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Trends in Immunology Apr 2023The emphasis on mechanisms driving multiple sclerosis (MS) symptomatic worsening suggests that we move beyond categorical clinical classifiers such as... (Review)
Review
The emphasis on mechanisms driving multiple sclerosis (MS) symptomatic worsening suggests that we move beyond categorical clinical classifiers such as relapsing-remitting MS (RR-MS) and progressive MS (P-MS). Here, we focus on the clinical phenomenon progression independent of relapse activity (PIRA), which begins early in the disease course. PIRA occurs throughout MS, becoming more phenotypically evident as patients age. The underlying mechanisms for PIRA include chronic-active demyelinating lesions (CALs), subpial cortical demyelination, and nerve fiber injury following demyelination. We propose that much of the tissue injury associated with PIRA is driven by autonomous meningeal lymphoid aggregates, present before disease onset and unresponsive to current therapeutics. Recently, specialized magnetic resonance imaging (MRI) has identified and characterized CALs as paramagnetic rim lesions in humans, enabling novel radiographic-biomarker-clinical correlations to further understand and treat PIRA.
Topics: Humans; Multiple Sclerosis; Meninges; Disease Progression; Multiple Sclerosis, Relapsing-Remitting
PubMed: 36868982
DOI: 10.1016/j.it.2023.02.002 -
Nature Communications Jan 2022Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures...
Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Case-Control Studies; Cranial Sinuses; Epilepsy; Female; Glymphatic System; Humans; Lymph Nodes; Magnetic Resonance Imaging; Male; Meninges; Middle Aged; Phantoms, Imaging; Retrospective Studies; Sex Factors
PubMed: 35017525
DOI: 10.1038/s41467-021-27887-0 -
Neurology India 2022Hypertrophic pachymeningitis (HPM) is a unique disorder characterized by thickening and fibrosis of the dura mater. Clinically it presents with headache, cranial nerve... (Observational Study)
Observational Study
BACKGROUND
Hypertrophic pachymeningitis (HPM) is a unique disorder characterized by thickening and fibrosis of the dura mater. Clinically it presents with headache, cranial nerve palsies, and other focal neurological deficits. Two forms exist, one is primary, where all other causes have been excluded and the other is secondary where an identifiable cause exists. It is important to recognize these secondary causes as treatment depends on the etiology.
OBJECTIVE
To elucidate the various characteristics of HPM. To delineate clinical-radiological features that help differentiate secondary from primary causes and to understand treatment response and disease outcomes of HPM.
METHODS
This retrospective observational study included 33 patients who presented with radiological diagnosis of HPM from January 2014 to July 2019. Spontaneous intracranial hypotension patients were excluded. All patients were extensively evaluated for secondary causes and treatment outcomes were analyzed on follow-up.
RESULTS AND CONCLUSIONS
Secondary causes of HPM were present in 48% cases. The clue for primary causes is an associated Tolosa-Hunt syndrome. Secondary causes in our series are immunological, infection, and malignancy. Clues to differentiate primary from these secondary causes are clinical like myelopathy, seizures, poor response to immunosuppression; radiological like hypertrophic cranial nerves, infarcts, bony erosion, and leptomeningeal involvement. There are case reports in literature but large Indian studies are lacking. This manuscript presents a large cohort of cases with HPM, which helps differentiate primary from secondary causes, as management and prognosis depend on etiology. An algorithm depicting the approach to the management of HPM has been presented.
Topics: Humans; Magnetic Resonance Imaging; Meningitis; Cranial Nerve Diseases; Headache; Treatment Outcome; Hypertrophy; Dura Mater
PubMed: 36537427
DOI: 10.4103/0028-3886.364052 -
The Journal of Neuroscience : the... Aug 2023Cortical spreading depolarization (CSD) is a key pathophysiological event that underlies visual and sensory auras in migraine. CSD is also thought to drive the headache...
Cortical spreading depolarization (CSD) is a key pathophysiological event that underlies visual and sensory auras in migraine. CSD is also thought to drive the headache phase in migraine by promoting the activation and mechanical sensitization of trigeminal primary afferent nociceptive neurons that innervate the cranial meninges. The factors underlying meningeal nociception in the wake of CSD remain poorly understood but potentially involve the parenchymal release of algesic mediators and damage-associated molecular patterns, particularly ATP. Here, we explored the role of ATP-P2X purinergic receptor signaling in mediating CSD-evoked meningeal afferent activation and mechanical sensitization. Male rats were subjected to a single CSD episode. , extracellular single-unit recording was used to measure meningeal afferent ongoing activity changes. Quantitative mechanical stimuli using a servomotor force-controlled stimulator assessed changes in the afferent's mechanosensitivity. Manipulation of meningeal P2X receptors was achieved via local administration of pharmacological agents. Broad-spectrum P2X receptor inhibition, selective blockade of the P2X7 receptor, and its related Pannexin 1 channel suppressed CSD-evoked afferent mechanical sensitization but did not affect the accompanying afferent activation response. Surprisingly, inhibition of the pronociceptive P2X2/3 receptor did not affect the activation or sensitization of meningeal afferents post-CSD. P2X7 signaling underlying afferent mechanosensitization was localized to the meninges and did not affect CSD susceptibility. We propose that meningeal P2X7 and Pannexin 1 signaling, potentially in meningeal macrophages or neutrophils, mediates the mechanical sensitization of meningeal afferents, which contributes to migraine pain by exacerbating the headache during normally innocuous physical activities. Activation and sensitization of meningeal afferents play a key role in migraine headache, but the underlying mechanisms remain unclear. Here, using a rat model of migraine with aura involving cortical spreading depolarization (CSD), we demonstrate that meningeal purinergic P2X7 signaling and its related Pannexin 1 pore, but not nociceptive P2X2/3 receptors, mediate prolonged meningeal afferent sensitization. Additionally, we show that meningeal P2X signaling does not contribute to the increased afferent ongoing activity in the wake of CSD. Our finding points to meningeal P2X7 signaling as a critical mechanism underlying meningeal nociception in migraine, the presence of distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for effective migraine therapy.
Topics: Rats; Male; Animals; Nociceptors; Migraine Disorders; Meninges; Headache; Adenosine Triphosphate
PubMed: 37487740
DOI: 10.1523/JNEUROSCI.0368-23.2023 -
Annals of Medicine Dec 2023Tuberculous meningitis is an infectious disease of the central nervous system caused by Mycobacterium tuberculosis (M. tuberculosis). It mainly involves the meninges... (Review)
Review
Tuberculous meningitis is an infectious disease of the central nervous system caused by Mycobacterium tuberculosis (M. tuberculosis). It mainly involves the meninges and brain parenchyma, as well as the spinal cord and meninges; Disability and mortality rates are high. In recent years, due to the increase of drug-resistant tuberculosis patients, population mobility and the prevalence of acquired immune deficiency syndrome, the incidence rate of tuberculosis has increased significantly, and tuberculous meningitis has also increased. At present, tuberculosis is still a worldwide infectious disease that seriously threatens human health, especially in underdeveloped and developing countries. China is the largest developing country in the world with a large population. The situation of tuberculosis prevention and control is grim. Its disability rate is the highest in tuberculosis infection. In addition to the common non-specific manifestations, tuberculous meningoencephalitis may also have rare manifestations of stroke, hearing loss and visual loss. Understanding and timely improvement of corresponding examinations and targeted treatment will help improve the prognosis of patients.
Topics: Humans; Tuberculosis, Meningeal; Mycobacterium tuberculosis; Brain; Meningoencephalitis; China
PubMed: 36598144
DOI: 10.1080/07853890.2022.2164348 -
Developmental Cell Apr 2023The arachnoid barrier, a component of the blood-cerebrospinal fluid barrier (B-CSFB) in the meninges, is composed of epithelial-like, tight-junction-expressing cells....
The arachnoid barrier, a component of the blood-cerebrospinal fluid barrier (B-CSFB) in the meninges, is composed of epithelial-like, tight-junction-expressing cells. Unlike other central nervous system (CNS) barriers, its' developmental mechanisms and timing are largely unknown. Here, we show that mouse arachnoid barrier cell specification requires the repression of Wnt-β-catenin signaling and that constitutively active β-catenin can prevent its formation. We also show that the arachnoid barrier is functional prenatally and, in its absence, a small molecular weight tracer and the bacterium group B Streptococcus can cross into the CNS following peripheral injection. Acquisition of barrier properties prenatally coincides with the junctional localization of Claudin 11, and increased E-cadherin and maturation continues after birth, where postnatal expansion is marked by proliferation and re-organization of junctional domains. This work identifies fundamental mechanisms that drive arachnoid barrier formation, highlights arachnoid barrier fetal functions, and provides novel tools for future studies on CNS barrier development.
Topics: Mice; Animals; beta Catenin; Meninges; Arachnoid; Blood-Brain Barrier; Central Nervous System; Tight Junctions
PubMed: 36996816
DOI: 10.1016/j.devcel.2023.03.005 -
Neuromolecular Medicine Sep 2021Traditionally, the primary role of the meninges is thought to be structural, i.e., to act as a surrounding membrane that contains and cushions the brain with... (Review)
Review
Traditionally, the primary role of the meninges is thought to be structural, i.e., to act as a surrounding membrane that contains and cushions the brain with cerebrospinal fluid. During development, the meninges is formed by both mesenchymal and neural crest cells. There is now emerging evidence that subsets of undifferentiated stem cells might persist in the adult meninges. In this mini-review, we survey representative studies of brain-meningeal interactions and discuss the hypothesis that the meninges are not just protective membranes, but instead contain multiplex stem cell subsets that may contribute to central nervous system (CNS) homeostasis. Further investigations into meningeal multipotent cells may reveal a "hidden" target for promoting neurovascular remodeling and repair after CNS injury and disease.
Topics: Adapalene; Adult Stem Cells; Animals; Brain Ischemia; Central Nervous System; Central Nervous System Diseases; Glymphatic System; Homeostasis; Humans; Male; Meninges; Multipotent Stem Cells; Neural Crest; Neural Stem Cells; Rats; Rats, Sprague-Dawley; Regeneration
PubMed: 33893971
DOI: 10.1007/s12017-021-08663-1 -
Communications Biology Feb 2024Crosstalk between central nervous system (CNS) and systemic responses is important in many pathological conditions, including stroke, neurodegeneration, schizophrenia,... (Review)
Review
Crosstalk between central nervous system (CNS) and systemic responses is important in many pathological conditions, including stroke, neurodegeneration, schizophrenia, epilepsy, etc. Accumulating evidence suggest that signals for central-systemic crosstalk may utilize glymphatic and lymphatic pathways. The glymphatic system is functionally connected to the meningeal lymphatic system, and together these pathways may be involved in the distribution of soluble proteins and clearance of metabolites and waste products from the CNS. Lymphatic vessels in the dura and meninges transport cerebrospinal fluid, in part collected from the glymphatic system, to the cervical lymph nodes, where solutes coming from the brain (i.e., VEGFC, oligomeric α-syn, β-amyloid) might activate a systemic inflammatory response. There is also an element of time since the immune system is strongly regulated by circadian rhythms, and both glymphatic and lymphatic dynamics have been shown to change during the day and night. Understanding the mechanisms regulating the brain-cervical lymph node (CLN) signaling and how it might be affected by diurnal or circadian rhythms is fundamental to find specific targets and timing for therapeutic interventions.
Topics: Central Nervous System; Lymphatic Vessels; Brain; Lymphatic System; Meninges
PubMed: 38402351
DOI: 10.1038/s42003-024-05911-5 -
International Journal of Infectious... Apr 2020To describe and analyse the epidemiological and clinical characteristics of imported human angiostrongyliasis in Europe. (Review)
Review
OBJECTIVES
To describe and analyse the epidemiological and clinical characteristics of imported human angiostrongyliasis in Europe.
METHODS
A systematic literature review of cases of human angiostrongyliasis in Europe was performed. Seven databases were searched. The epidemiological and clinical characteristics were extracted from included records and simple summary statistics were performed on extracted data.
RESULTS
Twenty-two cases reported between 1988 and 2019 were identified. They were mainly from French Polynesia, Southeast Asia, and the Caribbean Islands. The dominant suspected mode of transmission was ingestion of prawns, shrimp, or salad. For patients with data, 90% had a history of headache, often lasting, and half had paresthesia. Eighty-nine percent had eosinophilia, 93% had cerebrospinal fluid (CSF) eosinophilia, and 92% had elevated CSF protein. Central nervous system (CNS) imaging was normal in most cases. Two-thirds received albendazole or mebendazole treatment, although this is not currently recommended.
CONCLUSIONS
We have increased previous numbers to 22 reported cases in total since 1988. Angiostrongyliasis should generally be suspected in patients with a lasting headache who have returned from Southeast Asia, China, the Caribbean Islands, Australia, or French Polynesia, as well as parts of North America and Tenerife, Spain, although one autochthonous case from mainland Europe has also been reported. A dietary history should focus on prawns, shrimp, and salad, whilst also including slugs and snails and other paratenic hosts where relevant. The clinical diagnosis is supported by the presence of blood eosinophilia, CSF eosinophilia, and elevated CSF protein. A definitive laboratory diagnosis should be sought, and CNS imaging should be used to support, not to rule out the diagnosis. The most up-to-date evidence should always be consulted before initiating treatment. Current recommendations include analgesics, corticosteroids, and periodic removal of CSF for symptom relief, while antihelminthic treatment is debated.
Topics: Adolescent; Adult; Angiostrongylus cantonensis; Animals; Asia, Southeastern; Australia; Eosinophilia; Europe; Female; Humans; Infant; Male; Meningitis; Middle Aged; Polynesia; Seafood; Snails; Strongylida Infections; West Indies
PubMed: 31972289
DOI: 10.1016/j.ijid.2020.01.012 -
Cellular and Molecular Life Sciences :... Oct 2023Meningeal lymphatic vessels (MLVs) help maintain central nervous system (CNS) homeostasis via their ability to facilitate macromolecule waste clearance and neuroimmune... (Review)
Review
Meningeal lymphatic vessels (MLVs) help maintain central nervous system (CNS) homeostasis via their ability to facilitate macromolecule waste clearance and neuroimmune trafficking. Although these vessels were overlooked for centuries, they have now been characterized in humans, non-human primates, and rodents. Recent studies in mice have explored the stereotyped growth and expansion of MLVs in dura mater, the various transcriptional, signaling, and environmental factors regulating their development and long-term maintenance, and the pathological changes these vessels undergo in injury, disease, or with aging. Key insights gained from these studies have also been leveraged to develop therapeutic approaches that help augment or restore MLV functions to improve brain health and cognition. Here, we review fundamental processes that control the development of peripheral lymphatic networks and how these might apply to the growth and expansion of MLVs in their unique meningeal environment. We also emphasize key findings in injury and disease models that may reveal additional insights into the plasticity of these vessels throughout the lifespan. Finally, we highlight unanswered questions and future areas of study that can further reveal the exciting therapeutic potential of meningeal lymphatics.
Topics: Mice; Animals; Lymphatic Vessels; Meninges; Central Nervous System; Lymphatic System; Models, Animal
PubMed: 37872442
DOI: 10.1007/s00018-023-04984-5