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Biomarkers in Medicine Apr 2020Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still... (Review)
Review
Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still associated with significant morbidity and mortality. Delay in diagnosis contributes to poor outcomes. Cerebrospinal fluid cultures have been used traditionally but are time intensive and sensitivity is decreased by empiric treatment prior to culture. More rapid techniques such as the cryptococcal lateral flow assay (IMMY), GeneXpert MTB/Rif Ultra (Cepheid) and FilmArray multiplex-PCR (Biofire) are three examples that have drastically changed meningitis diagnostics. This review will discuss a holistic approach to diagnosing bacterial, mycobacterial, viral and fungal meningitis.
Topics: Adult; Diagnostic Techniques and Procedures; Humans; Meningitis; Time Factors
PubMed: 32270693
DOI: 10.2217/bmm-2019-0333 -
Revue Neurologique 2019Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. In 2017, approximately 10 million people developed TB worldwide, of whom more than... (Review)
Review
Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. In 2017, approximately 10 million people developed TB worldwide, of whom more than 100,000 new cases of TBM are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. GeneXpert represents the most significant advance in TBM diagnostics over the past decade, but it lacks sensitivity and cannot be used to rule out the diagnosis. Higher volume of cerebrospinal fluid (CSF) seems to be interesting to improve the diagnosis performances. New rapid and accurate diagnostic tools are necessary. Better advances have been made concerning the anti-tuberculosis chemotherapy of TBM, with the publication of clinical trials and pharmacokinetic studies exploring the use of higher rifampicin doses and fluoroquinolones. The rise of drug-resistant TBM is another challenge for management because TBM caused by multidrug resistant organisms results in death or severe disability in almost all sufferers.
Topics: Humans; Tuberculosis, Meningeal
PubMed: 31383464
DOI: 10.1016/j.neurol.2019.07.007 -
Science (New York, N.Y.) Jul 2021The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic...
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.
Topics: Aging; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow Cells; Cell Movement; Central Nervous System; Dura Mater; Fibroblasts; Homeostasis; Immune Privilege; Lymphopoiesis; Meninges; Mice; Plasma Cells; Single-Cell Analysis; Skull
PubMed: 34083450
DOI: 10.1126/science.abf9277 -
Archives of Disease in Childhood.... Feb 2020Meningitis is a critical diagnosis not to miss in children presenting with fever. Since the early 20th century, classical clinical signs have been used to aid the... (Review)
Review
Meningitis is a critical diagnosis not to miss in children presenting with fever. Since the early 20th century, classical clinical signs have been used to aid the diagnosis of meningitis. These classical signs are nuchal rigidity, Kernig's sign and Brudzinski's sign. Each of these relies on the principle that stretching the inflamed meningeal membranes causes clinically detectable irritation. Several primary studies have quantified the diagnostic performance of clinical examination in detecting meningitis in children. The results of these studies vary significantly due to methodological differences, clinical heterogeneity and interobserver variability. However, their findings demonstrate that positive meningitic signs increase the likelihood of a diagnosis of meningitis, and the absence of meningitic signs reduces this probability. These signs have greatest utility when combined with other features in the history and examination to contribute to a comprehensive clinical assessment.
Topics: Child; Diagnosis, Differential; Humans; Medical History Taking; Meningitis; Physical Examination
PubMed: 30692129
DOI: 10.1136/archdischild-2018-315428 -
Nature Nov 2020The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain...
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
Topics: Aged; Aging; Animals; Blood-Brain Barrier; Cranial Sinuses; Female; Fungi; Gastrointestinal Microbiome; Germ-Free Life; Humans; Immunoglobulin A, Secretory; Intestines; Male; Meninges; Mice; Mice, Inbred C57BL; Plasma Cells
PubMed: 33149302
DOI: 10.1038/s41586-020-2886-4 -
Arquivos de Neuro-psiquiatria Dec 2020Hypertrophic pachymeningitis (HP) is a non-usual manifestation of rheumatologic, infectious, and neoplastic diseases. Etiological diagnosis is a challenge, but when made...
IMPORTANCE
Hypertrophic pachymeningitis (HP) is a non-usual manifestation of rheumatologic, infectious, and neoplastic diseases. Etiological diagnosis is a challenge, but when made promptly it creates a window of opportunity for treatment, with the possibility of a total reversal of symptoms.
OBSERVATIONS
HP is an inflammatory process of the dura mater that can occur as a manifestation of sarcoidosis, granulomatosis with polyangiitis, and IgG4-related disease. The HP case evaluation is extensive and includes central nervous system imaging, cerebrospinal fluid analysis, serology, rheumatologic tests, and systemic survey for other manifestations sites. After systemic investigation, meningeal biopsy might be necessary. Etiology guides HP treatment, and autoimmune disorders are treated with corticosteroids alone or associated with an immunosuppressor.
CONCLUSION
HP is a manifestation of several diseases, and a precise etiological diagnosis is crucial because of the difference among treatments. An extensive investigation of patients with HP helps early diagnosis and correct treatment.
Topics: Adrenal Cortex Hormones; Dura Mater; Humans; Hypertrophy; Magnetic Resonance Imaging; Meningitis
PubMed: 33295420
DOI: 10.1590/0004-282X20200073 -
Cellular & Molecular Immunology Nov 2023Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages... (Review)
Review
Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.
Topics: Humans; Macrophages; Microglia; Brain; Meninges; Autoimmune Diseases
PubMed: 37365324
DOI: 10.1038/s41423-023-01053-6 -
Neuron Dec 2023Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal...
Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
Topics: Mice; Animals; Meninges; Arachnoid; Pia Mater; Choroid Plexus; Brain
PubMed: 37776854
DOI: 10.1016/j.neuron.2023.09.002 -
Molecular Neurodegeneration Aug 2023Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in... (Review)
Review
Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients. Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD. Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the CNS, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating CNS fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.
Topics: Animals; Humans; Alzheimer Disease; Amyloid beta-Peptides; Genome-Wide Association Study; Meninges; Lymphatic System; Brain; Mammals
PubMed: 37580702
DOI: 10.1186/s13024-023-00645-0 -
Nature Immunology Nov 2020Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies...
Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
Topics: Animals; Anxiety; Behavior, Animal; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Dura Mater; Gene Expression Profiling; Gene Expression Regulation; Interleukin-17; Meninges; Mice; Mice, Knockout; Neurons; Receptors, Antigen, T-Cell, gamma-delta; Signal Transduction; T-Lymphocyte Subsets; Transcriptome
PubMed: 32929273
DOI: 10.1038/s41590-020-0776-4