Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation

The leptomeninges covering the surface of the brain parenchyma play the physical role at the cerebrospinal fluid-blood barrier. We report here that leptomeningeal cells may transduce peripheral proinflammatory signals to the central anti-inflammatory response through the activation of glial cells in the brain parenchyma. After adjuvant injection, both microglia and astrocytes in the cerebral cortex localized in the proximity of the leptomeninges were activated. The protein levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the cortical extracts were significantly increased at different time after adjuvant injection. The TNF-alpha immunoreactivity was most prominent in the leptomeninges covering astrocytes. On the other hand, the IL-10 immunoreactivity was observed in both activated microglia and astrocytes localized along the leptomeninges. Cultured leptomeningeal cells covering the cerebral cortex released TNF-alpha which was significantly increased by lipopolysaccharide (LPS). Upon stimulation with LPS, cultured leptomeningeal cells also secreted interleukin-1beta and interleukin-6 with differential time-courses. When primary cultured rat astrocytes and microglia were treated with the conditioned medium of LPS-activated cultured leptomeningeal cells, the immunoreactivity of IL-10 was markedly increased. These observations strongly suggest that leptomeningeal cells release pro-inflammatory cytokines to activate both microglia and astrocytes during systemic inflammation. The activated astrocytes and microglia may in turn regulate anti-inflammatory response in the brain by providing IL-10.     

Tumor glioneuronal leptomeníngeo difuso: diagnóstico y tratamiento con un caso ilustrativo

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are a rare indolent neoplasm described in the 2016 WHO classification of tumors of the central nervous system (CNS). We describe a case of an 11 year old boy who initially presented intermittent headache, low back pain and communicating hydrocephalus, misdiagnosed as having tuberculous meningitis. Further clinical deterioration with seizures was observed and follow-up MRI showed further aggravation of leptomeningeal enhancement in the basal cisterns. Biopsy of the brain and leptomeninges revealed a diffuse leptomeningeal glioneuronal tumor. DLGNT should be considered in the differential diagnosis of conditions presenting as communicating hydrocephalus with nodular lesions and leptomeningeal enhancement. A timely histologic diagnosis through a biopsy of the brain is necessary to confirm the diagnosis.     

Effect of radiologic contrast media and local anaesthetics on the blood-brain barrier and on the leptomeninges

The leptomeninges of cats were exposed to lidocaine, metrizamide and methiodal sodïum and compared with control brains exposed to Ringer's solution.
As a sign of blood-brain barrier damage, an increased extravasation of albumin into the cerebral cortex was recorded after exposure to methiodal sodium; lidocaine or metrizamide did not produce such damage.
Scanning electron microscopy revealed minor cellular reactions in the mesothelial cells of the leptomeninges after application of metrizamide, lidocaine and Ringer's solution. Methiodal sodium produced an extensive cellular damage of the leptomeningeal cells
The importance of testing the leptomeningeal reactions and the reactions of the blood-brain barrier to all liquid media used on the brain surface is emphasized.     

神经皮肤黑变病合并Dandy-Walker畸形一例

目的 总结1例经病理确诊的神经皮肤黑变病患者的临床特征及病理表现.方法 患者女性,21岁,出生时全身即有多处皮肤大面积黑痣,因耳鸣、头痛、呕吐2个月,视力下降1个月就诊.头部MRI扫描显示后颅凹囊性占位,Dandy-Walker畸形,颈椎管内及颅内广泛脑脊膜强化并增厚.行后颅凹开颅囊肿切除术,切除标本行HE及免疫组织化学染色进行观察.结果 开颅后显示术野内囊肿及脑表面软脑膜均呈黑色.光镜下囊壁内见大量黑色素细胞,局灶呈瘤样增生,免疫组织化学染色显示黑色素细胞呈黑色素瘤抗体HMB45、MelanA、S100、波形蛋白(vimentin)阳性,核抗原ki-67阳性率＜1％.病理诊断:脑膜弥漫性黑色素细胞增多症.患者术后2个月死亡.结论 神经皮肤黑变病主要特点为皮肤及软脑膜弥漫性或局灶性黑色素细胞增生,可合并Dandy-Walker畸形.确诊需病理活体组织检查.     

Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy‐related inflammation

We report a 75‐year‐old man with a 3.5‐year history of cerebral amyloid angiopathy (CAA)‐related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aβ deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti‐neutrophil cytoplasmic autoantibodies (PR3‐ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aβ‐positive blood vessels with double‐barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3‐ANCA with the pathogenesis of Aβ‐associated vasculitis remained unclear, the present case represents a rare example of CAA‐related inflammation at the chronic stage.     

Primary leptomeningeal melanoma in a child

Primary malignant melanoma of the leptomeninges is a rare and aggressive tumor in children and accounts for less than 1% of all pediatric malignancies. Usually its symptoms include raised intracraneal pressure resulting from hydrocephalus secondary to tumoral obliteration of basal cisterns, but the passage of time from the initial symptomatology to diagnosis is frequently delayed. A 7-year-old male with primary leptomeningeal melanoma is reported. At the beginning, he presented ataxia and dysarthria followed by symptoms of raised intracranial pressure, complex partial seizures, progressive loss of consciousness, and coma. Cerebrospinal fluid analysis demonstrated raised opening pressure, normal glucose, and increased protein concentration, but malignant melanoma cells were not found. Magnetic resonance imaging scans depicted bright signals in the subarachnoid spaces on T₁ images and gadolinium-enhanced focal lesions. Cerebral biopsy was proposed, but it was not authorized. Definitive diagnosis was thus made by pathologic postmortem examination.     

An ultrastructural and immunocytochemical analysis of leptomeningeal and meningioma cultures

Using immunocytochemical methods, we localized several glycoproteins of the extracellular matrix to leptomeningeal cells and meningiomas in vitro. Three cell lines derived from normal human leptomeninges and seven from meningiomas were studied by indirect immunofluorescence to evaluate the cellular production of fibronectin, laminin, collagen type IV, and procollagen type III. All leptomeningeal cell lines stained intensely and uniformly for all matrix proteins; all meningioma cell cultures stained uniformly, but the intensity of staining varied considerably. After removal of the cells in culture adherent to glass with 25 mM ammonium hydroxide, indirect immunofluorescence demonstrated an exuberant residual extracellular residue enriched with fibronectin, laminin, collagen type IV, and procollagen type III. Electron microscopic examination of all leptomeningeal and meningioma cultures revealed desmosomes and dense tonofilament formation; in addition, granular, filamentous basement membrane-like material was abundant in the extracellular spaces of all cultures. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis of the cell layer of two leptomeningeal and four meningioma cultures showed production of interstitial collagen types I and III; diethylaminoethyl (DEAE)-cellulose chromatography of the medium demonstrated preferential production of procollagen type I. Our findings show conclusively that normal arachnoid cells in vitro synthesize several of the collagen subtypes and may be responsible for the "fibrous response" of the leptomeninges to trauma, infection, or infiltration by tumor. The similarities between leptomeningeal cells and meningiomas demonstrated by electron microscopy and by indirect immunofluorescence support the notion that meningiomas are derived from arachnoid cells. The localization of various mesenchymal glycoproteins within the intra- and extracellular spaces and the ubiquity of specialized intercellular junctions suggest that leptomeningeal cells in culture have the potential to behave like both stromal and epithelial cells.     

Involvement of prostaglandin E2 released from leptomeningeal cells in increased expression of transforming growth factor-beta in glial cells and cortical neurons during systemic inflammation

The leptomeninges play a central role in the antiinflammatory response through the glia-neuron interaction during systemic inflammation. In the present study, we examined the possible production of two potent antiinflammatory mediators, prostaglandin E(2) (PGE(2)) and transforming growth factor-beta1 (TGF-beta1) by leptomeningeal cells during systemic inflammation. After immunization with the complete Freund's adjuvant (CFA), cyclooxygenase (COX)-2 and membrane-bound PGE synthase-1 (mPGES-1) were induced in the leptomeninges. Primary cultured leptomeningeal cells secreted PGE(2) after treatment with lipopolysaccharide (LPS) or proinflammatory cytokines. The LPS-induced release of PGE(2) was depressed by a selective COX-2 inhibitor, NS-398. On the other hand, TGF-beta1 and TGF-beta receptor II (TGF-betaRII) both markedly increased in the leptomeninges and the parenchymal cells after the CFA injection. Double-staining immunohistochemistry demonstrated TGF-beta1 to be induced in both glial cells and cortical neurons, whereas TGF-betaRII was induced only in cortical neurons. Furthermore, the conditioned medium prepared from the leptomeningeal cells after LPS stimulation was able to induce an increased expression of TGF-beta1 and TGF-betaRII in the primary cultured glial cells and cortical neurons. This increased expression was suppressed by NS-398. PGE(2) was found to increase directly the production of TGF-beta1 and TGF-betaRII in the primary cultured cells. These observations strongly suggest that PGE(2), which is biosynthesized by the leptomeninges, mainly regulates the production of TGF-beta1 by glial cells and cortical neuron, thus playing a protective role in the cortical neurons during systemic inflammation. Furthermore, TGF-beta1 may also exert a protective effect directly on the cortical neurons.     

The Cranial Arachnoid and Pia Mater in Man: Anatomical and Ultrastructural Observations

The objects of the present study were: (1) to define the relationships of the arachnoid mater to blood vessels in the subarachnoid space; (2) to establish the structure of leptomeningeal trabeculae and their relationships to the pia mater; and (3) to investigate the fine structure of the human pia mater. Intracranial portions of vertebral artery were taken at post mortem, and normal cerebral cortex and overlying leptomeninges were obtained from surgical lobectomies. Tissue from these specimens was examined by scanning and transmission electron microscopy, by light microscopy and by immunocytochemistry for the presence of basement membrane, desmosomal proteins and vimentin. Results of the study showed that as the vertebral artery pierced the posterior atlanto-occipital membrane and entered the subarachnoid space, it acquired a leptomeningeal coat as the arachnoid was reflected on to it. It has been demonstrated previously that as vessels enter the brain, the leptomeningeal coat is reflected on to the surface of the cortex as the pia mater. The arachnoid mater was seen to consist of a subdural mesothelial layer and a compact central layer as previously reported. From the inner layer of the arachnoid, collagen bundles coated by leptomeningeal cells extended as trabeculae across the subarachnoid space to fuse with the pia mater. The pia itself was composed of a delicate but apparently continuous layer of cells joined by desmosomes and gap junctions but no tight junctions were observed. It was possible to detect pia mater cells in the perivascular spaces of the brain by immunocytochemical techniques using light microscopy. The significance of the observed anatomical arrangement for cerebrospinal fluid physiology is discussed.     

Meningioangiomatosis: clinical-radiological features and surgical outcome

Meningioangiomatosis (MA) is a rare, benign neoplastic disorder involving the cortex and leptomeninges, the sporadic form, commonly presents as refractory localization-related epilepsy, but could be asymptomatic especially in older patients. The imaging features may be entirely non-specific. Magnetic Resonance Imaging (MRI) erroneously suggests meningioma, lowgrade tumour or vascular malformations. The pathological findings are characterised by proliferation of meningothelial cells and leptomeningeal vessels and calcifications within the mass. Macroscopically there is dense thickening in the underlying cortex, often in a sharply defined area. In this article we report 3 cases of MA, neither of whom had a familiary history or stigmata of Neurofibromatosis (NF). We discuss and place particular emphasis on the clinical presentation and diagnosis imaging, as well as on the outcome. We also review the literature concerning about the aetiology, pathology findings and imaging features of MA.     

Primary leptomeningeal melanoma

Primary melanoma of the central nervous system is a rare melanocytic tumor typically located in the leptomeninges. We report a 57-year-old woman with an intracranial leptomeningeal melanoma who presented with myoclonic seizures. Brain CT scan and MRI revealed a hemorrhagic intracranial tumor. The tumor was completely removed and leptomeningeal melanoma was proven pathologically. Follow-up imaging studies up to 19 months showed no recurrence of the disease. Here we present radiological, gross, and pathological images of leptomeningeal melanoma, discuss its characteristics, and review the relevant literature.     

An unusual case of neurocutaneous melanosis.

The neurocutaneous melanosis (NCM) is a rare, neuroectodermal dysplasia defined by the association of giant or multiple, nonmalignant pigmented cutaneous nevi with leptomeningeal melanosis or melanoma. As a rule, the cerebral pathological substratum is characterized by a melanocytic infiltration of the leptomeninges, often leading to hydrocephalus. The most frequent clinical symptomatology starts early in life, with convulsive seizures, psychomotor delay, intracranial hyperpression: the prognosis is severe. Malignant melanomas can also occur. One 21 years-old patient affected by NCM with a giant bathing nevus and epilepsy is reported. Her psychomotor development was slightly delayed. Academic progress was disturbed by the frequency of seizures and the multiple dermatological surgeries, and she remained at the elementary school level. Her epilepsy appeared at seven years and became pharmacoresistant. It was a focal, left temporal epilepsy. Neuroimaging investigations were performed repeatedly, and demonstrated the progressive appearance of parenchymal lesions with T1 and T2 shortening, without contrast enhancement, at the pons (11 years), the two hippocampi (14 years), and of an atrophy of the cerebellum and the brainstem (19 years). No hydrocephalus, tumoral aspect, or meningeal involvement were demonstrated. This patient's case is peculiar because her neurological symptomatology consists only of focal epilepsy, unrelated to a tumor, with moderate cognitive impairment despite a rather long course of the disease. Her evolution raises the question of condidency to surgical treatment.     

Primary diffuse leptomeningeal gliomatosis: unusual MRI with non-enhancing nodular lesions on the cerebellar surface and spinal leptomeningeal enhancement

A 28 year old man presented with a 1 month history of symptoms of intracranial hypertension. Examination showed bilateral papilloedema and meningeal signs. Magnetic resonance imaging showed nodular lesions on the cerebellar and pontine surface and thickening of the thoracic spinal leptomeninges. Throughout the course of the disease, contrast enhancement was detected in the spinal leptomeninges but not intracranially. Primary diffuse leptomeningeal gliomatosis (PDLG) was diagnosed by biopsy and later confirmed on necropsy. The present case is remarkable for the nodular superficial cerebellar lesions and the absence of intracranial contrast enhancement of the leptomeninges.     

Characterization of fetal human brain cultures. Development of a potential model for selectively purifying human glial cells in culture

Seven fetal human brain and three fetal human leptomeningeal cultures were characterized according to cell morphology, ultrastructural features, antigen expression, and collagen biosynthesis capabilities. Primary cultures derived from mechanically and enzymatically dissociated samples of fetal human brain consisted of a heterogeneous cell population in which astrocytes, oligodendrocytes, neurons, mesenchymal (leptomeningeal) cells, and macrophages were identified by light and electron microscopy. With progressive subcultivation, a homogeneous, leptomeningeal cell-derived population predominated. Fetal human brain and leptomeningeal specimens embedded in paraffin were analyzed immunohistochemically for the distribution of glial fibrillary acidic protein (GFAP), vimentin, factor-VIII-related antigen, fibronectin, laminin, type IV collagen, and procollagen III. Only GFAP and vimentin identified astrocytes and radial glia in the developing human brain; fibronectin, laminin, and the collagen types were immunolocalized largely to the leptomeninges and to the cerebral vasculature. The percentage of cells positively identified by antiserum to GFAP was greatest in primary cultures of fetal human brain; by the fourth passage, none of the fetal brain cultures were GFAP positive. The progressive decrease in the percentage of GFAP-positive cells was accompanied by an increase in the percentage of cells identified by collagen immunomarkers. Furthermore, in double immunolabeling experiments, antibodies to GFAP recognized a population of cells that was not identified by antibodies to laminin, fibronectin, type IV collagen, or procollagen III. SDS-PAGE and DEAE-cellulose chromatography of [3H]-proline-labeled early-passage fetal human brain cultures revealed collagen profiles identical to those obtained from direct cultures of the leptomeninges. The characteristics of later-passage fetal human brain cultures were identical in all respects to those of the fetal human leptomeningeal cultures. The proliferation of leptomeningeal cells could be inhibited by exposing the cells to cis-hydroxyproline (200 micrograms/ml). Primary fetal human brain cultures similarly treated with the proline analogue were found to be highly enriched for glial cells; these cultures were more than 90% GFAP positive. We conclude that primary fetal human brain cultures consist of a heterogeneous population of cells, most of which under the present culture conditions can be identified as glial cells. Subcultivation of human fetal brain cultures results in the overgrowth of mesenchymal cells, which are presumably derived from the leptomeninges.(ABSTRACT TRUNCATED AT 400 WORDS)     

Primary leptomeningeal sarcomatosis. Case report

Primary intracranial sarcomas are very rare and aggressive tumors. A case of a 40-year-old woman with primary leptomeningeal sarcomatosis is presented. Initially her clinical symptoms resembled those of a pseudo tumor cerebri. Neuroimaging did not allow establishing a diagnosis of leptomeninges neoplastic infiltration. The patient died 8 months since the onset of symptoms. A neuropathological examination revealed diffuse thickening of leptomeninges. Microscopically a widespread sarcomatous infiltration of the subarachnoid space was shown, as well as a neoplastic infiltration of the choroid plexus and of some perivascular spaces in the cerebral cortex. On the grounds of a review of the literature diagnostic problems, differential diagnosis and clinical course of primary leptomeningeal sarcomatosis are discussed.     

In vitro induction of radial-like cells by leptomeningeal and cortical astroglial conditioned media. Effect of protease inhibitors

A population of subcultured astroglia from rat fetal cortex was transformed into radial-like cells after exposure to cerebral cortex astroglial conditioned medium in vitro. Such changes were also induced by basal medium modified by fetal leptomeningeal subcultures, but not by postnatal leptomeninges nor by fetal skin fibroblasts. The radializing effects of astroglial conditioned medium were inhibited by previous heat treatment. The addition of protease inhibitors to the basal medium did not cause spontaneous radialization of subcultured cortical astroglia, but increased the length of cell processes and incidence of radial-like forms when added to cortical astroglial conditioned medium. It is concluded that cortical astroglia and leptomeningeal cells share the capability of synthesizing and releasing diffusible molecules into the culture medium which act as morphogenetic inducers in vitro. Based on the present results, it is suggested that such effects would depend on the presence of instructive factor(s) in the conditioned medium which are able to induce rearrangement of the cytoskeleton, rather than on secreted molecules able to modify cell adhesion to the substrate.     

Case of rheumatoid meningitis: findings on diffusion-weighted image versus FLAIR image]

We report a 63-year-old man with rheumatoid meningitis. At 47-years-old, he developed rheumatoid vasculitis causing arthralgia and skin ulcer. Although the patient had been treated with prednisolone and cyclosporine A, headache and recurrent focal seizures of the right upper limb and generalized seizures developed. Brain magnetic resonance imaging showed high signal intensity lesions on FLAIR MRI and associated abnormal enhancement of the leptomeninges. Part of the lesions also showed patchy high signal intensity on diffusion-weighted imaging (DWI). This features may be useful for differentiating rheumatoid meningitis from subdural empyema, because the extent of the lesions on DWI matches the lesion on FLAIR imaging in patients with subdural empyema. Cerebrospinal fluid analysis revealed monocytic pleocytosis and negative findings for infection or malignancy. After intravenous administration of methylprednisolone (1,000 mg/day for 3 days), the patient showed improvements in headache, cerebrospinal fluid findings and abnormal hyperintensity on DWI. Rheumatoid meningitis is an extremely rare neurological manifestation, but careful attention should be paid even in the inactive stage of rheumatoid arthritis. This disease tends to present with unilateral supratentorial lesions. In this case, serial diffusion-weighted and FLAIR MRI was useful for following the leptomeningeal lesions.     

A patient with primary angiitis of the central nervous system: relation between MRI and pathological findings]

A 74-year-old woman, noticed sudden onset of quadriparesis when getting up in the morning on July 17th, 1992. At admission, she presented mild weakness of the limbs bilaterally, and deep tendon hyperreflexia, which were improved after about 4 hours. Serum and urinary laboratory examinations revealed no abnormal findings. Cerebrospinal fluid showed increased cells (75/mm3), and protein (58 mg/dl). Computed tomography revealed multiple low density lesions in the frontal, parietal, and occipital cortex. Magnetic resonance imaging showed low signal intensities on T1-weighted images and high signal intensities on T2-weighted images, suggesting tumorous lesions. On the gadolinium-enhanced images, the enhanced lesions were surrounded with low signal intensity. She developed hallucination and disorientation since around the 8th hospital day, and disturbance of consciousness at the 15th day, followed by coma, and she died from respiratory failure on the 17th hospital day. At autopsy, there were multiple small infarctions in the cerebral cortex and dark areas in the meninges, suggesting localized inflammation. On microscopical examination, remarkable proliferation of cells was seen at the small arteries of the leptomeninges and cerebral cortex. Parts of the vessels were replaced by multinucleated giant cells. No similar abnormalities were found in arteries in the other organs, except the central nervous system. The pathological diagnosis of primary angiitis of the central nervous system was made based on the above findings. The enhanced MRI findings were in excellent agreement with the pathological leptomeningeal vasculitis. The surrounding low intensity areas on the enhanced MRI were considered to reveal edematous change and infarction in the parenchymal lesions. We conclude that enhanced MRI is useful to make a diagnosis of CNS vasculitis.     

A case of primary diffuse leptomeningeal gliomatosis predominantly involving the cervical spinal cord and mimicking chronic meningitis

Gliomas may rarely arise in the leptomeninges without any evidence of intraaxial involvement. A case of primary diffuse leptomeningeal gliomatosis (PDLG) histologically diagnosed as oligoastrocytoma is presented. A 50-year-old woman presented with nausea, vomiting and headache. Magnetic resonance imaging (MRI) of cranium and cervical region revealed dural thickening starting from the craniocervical junction to the level of C4 without any parenchymal lesions. CSF examination showed an increase in protein and decrease in glucose levels. There were neither any kind of atypical cells nor any kind of growth in bacterial cultures. The patient underwent biopsy at the level of C1 for diagnosis. The specimen was diagnosed as primary diffuse leptomeningeal gliomatosis, with phenotypic features of astrocytoma and oligodendroglioma.