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Receiver operator characteristic (ROC) curves showing the accuracies of baseline CSF lipocalin-2/NGAL (A), sVCAM-1 (B), sRAGE (C), MMP-1 (D), CXCL10/IP-10 (E), and PDGF-AA (F) in indicating stroke among children diagnosed with TBM. ROC curves for analytes with AUC≥0.70 are shown.
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Introduction
Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins...
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Citations
... However, children with symptomatic malaria had increased GDF15 levels [64]. Tuberculous meningitis was also shown to correlate with increased GDF15 levels, which were further elevated in those with radiographic evidence of a stroke [65]. Paediatric patients with COVID also showed elevated GDF15 levels, further elevated with severe disease or cardiac symptoms [66]. ...
Background
Growth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF‐β superfamily, has a well‐established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.
Methods
This review follows the PRISMA‐ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.
Results
Sixty‐two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089 pg/mL (interquartile range 3805–13 306) and mitochondrial diseases 4640 pg/mL (1896–14 064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8 ± 221.0 pg/mL, with a range of 90–1134 pg/mL for study averages.
Conclusions
Circulating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.
... This highlights the complexity in the differential diagnosis of post-stroke cognitive decline, where changes in CSF biomarkers may be attributed to both the ischemic event and neurodegeneration (Danielski et al., 2018;Della Giustina et al., 2017;Kaerst et al., 2013). Investigating biomarkers in the CSF and serum of children with tuberculous meningitis (TBM) to detect stroke, proteins such as soluble vascular cell adhesion molecule (sVCAM-1), soluble receptor for advanced glycation end-products (sRAGE), MMP-1, and IP-10 CXCL10 (C-X-C motif chemokine ligand 10) in the CSF showed significant differences between groups with and without stroke, highlighting their potential for early stroke prediction (Manyelo et al., 2021). Similarly, in patients with acute ischemic stroke, neurotransmitter analyses in the CSF revealed varied associations, with 5-hydroxyindoleacetic acid being significantly correlated with progressive stroke and adverse long-term outcomes. ...
Ischemic stroke (IS) results in the interruption of blood flow to the brain, which can cause significant damage. The pathophysiological mechanisms of IS include ionic imbalances, oxidative stress, neuroinflammation, and impairment of brain barriers. Brain barriers, such as the blood–brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (B-CSF), protect the brain from harmful substances by regulating the neurochemical environment. Although the BBB is widely recognized for its crucial role in protecting the brain and its involvement in conditions such as stroke, the B-CSF requires further study. The B-CSF plays a fundamental role in regulating the CSF environment and maintaining the homeostasis of the central nervous system (CNS). However, the impact of B-CSF impairment during pathological events such as IS is not yet fully understood. In conditions like IS and other neurological disorders, the B-CSF can become compromised, allowing the entry of inflammatory substances and increasing neuronal damage. Understanding and preserving the integrity of the B-CSF are crucial for mitigating damage and facilitating recovery after ischemic stroke, highlighting its fundamental role in regulating the CNS during adverse neurological conditions.
... Furthermore, in uncomplicated and adequately treated patients with no disturbances in cerebral blood flow, CSF protein levels decrease in tandem with the leukocyte count. Ultimately, the CSF/serum albumin ratio during the course of the disease, which may function as a biomarker of microbial virulence and the intensity of the inflammatory process, could advance our comprehension of fluctuations in cerebral blood flow [65]. Thus, the higher CSF protein concentration in patients with cerebral infarction, wherein low cerebral flow rates dominate, may be indicative of more severe meningeal inflammation with greater blood brain barrier disruption, cerebral edema and intracranial pressure elevations. ...
... Further supportive evidence of the role of CSF ferritin in modulating cerebrovascular lesions during bacterial meningitis is evident from the observation that CSF ferritin levels are markedly increased in purulent meningitis, when compared to tuberculous meningitis. In fact, CSF ferritin levels are considerably lower in patients with tuberculous meningitis related stroke compared to patients with tuberculous meningitis without stroke [65]. Therefore, increased CSF ferritin concentrations reflect widespread blood brain barrier damage and dramatic inflammatory reactions, with rapid elaboration of proinflammatory cytokines, which upregulate local ferritin synthesis and leakage and the higher ferritin concentrations in purulent meningitis may reduce free iron levels in the CSF, thereby preventing against oxidative reductions and cerebrovascular lesions, accounting for a lower incidence of cerebral infarction, when compared with tubercular meningitis, wherein lower ferritin concentrations reflect less dramatic and subtle meningeal inflammation. ...
Bacterial meningitis poses a significant medical challenge, marked by high fatality rates and enduring neurological consequences. The complexities of the disease, including ischemic neuronal injury and diverse complications, are intricately linked to vascular abnormalities and neuropathological changes. Interactions among microbial virulence, immune responses, and cerebrospinal fluid (CSF) composition contribute to its severity. CSF, vital for CNS protection, becomes compromised in meningitis, allowing pathogens and inflammatory molecules to disrupt its balance. This review delves into the complex alterations in cerebrospinal fluid (CSF) chemistry that occur during bacterial meningitis, particularly examining variations in protein concentrations, inflammatory markers, and metabolic shifts. Understanding these mechanisms can identify therapeutic targets to mitigate neuronal damage and improve outcomes. Strategies targeting inflammatory cascades, metabolic imbalances, and blood-brain barrier integrity show promise for reducing the infection's burden and enhancing patient recovery.
... This is crucial for the clinical recognition of TBM and cryptococcal infection [6]. Again, early cerebrospinal fluid changes are highly suggestive of TBM, such as (i) elevated cell counts (100-500/μL), mainly lymphocytes and possibly neutrophils in the early stages of the disease; (ii) elevated protein levels (up to 1000-5000 mg/L); and (iii) decreased glucose levels (<2.5 mol/L) or cerebrospinal fluid/plasma ratios < 0:5 [7][8][9]. In the present study, the early cerebrospinal fluid leukocyte count, protein level, and glucose level of all enrolled patients were similar to the cerebrospinal fluid changes in TBM. ...
Purpose:
The diagnosis of tuberculous meningitis (TBM) is difficult and relies on the patient's clinical presentation and initial cerebrospinal fluid testing. Treatment outcomes for some patients with early consideration of TBM meningitis are often poor. Patients and Methods. In this study, we retrospectively analyzed 24 non-TBM patients whose early changes of cerebrospinal fluid were similar to those of TBM through the second-generation cerebrospinal fluid sequencing technology.
Results:
All patients included in this study had an acute onset, including 5 patients with a history of upper respiratory tract infection, 9 patients with fever, 6 patients with headache, 5 patients with psychiatric symptoms, 6 patients with cognitive impairment, 9 patients with signs of meningeal irritation, and 6 patients with seizures. Sixteen patients presented with altered content and level of consciousness during their admission. The leukocyte counts (median, 124.0 × 106/L) and total protein concentrations (median, 1300 mg/L) were higher than normal reference values in all patients, whereas glucose (median, 1.345 mmol/L) and chloride concentration values (average, 111.7 ± 5.2 mmol/L) were lower than normal reference values. The patients included 2 cases of Liszt's meningitis, 2 cases of Brucella infection in the CNS, 4 cases of Varicella zoster virus encephalitis, 2 cases of human herpes simplex virus type 1, 2 cases of lupus encephalopathy, 2 cases of anti-NMDAR receptor encephalitis, 2 cases of meningeal carcinomatosis, 5 cases of cryptococcal meningitis, 2 cases of CNS sarcoidosis, and a case of invasive Rhizopus oryzae infection. All patients were tested for NGS in cerebrospinal fluid. Eight patients were diagnosed with anti-NMDAR encephalitis, meningeal carcinomatosis, lupus encephalopathy, and CNS sarcoidosis. Nine patients experienced death; 15 patients had a good prognosis and left no significant sequelae.
Conclusion:
The analysis of patients with TBM-like cerebrospinal fluid changes will help improve the diagnostic accuracy of the disease and reduce misdiagnosis and underdiagnosis.
... High serum and CSF IL-4 and IL-1β levels are correlated with the presence of an MRI brain infarction [34]. In addition, increased lumbar and ventricular CSF TNF-α, macrophage in ammatory protein 1α, IL-6, IL-8, and markers of brain injury were also found to be associated with infarction in patients with TBM [35,36]. ...
Purpose: This study aimed to find predictors of stroke in patients with tuberculous meningitis.
Methods: This systematic review and meta-analysis were done using literature searches through online databases up to April 30th, 2022. Three independent authors performed literature screening, data extraction, and critical appraisal of the studies. Eight studies involving 1535 samples were included.
Results: We analyzed data regarding demographic, comorbidity, clinical presentation, radiologic, and laboratory parameters. Overall, clinical presentation that showed outcome difference was found in patients with findings of vomiting (OR = 2.71, 95% CI: 1.30-5.63), cranial nerve deficit (OR = 4.10, 95% CI: 1.83-9.21), focal deficit (OR = 5.56, 95% CI: 2.24-13.79), and altered consciousness (OR = 1.90, 95% CI: 1.24-2.92). Some comorbidities showed significant differences such as diabetes mellitus (OR = 2.58, 95% CI: 1.51-4.41), hypertension (OR = 5.73, 95% CI: 3.36-9.77), ischemic heart disease (OR = 2.18, 95% CI: 1.02-4.63), and smoking (OR = 2.65, 95% CI: 1.22-5.77). Two radiological changes shown to have significantly higher proportions are hydrocephalus (OR = 2.50, 95% CI: 1.74-3.58) and meningeal enhancements (OR = 3.99, 95% CI: 1.73-9.20).
Conclusion: Our analysis indicated that clinical presentations of vomiting, cranial nerve deficit, focal deficit, altered consciousness; comorbidity of diabetes mellitus, hypertension, smoking history, ischemic heart disease; and radiological findings of meningeal enhancement and hydrocephalus showed significant association with stroke incidence in tuberculous meningitis.
... The critical elements of managing pediatric meningitis involve prompt induction of therapy, use of the appropriate antimicrobial with correct dosing and duration, attention to anticipated complications, and appropriate follow-up [12]. Choice of antibiotic treatment entails the selection of agents that are effective against the probable pathogens and are able to attain adequate bactericidal activity in CSF. ...
Bacterial meningitis in children and infants is correlated with substantial morbidity and mortality. Bacterial meningitis is one of the most frequent central nervous system infections, which is prevalent in low-income countries. There are three types of neonatal meningitis such as early-onset meningitis (from 0-6 days); late-onset meningitis (from 7-29 days) and extremely late-onset meningitis (from 30-90 days). The intense inflammation within the subarachnoid space noted in lumbar cerebrospinal fluid, and the resulting neurological damage, are not the direct result of the pathogenic bacteria but rather of activation of the host's inflammatory pathways by the microorganisms or their products. All children who are suspected of having meningitis should have their cerebrospinal fluid examined unless lumbar puncture is contraindicated. The critical elements of managing pediatric meningitis involve prompt initiation of therapy, use of the appropriate antimicrobial with correct dosing and duration, attention to expected complications, and appropriate follow-up. In neonates, the primary empiric regimen used conventionally has been ampicillin and gentamycin. For infants whose cerebrospinal fluid is suspicious for bacterial meningitis, ampicillin (300 mg/kg per day divided every 6 hrs) and cefotaxime (200 to 300 mg/kg per day divided every 6 hrs) is appropriate.
... The upregulated inflammatory cytokines TNF-a, MIP-1a, IL-6, IL-8, IL-4 and IL-1b concentrations in CSF samples were correlated with the presence of infarcts in TBM patients (204,205). In another study, the concentrations of lipocalin-2, soluble receptor for advanced glycation end products (sRAGE) and CXCL10 were significantly higher in the CSF of children with TBM-related stroke compared to TBM without stroke (206). Moreover, Schoeman et al. reported a prothrombotic profile of TBM children, with increased procoagulant factor (Factor VIII) expression and decreased in both anticoagulant Protein S expression and fibrinolytic activity (207). ...
Tuberculosis (TB) remains one of the leading infectious killers in the world, infecting approximately a quarter of the world’s population with the causative organism Mycobacterium tuberculosis (M. tb). Central nervous system tuberculosis (CNS-TB) is the most severe form of TB, with high mortality and residual neurological sequelae even with effective TB treatment. In CNS-TB, recruited neutrophils infiltrate into the brain to carry out its antimicrobial functions of degranulation, phagocytosis and NETosis. However, neutrophils also mediate inflammation, tissue destruction and immunopathology in the CNS. Neutrophils release key mediators including matrix metalloproteinase (MMPs) which degrade brain extracellular matrix (ECM), tumor necrosis factor (TNF)-α which may drive inflammation, reactive oxygen species (ROS) that drive cellular necrosis and neutrophil extracellular traps (NETs), interacting with platelets to form thrombi that may lead to ischemic stroke. Host-directed therapies (HDTs) targeting these key mediators are potentially exciting, but currently remain of unproven effectiveness. This article reviews the key role of neutrophils and neutrophil-derived mediators in driving CNS-TB immunopathology.
... Whether the mycobacteria are contained or cause clinical disease, and the extent of clinical disease, is determined by an interplay of host immune response and M. tuberculosis virulence factors, however our understanding of these processes remains incomplete. Studies in paediatric [12][13][14] and adult TBM [13] demonstrate associations between immune mediators and clinical outcome, and suggest that a disequilibrium of pro-and anti-inflammatory cytokines underlies the severity and course of TBM. This balance can be regulated by Leukotriene A4 Hydroxylase (LTA4H); a gene that encodes an enzyme which influences the balance of pro-and anti-inflammatory eicosanoids seen in intracerebral inflammation. ...
... This balance can be regulated by Leukotriene A4 Hydroxylase (LTA4H); a gene that encodes an enzyme which influences the balance of pro-and anti-inflammatory eicosanoids seen in intracerebral inflammation. Variations of the LTA4H genotype may contribute to heterogeneity of the inflammatory response and outcomes in TBM [15] Studies are ongoing to further examine the role of the LTA4H genotype on the immunoinflammatory response and the possibility of personalising adjunctive anti-inflammatory therapy based on host genotype [13] Clues to further understanding the biology of cerebral injury in TBM have come from biomarker signatures in TBM-infected children presenting with stroke [1,14] and transcriptional profiles demonstrating compartmentalisation of the immune response within the CNS (ventricular vs. lumbar CSF) [16]. ...
Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.
Aim: Tuberculous meningitis (TBM) often causes cerebral infarction, but its predictive factors are not well understood. Methods: Patients aged ≥13 years admitted with TBM were enrolled prospectively. Cerebral infarction was diagnosed using magnetic resonance imaging. Results: Of 186 patients, 80 (43%) had infarction. Most infarctions were multiple and located in the cortical areas, basal ganglia and subcortical regions. Independent predictors of infarction at admission included high blood pressure, short illness duration, low Glasgow coma scale and hydrocephalus. Neuroimaging inflammation signs, cerebrospinal fluid analysis abnormalities and pre-existing cardiovascular risks did not predict infarction. In-hospital mortality was higher in TBM with infarction, particularly in those with advanced TBM (stage 3). Conclusion: Baseline parameters of raised intracranial pressure predict cerebral infarction in TBM.
