Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis.

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

Factores de riesgo asociados a la meningitis eosinofílica causada por Angiostrongylus cantonensis (Nematoda: Metastrongylidae) en Chone, Ecuador / Risk factors associated to eosinophilic meningitis caused by Angiostrongylus cantonensis (Nematoda: Metastrongylidae) in Chone, Ecuador

Introducción: El parásito Angiostrongylus cantonensis es el principal causante de meningitis eosinofílica. En el 2008 se reportó el primer caso en Ecuador y un estudio reciente en la Ciudad de Chone, Manabí, Ecuador determinó una alta prevalencia del parásito en el caracol africano (Achatina fulica). Objetivo: Identificar los factores de riesgo asociados a la meningitis eosinofílica causada por A. cantonensis en la ciudad de Chone. Métodos: Se entrevistaron a 500 personas residentes en la ciudad de Chone y se revisaron las historias clínicas del Hospital General de Chone. Resultados: Se observó que la población de Chone, está expuesta a los siguientes factores de riesgos: consumo de caracoles crudos (7,40 por ciento), el frecuente contacto de las personas con el caracol africano en la casa (67 por ciento), como en el trabajo (51,20 por ciento), el contacto que tienen los niños con caracoles, al jugar en el jardín (76,80 por ciento) y la incorrecta limpieza de los alimentos (54,40 por ciento). En el entorno de la población, se evidenció la presencia del caracol africano cerca de las casas en el 35,20 por ciento y las ratas, en el 50,80 por ciento. Además, el 34 por ciento de la muestra de estudio presentó sintomatología relacionada con meningitis eosinofílica. Se encontró que existía asociación entre la presencia de vectores cerca de las casas y la cantidad de síntomas manifestados por las personas. Conclusiones: Se evidenció que la población de Chone, manifiesta hábitos que exponen a la gente de esta localidad a un alto riesgo de contagio de meningitis eosinofílica(AU)

Introduction: The parasite Angiostrongylus cantonensis is the main causative agent of eosinophilic meningitis. The first case in Ecuador was reported in 2008, and a recent study conducted in the city of Chone, Manabí, Ecuador, determined a high prevalence of the parasite in the African snail (Achatina fulica). Objective: Identify the risk factors associated to eosinophilic meningitis caused by A. cantonensis in the city of Chone. Methods: Interviews were conducted with 500 residents from the city of Chone and a review was carried out of the medical records at Chone General Hospital. Results: It was found that the population of Chone is exposed to the following risk factors: eating raw snails (7.40 percent), frequent contact between people and African snails both at home (67 percent) and at work (51.20 percent), contact between children and snails while playing in gardens (76.80 percent) and washing food items incorrectly (54.40 percent). In the areas surrounding people's households the African snail was found in 35.20 percent and rats in 50.80 percent . Additionally, 34 percent of the study sample had symptoms of eosinophilic meningitis. An association was found between the presence of vectors near the houses and the number of symptoms occurring in people. Conclusions: It was evident that the population of Chone has habits which expose them to a high risk for eosinophilic meningitis(AU)

The meninges enhance leukaemia survival in cerebral spinal fluid.

Central nervous system (CNS) relapse is a common cause of treatment failure in patients with acute lymphoblastic leukaemia (ALL) despite current CNS-directed therapies that are also associated with significant short- and long-term toxicities. Herein, we showed that leukaemia cells exhibit decreased proliferation, elevated reactive oxygen species (ROS) and increased cell death in cerebral spinal fluid (CSF) both in vitro and in vivo. However, interactions between leukaemia and meningeal cells mitigated these adverse effects. This work expands our understanding of the pathophysiology of CNS leukaemia and suggests novel therapeutic approaches for more effectively targeting leukaemia cells in the CNS.

Current understanding of lymphatic vessels in the central nervous system.

Lymphangiogenesis is associated with some pathological conditions such as inflammation, tissue repair, and tumor growth. Recently, a paradigm shift occurred following the discovery of meningeal lymphatic structures in the human central nervous system (CNS); these structures may be a key drainage route for cerebrospinal fluid (CSF) into the peripheral blood and may also contribute to inflammatory reaction and immune surveillance of the CNS. Lymphatic vessels located along the dural sinuses absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system, which is composed of aquaporin-4 water channels expressed on perivascular astrocytic end-feet membranes. Magnetic resonance imaging (MRI) clearly visualized these lymphatic vessels in the human dura mater. The conception of some neurological disorders, such as multiple sclerosis and Alzheimer's disease, has been changed by this paradigm shift. Meningeal lymphatic vessels could be a promising therapeutic target for the prevention of neurological disorders. However, the involvement of meningeal lymphatic vessels in the pathophysiology has not been fully elucidated and is the subject of future investigations. In this article, to understand the involvement of meningeal lymphatic vessels in neurological disorders, we review the differences between lymphangiogenesis in the CNS and in other tissues during both developmental and adulthood stages, and pathological conditions that may be associated with meningeal lymphatic vessels in the CNS.

Current understanding of meningeal and cerebral vascular function underlying migraine headache.

BACKGROUND: The exact mechanisms underlying the onset of a migraine attack are not completely understood. It is, however, now well accepted that the onset of the excruciating throbbing headache of migraine is mediated by the activation and increased mechanosensitivity (i.e. sensitization) of trigeminal nociceptive afferents that innervate the cranial meninges and their related large blood vessels. OBJECTIVES: To provide a critical summary of current understanding of the role that the cranial meninges, their associated vasculature, and immune cells play in meningeal nociception and the ensuing migraine headache. METHODS: We discuss the anatomy of the cranial meninges, their associated vasculature, innervation and immune cell population. We then debate the meningeal neurogenic inflammation hypothesis of migraine and its putative contribution to migraine pain. Finally, we provide insights into potential sources of meningeal inflammation and nociception beyond neurogenic inflammation, and their potential contribution to migraine headache.

Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice.

Ischemic stroke is one of the most common diseases leading to death and is the primary cause of physical handicap. Recent studies have reported that chronic colitis increases the risk of ischemic stroke, but it is unknown whether chronic colitis participates in ischemic brain injury directly. A combined mouse model of chronic colitis induced by dextran sodium sulfate (DSS) and ischemic stroke induced by photochemical infarction was used in this study. We demonstrated that chronic colitis significantly increased the infarction volume, activated microglia/macrophage numbers, proliferation of M1 microglia/macrophage, non-gut-derived CD4+ T lymphocyte penetration and decreased neuron numbers in the peri-infarction at 7 d after stroke. Furthermore, gut-derived CD4+ T cell accumulation on the meninges was observed at 7 d after stroke. In addition, selective depletion of meningeal macrophages resulted in a reduction of infarction volume and the non-gut-derived CD4+ T lymphocyte penetration. We concluded that chronic colitis exacerbated ischemic stroke by promoting CD4+ T cell migration from the gut to the meninges and disequilibrium of M1 and M2 microglia/macrophages. We speculated that the gut-derived CD4+ T cells may interact with meningeal macrophages and result in non-gut-derived CD4+ T lymphocyte infiltration that aggravated brain injury in ischemic stroke.

Neurovascular contributions to migraine: Moving beyond vasodilation.

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine are still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder.

Severe meningeal calcification in a Crouzon patient carrying a mutant C342W FGFR2.

Crouzon is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of mineralization. Here, we presented a 5-year-old girl with severe meningeal calcification. Subsequently, we analyzed FGFR2 mutation and identified a mutation of Cys342Tyr. The findings suggest that abnormal calcification was atypical phenotype of Crouzon patients with Cys342Tyr mutation in FGFR2.

Meningeal and choroid plexus cells--novel drug targets for CNS disorders.

The meninges and choroid plexus perform many functions in the developing and adult human central nervous system (CNS) and are composed of a number of different cell types. In this article I focus on meningeal and choroid plexus cells as targets for the development of drugs to treat a range of traumatic, ischemic and chronic brain disorders. Meningeal cells are involved in cortical development (and their dysfunction may be involved in cortical dysplasia), fibrotic scar formation after traumatic brain injuries (TBI), brain inflammation following infections, and neurodegenerative disorders such as Multiple Sclerosis (MS) and Alzheimer's disease (AD) and other brain disorders. The choroid plexus regulates the composition of the cerebrospinal fluid (CSF) as well as brain entry of inflammatory cells under basal conditions and after injuries. The meninges and choroid plexus also link peripheral inflammation (occurring in the metabolic syndrome and after infections) to CNS inflammation which may contribute to the development and progression of a range of CNS neurological and psychiatric disorders. They respond to cytokines generated systemically and secrete cytokines and chemokines that have powerful effects on the brain. The meninges may also provide a stem cell niche in the adult brain which could be harnessed for brain repair. Targeting meningeal and choroid plexus cells with therapeutic agents may provide novel therapies for a range of human brain disorders.

Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6).

BACKGROUND: Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache. METHODS: Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation. RESULTS: Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment. CONCLUSIONS: Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.

Morphologic changes associated with intrathecal catheters for direct delivery to the central nervous system in preclinical studies.

A retrospective analysis of microscopic evaluation data from control (device and/or saline-treated) animals in intrathecal studies in monkeys, dogs, sheep, and rats was conducted. The studies were performed by multiple testing facilities. All slide preparation and microscopic evaluation were conducted in the laboratory of the author. The data were of observations made at the level of the catheter tip, which typically was located in the intrathecal space near the thoracolumbar region of the spinal canal. The most common microscopic changes in control animals were meningeal infiltrates, catheter track (CT) inflammation, spinal cord compression (at the CT), CT fibrosis, spinal cord gliosis (at the CT), and spinal cord nerve fiber degeneration. Although variable between studies (even within species), in general the average severity of these findings was minimal or less in control animals. CT inflammatory mass/pyogranuloma formation, a known complication following the administration of morphine at higher concentrations/doses, was noted in 3 of 25 control dogs and 2 of 77 control monkeys. These data show that inflammatory mass/pyogranuloma formation may occur in control animals, and this occurrence is most common in dogs as compared to monkeys, sheep, and rats.

Postural tremor as a manifestation of spontaneous intracranial hypotension.

Spontaneous intracranial hypotension (SIH) is a syndrome caused by low cerebrospinal fluid (CSF) pressure due to leakage of CSF. Clinically, orthostatic headache, neck pain, nausea, emesis, interscapular pain, diplopia, dizziness, changes in hearing, visual blurring and radicular upper extremity symptoms are most frequently observed. We describe a 57-year-old man with SIH who presented with postural tremor. CSF leakage was revealed by cranial MRI. Lumbar puncture identified low CSF pressure and intrathecal gadolinium enhanced MR cisternography showed diffuse CSF leakage in the thoracolumbar region. The patient underwent epidural blood patching, which resulted in complete resolution of postural tremor within 2 months.

Neuropeptide alpha-MSH exerts pro-inflammatory effects on Neisseria meningitidis infection in vitro.

OBJECTIVE AND DESIGN: alpha-Melanoycte stimulating hormone (alpha-MSH), a neuropeptide hormone with reported anti-microbial and immuno-modulatory properties in vitro, has previously been detected in the cerebrospinal fluid of children with bacterial meningitis. We investigated the therapeutic effects of alpha-MSH administration on Neisseria meningitidis infection of human meningeal cell cultures in vitro. MATERIALS AND METHODS: Meningeal cell lines (n = 2) were infected with meningococci (10(2)-10(8) cfu/monolayer), isolated bacterial outer membranes (OM; 1 microg/ml) or lipo-oligosaccharide (LOS; 1 microg/ml) with and without alpha-MSH (10(-5)-10 microM). Bacterial adherence was quantified at 6 h, and cytokine production and microbicidal activity of alpha-MSH for meningococci were assessed at 24 h. RESULTS: Compared with infection by meningococci alone, alpha-MSH (10 microM) up-regulated secretion of IL-6 and IL-8 (mean values increased from approximately 33 to 60 ng/ml), RANTES (mean values increased from approximately 26 to 105 ng/ml) and GM-CSF (mean values increased from approximately 0.3 to 1 ng/ml; P < 0.05). Upregulated secretion correlated with a neuropeptide-mediated rapid and >5-fold increase (P < 0.05) in bacterial adherence to cells and was dependent on OM components including LOS acting synergistically with alpha-MSH. Meningococci were resistant to the anti-microbial activity of alpha-MSH at all concentrations tested. CONCLUSIONS: Our study demonstrates that a potentially therapeutic neuropeptide exerts pro-inflammatory effects during meningococcal infection in vitro and its use in the treatment of meningitis is contra-indicated.

Epstein-Barr virus-associated meningoencephalomyelitis: intrathecal reactivation of the virus in an immunocompetent child.

Neurologic complications, including meningoencephalitis, transverse myelitis, and peripheral neuropathy, have been reported in patients with acute infectious mononucleosis. Chronic active Epstein-Barr virus and human immunodeficiency virus infections occasionally induce central nervous system lymphoma. On the other hand, central nervous system disease alone associated with Epstein-Barr virus rarely occurs in previously healthy individuals. A 15-year-old girl who developed acute disseminated encephalomyelitis-like disease presenting fever, anuresis, diplopia, and muscle weakness is described here. Clinical and neuroimaging studies led to the diagnosis of encephalomyelitis. Despite the absence of infectious mononucleosis-like symptoms, anti-Epstein-Barr virus antibody titers in serum and cerebrospinal fluid showed the virus reactivation. The copy number of Epstein-Barr virus DNA increased in cerebrospinal fluid but not in peripheral blood. Ganciclovir and repeated methyl-prednisolone pulse therapy resulted in complete resolution. Central nervous system disease on the limited intrathecal reactivation of Epstein-Barr virus in immunocompetent children should be differentiated from acute disseminated encephalomyelitis.