Nonlinear dynamic monitoring is crucial for assessing l-tryptophan (l-Trp) dysregulation progression in tuberculous meningitis (TBM); yet remains challenging due to conventional sensing probes' inherent nondirectionality and poor interfacial response control. Herein, we present a programmable organic-ligand-based self-assembly strategy to construct superlattice nanoprobes with structurally responsive, tunable interfaces. Precisely regulating ligand assembly integrates atomically dispersed platinum layers with organic ligand bilayers, forming an interactive nanobiosensing interface for real-time, quantitative detection of nonlinear l-Trp dynamics. The nanoplatform shows threshold-dependent colorimetric response: subtle monochromatic brightness shifts below 0.2 μM, and distinct multiphase color transitions via chromatic superposition above it, enabling visual discrimination of pathological l-Trp fluctuations in TBM. Integrated with machine learning-enhanced pattern recognition, it achieves robust self-calibration and zero false positives in complex clinical matrices. Compared to conventional methods (acid-fast staining, culture), it reduces processing time by >50%, boosts accuracy by >13%, and cuts reagent costs by >74%, establishing an effective paradigm for neuroinflammatory biomarker monitoring and enabling precise TBM diagnosis.

Clinical characteristics of childhood tuberculous meningitis and risk factors for severe neurological sequelae disaggregated by age group.

Introduction: Clear cerebrospinal fluid (CSF) meningitis represents a major public health problem in resource‑limited countries. It is characterized by CSF pleocytosis with a macroscopically clear appearance, and its etiologies are mainly viral, tuberculous, or undetermined. Objective: This study aimed to analyze clear CSF samples from a cytological and biochemical perspective, identify the main pathogens, and assess the diagnostic yield of examinations performed at the Brazzaville University Hospital laboratory. Methods: An analytical cross‑sectional study with prospective data collection was conducted from April 1 to September 30, 2021, including all clear CSF samples received at the bacteriology‑virology‑immunology laboratory of CHU‑B. Analyses included cytology, biochemistry, and PCR detection of Mycobacterium tuberculosis, HSV‑1, and Enterovirus. Results: The frequency of clear CSF meningitis was 48.6%. Patients under 5 years accounted for 67.9% of cases, with a slight male predominance (sex ratio 1.03). Cytology showed a mean of 245 leukocytes/mm³, with lymphocytic predominance. Protein levels were elevated (2.02 g/L) in all cases, while hypoglycorrhachia was observed only in tuberculous meningitis. The pathogens identified were mainly Enterovirus (20.3%), followed by Mycobacterium tuberculosis (5.8%) and HSV‑1 (11.6%). A large proportion of cases (63.8%) remained of undetermined etiology. Diagnostic yield was higher among infants (<1 year, 53.6%) and young adults (20–40 years, 61.5%). Conclusion: Clear CSF meningitis is frequent in Brazzaville, predominantly affecting young children. Cytological and biochemical CSF profiles were consistent with the identified etiologies. Improving laboratory capacity, particularly through systematic integration of multiplex film array nucleic acid amplification tests, is essential to reduce the number of undetermined cases and strengthen diagnostic and therapeutic management.

Background: Acute meningitis is a life-threatening neurological emergency with substantial global morbidity and mortality. Adjunctive corticosteroid therapy aims to mitigate the inflammatory response and improve clinical outcomes. Methods: We analyzed data from randomized controlled trials, meta-analyses, Cochrane reviews, and international guidelines (e.g., WHO, IDSA, NICE), integrating findings from high-income and resource-limited settings. Key outcomes assessed include mortality, neurological sequelae (e.g., hearing loss, hydrocephalus), length of hospital stay, and treatment-related adverse events. Results: Corticosteroids significantly reduce mortality and neurological sequelae in acute bacterial meningitis (particularly pneumococcal), especially when administered before or with antibiotics. In tuberculous meningitis, steroids (dexamethasone or prednisolone) improve survival by 25%–30%, though long-term neurological outcomes remain inconsistent. In contrast, viral meningitis shows no clear benefit, and steroids are contraindicated in cryptococcal meningitis due to increased adverse events and worse outcomes. Limited evidence supports steroid use in parasitic meningitis (e.g., Angiostrongylus cantonensis ) and non-infectious meningitis (e.g., neurosarcoidosis), where they reduce inflammation and symptom burden. Neonatal meningitis lacks sufficient evidence to support routine corticosteroid use due to potential harms. Conclusion: Adjunctive corticosteroids are a valuable intervention in specific forms of meningitis, particularly bacterial and tuberculous types, where they improve survival and reduce complications. Their use must be tailored to the etiology, timing, and patient population to avoid harm. Global and regional guidelines recommend dexamethasone as part of initial empiric therapy in suspected bacterial meningitis (excluding neonates), and in all cases of TB meningitis.

Central nervous system (CNS) infections are an important cause of morbidity and mortality among people living with HIV (PLWHIV), particularly in resource-limited settings. Cryptococcosis, toxoplasmosis and cerebral malaria often present with overlapping neurological symptoms, complicating diagnosis where confirmatory tests are unavailable. This study aimed to determine the prevalence and associated signs and symptoms of parasitic and fungal infections with neurological tropism in PLWHIV hospitalized in Libreville. A retrospective review was conducted at the Infectious Diseases Ward of the Centre Hospitalier Universitaire de Libreville (IDW-CHUL) between April and September 2021. Data were recorded from the medical files of PLWHIV hospitalised for suspected cryptococcal meningoencephalitis presenting with fever and headache alone or associated with other neurological signs. Diagnoses of cryptococcosis, toxoplasmosis, and malaria were based on microscopy, cryptococcal antigen testing, and brain CT scan. Cases of tuberculosis, other bacterial or viral meningitis were not included. Sociodemographic, clinical, and immunological data were analysed, and associations between symptoms and CNS infections were assessed. Among 255 hospitalised PLHIV, most were aged under 55 years (86.3%, n = 220), female (72.5%, n = 185), and severely immunosuppressed (CD4 < 200 cells/mm³, 57.2%, n = 127). Parasitic or fungal infections were identified in 32.9% (n = 84) of cases: cryptococcosis (14.5%), cerebral toxoplasmosis (13.7%), and complicated malaria (9.8%), with 5.1% presenting co-infections. Advanced HIV disease (WHO stage III-IV) was significantly associated with cryptococcosis and toxoplasmosis (p < 0.01). Fever and headache (81.2%, n = 207) were the most common symptoms. According to diagnosis, fever, headache, seizures, and/or focal deficits were more suggestive of toxoplasmosis (cOR 3.5, 95%CI [1.0-12.4], p = 0.05), while prostration was more frequent in malaria (cOR 2.9, 95%CI [0.98-9.0], p = 0.05), and neck stiffness was characteristic of cryptococcosis. Parasitic and fungal CNS infections remain frequent and severe in hospitalised PLWHIV in Libreville, mainly in advanced disease with profound immunosuppression. In the absence of diagnostic tools, recognition of symptom clusters may guide syndromic triage and empirical therapy.

The aim of our paper is to present and discuss in detail the pathological lesions suggestive of tuberculosis observed in a skeleton (MMG3-75) that was excavated from the 16th-century-CE mass grave No. 3 of the Mohács National Memorial Site (Sátorhely, southwestern Hungary). The differential diagnoses of the observed bony changes, with special attention to the clival alterations, are presented. During the macromorphological, radiological, and digital microscopic examination of MMG3-75, the skull base showed mild cortical erosion and multiple, well-circumscribed osteolytic lesions at the clivus clearly evidenced by 3D imaging. In addition, endocranial granular impressions and abnormal blood vessel impressions were observed in multiple locations on the inner skull surface. Based on the differential diagnosis of the clival changes and their co-occurrence with endocranial alterations indicative of tuberculous meningitis (granular impressions and abnormal blood vessel impressions), they were most likely due to tuberculous involvement of the skull base. Additional aDNA analysis provided no evidence for the presence of Mycobacterium tuberculosis DNA in MMG3-75. To the best of our knowledge, MMG3-75 is the first reported archaeological case of tuberculous clival osteomyelitis with associated meningitis, giving us a unique insight into the occurrence of an extremely rare manifestation of tuberculosis in mediaeval Hungary.

The aim of our paper is to present and discuss in detail the pathological lesions suggestive of tuberculosis observed in a skeleton (MMG3–75) that was excavated from the 16th-century-CE mass grave No. 3 of the Mohács National Memorial Site (Sátorhely, southwestern Hungary). The differential diagnoses of the observed bony changes, with special attention to the clival alterations, are presented. During the macromorphological, radiological, and digital microscopic examination of MMG3–75, the skull base showed mild cortical erosion and multiple, well-circumscribed osteolytic lesions at the clivus clearly evidenced by 3D imaging. In addition, endocranial granular impressions and abnormal blood vessel impressions were observed in multiple locations on the inner skull surface. Based on the differential diagnosis of the clival changes and their co-occurrence with endocranial alterations indicative of tuberculous meningitis (granular impressions and abnormal blood vessel impressions), they were most likely due to tuberculous involvement of the skull base. Additional aDNA analysis provided no evidence for the presence of Mycobacterium tuberculosis DNA in MMG3–75. To the best of our knowledge, MMG3–75 is the first reported archaeological case of tuberculous clival osteomyelitis with associated meningitis, giving us a unique insight into the occurrence of an extremely rare manifestation of tuberculosis in mediaeval Hungary.

Adjunctive corticosteroids such as dexamethasone are recommended in tuberculous meningitis treatment, despite modest and heterogeneous survival benefit. Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes. Here, in a phase 3, placebo-controlled trial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6-8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratio margin of 0.75) or its superiority. Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized. A total of 89 TT-genotype participants received open-label dexamethasone. In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratio of 0.99, 96% confidence interval (adjusted for multiple testing) 0.748-1.31). The number of observed primary endpoints (n = 218) exceeded the prespecified number (n = 184) used to calculate the trial's sample size and power. Placebo noninferiority was not established in the CC and CT population or in individual genotype subpopulations. Benefit or heterogeneity of effect was not observed by any prespecified subgroup. In TT-genotype participants, the primary endpoint occurred in 28/89 (31.5%) participants, similar to CC and CT participants. Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants. In CC- and CT-genotype participants, serious adverse events occurred in 161/305 (52.8%) dexamethasone-treated participants and 160/308 (51.9%) placebo-treated participants. In conclusion, neither noninferiority nor superiority of placebo was established in human immunodeficiency virus-negative LTA4H CC- and CT-genotype adults with tuberculous meningitis, and dexamethasone was safe. The modest and heterogeneous benefit of dexamethasone indicates that greater understanding of tuberculous meningitis pathophysiology is needed, alongside better targeted, more effective anti-inflammatory agents than corticosteroids (ClinicalTrials.gov NCT03100786 ).

Cerebral infarction is a frequent and serious complication of tuberculous meningitis (TBM), contributing substantially to morbidity and mortality. Moreover, studies on infarct patterns and associated factors/predictors remain limited in TBM. ACT-TBM trial (Aspirin or Clopidogrel Therapy in the Treatment of Tuberculous Meningitis) evaluated the efficacy and safety of adjunctive antiplatelet therapy (aspirin or clopidogrel) to standard antitubercular therapy in TBM for the occurrence of stroke or cerebral infarction. Here, we conducted a secondary analysis of the ACT-TBM trial to characterize the patterns, associated factors, and predictors of cerebral infarction in TBM. We utilized data of 237 patients from the ACT-TBM randomized controlled trial conducted at 2 tertiary centers in India (2019-2023). Serial magnetic resonance imaging and magnetic resonance angiography were performed at baseline, 1 month, and 3 months in the primary trial. Cerebral infarctions were categorized by size, vascular territory, and number. Multivariable logistic regression models were performed using variables with P<0.1 on univariable analysis and clinical relevance. Model estimates are reported as adjusted odds ratios (aORs) with 95% CIs. Of the 237 patients enrolled, 226 were included after excluding 11 with missing imaging or incomplete follow-up data. Among these, 84 (37%) had cerebral infarction. Median age of the entire cohort was 26 years (interquartile range, 20-36), and 134 (59.29%) were females. Multiple infarcts were observed in 66 (78.6%) patients, most frequently in the basal ganglia (n=61, 72.6%), subcortical white matter (n=44, 52.4%), and cortex (n=32, 38.1%). Arterial occlusion occurred in 52 (61.25%) patients with cerebral infarction versus 36 (25.55%) without (P<0.001). In multivariable adjusted models, Grade 3 TBM (aOR, 3.94 [95% CI, 1.19-13.08]; P=0.025), and arterial occlusion (aOR, 4.43 [95% CI, 2.19-8.96]; P<0.001) were associated with infarction. Among those with infarction, 27 (32.14%) patients (13.17% of the total cohort) developed new infarctions on follow-up. Modified antitubercular therapy (antitubercular therapy; aOR, 3.10 [95% CI, 1.18-8.09]; P=0.021) and arterial occlusion (aOR, 4.23 [95% CI, 1.40-12.75]; P=0.01) significantly predicted new infarctions. Presence of exudates was associated with arterial occlusion (aOR, 2.86 [95% CI, 1.08-7.56]; P=0.034). Cerebral infarction is common in TBM and associated with disease severity and arterial occlusion. Modified antitubercular therapy predicted new infarcts, while basal exudates were associated with vascular occlusion, highlighting the need for vigilant monitoring and optimized therapeutic strategies.

Outcomes in tuberculous meningitis (TBM) are closely linked to host inflammation. Anti-inflammatory corticosteroid therapy improves survival in HIV-negative TBM, but not in people with HIV. In people with HIV, TBM is fatal in 40-50% of cases. Therefore, we investigated how mortality is associated with the local immune response in people with HIV-associated TBM. We measured baseline concentrations of immune signalling mediators in cerebrospinal fluid (CSF) of 149 adults with HIV in Uganda, who presented with definite or probable TBM. Participants received both antimycobacterial and corticosteroid therapy. At baseline, non-survivors had more severe TBM disease and lower blood CD4 T cells than survivors. Mortality at 90 days was strongly associated with CSF hypo-inflammation. CSF interferon gamma (IFN-γ) was most differentially expressed by survivors (2.2 log2-fold change higher, p=.003), and 90-day mortality was lower with increasing concentrations (Tertile-1=50%, Tertile-2=41%, Tertile-3=18%; p=.006). Even among people who successfully mounted a CSF cellular immune response (>5 white cells/μL CSF), those with low CSF IFN-γ had higher risk of death (Hazard Ratio =3.10 (1.44-6.68). Interleukin-13 had a more complex relationship, with lower mortality among people with intermediate CSF interleukin-13 concentrations but higher at the two extremes (Tertile-1=45%, Tertile-2=22%, Tertile-3=40%; p=.017). Of all sub-groups, those with both peripheral CD4 depletion and low CSF IFN-γ had the highest mortality (63%). In adults with HIV-associated TBM receiving dexamethasone, mortality was strongly associated with CSF hypo-inflammation. Although steroids may be appropriate in those with high inflammation, personalized approaches to immunotherapy are likely necessary to improve outcomes.

333. Comparative Efficacy of Rifamycin-containing Regimens in a Murine Model of Tuberculous Meningitis

Background: Tuberculous meningitis (TBM) is a severe central nervous system infection that can lead to cerebral vasculitis and infarction. This study aimed to evaluate changes in cerebral perfusion and vasculitis on magnetic resonance imaging (MRI) before and after anti-tuberculosis treatment, focusing on both infarcted and non-infarcted brain regions and comparing them with age-matched controls. Methods: Quantitative arterial spin labeling (ASL) perfusion and black-blood vessel wall MRI were performed at diagnosis and after 3–6 months of treatment in TBM patients and healthy controls. Regions of interest included infarcted areas, the contralateral normal brain, and TBM-affected regions without infarction. Cerebral blood flow (CBF), perfusion grading, and vasculitis were assessed and correlated with clinical stage and disease severity. Results: In total, 73 TBM patients and 26 controls were included. Among the patients, 26 (35.6%) had acute infarctions, mainly in the basal ganglia and corona radiata, and 65 (89.0%) exhibited vasculitis predominantly involving anterior circulation. Pretreatment MRI showed significantly reduced CBF in infarcted regions compared with contralateral brain and controls (p < 0.05), and both contralateral and non-infarcted TBM regions also showed lower CBF than controls (p < 0.05). After treatment, CBF increased significantly in non-infarcted regions (p < 0.05), and post-treatment perfusion grade correlated with TBM stage and vasculitis severity. Conclusions: TBM-related infarcts demonstrated marked hypoperfusion, while non-infarcted regions exhibited reversible ischemic changes. ASL and vessel wall imaging can quantitatively monitor treatment response and vascular inflammation, as well as predict late infarction in TBM patients.

Possible tuberculous meningitis presenting with predominant voiding dysfunction in an elderly patient: A case report.

Characterization of CSF tryptophan metabolites in South African children with tuberculous meningitis.

Status epilepticus in scrub typhus versus tuberculous meningitis: A comparative study.

This case highlights a rare presentation of disseminated tuberculosis in a child, manifesting as tuberculous meningitis and flaccid paralysis due to spinal tuberculosis. Timely initiation of antitubercular therapy, corticosteroids, and ventriculoperitoneal shunt placement led to full recovery, emphasizing tuberculosis consideration in atypical neurological presentations in unvaccinated children with exposure.

The etiological profile of acute febrile encephalopathy (AFE) varies across different geographic areas and in different seasons across the world. Limited literature in children suggests central nervous system (CNS) infections to be the most common cause of AFE in India and developing countries. Most of these studies have been done in the plains of India, and no study has been done in the Himalayan region of northwestern India, where most of the vectors causing AFE in other parts of India, like mosquitoes, are not found. Therefore, this leads to a lacuna in available data on the etiological profile in this region with an elevation of 1000-21,000 ft from the sea level. Our aim was to study the clinical and etiological profile of pediatric AFE and the risk factors associated with mortality in AFE in Himachal Pradesh, a hilly Himalayan state of India located in northwestern Himalayas. This was a prospective, descriptive, observational study conducted in the pediatric intensive care unit (PICU) of Indira Gandhi Medical College Shimla, for a period of 1 year, in which all children aged from 1 to 18 years with clinical evidence of AFE and meeting the inclusion criteria were enrolled and studied for the clinical features, etiology, and risk factors for mortality. Chi-square test was used to find the significance of study parameters on a categorical scale between two or more groups. A P value of 0.05 or less was considered as statistically significant. Sixty-nine patients were enrolled in the study. Fever, altered sensorium, vomiting, seizures, and headache were the most common symptoms. The most common clinical sign was raised ICT, followed by low Glasgow coma scale (GCS). The most common etiology was CNS infections. Among these, scrub encephalitis was the most common cause that was seen in 15.8%, followed by viral and tubercular meningitis in 14.4% and 11.1%, respectively. Eighteen patients out of 69 with AFE died, giving a case fatality rate of 26%. Shock, GCS <8, ventilatory support, MODS, DIC, and delayed presentation were significant risk factors associated with mortality. Infectious causes attributed maximum to the etiology of AFE, and among them, scrub encephalitis was the most common cause of AFE.

Tuberculous meningitis (TBM) is one of the tuberculosis forms that attacks the central nervous system caused by Mycobacterium tuberculosis (MTB). This illness generally happens through developed countries, especially to the kids and having high mortality levels even after modern treatment exists. The TBM happens when the MTB spreads from the lungs into the brain, crossing the brain's blood barrier, and causing inflammation. People with low-immune levels could possibly let MTB spread easily through the body. The pathophysiology of TBM is influenced by the genetics, immune responses, also the microbiota as the factors. The genetics' variation on the immune system could increase the risk of getting the illness, while the microbiota imbalance could affect the immune functions. Furthermore, this condition impacts kids and the adults. The kids get affected more severely and the people with HIV will face complications caused by immune pressure. The deeper understanding through TBM mechanisms including immune factors, also genetics are important in aim to increase prevention and treatment. The modulation immune and microbiota approaches as targeted therapy highlights a positive potential in terms of improving the patient's treatment result and decreasing the TBM's global burden.

Early diagnosis of tuberculous meningitis (TBM) is critical to favorable outcomes. We investigated whether a 3-gene host response signature in whole blood can distinguish TBM from symptomatic controls in children. Whole-blood RNA sequencing was performed in children with TBM and controls. Expression of the 3-gene signature, [guanylate-binding protein (GBP5), dual specificity phosphatase 3 (DUSP3) and Krupple-like factor 2 (KLF2)] was quantified and a tuberculosis (TB) score was calculated using (GBP5+DUSP3)/2-KLF2. Discriminatory performance was obtained using receiver-operator characteristic curve analysis against microbiological and composite reference standards. TB score and 3-gene expression in children were compared against adults with TBM. In parallel, an exploratory transcriptome-wide analysis was performed, applying bootstrapped least absolute shrinkage and selection operator regression to identify additional genes associated with TBM. Forty-two children had TBM and 41 were controls. KLF2 was upregulated in TBM compared to controls (P = 0.043); while GBP5, DUSP3 and TB score showed no difference. The diagnostic performance of GBP5 alone (area under the curves: 0.64; 95% confidence interval: 0.46-0.83) and TB score (area under the curves: 0.59; 95% confidence interval: 0.41-0.77) was poor against the reference standard of definite TBM. GBP5 in children with TBM was lower than in adults without HIV (median 13.04; interquartile ranges: 11.91-14.29 vs. median 13.72; interquartile ranges: 12.58-14.53, P = 0.036), and expression was nonlinear across the age spectrum; lowest in young children. Exploratory transcriptomic analysis suggests that novel genes may contribute a discriminatory signal. The 3-gene host response signature does not discriminate TBM from controls in children and was much less discriminative compared to adults. An alternative set of pediatric-specific signatures may exist, but further discovery and validation are required.

BackgroundTuberculous meningitis is often lethal, and many survivors have disabilities despite antimicrobial treatment and adjunctive glucocorticoid therapy. Standard-dose rifampin has limited central nervous system penetration. Whether high-dose rifampin could improve survival outcomes is unknown.MethodsWe performed a double-blind, randomized, placebo-controlled clinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda. We assigned persons with and those without human immunodeficiency virus (HIV) coinfection to receive standard daily isoniazid, rifampin (at a dose of 10 mg per kilogram of body weight), ethambutol, and pyrazinamide plus either additional rifampin (for a cumulative dose of 35 mg per kilogram; high-dose group) or matched placebo (standard-dose group) for 8 weeks; participants in both groups received standard therapy for the remainder of the 9-to-12-month treatment course. The primary outcome was 6-month mortality.ResultsA total of 499 participants were included in the intention-to-treat population (249 randomly assigned to the high-dose group and 250 to the standard-dose group), of whom 304 (60.9%) were persons living with HIV and 428 (85.8%) had definite or probable tuberculous meningitis. During 6 months of follow-up, 109 participants (Kaplan–Meier estimate, 44.6%) in the high-dose group and 100 participants (Kaplan–Meier estimate, 40.7%) in the standard-dose group died (hazard ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P=0.25). Among the participants who died within 6 months, the median time to death was 13 days (interquartile range, 4 to 39) in the high-dose group and 24 days (interquartile range, 6 to 56) in the standard-dose group. Drug-induced liver injury occurred in 8.0% of the participants in the high-dose group and in 4.4% of those in the standard-dose group, but no deaths from drug-induced liver injury occurred.ConclusionsAmong persons with tuberculous meningitis, no evidence of beneficial effect from high-dose rifampin was observed, and the potential for a harmful effect cannot be ruled out. (Funded by the U.K. Medical Research Council and others; ISRCTN Registry number, ISRCTN15668391.)