroundTuberculous meningitis, a rare but severe form of extrapulmonary tuberculosis, frequently affects cranial nerves. While nerves III, VI and VII are commonly involved, involvement of caudal cranial nerves is rarely described. Here, we report a rare case of bilateral vocal cord palsy secondary to caudal cranial nerve involvement in tuberculous meningoencephalitis, that occurred in Germany, a country with low tuberculosis incidence.Case presentationA 71-year-old woman was transferred for further treatment of hydrocephalus as a complication of presumed bacterial meningitis with unknown pathogen at that time. Because of decreased consciousness, intubation was performed and an empiric antibiotic therapy with ampicillin, ceftriaxone and acyclovir was initiated. Upon admission to our hospital, an external ventricular drainage was placed. Cerebrospinal fluid analysis revealed Mycobacterium tuberculosis as the causative pathogen, and antitubercular treatment was initiated. Extubation was possible one week after admission. Eleven days later, the patient developed inspiratory stridor that worsened within a few hours. Flexible endoscopic evaluation of swallowing (FEES) revealed new-onset bilateral vocal cord palsy as the cause of respiratory distress, which required re-intubation and tracheostomy. The bilateral vocal cord palsy persisted despite continued antitubercular therapy on the follow-up examination.ConclusionConsidering the aetiology of infectious meningitis, cranial nerve palsies may be suggestive for tuberculous meningitis as underlying disease given their rarity in other bacterial forms of meningitis. Nevertheless, intracranial involvement of inferior cranial nerves is rare even in this specific entity, as only extracranial lesions of inferior cranial nerves have been reported in tuberculosis. With this report of a rare case of bilateral vocal cord palsy due to intracranial involvement of the vagal nerves, we emphasize the importance of timely initiation of treatment for tuberculous meningitis. This may help to prevent serious complications and associated poor outcome since the response to anti-tuberculosis therapy may be limited.

Intracranial Aneurysm In a Case of Tubercular Meningoencephalitis, a Rare Presentation (P3-10.001)

<h3>Objective:</h3> NA <h3>Background:</h3> In this era of advanced medical science and technology, tuberculosis remains as a major health problem in developing countries like India. While pulmonary TB is the most common manifestation of TB, incidence of extrapulmonary TB is also gradually increasing. Affliction of central nervous system is considered one of the most severe forms of extrapulmonary tuberculosis. Central nervous system (CNS) tuberculosis(TB) comprises 15%–20% of the total cases of extra-pulmonary TB and it is associated with a high mortality rate. Surprisingly a little less than 5% of patients with pulmonary TB develop CNS TB and not all patients with CNS TB have pulmonary TB. Although CNS involvement by tuberculosis is seen in all age groups, there is a predilection for younger and immunocompromised patients. Central nervous system tuberculosis may present as tubercular meningitis, meningoencephalitis, tuberculoma, tubercular abscess. Vasculitis, secondary to TBM can cause infarcts commonly but development of an intracranial tuberculous aneurysm is a rare complication. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Report:</h3> A 33-year-old male presented with a low grade fever, meningism for weeks, diagnosed to have tubercular meningoencephalitis after supportive brain imaging and CSF assay. During course of hospitalization developed left ptosis, binocular horizontal diplopia, dimness of vision of left eye with diminished left periorbital sensation suggestive of a left anterior cavernous sinus syndrome. Brain imaging with angiogram of cerebral vasculature revealed an aneurysm at left ICA-MCA junction, probably a sequalae of granulomatous vasculitis <h3>Conclusions:</h3> <h3>Discussion:</h3> This case report shows an unusual case of intracranial tuberculomas complicated by intralesional haemorrhage due to an infective tubercular aneurysm. During disease course, MTB may colonize the arterial wall and erode its entire thickness with caseating necrosis, forming an aneurysm. These aneurysms are prone to rupture with fatal complications. Early identification of the disease with proper treatment is critical for the prevention of fatal complications. <b>Disclosure:</b> Dr. Biswas has nothing to disclose. Dr. Das has nothing to disclose. Dr. Chintha has nothing to disclose. Dr. Bhattacharya has nothing to disclose. Dr. Biswas has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for INTAS Pharmaceuticals. Dr. Biswas has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for lupin Limited. Dr. Biswas has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Diagnostic. Dr. Biswas has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Health N U. Dr. Chakraborty has nothing to disclose.

Leukotriene A4 hydrolase (LTA4H rs17525495) gene polymorphisms and paradoxical reactions in extrapulmonary tuberculosis

Paradoxical reactions (PRs) are poorly studied complex immunological phenomena, among patients with tuberculosis (TB). When PRs involves critical structures like the central nervous system (CNS), immunomodulatory therapy is often required. Predictors for PRs in TB to pre-empt appropriate treatment strategies in high-risk groups are lacking. TT genotype of Leukotriene A4 hydrolase (LTA4H) promoter region rs17525495 polymorphisms are associated with exaggerated immune responses in Tuberculous meningitis (TBM), the most severe form of extrapulmonary tuberculosis (EPTB). The association of these polymorphisms with PRs is not known. We evaluated this plausibility among 113 patients with EPTB, at high risk of PRs. Majority [81 (71.7%)] had disseminated tuberculosis with prominent CNS [54 (47.8%)] and lymph node involvement [47 (41.6%)]. Human immunodeficiency Virus (HIV) co-infection was seen among 23 (20.3%) patients. PRs were noted in 38.9% patients, at a median duration of 3 months (IQR 2–4). LTA4H rs17525495 single nucleotide polymorphism (SNP) analysis showed 52 (46%) patients had CC, 43 (38.1%) had CT and 18 (15.9%) had TT genotypes. There was no statistically significant difference in occurrence [CC 38.5% vs CT 39.5% vs TT 38.7%] and time of onset [median (IQR)] of PRs across the genotypes [CC 3 (1–4.7), CT 3 (2–5), TT 2 (2–3)]. PRs was shown to be significantly linked with HIV co-infection (RR 0.6, 95% CI 0.29–1.28), culture positivity (RR 0.5, 95% CI 0.28–1.14), TB Lymphadenitis (RR 0.7, 95% CI 0.44–1.19) and CNS involvement RR 2.1, 95% CI 1.27–3.49) in the univariate analysis (p < 0.2). On multivariate analysis, CNS involvement alone was associated with PRs (aRR 3.8 (1.38–10.92); p < 0.01). PRs were associated with CNS involvement but not with LTA4H rs17525495 polymorphisms.

Outcomes of Tuberculous Meningitis Patients with or without Hydrocephalus from a Tertiary Hospital in West Java, Indonesia

Background: Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis. One of the most common complications of TBM is hydrocephalus, with a higher risk of mortality. This study aimed to evaluate the outcome among TBM patients with or without hydrocephalus.Methods: This study was a retrospective cross-sectional comparative analytical study. A total sampling was employed based on the number of traceable resumes of TBM patients treated at the Department of Neurology Dr. Hasan Sadikin General Hospital, Bandung, Indonesia in 2018. Results: Of the 127 data of TBM patients, 55 (43.3%) had hydrocephalus, and 72 (56.7%) did not. The median age of TBM patients with and without hydrocephalus was 34 years (IQR 26–45) and 35 years (IQR 24–44), respectively. Decreased consciousness dominated the clinical symptoms for 94.5% in the hydrocephalus group and 84.7% in the non-hydrocephalus group. Hospital-acquired pneumonia occurred mainly in the hydrocephalus group (29.1%), whereas urinary tract infections mainly occurred in without hydrocephalus group (18%). There was a significant difference between the outcome of hydrocephalus and non-hydrocephalus (p=0.005). Mortality was higher in patients with hydrocephalus compared to those without hydrocephalus.Conclusions: The outcome of TBM patients with hydrocephalus is worse than those without hydrocephalus, as reflected by a higher grade of TBM, higher mortality rate, and lower good recovery upon treatment administration. Therefore, prompt diagnosis and treatment are needed to improve the outcome and survival among TBM patients with hydrocephalus.

Clinical Management of Pathogen-Negative Tuberculous Meningitis in Adults: A Series Case Study

Tuberculosis remains a serious world public health problem. Tuberculous meningitis (TBM) is the one of most severe forms of extrapulmonary tuberculosis. However, the insensitivity and time-consuming requirement of culturing the pathogen Mycobacterium tuberculosis, the traditional "gold standard" diagnostic test for TBM, often delays timely diagnosis and treatment, resulting in high disability and mortality rates. In our series case study, we present five pathogen-negative TBM cases who received empirical anti-tuberculosis therapy with a good clinical outcome. We describe in detail the clinical symptoms, laboratory test results, and imaging findings of the five patients from symptom onset to dynamic follow-up. We then summarize the similarities of the clinical characteristics of the presented patients, as well as shared features in laboratory and imaging tests, and proceed to analyze the challenges in the timely diagnosis of TBM. Finally, we argue that monitoring of cerebrospinal fluid markers and imaging are critical for the diagnosis and treatment of TBM, and emphasize the importance of differential diagnosis in cases when tuberculous meningitis is highly suspected despite negative findings for that etiology.

Pregnancy-Related Tuberculous Meningitis and Immune Reconstitution Inflammatory Syndrome: A Case Series and Systematic Review.

BackgroundTuberculosis is a leading cause of death among women of reproductive age. However, tuberculous meningitis, the most severe form of extrapulmonary tuberculosis, is rarely discussed in pregnancy despite this being a unique period of immune modulation that may predispose women to active disease.MethodsWe identified and described cases of tuberculous meningitis among pregnant or postpartum women screened during meningitis clinical trials in Uganda from 2018 to 2022. We conducted a systematic literature review via PubMed/Medline and Embase for all English-language publications from 1970 to 10 July 2022, to identify additional cases.ResultsWe identified 8 cases of pregnancy-related tuberculous meningitis in Ugandan women living with human immunodeficiency virus (HIV) and 40 additional cases via systematic literature review (none HIV-positive). Of all combined cases, 50% (24/48) were diagnosed postpartum; 50% (24/48) had initial onset during pregnancy, of which 38% (9/24) had worsening of symptoms or disease relapse following pregnancy cessation. Diagnosis was missed or delayed in 33% (16/48) of cases. For those with known outcomes, maternal mortality was 23% (11/48) and fetal/neonatal mortality was 30% (13/44). Of maternal survivors, 30% (11/37) had residual neurologic deficits.ConclusionsThe true incidence of tuberculous meningitis in pregnancy or the postpartum period is unclear but likely underappreciated. To date, nearly all published cases have occurred in HIV-negative or otherwise immunocompetent women. Given the well-described physiological immunosuppression during pregnancy and subsequent reconstitution postpartum, physicians must be aware of tuberculous meningitis and pregnancy-related immune reconstitution inflammatory syndrome, especially in countries with a high burden of tuberculosis and in women living with HIV.

Bacteremia tuberculosis among HIV-negative children in China.

ABSTRACTImportanceBacteremia tuberculosis (TB) is a severe form of extrapulmonary TB. Studies assessing bacteremia TB in children are limited, especially for HIV‐negative children.ObjectiveTo explore the detailed clinical features of the bacteremia TB in children under 18 years of age.MethodsWe reviewed the clinical records of the patients retrospectively and collected the strains isolated from their blood cultures. We used mycobacterial interspersed repetitive‐unit‐variable‐number tandem‐repeat (MIRU‐VNTR) to characterize the bacterial genotypes and alamarBlue to determine their drug susceptibility profiles. Polymerase chain reactions and DNA sequencing were used to identify drug‐resistant mutations.ResultsThere were 13 pediatric bacteremia TB patients, 10 of whom were diagnosed with Bacillus Calmette–Guérin (BCG) bacteremia TB. Thirteen patients aged from 0.30 to 11.58 years were enrolled, of whom 76.92% were boys. All had fevers before hospitalization, and 76.92% had respiratory symptoms. All had received BCG vaccinations, and 46.15% had adverse post‐vaccination reactions. Compared with Mycobacterium tuberculosis, BCG bacteremia was more likely to appear in younger children. Patients with BCG bacteremia had primary immunodeficiency diseases, and lower CD4, IgA, and IgE levels.InterpretationBacteremia TB was rapidly fatal in a large proportion of the immunodeficient children. Because classic findings may not be diagnostically specific, a high level of clinical suspicion is required, especially for patients with certain types of immunosuppression. Studies are needed to develop rapid diagnostic tests and to determine the value of empirical therapy in childhood bacteremia TB.

Deciphering Genetic Susceptibility to Tuberculous Meningitis.

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB) that arises when a caseating meningeal granuloma discharges its contents into the subarachnoid space. It accounts for ~1% of all disease caused by Mycobacterium tuberculosis and the age of peak incidence is from 2–4 years. The exact pathogenesis of TBM is still not fully understood and the mechanism(s) by which the bacilli initially invade the blood-brain-barrier are still to be elucidated. This study investigated the involvement of the host genome in TBM susceptibility, by considering common variants (minor allele frequency (MAF) >5%) using microarray genotyping and rare variants (MAF <1%) via exome sequencing. A total of 123 TBM cases, 400 pulmonary TB (pTB) cases and 477 healthy controls were genotyped on the MEGA array. A genome-wide association study (GWAS) comparing 114 TBM cases to 395 healthy controls showed no association with TBM susceptibility. A second analysis comparing 114 TBM cases to 382 pTB cases was conducted to investigate variants associated with different TB phenotypes. No significant associations were found with progression from pTB to TBM. Ten TBM cases and 10 healthy controls were exome sequenced. Gene set association tests SKAT-O and SKAT Common Rare were used to assess the association of rare SNPs and the cumulative effect of both common and rare SNPs with susceptibility to TBM, respectively. Ingenuity Pathway Analysis (IPA) of the top-hits of the SKAT-O analysis showed that NOD2 and CYP4F2 are both important in TBM pathogenesis and highlighted these as targets for future study. For the SKAT Common Rare analysis Centriolar Coiled-Coil Protein 110 (CCP110) was nominally associated (p = 5.89x10−6) with TBM susceptibility. In addition, several top-hit genes ascribed to the development of the central nervous system (CNS) and innate immune system regulation were identified. Exome sequencing and GWAS of our TBM cohort has identified a single previously undescribed association of CCP110 with TBM susceptibility. These results advance our understanding of TBM in terms of both variants and genes that influence susceptibility. In addition, several candidate genes involved in innate immunity have been identified for further genotypic and functional investigation.

Diagnostic role of Xpert-MTB RIF assay in osteoarticular tuberculosis: A retrospective study

BACKGROUNDOsteoarticular tuberculosis (OATB) is a severe form of extrapulmonary tuberculosis (TB), which causes notable morbidity and warrants a high index of suspicion for prompt management. The diagnosis of OATB poses a challenge, because of the difficulty of collecting the samples and, secondarily, the paucibacillary nature of lesion, which gives poor sensitivity and reproducibility, with long turnaround time of routine/conventional laboratory tests and the requirement for invasive procedures and expertise. The Xpert MTB/RIF assay has been approved by the World Health Organization as a rapid diagnostic tool for diagnosing pulmonary and extrapulmonary TB.AIMTo emphasize the diagnostic efficiency of gene Xpert for OATB in suspected patients in a tertiary care hospital of Eastern India.METHODSThis retrospective study was conducted in the Department of Microbiology and Orthopaedics by analyzing the data of the gene Xpert assay over a 3-year duration from January 2018 to February 2021. Demographic and clinical data were recorded. The diagnostic efficiency of gene Xpert was evaluated against the composite reference standard (CRS).RESULTSA total of 37 cases fell into positive, probable, and possible categories of osteoarticular TB out of 112 patients included in the study by CRS; gene Xpert result was positive in 35 out of the 37 different CRS categorized cases. Of the 112 cases, culture was put in 40 cases, and, of these cultures, 5 cases showed the growth of MTB. Of these, 4 cases were included in the 35 cases diagnosed by gene Xpert. Smear microscopy was positive in 6 out of 37 CRS categorized cases. When compared with CRS, the sensitivity of gene Xpert assay, culture, and smear was found to be 94.6%, 13.5%, and 16.2%, respectively, while specificity in all the three types of tests was 100%. When kappa statistics were applied, the percentage of agreement gene Xpert, culture, and microscopy with CRS was found to be 95%, 20%, and 22.6%, respectively. Follow-up of the gene Xpert positive patients after getting anti-tubercular treatment revealed improved conditions.CONCLUSIONGene Xpert could detect 31 extra cases with a low and very low mycobacterial load that were missed by the routine culture methods. Hence, more samples should be processed for molecular diagnostic methods like gene Xpert along with other conventional methods for the validation of the molecular test prospectively for the timely diagnosis of osteoarticular TB.

Evolving Stroke in Tuberculous Meningitis

Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis which carries high mortality with 100% mortality without treatment. A neurological complication of TBM includes hydrocephalus, brain abscess and stroke. In this report, we would like to illustrate a case of stroke in a patient with TBM. In this case, a 37-year old man initially presented with fever for 1 week associated with severe headache and occasional vomiting. Computed tomography (CT) of the brain showed leptomeningeal enhancement and lumbar puncture findings consistent with infective in nature. His MARAIS score was 13 and was treated as tuberculous meningitis with anti-tuberculous therapy. While in the ward, he developed right-sided body weakness with evolving CT brain findings. His condition then stabilized with anti-tuberculous treatment which consists of isoniazid, rifampicin, pyrazinamide and streptomycin. Dexamethasone was also initiated. On follow up, his condition further improves and is functionally independent. In conclusion, tuberculous meningitis is an aggressive disease with high morbidity. Stroke can occur as a result of TBM. Timely initiation of treatment is important in improving the outcome of the patients.

Affinity of Mycobacterium tuberculosis strains for M059K microglial cells after migration through A549 alveolar epithelium.

Tuberculosis (TB) remains a major threat worldwide while central nervous system TB (CNS-TB) is one of the most severe forms of extrapulmonary TB. CNS-TB develops as a secondary infection during the hematogenous spread of Mycobacterium tuberculosis (M. tuberculosis) from the lungs to the CNS. Factors influencing the dissemination of the bacilli to the CNS have not been studied extensively. This study evaluated the transmigration ability through the alveolar epithelium and adhesion and invasion capacity of glial cells of M. tuberculosis strains of varying drug susceptibility and genotype profiles using an in vitro co-culture model. A549 alveolar epithelial cells and M059K glial cells were co-cultured in a Transwell plate with A549 cells cultured in the upper chamber and M059K glial cells in the lower chamber. A549 epithelial cells were infected with F15/LAM4/KZN (susceptible, MDR, XDR), Beijing (susceptible, XDR), F11 (susceptible), F28 (MDR), and H37Rv strains of M. tuberculosis. The transmigration of an A549 monolayer and subsequent adhesion and invasion rates of M059K cells were established. The susceptible and XDR variants of the F15/LAM4/KZN strain transmigrate the alveolar epithelial cell monolayer more efficiently than the MDR variant. The Beijing-XDR variant showed a high transmigration rate, while the susceptible variant showed no transmigration ability. Similar to the MDR F15/LAM4/KZN, the F28 and F11 strains showed a low dissemination ability. The bacteria were still capable to adhere to M059K glial cells after passage through the A549 cells. We conclude that M. tuberculosis isolates that passed through a monolayer of A549 alveolar epithelium by transcellular migration can still adhere to M059K glial cells. There is no genetic link between resistance and transmigration.

Neurotuberculosis: an update.

Tuberculous (TB) meningitis (TBM), accounting for 70-80% of cases of neurotuberculosis, is one of the most severe forms of extrapulmonary tuberculosis. Two-thirds of new TB cases come from eight countries. Polymorphisms in toll-interleukin-1 receptor domain and in leukotriene A4 hydrolase (LTA4H) gene, affect the risk of inflammation in TBM. The common site of tuberculoma in children is cerebellum, and they may rarely develop tuberculous encephalopathy which has a high mortality. Young females with a high cerebrospinal fluid (CSF) protein have an increased predisposition to develop optochiasmatic arachnoiditis. Spinal TB meningitis may mimic transverse myelitis or Guillain-Barre syndrome. An extra-neural focus of TB should be sought clinically and radiologically as it may indicate safer and more accessible sites for diagnostic samplings. Cartridge-based nucleic acid amplification test (CBNAAT), also known as Genexpert test, is a polymerase chain reaction (PCR)-based method for detection of TB which also detects rifampicin resistance as it targets the rpob gene of mycobacteria. Line probe assays, based on PCR and reverse hybridization methods, identify mutations associated with drug resistance within a week. TBM being a paucibacillary disease, often evades a definite diagnosis and empirical treatment for a minimum of 9months is warranted based on clinical judgement. All TBM patients should receive adjunctive corticosteroids, even those with HIV infection. Drug resistance is strongly associated with previous treatment and bedaquiline as well as delamanid have received approvals for multidrug resistant (MDR) TB. The key principle of managing MDR TB is never to add a single drug to a failing regimen. Correct combination and duration of most effective second line drugs in MDR TB require further modifications. Early shunting should be considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the stage of TBM at which treatment has been started.

Metagenomic next generation sequencing for the diagnosis of tuberculosis meningitis: A systematic review and meta-analysis.

BackgroundTuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis and its early diagnosis is very difficult leading to present with severe disability or die. The current study aimed to assess the accuracy of metagenomic next generation sequencing (mNGS) for TBM, and to identify a new test for the early diagnosis of TBM.MethodsWe searched for articles published in Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data up to June 30, 2020 for studies that assessed the efficacy of mNGS for the diagnosis of TBM. Then, the accuracy between mNGS and a composite reference standard (CRS) in these articles was compared using the meta-analysis approach.ResultsFour independent studies with 342 samples comparing mNGS and a CRS were included in this study. The sensitivity of mNGS for TBM diagnosis ranged from 27% to 84%. The combined sensitivity of mNGS was 61%, and the I2 value was 92%. Moreover, the specificity of mNGS for TBM diagnosis ranged from 96% to 100%. The combined specificity of mNGS was 98%, and the I2 value was 74%. The heterogeneity between studies in terms of sensitivity and specificity was significant. The area under the curve (AUC) of the summary receiver operating characteristic curve (SROC) of mNGS for TBM was 0.98.ConclusionsThe sensitivity of mNGS for TBM diagnosis was moderate. Furthermore, the specificity was extremely high, and the AUC of the SROC indicated a very good diagnostic efficacy. mNGS could be used as an early diagnostic method for TBM, however, the results should be treated with caution for the heterogeneity between studies was extremely significant.Systematic review registrationINPLASY202070100.

Tuberculous Meningitis in an Immunocompetent Host: A Diagnostic Challenge

Tuberculosis is a major global public health problem, which poses significant diagnostic and treatment challenges. Tuberculous meningitis is the most severe form of extrapulmonary tuberculosis, which approximately affects 1% of all patients with active tuberculosis. It is considered a medical emergency as it causes neurological deficits in more than half of those affected and may lead to death despite advancement in antituberculous medications. In this article, we are reporting a challenging case of tuberculous meningitis with a delay in diagnosis and initiation of treatment. In addition, we summarize the challenges regarding the diagnosis and management of this disease. Although central nervous system tuberculosis is rare in immunocompetent hosts, such cases can be seen in neurology practice and represent a major clinical and diagnostic challenge. Although this case is not an uncommon scenario and no alternative diagnosis is suspected, the patient was not started on antituberculous medications because of an unjustified request for pathological diagnosis by the admitting team. Although Saudi Arabia is not one of the 22 countries with the highest number of tuberculosis cases worldwide, tuberculosis continues to represent a major health problem. Treating clinicians should try to use methods to increase the mycobacterial yield of cerebrospinal fluid smear examination. Multidisciplinary care, not a one-man show, should be practiced with cooperation and exchange of opinions between neurologists, infectious diseases specialists, neurosurgeons, and intensivists. Brain or meningeal biopsy is not a routine investigation tool and should never delay the initiation of antituberculous medications. Despite advancements in the field of tuberculosis science, it continues to represent a clinical and diagnostic challenge with a substantial percentage of morbidity and mortality.

Challenges in the diagnosis of tuberculous meningitis

Tuberculosis (TB) continues to pose a significant public health problem. Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary TB. TBM carries a high mortality rate, including for those receiving treatment for TB. Diagnosis of TBM is difficult for clinicians as it can clinically present similarly to other forms of meningitis. The difficulty in diagnosis often leads to a delay in treatment and subsequent mortality. Those who survive are left with long-term sequelae leading to lifelong disability. The microbiologic diagnosis of TBM requires the isolation of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) of an infected patient. The diagnosis of tuberculous meningitis continues to be challenging for clinicians. Unfortunately, many cases of TBM cannot be confirmed based on clinical and imaging findings as the clinical findings are nonspecific, while laboratory techniques are largely insensitive or slow. Until recently, the lack of accessible and timely tests has contributed to a delay in diagnosis and subsequent morbidity and mortality for many patients, particularly those in resourcelimited settings. The availability of Xpert Ultra and point-of-care lipoarabinomannan (LAM) testing could represent a new era of prompt diagnosis and early treatment of tuberculous meningitis. However, clinicians must be cautious when ruling out TBM with Xpert Ultra due to its low negative predictive value. Due to the limitations of current diagnostics, clinicians should utilize a combination of diagnostic modalities in order to prevent morbidity in patients with TBM.