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Veterinary Journal (London, England :... 2023Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle,... (Review)
Review
Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle, SRMA is divided into two clinical courses: during the typical acute form, dogs are presented with fever, cervical hyperaesthesia, and reluctance to move. The more protracted form most probably emerges after insufficient immunosuppressive treatment or relapses, with additional neurologic deficits localized in the cervical and thoracolumbar spinal cord or multifocally. The trigger leading to SRMA still remains an unsolved riddle for immunologists and clinical neurologists. In the past, many attempts have been made to clarify the etiology of this disease without success. The purpose of writing this narrative review about SRMA is to summarize new insights on the pathogenesis of SRMA with a focus on immunologic dysregulation. Furthermore, unusual manifestations of the disease, new diagnostic approaches using possible laboratory biomarkers or diagnostic imaging tools, and potential innovative treatment strategies are discussed.
Topics: Animals; Dogs; Meningitis; Arteritis; Biomarkers; Steroids; Dog Diseases
PubMed: 37704169
DOI: 10.1016/j.tvjl.2023.106030 -
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 -
The New England Journal of Medicine Oct 2023Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy.
METHODS
We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization.
RESULTS
A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52).
CONCLUSIONS
Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).
Topics: Adult; Humans; Dexamethasone; Double-Blind Method; Glucocorticoids; HIV; HIV Infections; HIV Seropositivity; Tuberculosis, Meningeal; Antitubercular Agents; Drug Therapy, Combination; Anti-Retroviral Agents
PubMed: 37819954
DOI: 10.1056/NEJMoa2216218 -
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 -
Clinical Infectious Diseases : An... Dec 2023Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed.
METHODS
In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA).
RESULTS
We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04).
CONCLUSIONS
This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin.
CLINICAL TRIALS REGISTRATION
NCT04031833.
Topics: Humans; Meningitis, Cryptococcal; Amphotericin B; Flucytosine; Drug Therapy, Combination; Antifungal Agents; Fluconazole; Vaccines; Lipids
PubMed: 37606364
DOI: 10.1093/cid/ciad440 -
Microbiology Spectrum Jun 2023Central nervous system (CNS) infections such as meningitis and encephalitis are life-threatening conditions that demand hospital care and prompt identification of the...
Central nervous system (CNS) infections such as meningitis and encephalitis are life-threatening conditions that demand hospital care and prompt identification of the causative agent. Since 2015, there has been only one CE-IVD-marked rapid multiplexed diagnostic assay in cassette format for bacterial and viral detection from cerebrospinal fluid (CSF): the BioFire FilmArray meningitis/encephalitis (ME) panel. In the beginning of 2022, Qiagen introduced the QIAstat-Dx meningitis/encephalitis panel. It is a CE-IVD-marked multiplex PCR cassette test intended for the identification of suspected infectious meningitis, encephalitis, or meningoencephalitis caused by bacterial, viral, or fungal pathogens. In this study, we evaluated patient and quality control samples using the QIAstat-Dx meningitis/encephalitis panel and compared the results to those of the BioFire FilmArray meningitis/encephalitis panel and reference methods (current routine analysis methods in our laboratory, PCR, or cultivation). The combined positive percent agreement between the two panel assays was 100%, and the negative percent agreement was 94%. We further compared specifically herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) dilution series using six commercial herpesvirus assays, including the two cassette tests. The results suggested that real-time PCR methods (with separate extraction) were the most sensitive methods. When comparing the cassette tests, the BioFire FilmArray meningitis/encephalitis panel produced more positive results than the QIAstat-Dx meningitis/encephalitis panel in the herpesvirus analyses. The diagnosis of infectious meningitis and encephalitis relies mostly on specific PCR and culturing methods, but commercial syndromic panel assays are bringing a change in diagnostics. With multiplexed analysis, the identification of the pathogen is potentially faster, and less sample material is needed. The novel QIAstat-Dx meningitis/encephalitis panel assay is intended for the rapid identification of pathogens from cerebrospinal fluid for suspected central nervous system (CNS) infection, which is a life-threatening condition and difficult to diagnose. We studied the performance of this panel assay using patient samples and dilution series of selected viruses. The evaluation data for this novel meningitis/encephalitis panel assay are useful for other clinical laboratories and organizations using or considering using this test.
Topics: Humans; Multiplex Polymerase Chain Reaction; Meningitis; Encephalitis; Viruses; Bacteria
PubMed: 37042772
DOI: 10.1128/spectrum.05144-22 -
The Lancet. Neurology Aug 2023Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by...
BACKGROUND
Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories.
METHODS
We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category.
FINDINGS
In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000-277 000) and 2·51 million (2·11-2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400-145 000) and 1·28 million incident cases (0·947-1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6-8·4) per 100 000 population in 1990 to 3·3 (2·8-3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1-19·2]), followed by N meningitidis (13·6% [12·7-14·4]) and K pneumoniae (12·2% [10·2-14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5-81·8]), followed by N meningitidis (72·3% [64·4-78·5]) and viruses (58·2% [47·1-67·3]).
INTERPRETATION
Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Child; Humans; Global Burden of Disease; Bayes Theorem; Meningitis; Risk Factors; Global Health
PubMed: 37479374
DOI: 10.1016/S1474-4422(23)00195-3