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Oncotarget Dec 2015Tuberculosis (TB) is a common disease to threaten human health. TB of the central nervous system (CNS) is rare but the most serious type of systemic TB because of its... (Review)
Review
Tuberculosis (TB) is a common disease to threaten human health. TB of the central nervous system (CNS) is rare but the most serious type of systemic TB because of its high mortality rate, serious neurological complications and sequelae. In this case report, we describe a woman who presented with walking instability, intracerebral hemorrhage and leptomeningeal enhancement due to tuberculosis meningitis. The patient had no significant medical history and the initial clinical symptoms were walking instability. On analysis, the cerebrospinal fluid was colorless and transparent, the pressure was more than 400 mm H2O, there was lymphocytic pleocytosis, increased protein, and decreased glucose levels present. No tuberculosis or other bacteria were detected. The patient's brain computed tomography image showed intra-cerebral hemorrhage (ICH) and contrast magnetic resonance imaging showed ICH in the right frontal lob, and leptomeningeal enhancement. CNS TB is rare but has a high mortality rate. As this disease has no unique characteristics at first presentation such as epidemiology and obvious clinical manifestation, a diagnosis of CNS TB remains difficult.
Topics: Aged; Cerebral Angiography; Cerebral Hemorrhage; Fatal Outcome; Female; Gait; Humans; Magnetic Resonance Angiography; Meninges; Predictive Value of Tests; Tomography, X-Ray Computed; Tuberculosis, Meningeal; Walking
PubMed: 26675758
DOI: 10.18632/oncotarget.6528 -
Progress in Neurobiology Sep 2017Rapid progress is being made in understanding the roles of the cerebral meninges in the maintenance of normal brain function, in immune surveillance, and as a site of... (Review)
Review
Rapid progress is being made in understanding the roles of the cerebral meninges in the maintenance of normal brain function, in immune surveillance, and as a site of disease. Most basic research on the meninges and the neural brain is now done on mice, major attractions being the availability of reporter mice with fluorescent cells, and of a huge range of antibodies useful for immunocytochemistry and the characterization of isolated cells. In addition, two-photon microscopy through the unperforated calvaria allows intravital imaging of the undisturbed meninges with sub-micron resolution. The anatomy of the dorsal meninges of the mouse (and, indeed, of all mammals) differs considerably from that shown in many published diagrams: over cortical convexities, the outer layer, the dura, is usually thicker than the inner layer, the leptomeninx, and both layers are richly vascularized and innervated, and communicate with the lymphatic system. A membrane barrier separates them and, in disease, inflammation can be localized to one layer or the other, so experimentalists must be able to identify the compartment they are studying. Here, we present current knowledge of the functional anatomy of the meninges, particularly as it appears in intravital imaging, and review their role as a gateway between the brain, blood, and lymphatics, drawing on information that is scattered among works on different pathologies.
Topics: Allergy and Immunology; Animals; Brain; Intravital Microscopy; Meninges; Mice
PubMed: 28552391
DOI: 10.1016/j.pneurobio.2017.05.002 -
Brain : a Journal of Neurology May 2022Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through CSF. However, animal studies have also...
Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through CSF. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We used MRI and a CSF tracer to investigate in vivo whether intracranial molecules can move via dura to skull bone marrow in patients with suspicion of CSF disorders. Tracer enrichment in CSF, dural regions and within skull bone marrow was assessed up to 48 h after intrathecal administration of gadobutrol (0.5 ml, 1 mmol/ml) in 53 patients. In participants diagnosed with disease, tracer enrichment within diploe of skull bone marrow was demonstrated nearby the parasagittal dura, nearby extensions of parasagittal dura into diploe, and in diploe of skull bone remote from the dura extensions. This crossing of meningeal and skull barriers suggests that bone marrow may contribute in brain immune surveillance also in humans.
Topics: Animals; Bone Marrow; Dura Mater; Head; Humans; Meninges; Skull
PubMed: 34849609
DOI: 10.1093/brain/awab388 -
Annals of Clinical and Translational... Mar 2019Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal...
OBJECTIVE
Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP.
METHODS
We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined.
RESULTS
LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220 B cells, IgG1 cells, CD138 plasma cells, CD3 T cells, F4/80 macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF- RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-1, TGF- RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF- RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3.
INTERPRETATION
TGF-1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.
Topics: Adaptor Proteins, Signal Transducing; Animals; Dura Mater; Fibrosis; Humans; Hypertrophy; Inflammation; Irbesartan; Membrane Proteins; Meningitis; Mice; Mice, Transgenic; Models, Animal; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1
PubMed: 30911567
DOI: 10.1002/acn3.715 -
Journal of Neuroradiology = Journal de... Jun 2023Meningeal lymphatic vessels (MLVs) along the dural venous sinuses are suspected to be important in connecting the glymphatic and peripheral lymphatic system....
BACKGROUND AND PURPOSE
Meningeal lymphatic vessels (MLVs) along the dural venous sinuses are suspected to be important in connecting the glymphatic and peripheral lymphatic system. Understanding the topography of MLVs may clarify the role of the glymphatic system in neurological diseases. The aim of this analysis was to use high resolution pre- and post-contrast FLAIR 7T MRI to identify and characterize the morphology of MLV in a cohort of healthy volunteers.
MATERIALS AND METHODS
MRI examinations of seventeen healthy volunteers enrolled as controls in a larger 7T MRI study were reviewed. Pre- and post-contrast 3-D FLAIR subtractions and MP2RAGE sequences were spatially normalized and reviewed for signal intensity and enhancement patterns within putative MLVs along pre-determined dural and venous structures. Frequency of occurrence of MLVs at the above-described locations and patterns of their enhancement were analyzed.
RESULTS
Putative MLVs are commonly located along the superior sagittal sinus (SSS) and cortical veins. A "fixed enhancement" signal pattern was more frequent at these locations (p<.05). The morphology of MLVs along the SSS qualitatively changes in an antero-posterior direction. Lack of signal was more frequent along the straight and transverse sinuses (p<.05).
CONCLUSION
Putative MLVs in healthy individuals are concentrated along the SSS and cortical veins. FLAIR signal and enhancement characteristics suggest these structures may transport proteinaceous fluid. Pathways connecting MLVs to cervical lymph nodes however remain unclear.
Topics: Humans; Adult; Meninges; Magnetic Resonance Imaging; Cranial Sinuses; Glymphatic System
PubMed: 36918053
DOI: 10.1016/j.neurad.2023.03.002 -
Journal of Neuroinflammation May 2024Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders... (Review)
Review
Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders the post-traumatic brain vulnerable to poor outcomes, and susceptible to neurological disease, is incomplete. It is well established that dysregulated and sustained immune responses elicit negative consequences after TBI; however, our understanding of the neuroimmune interface that facilitates crosstalk between central and peripheral immune reservoirs is in its infancy. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in both healthy and disease settings. It has been previously shown that disruption of this system exacerbates neuroinflammation in age-related neurodegenerative disorders such as Alzheimer's disease; however, we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. In this manuscript, we will offer a detailed overview of the holistic nature of neuroinflammatory responses in TBI, including hallmark features observed across clinical and animal models. We will highlight the structure and function of the meningeal lymphatic system, including its role in immuno-surveillance and immune responses within the meninges and the brain. We will provide a comprehensive update on our current knowledge of meningeal-derived responses across the spectrum of TBI, and identify new avenues for neuroimmune modulation within the neurotrauma field.
Topics: Brain Injuries, Traumatic; Humans; Animals; Meninges; Neuroinflammatory Diseases; Neuroimmunomodulation
PubMed: 38802931
DOI: 10.1186/s12974-024-03122-7 -
Journal of Visualized Experiments : JoVE Jul 2021The cranial meninges, comprised of the dura mater, arachnoid, and pia mater, are thought to primarily serve structural functions for the nervous system. For example,...
The cranial meninges, comprised of the dura mater, arachnoid, and pia mater, are thought to primarily serve structural functions for the nervous system. For example, they protect the brain from the skull and anchor/organize the vascular and neuronal supply of the cortex. However, the meninges are also implicated in nervous system disorders such as migraine, where the pain experienced during a migraine is attributed to local sterile inflammation and subsequent activation of local nociceptive afferents. Of the layers in the meninges, the dura mater is of particular interest in the pathophysiology of migraines. It is highly vascularized, harbors local nociceptive neurons, and is home to a diverse array of resident cells such as immune cells. Subtle changes in the local meningeal microenvironment may lead to activation and sensitization of dural perivascular nociceptors, thus leading to migraine pain. Studies have sought to address how dural afferents become activated/sensitized by using either in vivo electrophysiology, imaging techniques, or behavioral models, but these commonly require very invasive surgeries. This protocol presents a method for comparatively non-invasive application of compounds on the dura mater in mice and a suitable method for measuring headache-like tactile sensitivity using periorbital von Frey testing following dural stimulation. This method maintains the integrity of the dura and skull and reduces confounding effects from invasive techniques by injecting substances through a 0.65 mm modified cannula at the junction of unfused sagittal and lambdoid sutures. This preclinical model will allow researchers to investigate a wide range of dural stimuli and their role in the pathological progression of migraine, such as nociceptor activation, immune cell activation, vascular changes, and pain behaviors, all while maintaining injury-free conditions to the skull and meninges.
Topics: Animals; Dura Mater; Headache; Meninges; Mice; Migraine Disorders; Rats; Rats, Sprague-Dawley
PubMed: 34398161
DOI: 10.3791/62867 -
Journal of Internal Medicine Aug 2006To date, intravenous immunoglobulin (IvIg) has more often been considered as a safe medication. However, with the wider use of IvIg, severe side effects have also been... (Review)
Review
To date, intravenous immunoglobulin (IvIg) has more often been considered as a safe medication. However, with the wider use of IvIg, severe side effects have also been reported to occur in IvIg-treated patients, notably aseptic meningitis. Other neurological complications have more rarely been described in patients receiving IvIg therapy, e.g. stroke or acute encephalopathy. We recently observed a case which is of particular interest, as the patient with steroid-refractory polyarteritis nodosa developed cranial pachymeningitis related to IvIg therapy. To our knowledge, this is the first reported case of cranial pachymeningitis complicating IvIg therapy. Our findings emphasize the importance of recognizing IvIg-related neurological complications in IvIg-treated patients. As cranial pachymeningitis is a fibrosing process, both recognition and management at an early stage are required to prevent definite neurological impairment in patients.
Topics: Adult; Dura Mater; Gadolinium; Humans; Immunoglobulins, Intravenous; Kidney Diseases; Magnetic Resonance Imaging; Male; Meningitis, Aseptic; Polyarteritis Nodosa; Radioisotopes; Tomography, X-Ray Computed
PubMed: 16882281
DOI: 10.1111/j.1365-2796.2006.01676.x -
Frontiers in Immunology 2022As a rare complication of rheumatoid arthritis (RA) in the central nervous system (CNS), rheumatoid meningitis (RM) mainly affects the meninges and has various clinical...
As a rare complication of rheumatoid arthritis (RA) in the central nervous system (CNS), rheumatoid meningitis (RM) mainly affects the meninges and has various clinical symptoms. The diagnostic and treatment approaches currently used are not practical. RM cases with positive NMDAR antibodies (Abs) have never been reported. In the present study, a 66-year-old man with a 1-year history of RA presented recurrent left lower limb weakness during activities for 1 month. The results showed that rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were positive in the serum, and NMDAR Abs were present in cerebrospinal fluid (CSF). Hyperintensity was observed in the leptomeninges of the right frontal and parietal lobes, and subtle hyperintensity was observed in the left frontal and parietal lobes, as indicated by brain MRI. A meningeal biopsy revealed non-specific inflammation with the absence of rheumatoid nodules. The patient was given IVIg on day 7 after admission. The clinical symptoms were relieved, the lesions were alleviated, and abnormal biochemical indicators were gradually recovered 1 week after initiation of the treatment, while NMDAR Abs were present in CSF even after treatment. After 5 months of follow-up, the patient's serum and CSF ACPA and IL-6 levels were still high. The findings showed that brain MRI was adequate for the diagnosis of RM. ACPA and IL-6 might be the specific biomarkers for disease activity in RM. IVIg was effective as induction therapy for RM. Further studies should explore whether the presence of NMDAR Abs is associated with RM.
Topics: Male; Humans; Aged; Rheumatoid Factor; Immunoglobulins, Intravenous; Interleukin-6; Meningitis; Arthritis, Rheumatoid; Autoantibodies; Biomarkers
PubMed: 36275742
DOI: 10.3389/fimmu.2022.971934 -
Tuberculosis (Edinburgh, Scotland) May 2020Tuberculous meningitis (TBM) is the most devastating form of TB, resulting in death or neurological disability in up to 50% of patients affected. Treatment is similar to...
Tuberculous meningitis (TBM) is the most devastating form of TB, resulting in death or neurological disability in up to 50% of patients affected. Treatment is similar to that of pulmonary TB, despite poor cerebrospinal fluid (CSF) penetration of the cornerstone anti-TB drug rifampicin. Considering TBM pathology, it is critical that optimal drug concentrations are reached in the meninges, brain and/or the surrounding CSF. These type of data are difficult to collect in TBM patients. This review aims to identify and describe a preclinical model representative for human TBM which can provide the indispensable data needed for future pharmacological characterization and prioritization of new TBM regimens in the clinical setting. We reviewed existing literature on treatment of TBM in preclinical models: only eight articles, all animal studies, could be identified. None of the animal models completely recapitulated human disease and in most of the animal studies key pharmacokinetic data were missing, making the comparison with human exposure and CNS distribution, and the study of pharmacokinetic-pharmacodynamic relationships impossible. Another 18 articles were identified using other bacteria to induce meningitis with treatment including anti-TB drugs (predominantly rifampicin, moxifloxacin and levofloxacin). Of these articles the pharmacokinetics, i.e. plasma exposure and CSF:plasma ratios, of TB drugs in meningitis could be evaluated. Exposures (except for levofloxacin) agreed with human exposures and also most CSF:plasma ratios agreed with ratios in humans. Considering the lack of an ideal preclinical pharmacological TBM model, we suggest a combination of 1. basic physicochemical drug data combined with 2. in vitro pharmacokinetic and efficacy data, 3. an animal model with adequate pharmacokinetic sampling, microdialysis or imaging of drug distribution, all as a base for 4. physiologically based pharmacokinetic (PBPK) modelling to predict response to TB drugs in treatment of TBM.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Host-Pathogen Interactions; Humans; Meninges; Mycobacterium tuberculosis; Species Specificity; Tuberculosis, Meningeal
PubMed: 32501258
DOI: 10.1016/j.tube.2020.101924