Tuberculous Meningitis Research Articles

Paradoxical deterioration during treatment of tuberculous meningitis responded to infliximab but not to steroids

Paradoxical deterioration in patients with tuberculous meningitis is a significant diagnostic and treatment challenge. We present the case of a 55-year-old previously healthy male, human immunodeficiency virus (HIV)-negative, presenting with headache, fever, agitation and slurred speech, who was ultimately diagnosed with tuberculous meningoencephalitis confirmed by cerebrospinal fluid polymerase chain reaction positive for Mycobacterium tuberculosis complex. After initiation of a standard antitubercular therapy combined with glucocorticoids, the patient experienced an initial neurological improvement. However, after 3 months of therapy, he had a major stroke with neurological deterioration, clinically and radiologically attributable to a paradoxical deterioration or an immune reconstruction syndrome as described in HIV-positive patients. Due to the persistence of inflammatory symptoms and radiological evidence of worsening tuberculomas despite ongoing antituberculosis therapy, off-label use of the tumour necrosis factor (TNF) inhibitor infliximab was initiated. The patient received three doses of infliximab at 5 mg/kg at monthly intervals, which led to marked clinical and radiological improvement. Follow-up magnetic resonance imaging showed regression of lesions, and the patient was eventually discharged with a significant recovery of motor and speech functions. This case underscores the potential of TNF inhibitors in managing severe cases of paradoxical deterioration in patients with tuberculous meningitis, challenging existing treatment paradigms and suggesting a need for further research into the pathophysiology and treatment of this condition.

Clinical significance of hyponatremia in tuberculous meningitis: a prospective cohort in Indonesia

Clinical significance of hyponatremia in tuberculous meningitis: a prospective cohort in Indonesia

A Case of Pott’s Disease Complicated by Tuberculous Meningitis and Psoas Abscess Diagnosed by Computed Tomography-Guided Percutaneous Drainage

A Case of Pott’s Disease Complicated by Tuberculous Meningitis and Psoas Abscess Diagnosed by Computed Tomography-Guided Percutaneous Drainage

Case Report: Multi drug resistant tuberculosis in an 18-month-old boy with seizure, vomiting, and loss of vision

Multi drug resistant tuberculosis (MDR-TB) in children is rare and requires tremendous skill and knowledge of clinicians for early detection and treatment. This case highlights the complexities in diagnosing and treating MDR-TB in young children. An 18-month-old immunocompetent boy presented with prolonged fever, sudden onset of vision loss, vomiting, and seizures, which led to a suspicion of meningitis. Given his family history of treated pulmonary TB (TB) in the father and uncle one year ago, the initial treatment followed the Nepali national protocol for non-MDR tuberculous meningitis (TBM). However, the child's lack of response to this treatment raised concerns about MDR-TB, particularly after discovering on close questioning that the uncle, who lived with the boy’s family, had actually been diagnosed with MDR-TB. The diagnosis was confirmed by molecular tests of cerebrospinal fluid (CSF) and customized treatment for MDR TBM administered. The boy then slowly improved and became less irritable, afebrile, seizure-free, developed spontaneous movements of all four limbs, and was discharged after one month. Delays in suspicion, confirmation, and treatment of MDR TBM led to complications of leptomeningitis with non-communicating hydrocephalus and bilateral optic atrophy, which was confirmed by magnetic resonance imaging (MRI) scan of the brain. This case highlights the importance of taking a very thorough and proper history and considering the possibility of MDR, especially in countries like Nepal where TB in general is rampant so that timely diagnosis and treatment is possible and complications are avoided.

Spatially heterogeneous lipid dysregulation in tuberculous meningitis

Tuberculous (TB) meningitis is the deadliest form of extrapulmonary TB which disproportionately affects children and immunocompromised individuals. Studies in pulmonary TB have shown that Mycobacterium tuberculosis can alter host lipid metabolism to evade the immune system. Cholesterol lowering drugs (i.e., statins) reduce the risk of infection, making them a promising host-directed therapy in pulmonary TB. However, the effect of M. tuberculosis infection on the young or adult brain lipidome has not been studied. The brain is the second-most lipid-rich organ, after adipose tissue, with a temporally and spatially heterogeneous lipidome that changes from infancy to adulthood. The young, developing brain in children may be uniquely vulnerable to alterations in lipid composition and homeostasis, as perturbations in cholesterol metabolism can cause developmental disorders leading to intellectual disabilities. To begin to understand the alterations to the brain lipidome in pediatric TB meningitis, we utilized our previously published young rabbit model of TB meningitis and applied mass spectrometry (MS) techniques to elucidate spatial differences. We used matrix assisted laser desorption/ionization-MS imaging (MALDI-MSI) and complemented it with region-specific liquid chromatography (LC)-MS/MS developed to identify and quantify sterols and oxysterols difficult to identify by MALDI MSI. MALDI-MSI revealed several sphingolipids, glycerolipids and glycerophospholipids that were downregulated in brain lesions. LC-MS/MS revealed the downregulation of cholesterol, several sterol intermediates along the cholesterol biosynthesis pathway and enzymatically produced oxysterols as a direct result of M. tuberculosis infection. However, oxysterols produced by oxidative stress were increased in brain lesions. Together, these results demonstrate significant spatially regulated brain lipidome dysregulation in pediatric TB meningitis.

Diagnostic value of nanopore sequencing of cerebrospinal fluid samples in tuberculous meningitis

ObjectiveTo investigate the diagnostic efficacy of nanopore sequencing technology in tuberculous meningitis (TBM). MethodsCerebrospinal fluid samples were collected from patients for acid-fast staining microscopy, Mycobacterium tuberculosis solid culture, DNA detection, and nanopore sequencing. Lastly, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) were calculated and compared among these detection methods. ResultsIn this study, 30 TBM patients and 18 non-TBM patients were included. Nanopore sequencing showed higher sensitivity (43.30%) and AUC (0.661) compared to the other methods. Combining nanopore sequencing and imaging achieved the highest diagnostic performance with sensitivity (60.00%), specificity (88.90%), PPV (90.00%), NPV (57.10%), and AUC (0.744). ConclusionNanopore sequencing demonstrated superior diagnostic accuracy for TBM, outperforming acid-fast staining, Mycobacterium tuberculosis culture, and DNA detection. When combined with imaging, nanopore sequencing significantly enhanced diagnostic sensitivity and accuracy for TBM.

Perplexing paradoxical reactions: navigating the complexity of protracted tuberculosis meningitis—a case report

Tuberculous meningitis (TBM) has considerable mortality and morbidity, and it often presents therapeutic challenges when complicated by paradoxical reactions (PRs). Here, the clinical course of four cases of TBM patients complicated by PRs in a longitudinal TB cohort is described while also providing insights from the larger clinical cohort. Research flow cytometry, biomarker analysis, and drug concentrations were performed on available samples. All participants were initiated on standard antituberculosis therapy (ATT) and enrolled at the onset of PRs (PR group) or 2–4 months after the start of ATT (controls). The four TBM participants highlighted here presented with fevers, headaches, neurological deficits, and fatigue at the initial presentation. Upon diagnosis, all were initiated on rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) at standard doses and on corticosteroids. The median time to first PR was 37 days with recrudescence of initial TBM signs and symptoms at the time of PR. At the time of referral, all participants had low drug concentrations requiring dose optimization and regimen intensification as well as recrudescent flares upon corticosteroid taper, with one individual developing enlargement of tuberculoma 1 year following completion of ATT. Based on biomarkers and flow cytometry, PRs are characterized by elevated interferon-gamma and ferritin levels in the plasma compared to controls. In the TBM participants, T-cell activation with elevated levels of inflammatory biomarkers in the cerebrospinal fluid (CSF) was seen at the time of PR. These unique and highly detailed TBM cases provide insights into the pathogenesis of PRs, which may assist with future diagnostics and treatment.

Tuberculous meningitis and cryptococcal meningitis co-infection in hospitalised patients in Durban, Kwa Zulu Natal (KZN), South Africa

Tuberculous meningitis and cryptococcal meningitis co-infection in hospitalised patients in Durban, Kwa Zulu Natal (KZN), South Africa

Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis.

Mortality and morbidity from tuberculous meningitis (TBM) are common, primarily due to inflammatory response to Mycobacterium tuberculosis infection, yet the underlying mechanisms remain poorly understood. We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals. We employed multivariate elastic-net Cox regression to select candidate predictors of death, then logistic regression and internal bootstrap validation to choose best predictors. Increased neutrophil activation and decreased T and B cell activation pathways were associated with TBM mortality. Among HIV-positive individuals, mortality associated with increased angiogenesis, while HIV-negative individuals exhibited elevated TNF signaling and impaired extracellular matrix organization. Four hub genes-MCEMP1, NELL2, ZNF354C, and CD4-were strong TBM mortality predictors. These findings indicate that TBM induces a systemic inflammatory response similar to PTB, highlighting critical genes and pathways related to death, offering insights for potential therapeutic targets alongside a novel four-gene biomarker for predicting outcomes.

Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

Mortality and morbidity from tuberculous meningitis (TBM) are common, primarily due to inflammatory response to Mycobacterium tuberculosis infection, yet the underlying mechanisms remain poorly understood. We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals. We employed multivariate elastic-net Cox regression to select candidate predictors of death, then logistic regression and internal bootstrap validation to choose best predictors. Increased neutrophil activation and decreased T and B cell activation pathways were associated with TBM mortality. Among HIV-positive individuals, mortality associated with increased angiogenesis, while HIV-negative individuals exhibited elevated TNF signaling and impaired extracellular matrix organization. Four hub genes—MCEMP1, NELL2, ZNF354C, and CD4—were strong TBM mortality predictors. These findings indicate that TBM induces a systemic inflammatory response similar to PTB, highlighting critical genes and pathways related to death, offering insights for potential therapeutic targets alongside a novel four-gene biomarker for predicting outcomes.

Tuberculous meningitis in an intravenous drug user: A case report

Tubercle bacilli can cause tuberculous meningitis by hematogenous spread from a primary focus. A 49-year-old foreign national male patient was admitted to the emergency department with complaints of joint pains, fever, cough and malaise. He was diagnosed with a viral upper respiratory tract infection and discharged after treatment was organised. The patient was admitted again the next day with the complaint of inability to urinate, and suprapubic tenderness was also present on physical examination. The patient's laboratory values, different from the previous day, were determined as WBC:16000/µL CRP:115 mg/L, and he was discharged again after oral treatment. On his 3rd admission to the emergency department, he had complaints of weakness and numbness in the legs and spasm in the neck. It was learned that the patient had a history of intravenous substance use. Following the tests, the patient was initially diagnosed with atypical meningitis and was taken to the intensive care unit. As a result of advanced examinations performed here, the patient was diagnosed with tuberculous meningitis and treated. Patients who experience repeated hospitalisations and exhibit abnormal neurological symptoms should have a thorough physical examination, deeper anamnesis, and considered in the diagnosis that takes uncommon illnesses like atypical meningitis into account.

Paediatric cerebral palsy in South Africa: Prevention and care gaps at hospital level.

Population-based data show high proportions of severe cases of cerebral palsy (CP) in resource-poor regions such as sub-Saharan Africa, where most children have potentially preventable risk factors (factors that may increase the likelihood of CP occurrence but can be mitigated through medical interventions). This study aimed to describe the demographic and clinical profile of children living with CP accessing services at Tygerberg Hospital over a period of 10 years (2010-2020), identify the potential gaps in care (proportion of individuals in a country requiring but not receiving suboptimal or inadequate care), and comparison with a similar study at the same centre two decades ago. This 10-year retrospective study investigated causes and morbidities in children with CP, attending a central hospital in the Western Cape, South Africa. A total of 613 children with CP were identified. Perinatal causes were predominant, especially in 57.7% (n = 354) of the cohort: perinatal asphyxia (41.1%) and preterm birth (16.6%). Postnatal causes constituted 15.2% (n = 93), which included tuberculous meningitis (3.6%) and bacterial meningitis (3.6%). The most common complications were intellectual impairment (61.8%; n = 379); epilepsy (30.8%; n = 189) and visual impairment (54.7%; n = 234). A third of the cohort had severe CP, classified as Gross Motor Function Classification System IV and V (38%). Most of the previously documented main drivers of CP are still present and the implementation of healthcare prevention strategies remains inadequate. This study provides longitudinal evidence to confirm that CP in a South African setting is associated with a high burden of potentially preventable causes.

Etiology of Acute Encephalitis Syndrome in Adults in a Tertiary Care Center in Eastern Uttar Pradesh

Seasonal outbreaks of acute encephalitis syndrome (AES) with high case fatality rates have been commonly reported among adults in India. With an increase in Japanese encephalitis virus (JEV) vaccination, the etiology of AES is also changing. However, most studies on AES in India have focused only on children and on JEV. This study was conducted in the Department of Medicine, Institute of Medical Sciences, Banaras Hindu University between 2020 and 2022 to determine the etiology of AES in adults. Blood and cerebrospinal fluid (CSF) were collected from patients 18 years or older with fever and altered sensorium for ≤15 days. We did IgM ELISA for dengue, chikungunya, West Nile virus, scrub typhus, leptospirosis from serum, CSF-IgM for JEV, and CSF–polymerase chain reaction for herpes simplex virus 1 and 2, varicella-zoster virus, enterovirus, and cartridge-based nucleic acid amplification test (CBNAAT) for tuberculous meningitis (TBM). The most common cause of AES identified in our study was TBM (16.7%), followed by leptospirosis (15.1%) and scrub typhus (11.9%). The high occurrence of TBM in our study highlights the importance of CSF-CBNAAT for all AES patients. As leptospirosis and scrub typhus are easily treatable, early detection and treatment of these infections should be recommended.

Tuberculosis in infertility and in vitro fertilization-embryo transfer.

Tuberculosis (TB) is a prominent infectious disease globally that imposes a substantial health burden. Genital TB (GTB), an extrapulmonary manifestation, leads to complications such as tubal adhesions, blockage, and diminished ovarian function, culminating in infertility, and is recognized as a prevalent cause of infertility in nations with high-burden TB. In regions with low TB rates, infertility and active TB during pregnancy have been reported to be most common among female immigrants from countries with high-burden TB. In the context of TB, pregnant women often exhibit exacerbated symptoms after in vitro fertilization-embryo transfer (IVF-ET), heightening the risk of dissemination. Miliary pulmonary TB and tuberculous meningitis pose a serious threat to maternal and fetal health. This article integrates recent epidemiological data and clinical research findings, delineating the impact of TB on infertility and assisted reproduction and particularly focusing on the diagnosis and treatment of GTB, underscored by the imperative of TB screening before IVF-ET. Our objective is to increase awareness among respiratory and reproductive health professionals, promoting multidisciplinary management to enhance clinical vigilance. This approach seeks to provide patients with judicious reproductive plans and scientifically rigorous pregnancy management, thereby mitigating adverse pregnancy outcomes related to TB activity.

Comparative study of pathogen detection methods for central nervous system infections: laboratory testing of tuberculous meningitis

BackgroundTuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with a challenging diagnosis due to inadequate detection methods. This study evaluated current clinical detection methods and their applicability.MethodsA cohort of 514 CNS infection patients from 2018 to 2020 was studied. Data on general demographics, Cerebrospinal Fluid (CSF) analysis, epidemiology, and clinical outcomes were collected. TBM patients were identified, and the sensitivities of mmetagenomic next-generation sequencing (NGS), GeneXpert, and microbial culture were compared. Kappa statistic assessed the consistency between methods.ResultsAmong the patients involved, TBM (29%) and neurosyphilis (25%) were the two most prevalent CNS infections. CSF analysis indicated that 76% of patients had leukocytosis, suggesting a potential CNS inflammation. In TBM cases, 92.5% had elevated CSF protein and leukocyte counts. Moreover, the percentage of positive mNGS results was 55.6%. GeneXpert and MTB cultures alone had lower sensitivity, but combined use resulted in a 53.4% positive rate.ConclusionsThis study highlights the high sensitivity of mNGS, comparable to GeneXpert and MTB culture. The combined methods are cost-effective and straightforward, and can partially substitute for mNGS, offering valuable alternatives for TBM diagnosis and providing insights into multiple diagnostic strategies in clinical practice.

Case Report: An Atypical Sellar Mass - Sellar Tuberculoma in a Young Patient

Background: Tuberculosis of the central nervous system is an uncommon but one of the most severe forms. It manifests as tuberculoma and tuberculous meningitis, with the majority of cases affecting children and immunocompromised patients. Overall, tuberculomas make up to 0.15–2 % of all intracranial lesions but sellar tuberculoma is extremely rare. The Case: An 18-year-old female patient presented with complaint of generalized weakness, eye pain and headache for 3-4 months. Magnetic resonance imaging (MRI) of brain showed sellar and suprasellar space occupying lesion. Trans sphenoidal approach was used to remove the lesion completely. A sellar tuberculoma was confirmed on pathological evaluation and the patient was put on postoperative anti-tubercular therapy. Conclusion: Although rare, intracranial tuberculomas, particularly those that originate in the sellar, are notorious for mimicking pituitary tumors by jeopardizing pituitary hormonal function and applying compressive forces on surrounding intracranial structures. However, a prompt assessment can help overcome this diagnostic difficulty with the timely initiation of anti-tubercular therapy (ATT).

Intracranial manifestations of central nervous system tuberculosis in children.

Tuberculosis remains a significant global health challenge, with central nervous system tuberculosis (CNS-TB) posing a substantial threat, accounting for 1-10% of all tuberculosis cases. This article explores the diverse manifestations of CNS-TB in children, with a particular focus on tuberculous meningitis and tuberculomas, as well as their associated complications. Diagnostic imaging, including CT and MRI, plays a crucial role in the early detection of CNS-TB. The article emphasizes the pivotal role of imaging in the diagnosis and management of these manifestations, underscoring the importance of early recognition by healthcare professionals. Ultimately, raising awareness among pediatric radiologists, pediatricians, and pediatric neurologists is crucial for prompt intervention and improved outcomes in cases of CNS-TB.

The challenge of etiologic diagnosis of subacute and chronic meningitis: an analysis of 183 patients.

Subacute and chronic meningitis (SCM) presents significant diagnostic challenges, with numerous infectious and non-infectious inflammatory causes. This study examined patients aged 16 and older with SCM admitted to referral centers for neuroinfections and neuroinflammations in Mashhad, Iran, between March 2015 and October 2022. Among 183 episodes, tuberculous meningitis was the most common infectious cause (46.5%), followed by Brucella meningitis (24.6%). The cause of SCM was definitively proven in 40.4%, presumptive in 35.0%, and unknown in 24.6% of cases. In-hospital mortality was 14.4%, and 30.5% of survivors experienced unfavorable outcomes (Glasgow Outcome Scale 2-4). Patients with unknown causes had a significantly higher risk of death compared to those with presumptive or proven diagnoses (risk ratio 4.18). This study emphasizes the diagnostic difficulties of SCM, with one-quarter of cases remaining undiagnosed and over one-third having only a presumptive diagnosis. Improving diagnostic methods could potentially enhance prognosis and reduce mortality.

Early screening of miliary tuberculosis with tuberculous meningitis based on few-shot learning with multiple windows and feature granularities

Tuberculous meningitis (TBM) is a fatal tuberculosis caused by a large number of Mycobacterium tuberculosis (M. tuberculosis) spread by blood flow, with a case fatality rate of more than 50%. It is one of the most serious complications of miliary tuberculosis (MT), whose incidence is closely related to MT. If doctors can provide early diagnosis and active treatment for TBM, the case fatality rate will be significantly reduced. At present, there is a lack of methods to predict the progression of MT to TBM in clinic. To explore whether MT cases will experience TBM, we propose an early screening model of miliary tuberculosis with tuberculous meningitis (MT-TBM) based on few-shot learning with multiple windows and feature granularities (MWFG). This model aims to screen potential TBM cases through chest computerized tomography (CT) images of MT cases. Chest CT is a routine examination for MT cases. The MWFG module can extract more comprehensive features from a set of CT images of each MT case. The softmax classifier with adaptive regularization is trained on the cooperation of support set and query set, which can effectively prevent overfitting. Experiments on a dataset of 40 MT cases with chest CT images established by the medical records demonstrate that our proposed model achieves state-of-the-art performance in the early screening of MT-TBM. It can establish the connection between MT and MT-TBM through chest CT images of MT cases. The early screening model of MT-TBM based on few-shot learning with MWFG fills the research gap in computer-aided predicting TBM and has certain clinical effects. This research can provide some reference for clinicians in early diagnosis of MT-TBM and help clinicians in the early prevention and treatment of TBM for MT patients.

Nanopore-targeted sequencing (NTS) for intracranial tuberculosis: a promising and reliable approach

BackgroundThe World Health Organization predicted 10.6 million new tuberculosis cases and 1.5 million deaths in 2022. Tuberculous meningitis, affecting 1% of active TB cases, is challenging to diagnose due to sudden onset, vague symptoms, and limited laboratory tests. Nanopore-targeted sequencing (NTS) is an emerging third-generation sequencing technology known for its sequencing capabilities. We compared its detection efficiency with Xpert, MTB culture, PCR, and AFB smear in cerebrospinal fluid samples to highlight the substantial potential of NTS in detecting intracranial tuberculosis.MethodsThis study included 122 patients suspected of having intracranial tuberculosis at the Second Hospital of Nanjing in Jiangsu Province, China, between January 2021 and January 2024. The Univariate logistic regression and random forest regression identified risk factors and clinical markers. A chi-square test evaluated diagnostic accuracy for different image types of intracranial tuberculosis.ResultsThe research involved 100 patients with intracranial tuberculosis. Among them, 41 had tuberculous meningitis, 27 had cerebral parenchymal tuberculosis, and 32 had mixed intracranial tuberculosis. Besides, 22 patients were diagnosed with other brain conditions. In diagnosing intracranial tuberculosis, NTS demonstrated a sensitivity of 60.0% (95% CI: 49.7-69.5%) and a specificity of 95.5% (95% CI:75.1-99.8%), with an AUC value of 0.78 (95% CI: 0.71 to 0.84), whose overall performance was significantly better than other detection methods. There was no notable difference (P > 0.05) in diagnostic accuracy between NTS and the final diagnosis for intracranial tuberculosis patients with varying imaging types. Furthermore, patients who tested positive had a 31.500 (95% CI: 6.205-575.913) times higher risk of having intracranial tuberculosis compared to those with negative results.ConclusionDue to its convenience, efficiency, quick turnaround time, and real-time sequencing analysis, NTS might become a promising and reliable method for providing microbiological diagnoses for patients with intracranial tuberculosis and for screening populations at risk.