Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis.

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

Balamuthia mandrillaris amoebic encephalitis mimicking tuberculous meningitis.

A 76-year-old female with no apparent immunosuppressive conditions and no history of exposure to freshwater and international travel presented with headache and nausea 3 weeks before the presentation. On admission, her consciousness was E4V4V6. Cerebrospinal fluid analysis showed pleocytosis with mononuclear cell predominance, elevated protein, and decreased glucose. Despite antibiotic and antiviral therapy, her consciousness and neck stiffness gradually worsened, right eye-movement restriction appeared, and the right direct light reflex became absent. Brain magnetic resonance imaging revealed hydrocephalus in the inferior horn of the left lateral ventricle and meningeal enhancement around the brainstem and cerebellum. Tuberculous meningitis was suspected, and pyrazinamide, ethambutol, rifampicin, isoniazid, and dexamethasone were started. In addition, endoscopic biopsy was performed from the white matter around the inferior horn of the left lateral ventricle to exclude brain tumor. A brain biopsy specimen revealed eosinophilic round cytoplasm with vacuoles around blood vessels, and we diagnosed with amoebic encephalitis. We started azithromycin, flucytosine, rifampicin, and fluconazole, but her symptoms did not improve. She died 42 days after admission. In autopsy, the brain had not retained its structure due to autolysis. Hematoxylin and eosin staining of her brain biopsy specimen showed numerous amoebic cysts in the perivascular brain tissue. Analysis of the 16S ribosomal RNA region of amoebas from brain biopsy and autopsy specimens revealed a sequence consistent with Balamuthia mandrillaris. Amoebic meningoencephalitis can present with features characteristic of tuberculous meningitis, such as cranial nerve palsies, hydrocephalus, and basal meningeal enhancement. Difficulties in diagnosing amoebic meningoencephalitis are attributed to the following factors: (1) excluding tuberculous meningitis by microbial testing is difficult, (2) amoebic meningoencephalitis has low incidence and can occur without obvious exposure history, (3) invasive brain biopsy is essential in diagnosing amoebic meningoencephalitis. We should recognize the possibility of amoebic meningoencephalitis when evidence of tuberculosis meningitis cannot be demonstrated.

[The effect of surgical treatment of tuberculous abscesses and tuberculoma of the brain on the dynamics of neurological symptoms]. / Vliyanie khirurgicheskogo lecheniya tuberkuleznykh abstsessov i tuberkulem golovnogo mozga na dinamiku nevrologicheskoi simptomatiki.

OBJECTIVE: To evaluate the efficacy of surgery in reducing neurological symptoms in patients with focal brain tuberculosis. MATERIAL AND METHODS: Seventy-four patients with tuberculosis meningoencephalitis were studied. Among them, 20 people with a life expectancy of at least 6 months were identified, in whom foci with a ring-shaped accumulation of contrast along the periphery were determined during MSCT of the brain. Formed tuberculomas and abscesses were removed from 7 patients (group 1) under neuronavigation control. Indications for the operation were: the absence of a reduction in size for 3-4 months, the limitation of the lesion to 1-2 foci with reduction of perifocal edema according to MSCT and normalization of cerebrospinal fluid. Six patients had contraindications or refusals from operations (group 2). In 7 patients, there was a decrease in formations by the control period (group 3). Neurological symptoms in the groups at the beginning of the observation were similar. The duration of observation was 6-8 months. RESULTS: In group 1, patients were discharged with improvement, postoperative cysts were determined in all of them at discharge. In group 2, 67% died. In group 3, 43% of patients had a complete reduction of foci during conservative treatment, in 57% cysts formed in place of foci. Neurological symptoms decreased in all groups, with the most decrease in group 1. However, statistical analysis did not show significant differences between the groups regarding the reduction of neurological symptoms. A significant difference in the mortality criterion between groups 1 and 2 was obtained. CONCLUSION: Despite the absence of a significant effect on the reduction of neurological symptoms, the high survival rate of operated patients shows the need to remove tuberculosis formations in all the cases.

Cerebrospinal Fluid Flow Analysis in Tuberculous Meningitis Using Phase Contrast Technique on 3 Tesla MRI: A New Paradigm and Our Initial Experience.

Background: Phase-contrast magnetic resonance imaging (PC-MRI) has been used for studying cerebrospinal fluid (CSF) dynamics in various CSF related disorders at aqueduct of Sylvius. Objective: To analyze the CSF flow dynamics qualitatively and quantitatively using PC-MRI across the aqueduct of Sylvius in diagnosed patients of tuberculous meningitis. Methods: Thirty patients, clinically diagnosed with tuberculous meningitis and mean age of 24 years (range: 12-60 years) were taken up to study the changes in CSF flow dynamics using PC-MRI with retrospective cardiac gating. Thirty age and sex matched healthy volunteers were also included for comparison and reference values. Flow quantification was done by through-plane scans acquired in the axial plane perpendicular to the aqueduct. For qualitative examination, in-plane phase contrast scans were acquired in the mid-sagittal plane. Encoding velocity was kept in craniocaudal direction. Calculated parameters were peak velocity (cm/s), average velocity (cm/s), average flow (mL/s), net forward volume (mL), and stroke volume (µL). Results: Qualitatively, loss of normal sinusoidal waveform of CSF flow was noted in two cases of hydrocephalus with exaggerated flows. Quantitatively, CSF flow parameters showed marked numerical difference in tuberculous meningitis patients with hydrocephalus on comparison with healthy volunteers and with cases without hydrocephalus. Conclusion: PC-MRI is a sensitive technique to analyze altered CSF flow dynamics in tuberculous meningitis patients. This is a useful adjunct in imaging these patients to extract both the qualitative and quantitative information about CSF flow for comprehensive evaluation.

Central Inflammatory Cytokines in Tuberculous Meningitis: A Systematic Review and Meta-analysis.

No formal agreement exists regarding central inflammatory cytokine aberrations in tuberculosis (TB). We undertook a systematic review and meta-analysis of studies comparing cytokine levels in cerebrospinal fluid (CSF) from patients with TB compared with controls. We searched PubMed, Scopus, and Web of Science for articles published up to June 22, 2021. Studies were included in the meta-analysis if they assessed unadjusted levels of cytokines in unstimulated CSF samples and drew the comparison(s) between any of the following pairs: patients with TB versus controls without central nervous system (CNS) infection and meningitis, patients with TB versus patients with meningitis of etiologies other than Mycobacterium tuberculosis, HIV-infected patients with TB versus HIV-uninfected patients with TB, and HIV-infected patients with TB versus HIV-infected patients without TB. The primary outcome was the difference in mean CSF inflammatory cytokine levels between each of the 2 groups mentioned. The standardized mean difference was chosen to measure effect using a restricted maximum-likelihood estimator random-effects model. Of 1170 records identified, 40 studies were included in the meta-analysis. We calculated effect sizes for 30 different cytokines. About half of the studies took place in South Africa and India (18 out of 40 studies). Studies were mostly (92.5%) on patients with tuberculous meningitis (TBM), with only 3 articles of patients with neurotuberculosis and spinal TB. The quality of studies was rated as low to moderate and high with a 1.2:1 ratio. Compared with controls without CNS infection and meningitis, interferon-gamma (IFNγ), interleukin (IL)-12p40, IL-17F, IL-1ß, IL-2, IL-4, IL-6, IL-8, sIL-2R, transforming growth factor beta (TGFß), TGFß1, and tumor necrosis factor alpha (TNFα) were increased in patients with TBM. Compared with patients with meningitis of etiologies other than M. tuberculosis or combined meningitis and nonmeningitis patients, patients with TBM had higher CSF concentrations of IFNγ, IL-13, and sIL-2R, whereas levels of IL-12p70, IL-15, IL-1Ra, IL-5, IL-7, IL-9, and sTNFR55 were decreased. Compared with patients with meningitis of bacterial etiologies other than M. tuberculosis, CSF levels of IFNγ and sIL-2R were increased in patients with TBM, whereas levels of IL-1Ra, IL-13, IL-17, and TNF R55-BP were decreased. Patients with TBM were not different from patients with CM for most CSF cytokines assessed, but IFNγ and IL-1ß were increased. TNFα, IL-1ß, IL-1Ra, IL-8, IFNγ, sIL-2R, IL-13, and IL-17 were higher in patients with TBM than those with viral or aseptic meningitis. Compared with HIV-negative patients with TBM, IFNγ, IL-10, IL-12p70, and IL-5 were decreased in HIV-positive patients with TBM, whereas IL-1ß, TNFα, and IL-2 were increased. Elevated TNFα, IL-1ß, IFNγ, IL-6, IL-17, and IFNα2 were found in HIV-positive patients with TBM compared with their counterparts without TBM. This study should be considered an explorative meta-analytic review, leading us to offer the best TBM-associated central inflammatory cytokines. Our study could prepare a panel of central cytokines as a potential aid in diagnosing TBM and its differentiation from meningitis of other etiologies.

Tuberculosis in Children in a Pediatric Hospital in Mexico.

Tuberculosis (TB) remains a global problem and a diagnostic challenge, especially in pediatrics. The aim of this study was to describe the clinical, microbiological, radiological, and histopathological data of TB in children. A 7-year retrospective and descriptive cohort study that included 127 patients under 18 years of age with diagnosis of active TB was conducted from 2011 to 2018 in a pediatric hospital. Tuberculosis was microbiologically confirmed using Ziehl-Neelsen (ZN) staining, culture or polymerase chain reaction (PCR) in a total of 94 (74%) cases. Thirty-three cases were defined as probable TB based on tuberculin skin test result and epidemiological evaluation. The TB forms found were lymph node (39.3%), bone (15.7%), lung (13.6%), and meningeal TB (8.6%). The most common symptoms were fever (48.8%) and adenopathy (45.6%). History of contact was established in 34.6%. Positive ZN staining (sensitivity 30%) and culture (sensitivity 37%) were found in 29% and 37.7% of subjects, respectively. About 64.5% depicted abnormal chest X-ray. Xpert MTB/RIF® (PCR) was positive in 9.4% and biopsy was compatible in 52.7% of these samples. It is fundamental to have laboratory and epidemiological evaluation that support the diagnosis of the disease in children and thus, define its management; since, in most cases, early microbiologic confirmation is lacking.

Risk factors for poor outcome in childhood tuberculous meningitis.

Tuberculous meningitis (TBM) remains a serious disease for children and its risk factors of poor outcome remain unclear. Therefore, a retrospective study was conducted aiming to investigate the risk factors associated with poor outcome of childhood TBM. Between January 2006 and December 2019, consecutive children patients (≤ 15 years old) who had a diagnosis of TBM were included for the analysis. The demographic, clinical, laboratory, and radiographic data were collected from the electronic medical records retrospectively. Poor outcome was defined as death or transfer to a higher-level hospital. Patients were then divided into good and poor outcome groups. Subsequently, risk factors for poor outcome were estimated using univariate and multivariate logistic regression analysis. A total of 149 children with TBM was enrolled, twenty-two patients suffered poor outcome, including 16 transfers to a higher-level hospital and 6 deaths, and the remaining 127 patients were classified as good outcome group. Further multivariate analysis revealed that coma (age- and sex-adjusted OR = 6.425, 95% CI: 1.743, 23.676; P < 0.01) and cerebrospinal fluid (CSF) protein (> 1188.3 mg/L; age- and sex-adjusted OR = 4.680, 95% CI: 1.469, 14.902; P < 0.01) were associated with the poor outcome of childhood TBM. Childhood TBM remains to have a high mortality rate in China. High CSF protein and coma were identified as risk factors for poor outcome of childhood TBM. Hence, more attention is required to be paid to suspected patients with such characteristics, thus facilitating access to optimum treatment.

A pilot study of inflammatory mediators in brain extracellular fluid in paediatric TBM.

Tuberculous meningitis (TBM) is the most fatal form of tuberculosis and frequently occurs in children. The inflammatory process initiates secondary brain injury processes that lead to death and disability. Much remains unknown about this cerebral inflammatory process, largely because of the difficulty in studying the brain. To date, studies have typically examined samples from sites distal to the site of disease, such as spinal cerebrospinal fluid (CSF) and blood. In this pilot study, we examined the feasibility of using direct brain microdialysis (MD) to detect inflammatory mediators in brain extracellular fluid (ECF) in TBM. MD was used to help guide neurocritical care in 7 comatose children with TBM by monitoring brain chemistry for up to 4 days. Remnant ECF fluid was stored for offline analysis. Samples of ventricular CSF, lumbar CSF and blood were collected at clinically indicated procedures for comparison. Inflammatory mediators were quantified using multiplex technology. All inflammatory markers, with the exception of interleukin (IL)-10 and IL-12p40, were detected in the ECF. Cytokine concentrations were generally lower in ECF than ventricular CSF in time-linked specimens. Individual cases showed ECF cytokine increases coinciding with marked increases in ECF glycerol or decreases in ECF glucose. Cytokine levels and glycerol were generally higher in patients with more severe disease. This is the first report of inflammatory marker analysis from samples derived directly from the brain and in high temporal resolution, demonstrating feasibility of cerebral MD to explore disease progression and possibly therapy response in TBM.

Tracking down the White Plague. Chapter three: Revision of endocranial abnormally pronounced digital impressions as paleopathological diagnostic criteria for tuberculous meningitis.

Abnormally pronounced digital impressions (APDIs) on the endocranial surface develop secondary to a prolonged rise in the intracranial pressure. This can result from a number of pathological conditions, including hydrocephalus due to tuberculous meningitis (TBM). APDIs have been described with relation to TBM not only in the modern medical literature but also in several paleopathological studies. However, APDIs are not pathognomonic for TBM and their diagnostic value for identifying TBM in past human populations has not been evaluated in identified pre-antibiotic era skeletons. To assess the diagnostic value of APDIs for the first time, a macroscopic investigation was performed on skeletons from the Terry Collection (Smithsonian Institution, Washington, DC, USA). Our material consisted of 234 skeletons with tuberculosis (TB) as the cause of death (TB group) and 193 skeletons with non-tuberculous (NTB) causes of death (NTB group). The macroscopic examination focused on the stage of the prominence and frequency of APDIs in the TB group and NTB group. To determine the significance of difference (if any) in the frequency of APDIs between the two groups, χ2 testing of our data was conducted. We found that APDIs were twice as common in the TB group than in the NTB group. The χ2 comparison of the frequencies of APDIs revealed a statistically significant difference between the two groups. In addition, APDIs with more pronounced stages were recorded more frequently in the TB group. Our results indicate that APDIs can be considered as diagnostic criteria for TBM in the paleopathological practice. With suitable circumspection, their utilization provides paleopathologists with a stronger basis for identifying TB and consequently, with a more sensitive means of assessing TB frequency in past human populations.

Changing Clinicoradiologic Spectrum of Intracranial Neurotuberculosis in Children: A Cross-sectional Study.

BACKGROUND: Neurotuberculosis is among the most severe type of tuberculosis with high mortality and morbidity in all age groups. Various sociodemographic and disease-/treatment-related factors have emerged over the years that can affect clinical and radiologic features of neurotuberculosis. OBJECTIVE: To investigate various clinical and neuroradiologic presentations of neurotuberculosis. METHODOLOGY: This cross-sectional study was done in a tertiary care center of northern India. The patients between the ages of 3 months and 18 years with newly diagnosed neurotuberculosis were enrolled after taking informed consent. RESULTS: A total of 78 patients (37% males) were enrolled. Fifty-six patients (72%) had tubercular meningitis (TBM) and 22 (28%) isolated tuberculomas. Very high percentage of patients in both the groups was BCG vaccinated. In the tubercular meningitis group, fever (68%), headache (59%), and vomiting (54%) were the most common complaints whereas in the tuberculoma group, seizures (95.5%) were the main complaint and systemic symptoms were rare. In tubercular meningitis patients, cerebrospinal fluid-based studies showed cartridge-based nucleic acid amplification test (Xpert MTB/RIF) positivity for Mycobacterium tuberculosis in 17.6% cases, whereas on gastric aspirate and sputum examination, acid-fast bacilli were seen in 30.7% and cartridge-based nucleic acid amplification test was positive in 19% patients. On neuroimaging, hydrocephalus was seen in 44.6% of tubercular meningitis patients, infarcts in 32%, and basal exudates in 12% patients only; coexistent tuberculomas were seen in 53%. CONCLUSION: Compared with the available literature, the present study showed a smaller percentage of children <5 years of age, stage III tubercular meningitis cases, and typical neuroradiologic findings like hydrocephalus and basal exudates and more tuberculomas associated with tubercular meningitis.

Real-time Polymerase Chain Reaction for Mycobacterium tuberculosis Meningitis is More Sensitive in Patients with HIV Co-Infection.

BACKGROUND: Tuberculous meningitis (TbM) is the most severe complication of extra pulmonary tuberculosis (Tb). There is a higher frequency of positive cerebrospinal fluid (CSF) cultures for Mycobacterium tuberculosis (MTb) in samples from human immunodeficiency virus (HIV) co-infected patients than in those from HIV-negative patients. We hypothesized that real time PCR assays for MTb (MTb qPCR) using CSF would be more sensitive in HIV co-infected patients owing to a greater MTb burden. The present study aimed to verify the diagnostic performance of MTb qPCR in CSF of TbM patients who either were co-infected with HIV or were HIVnegative. METHODS: A total of 334 consecutive participants with suspected TbM were divided into two groups: HIV co-infected and HIV-negative; each group was categorized into definite TbM, probable TbM, possible TbM, and TbM-negative subgroups based on clinical, laboratory and imaging data. We evaluated the diagnostic characteristics of MTb qPCR analysis to detect TbM in CSF by comparing the results to those obtained for definite TbM (i.e., positive MTb culture) and/or probable TbM in CSF, as gold standard. RESULTS: The sensitivity of MTb qPCR in the definite and probable subgroups of the HIV coinfected participants (n = 14) was 35.7%, with a specificity of 93.8%, negative predictive value (NPV) of 94.4%, and negative clinical utility index (CUI-) of 0.89. Results of the HIV-negative group (n = 7) showed lower sensitivity (14.3%) and similar specificity, NPV, and CUI-. CONCLUSION: The findings confirmed our hypothesis, despite the low sensitivity. MTb qPCR may significantly contribute to diagnosis when associated with clinical criteria and complementary examinations.

Cerebrovascular complications in tuberculous meningitis-A magnetic resonance imaging study in 90 patients from a tertiary care hospital.

BACKGROUND: Cerebrovascular complications of tuberculous meningitis (TBM) are associated with increased morbidity and mortality. We retrospectively reviewed clinicoradiological findings of 90 TBM patients who presented to a tertiary care hospital, with emphasis on frequency and distribution of infarcts on diffusion imaging and pattern of vascular involvement on magnetic resonance (MR) angiography (MRA). MATERIALS AND METHODS: MR images of 90 TBM patients at presentation (2012-2018) were coanalyzed by two radiologists for tuberculomas, leptomeningeal enhancement (LM), hydrocephalus, infarct and vascular abnormalities. Infarcts were categorized based on location ("tubercular" (TB) or "ischemic" zones) and arterial supply (perforators and cortical branches). Clinical and laboratory findings were correlated with imaging data. RESULTS: Ninety TBM patients (age 10-82 years) were enlisted after application of inclusion criteria. Tuberculomas were most common (100%) followed by LM (84.4%), cerebral infarcts (57.7%) and hydrocephalus (29%). Location-wise, 35% infarcts were in ischemic, 13% in TB and 15% in both zones. According to arterial supply, infarcts equally (50%) involved perforators from the lateral lenticulostriate and posterior cerebral (PCA)/basilar artery (BA) followed by medial lenticulostriate arteries (23%). MRA was available in 74.4% and abnormal in 43.2%. The middle cerebral artery was frequently involved (76%) followed by the anterior cerebral artery (38%), internal carotid artery (31%), PCA and BA. Six had diffuse narrowing with a paucity of distal vessels. Cerebral infarction was associated with hydrocephalus (p = .0019) and vasculitis (p < .001). CONCLUSION: In TBM, strokes are common and mainly involve the perforators and cortical branches. MR is the imaging modality of choice for early diagnosis and timely management.

Rapid Diagnosis of Tuberculosis Meningitis by Detecting Mycobacterium tuberculosis Cell-Free DNA in Cerebrospinal Fluid.

OBJECTIVES: Tuberculosis meningitis (TBM) is one of the most severe forms of tuberculosis. However, TBM diagnosis is quite challenging due to nonspecific clinical presentation and the paucity of the pathogen in cerebrospinal fluid (CSF) samples. In this study, we report a new method for detecting cell-free Mycobacterium tuberculosis DNA (cf-TB) in CSF and evaluate its clinical value for TBM diagnosis. METHODS: Of 68 patients prospectively recruited, 46 were diagnosed as having TBM and 22 as non-TBM. We compared the cf-TB method with CSF smear microscopy, mycobacterial culture, and the Xpert MTB/RIF assay (Xpert) using the consensus case definition for TBM proposed in 2009 as a reference standard. RESULTS: The sensitivity of the cf-TB test was 56.5% (26/46) in patients with TBM, and it was significantly higher than other methods: microscopy (2.2%, 1/46; P < .001), mycobacterial culture (13.0%, 6/46; P < .001), and Xpert (23.9%, 11/46; P = .001). For specificity, none of the four methods reported false-positive results in the non-TBM group. CONCLUSIONS: The new method detecting cell-free M tuberculosis DNA in CSF is rapid and accurate for diagnosis of TBM and easily incorporated into regular laboratory tests.

Genome-Wide miRNA Analysis Identifies Potential Biomarkers in Distinguishing Tuberculous and Viral Meningitis.

Tuberculous meningitis (TBM) is the most common and severe form of central nervous system tuberculosis. Due to the non-specific clinical presentation and lack of efficient diagnosis methods, it is difficult to discriminate TBM from other frequent types of meningitis, especially viral meningitis (VM). In order to identify the potential biomarkers for discriminating TBM and VM and to reveal the different pathophysiological processes between TBM and VM, a genome-wide miRNA screening of PBMCs from TBM, VM, and healthy controls (HCs) using microarray assay was performed (12 samples). Twenty-eight differentially expressed miRNAs were identified between TBM and VM, and 11 differentially expressed miRNAs were identified between TBM and HCs. The 6 overlapping miRNAs detected in both TBM vs. VM and TBM vs. HCs were verified by qPCR analysis and showed a 100% consistent expression patterns with that in microarray test. Statistically significant differences of 4 miRNAs (miR-126-3p, miR-130a-3p, miR-151a-3p, and miR-199a-5p) were further confirmed in TBM compared with VM and HCs in independent PBMCs sample set (n = 96, P < 0.01). Three of which were also showed significantly different between TBM and VM in CSF samples (n = 70, P < 0.05). The receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve (AUC) of these 4 miRNAs in PBMCs were more than 0.70 in discriminating TBM from VM. Combination of these 4 miRNAs could achieve better discriminative capacity [AUC = 0.893 (0.788-0.957)], with a sensitivity of 90.6% (75.0-98.0%), and a specificity of 86.7% (69.3-96.2%). Additional validation was performed to evaluate the diagnostic panel in another independent sample set (n = 49), which yielded a sensitivity of 81.8% (9/11), and specificity of 90.0% (9/10) in distinguishing TBM and VM, and a sensitivity of 81.8% (9/11), and a specificity of 84.6% (11/13) in discriminating TBM from other non-TBM patients. This study uncovered the miRNA profiles of TBM and VM patients, which can facilitate better understanding of the pathogenesis involved in these two diseases and identified 4 novel miRNAs in distinguishing TBM and VM.

Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis.

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurologic injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms, we used a lipid mediator-profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized proresolving mediators (SPMs), in the cerebrospinal fluid (CSF) of adults with TBM. Herein, using CSF from patients enrolled into a randomized placebo-controlled trial of adjunctive aspirin treatment, we found distinct lipid mediator profiles with increasing disease severity. These changes were linked with an up-regulation of inflammatory eicosanoids in patients with severe TBM and a decrease in the production of a number of SPMs. CSF proresolving mediator concentrations were also associated with 80-d survival. In survivors, we found a significant increase in proresolving mediator concentrations, including the lipoxygenase 5-derived 13-series resolvin (RvT)2, RvT4, and 15-epi-lipoxin B4, compared with those who died. Of note, treatment of patients with high-dose aspirin led to a decrease in the concentrations of the prothrombic mediator thromboxane A2, reduced brain infarcts, and decreased death in patients with TBM. Together, these findings identify a CSF SPM signature that is associated with disease severity and 80-d mortality in TBM.-Colas, R. A., Nhat, L. T. H., Thuong, N. T. T., Gómez, E. A., Ly, L., Thanh, H. H., Mai, N. T. H., Phu, N. H., Thwaites, G. E., Dalli, J. Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis.

Role of Oxidative Stress in Tuberculous Meningitis: a Clinico-Radiological Correlation.

Central nervous system infection may be associated with oxidative stress and may influence clinical severity and outcome. We report oxidative stress markers in the patients with tuberculous meningitis (TBM) and correlate these with clinico-radiological severity and outcome. Fifty-six patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF), and magnetic resonance (MRI) were included. Plasma glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured in the patients and 55 matched healthy controls. Hospital death was noted. Disabilities at 3 and 6 months were categorized using the modified Rankin Scale (mRS) as poor (mRS > 2) or good (mRS ≤ 2). The patients had lower levels of GSH (1.49 ± 0.49 vs 2.57 ± 0.39 mg/dL, p Ë‚ 0.001) and TAC (0.25 ± 0.17 vs 2.20 ± 0.31 mmol Trolox Eq/L, p Ë‚ 0.001), and higher level of MDA (6.61 ± 1.72 vs 3.09 ± 0.38 nmol/mL, p < 0.001) compared to controls. Total antioxidant capacity correlated with cranial nerve palsy and CSF pleocytosis. Patients with tuberculoma had lower GSH compared to those without. Six patients died in the hospital, and they had lower GSH (p < 0.01) and TAC (p = 0.02) levels compared to those who survived. Thirty-one and 36 patients had a good outcome at 3 and 6 months respectively. The patients with good outcome had higher GSH level.

Imaging in Pediatric Extra-Pulmonary Tuberculosis.

Extrapulmonary tuberculosis in children tends to be more severe than the adults. It can affect almost any organ system of the body. The clinical manifestations are often non-specific. Imaging findings are also not always very specific. This article describes the imaging spectrum of pediatric extrapulmonary tuberculosis.

The pathogenesis of tuberculous meningitis.

Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested.