Carotid-cavernous sinus fistula following mechanical thrombectomy in acute ischaemic stroke: a rare complication.

Carotid-cavernous sinus fistulas (CCFs) are abnormal communications between the internal carotid artery (ICA) and the cavernous sinus (CS). Direct CCFs are associated with trauma or are iatrogenic complications of neuroendovascular procedures. Meanwhile, mechanical endovascular thrombectomy (MT) in acute ischaemic stroke (AIS) patients with large vessel occlusion (LVO) has been established as a common treatment approach. However, MT is not without its risks of complications, and only a few reports exist on CCF occurring after MT. Here, we present a case of a 63-year-old patient with iatrogenic high-flow CCF of the right horizontal cavernous ICA segment (C4) following repeated MT due to LVO of the middle cerebral artery, and the recent literature is reviewed.

Clearance of neurotoxic peptides and proteins by meningothelial cells.

Meningothelial cells (MECs) are the cellular component of the meninges that provide physical protection to the central nervous system (CNS). Their main function is the formation of a barrier enclosing the brain including the cerebrospinal fluid (CSF). Further, MECs are involved in maintaining CSF homeostasis by clearing CSF from bacteria and apoptotic cells. Furthermore, secretion of pro- and anti-inflammatory cytokines and chemokines involves MECs in immunological processes in the CNS. We demonstrated that meningothelial Ben-Men-1 cells ingest neurotoxic peptides amyloid-ß (Aß1-40) and protein α-synuclein up to about 10-fold more efficiently compared to neuronal-like SH-SY5Y cells. Aß1-40 and α-synuclein are mainly taken up via macropinocytosis. Caveolar endocytosis in addition contributes to α-synuclein ingestion. Upon uptake, both are trafficked towards lysosomal degradation. While production of reactive oxygen species (ROS) following exposure to Aß25-35 and α-synuclein was similar between Ben-Men-1 and SH-SY5Y cells, mitochondrial function in Ben-Men-1 was significantly more robust to Aß25-35 treatment compared to neuronal-like SHSY5Y cells. Similarly, Ben-Men-1 were significantly less susceptible to Aß25-35-induced cell death than neuronal-like cells. Furthermore, co-culture with Ben-Men-1 offered significant protection to neuronal-like cells against Aß25-35-induced apoptosis. This study reveals for the first time the function of MECs as scavengers of neurotoxic Aß and α-synuclein, thereby connecting these cells to neuroprotective processes and suggesting a new mechanism and pathway for clearing neurotoxic substances from the CSF.

Brain activation patterns in medicated versus medication-naïve adults with attention-deficit hyperactivity disorder during fMRI tasks of motor inhibition and cognitive switching.

BACKGROUND: Adult-attention-deficit-hyperactive-disorder (ADHD) is often unrecognized condition. FMRI examination along with neuropsychological testing might strengthen the diagnosis. We hypothesized that ADHD-adults with and without medication would show different fMRI pattern compared to healthy controls while testing tasks of motor inhibition and cognitive switching. METHODS: 45 subjects in three age-matched groups: (1) controls, (2) ADHD-adults under medication (ADHD+) and (3) medication-naïve adults with ADHD (ADHD-) underwent fMRI and neuropsychological testing. Group analysis and population-based statistics were performed. RESULTS: DTVP-A, intellectual ability as well as attention capability, visual-perceptual and visual-motor abilities showed no significant differences between the groups. However, fMRI revealed statistically significant differences between the ADHD+, ADHD- and control groups on tasks of motor inhibition and cognitive switching on adults in bilateral fronto-striatal brain regions, inferior fronto-frontal, fronto-cingulate and fronto-parietal networks as well as in the parietal lobe (p < 0.05). CONCLUSIONS: fMRI offers the potential to differentiate between the ADHD+, ADHD- and control groups. FMRI possibly opens a new window for monitoring the therapeutic effect of ADHD medication. TRIAL REGISTRATION: NCT02578342, registered at August 2015 to clinical trial registry ( https://ichgcp.net/clinical-trials-registry/NCT02578342 ).

Persistent Globe Flattening in Astronauts following Long-Duration Spaceflight.

Posterior globe flattening has been well-documented in astronauts both during and after long-duration space flight (LDSF) and has been observed as early as 10 days into a mission on the International Space Station. Globe flattening (GF) is thought to be caused by the disc centred anterior forces created by elevated volume and/or pressure within the optic nerve sheath (ONS). This might be the result of increased intracranial pressure, increased intraorbital ONS pressure from compartmentalisation or a combination of these mechanisms. We report posterior GF in three astronauts that has persisted for 7 years or more following their return from LDSFs suggesting that permanent scleral remodelling may have occurred.

The extracellular matrix composition of the optic nerve subarachnoid space.

The meninges not only surround the brain and the spinal cord but also the optic nerve. Meningeal-derived extracellular matrix (ECM) is a crucial component of the pial basement membrane, glia limitans and important for maintenance of optic nerve axon integrity, homeostasis and retinal ganglion cell health. To get closer insight into optic nerve meningeal-derived ECM composition, we performed proteomic analysis of the sheep optic nerve subarachnoid space (SAS). Candidate components were confirmed in cultures of primary human meningothelial cells (phMECs) and human optic nerve samples. Sheep optic nerve SAS samples were analysed by LC-MS, identified proteins were matched to their human orthologs and filtered using gene lists representing all major ECM components. To validate these findings digital droplet PCR (ddPCR) to evaluate mRNA expression of all candidate components identified was performed on cultures of phMECs. In addition, one protein per major ECM group was stained on human optic nerve sections and on phMEC cultures. Employing LC-MS, 1273 proteins were identified and subjected to bioinformatic analysis. Gene ontology analysis revealed six out of forty-four collagen types (1A1, 1A2, 3A1, 6A2, 6A3 and 14A1), three out of eleven laminin subunits (A4, B2, C1) and six out of twenty-seven hyaluronan binding proteins (CD44, versican (VCAN), C1q binding protein, neurocan (NCAN), brevican (BCAN) and hyalaluronan proteoglycan link protein 2 (HAPLN2)) were present in our cohort. DdPCR in phMEC cell culture confirmed presence of all candidate components except NCAN, BCAN and HAPLN2. Immunohistochemistry (IHC) staining on human optic nerve sections and immunofluorescence (IF) staining on in vitro cultured phMECs showed strong immunopositivity for collagen-typeI-α1 (COL1A1), lamininγ1 (LAMC1), and VCAN. Fibronectin (FN1) was exclusively present in cultures of phMECs. Using a combined bioinformatics and immunohistological approach, we describe the ECM composition of the optic nerve subarachnoid space. As this space plays an important role in maintaining optic nerve function, a better understanding of ECM composition in this delicate environment might be key to further pathophysiological insight into optic nerve degeneration and associated disorders.

Cerebrospinal fluid and optic nerve sheath compartment syndrome: A common pathophysiological mechanism in five different cases?

IMPORTANCE: Optic nerve (ON) dysfunction is a common feature of different diseases. The pathophysiology is not yet fully understood. BACKGROUND: This study describes five patients with ON sheath (ONS) compartment syndrome (ONSCS) and contributes to the hypothesis that impaired cerebrospinal fluid (CSF) flow can play a role in the development of ON dysfunction. DESIGN: Retrospective case series. PARTICIPANTS: Five patients with ONSCS were included in the study. METHODS: Elaboration of medical histories and clinical and diagnostic findings over a long time period was carried out by analysing medical records and by a detailed medical consultation. MAIN OUTCOME MEASURES: The main outcome measures include clinical history; visual acuity; field, intraocular and CSF pressures; and contrast-loaded computed tomographic (CT) cisternography. RESULTS: Compartmentation of the ONS demonstrated by contrast-loaded CT cisternography was the consistent finding in all five patients who demonstrated findings of ON dysfunction. The aetiologies varied and included meningitis, papilloedema, sphenoid wing meningioma, disc herniation and normal-tension glaucoma. CONCLUSION AND RELEVANCE: Compartmentation of the ONS with consecutively impaired CSF dynamics within the ON subarachnoid space can lead to ON dysfunction. Different aetiologies can cause the development of ONSCS.

Flow dynamics of cerebrospinal fluid between the intracranial cavity and the subarachnoid space of the optic nerve measured with a diffusion magnetic resonance imaging sequence in patients with normal tension glaucoma.

IMPORTANCE: This study offers a new approach for the quantification of CSF dynamics. BACKGROUND: Non-invasive method to quantify the CSF dynamics in the subarachnoid space of the optic nerve is highly desirable. The aim of the study was to measure slow-flow CSF velocities in healthy controls and normal tension glaucoma patients between the intracranial cavity and the subarachnoid space of the optic nerve. DESIGN: Prospective observational study. PARTICIPANTS: Eleven age-matched healthy volunteers and 15 normal tension glaucoma patients. METHODS: Using phase contrast images, the phase shift in MRI diffusion images can be used to determine the flow velocity. Flow-range ratio between the intracranial cavity and the subarachnoid space of the optic nerve was calculated. MAIN OUTCOME MEASURE: Flow-range ratio between the intracranial cavity and the subarachnoid space of the optic nerve was calculated. RESULTS: First, phantom measurements were provided to validate the slow-flow velocity calculations. Second, flow-range ratio was validated for the healthy controls (0.63 ± 0.05), with the range being similar for the right and left optic nerve (P = 0.1). Statistically significant results were obtained (P < 0.05) when comparing the flow-range ratio in the optic nerve of healthy controls (n = 22 eyes, 0.63 ± 0.05) with the flow-range ratio in pathological optic nerves (n = 23, 0.55 ± 0.08) of normal tension glaucoma patients. MANOVA revealed no dependency between flow-range ratio and patient dependent variables. CONCLUSION AND RELEVANCE: Diffusion-weighted imaging provides a method to evaluate CSF flow within the subarachnoid space of the optic nerve in a non-invasive manner. Compared to healthy controls, patients with normal tension glaucoma measure a significantly lower flow-range ratio. This finding suggests a possible role of impaired CSF dynamics in the pathophysiology in normal tension glaucoma.

Anti-inflammatory response following uptake of apoptotic bodies by meningothelial cells.

BACKGROUND: Meningothelial cells (MECs) are the cellular components of the meninges. As such, they provide important barrier function for the central nervous system (CNS) building the interface between neuronal tissue and the cerebrospinal fluid (CSF), and are also part of the immune response of the CNS. METHODS: Human, immortalized MECs were analyzed by flow cytometry and confocal microscopy to study the uptake of apoptotic cells. Furthermore, cytokine and chemokine production by MECs was analyzed by cytokine array and ELISA. RESULTS: We found that MECs are highly active phagocytes able of ingesting and digesting large amounts of apoptotic cells. Furthermore, the uptake of apoptotic cells by MECs was immune suppressive via inhibiting the secretion of pro-inflammatory and chemoattractant cytokines and chemokines IL-6, IL-8, IL-16, MIF, and CXCL1, while increasing the secretion of anti-inflammatory IL-1 receptor antagonist by MECs. CONCLUSION: MECs respond with the secretion of anti-inflammatory cytokines and chemokines following the uptake of apoptotic cells potentially connecting these cells to processes important for the shut-down of immune responses in the brain.

Meningothelial cells as part of the central nervous system host defence.

BACKGROUND INFORMATION: Meningothelial cells (MECs) are the cellular components of the meninges protecting the brain and as such provide important barrier function for the central nervous system building the interface between neuronal tissue and the cerebrospinal fluid (CSF). MECs were previously shown to be involved in the clearance of waste products from the CSF and in maintaining the optic nerve microenvironment. In addition, MECs are involved in immunological processes in the brain by secretion of pro-inflammatory cytokines in response to various pathologically relevant stress conditions. RESULTS: In this study, we analysed the uptake of latex beads as well as bacteria by human MECs using flow cytometric analyses. We found that MECs are highly active phagocytes able of ingesting large amounts of latex beads, as well as Gram-positive and Gram-negative bacteria. Phagocytic activity of MECs was sensitive to nocodazole and cytochalasin D treatment to a varying degree depending on particle composition. Interestingly, Gram-positive bacteria such as Staphylococcus aureus are more readily taken up compared with Gram-negative Escherichia coli. In addition, pre-treatment of MECs with lipopolysaccharide (LPS) or phorbol-12-myristate-13-acetate (PMA) enhanced S. aureus uptake, whereas PMA but not LPS was effective in enhancing E. coli uptake. CONCLUSIONS: Thus, MECs are highly active facultative phagocytes likely important for the maintenance of CSF homeostasis and host defence in the central nervous system especially against Gram-positive bacteria.

Age related cerebrospinal fluid flow dynamics in the subarachnoid space of the optic nerve in patients with normal tension glaucoma, measured by diffusion weighted MRI.

BACKGROUND/OBJECTIVES: We aimed to measure cerebrospinal fluid (CSF) flow rates in the subarachnoid space (SAS) of the optic nerve (ON) by applying non-invasive diffusion-weighted MRI in patients with normal tension glaucoma (NTG) compared to age-matched controls. SUBJECTS/METHODS: In this prospective study, an analysis of diffusion-weighted images of 26 patients with NTG (49ONs) and age-matched volunteers (52ONs) was conducted. Subjects were classified into 4 groups: group I (50-59 y., n = 12 eyes), group II (60-69 y., n = 16 eyes), group III (70-79 y., n = 18 eyes) and group IV ( > 80 y., n = 6 eyes) for NTGs and healthy volunteers, respectively. The flow-range ratio (FRR) between the frontal lobe SAS and the SAS of the ON was calculated for each age category group and then compared between age-categories as well as between NTGs and controls. RESULTS: The mean FRR for age groups were (I) 0.54 ± 0.06 and 0.62 ± 0.03 (p < 0.05), (II) 0.56 ± 0.08 and 0.63 ± 0.03 (p < 0.05), (III) 0.54 ± 0.06 and 0.62 ± 0.02 (p < 0.001) as well as (IV) 0.61 ± 0.03 and 0.61 ± 0.04, for NTGs and controls, respectively. Using pooled data, the difference between the FRR in NTGs and controls was statistically significant (p < 0.0001). There were no statistically significant differences within the age categories of the control group. When comparing the FRR of NTGs by age categories, no statistically significant difference was found between the subgroups. CONCLUSIONS: FRR was significantly reduced in NTGs compared to age-matched controls without any significant differences within the age groups themselves. Given the physiological importance of CSF for the integrity of neurons, axons and glial cells, reduced CSF flow dynamics might be part of the underlying neurodegenerative process of NTG.

Changes in the amygdala produced by viewing strabismic eyes.

PURPOSE: The aim of this study was to look for the response to strabismus images in the limbic network (amygdala, hippocampus, parahippocampus) of healthy volunteers and to compare it with their reaction to viewing normal eyes. DESIGN: Prospective, observational study. PARTICIPANTS: Thirty-one healthy volunteers underwent functional magnetic resonance imaging (fMRI). METHODS: Functional magnetic resonance imaging data and blood oxygen level-dependent signal changes were analyzed using the BrainVoyager QX software package (Brain Innovation, Maastricht, The Netherlands). MAIN OUTCOME MEASURES: Responses to viewing strabismus images were compared with those observed while viewing normal eye images. RESULTS: Strabismus images led to significant activation of the amygdala, hippocampus, parahippocampal, and fusiform gyri in 30 of 31 subjects compared with normal eye images, indicating a negative emotional response. CONCLUSIONS: These fMRI results confirm that strabismus influences organically not only the patient with nonparallel eyes but also observers. Treatment of strabismus therefore changes the interpersonal dynamic for patients with strabismus on a demonstrable organic basis. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Optic disc edema in an astronaut after repeat long-duration space flight.

BACKGROUND: A number of ophthalmic findings including optic disc edema, globe flattening, and choroidal folds have been observed in several astronauts after long-duration space flights. The authors report the first astronaut with previously documented postflight ophthalmic abnormalities who developed new pathological changes after a repeat long-duration mission. METHODS: A case study of an astronaut with 2 long-duration (6 months) exposures to microgravity. Before and after his first long-duration space flight, he underwent complete eye examination, including fundus photography. Before and after his second flight, 9 years later, he underwent fundus photography, optical coherence tomography, ocular ultrasonography, and brain magnetic resonance imaging, as well as in-flight fundus photography and ultrasound. RESULTS: After his first long-duration mission, the astronaut was documented to have eye findings limited to unilateral choroidal folds and a single cotton wool spot. During a subsequent 6-month mission, he developed more widespread choroidal folds and new onset of optic disc edema in the same eye. CONCLUSION: Microgravity-induced anatomical changes that occurred during the first mission may have set the stage for recurrent or additional changes when the astronaut was subjected to physiological stress of repeat space flight.

Impact of aging on meningeal gene expression.

BACKGROUND: The three-layered meninges cover and protect the central nervous system and form the interface between cerebrospinal fluid and the brain. They are host to a lymphatic system essential for maintaining fluid dynamics inside the cerebrospinal fluid-filled subarachnoid space and across the brain parenchyma via their connection to glymphatic structures. Meningeal fibroblasts lining and traversing the subarachnoid space have direct impact on the composition of the cerebrospinal fluid through endocytotic uptake as well as extensive protein secretion. In addition, the meninges are an active site for immunological processes and act as gatekeeper for immune cells entering the brain. During aging in mice, lymphatic drainage from the brain is less efficient contributing to neurodegenerative processes. Aging also affects the immunological status of the meninges, with increasing numbers of T cells, changing B cell make-up, and altered macrophage complement. METHODS: We employed RNASeq to measure gene expression and to identify differentially expressed genes in meninges isolated from young and aged mice. Using Ingenuity pathway, GO term, and MeSH analyses, we identified regulatory pathways and cellular functions in meninges affected by aging. RESULTS: Aging had profound impact on meningeal gene expression. Pathways related to innate as well as adaptive immunity were affected. We found evidence for increasing numbers of T and B lymphocytes and altered activity profiles for macrophages and other myeloid cells. Furthermore, expression of pro-inflammatory cytokine and chemokine genes increased with aging. Similarly, the complement system seemed to be more active in meninges of aged mice. Altered expression of solute carrier genes pointed to age-dependent changes in cerebrospinal fluid composition. In addition, gene expression for secreted proteins showed age-dependent changes, in particular, genes related to extracellular matrix composition and organization were affected. CONCLUSIONS: Aging has profound effects on meningeal gene expression; thereby affecting the multifaceted functions meninges perform to maintain the homeostasis of the central nervous system. Thus, age-dependent neurodegenerative processes and cognitive decline are potentially in part driven by altered meningeal function.

Elevated perioptic lipocalin-type prostaglandin D synthase concentration in patients with idiopathic intracranial hypertension.

The pathophysiology of vision loss and loss of visual field in patients with idiopathic intracranial hypertension with papilloedema is not fully understood. Although elevated CSF pressure induces damage to the optic nerve due to stasis of axoplasmic flow, there is no clear relationship between the severity of papilloedema and CSF pressure. Furthermore, there are cases of purely unilateral papilloedema and cases without papilloedema despite significantly elevated intracranial pressure as well as papilloedema that can persist despite a successfully lowered intracranial pressure. We hypothesize that at least in some of such cases, in addition to purely pressure-induced damage to the optic nerve, the biochemical composition of the CSF in the subarachnoid space surrounding the orbital optic nerve may play a role in the pathogenesis of vision loss. In this retrospective study, we report on lipocalin-type prostaglandin D synthase concentrations in the CSF within the perioptic and lumbar subarachnoid space in 14 patients with idiopathic intracranial hypertension (13 females, mean age 45 ± 13 years) with chronic persistent papilloedema resistant to maximum-tolerated medical therapy and visual impairment. CSF was collected from the subarachnoid space of the optic nerve during optic nerve sheath fenestration and from the lumbar subarachnoid space at the time of lumbar puncture. CSF was analysed for lipocalin-type prostaglandin D synthase and the concentrations compared between the two sites using nephelometry. The mean lipocalin-type prostaglandin D synthase concentration in the perioptic subarachnoid space was significantly higher compared with the concentration in the lumbar subarachnoid space (69 ± 51 mg/l without correction of serum contamination and 89 ± 67 mg/l after correction of serum contamination versus 23 ± 8 mg/l; P < 0.0001, Mann-Whitney U-test). These measurements demonstrate a change and imbalance in the biochemical environment of the optic nerve. Its possible effect is discussed.

Lipocalin-type Prostaglandin D Synthase Concentration Gradients in the Cerebrospinal Fluid in Normal-tension Glaucoma Patients with Optic Nerve Sheath Compartmentation.

OBJECTIVE: To report on the lipocalin-type prostaglandin D synthase (L-PGDS) concentrations in the cerebrospinal fluid (CSF) of the perioptic and lumbar subarachnoid space (SAS) in patients with radiologically proven optic nerve (ON) sheath compartmentation presenting as normal-tension glaucoma (NTG). METHODS: Retrospective biochemical analysis of CSF in thirteen patients with ON sheath compartmentation presenting as NTG (four females, mean age 70±8 years). CSF was sampled from the SAS of the ON during ON sheath fenestration for ON sheath compartmentation and from the lumbar SAS at the time of lumbar puncture. Nephelometry was used for the quantification of L-PGDS and albumin concentration. Albumin was measured in order to assess the amount of contamination with serum in the CSF samples taken from the ON SAS. Main outcome measures were L-PGDS concentrations in the CSF of the perioptic and lumbar SAS. RESULTS: Mean L-PGDS concentration was 24±8 mg/L in the lumbar SAS compared to 33±27 mg/L without correction of serum contamination and 45±39 mg/L after correction of serum contamination in the perioptic SAS. The difference between the lumbar and the perioptic SAS was statistically significant (P=0.0047 without correction of serum contamination, P=0.0002 with correction of serum contamination; Mann-Witney U-test). CONCLUSION: This study demonstrates a concentration gradient of L-PGDS levels within the CSF with a statistically significant higher concentration in the compartmentalized perioptic SAS compared to that in the lumbar SAS. Biochemical changes in the perioptic SAS might be involved in the pathophysiology in NTG patients with ON sheath compartmentation.

Primary cell culture of meningothelial cells--a new model to study the arachnoid in glaucomatous optic neuropathy.

BACKGROUND: In a previous report, we found that the occurrence and amount of meningothelial cell nests in the subarachnoid space are significantly increased in glaucomatous optic nerves compared to normals. In order to allow research into the role of meningothelial cells during diseases of the optic nerve, an in vitro model is necessary. For this purpose, we developed a culture method for porcine meningothelial cells from the arachnoid layer covering the optic nerve. METHODS: Meningothelial cells were scraped from the arachnoid layer of porcine optic nerves and cultured for 2-3 weeks until the cells formed a monolayer. To eliminate contaminating fibroblasts from the culture, cells were negatively selected using magnetic anti-fibroblast beads after the first passage. Cells were detached using 0.05% Trypsin-EDTA, incubated with anti-fibroblast beads, separated using a magnetic column and the flow-through was collected. The purified primary meningothelial cells were characterized by electron microscopy and immunocytochemistry using anti-glial fibrillary acidic protein (GFAP) and anti-keratan sulfate antibodies. RESULTS: Primary cells grew out after dissection and formed a monolayer within 2-3 weeks, which was composed of two morphologically different cell types, flattened cells with round nuclei and fibroblast-like cells with long processes. The fibroblast-like cells in the culture could be labelled and selected using anti-fibroblast microbeads. The second cell type did not bind to the anti-fibroblast beads, and upon immunocytochemistry showed a marked expression of both GFAP and keratan sulphate. In addition, examination of these cells by electron microscopy revealed morphological characteristics of meningothelial cells, including hemidesmosomes and cytoplasmatic filaments. CONCLUSIONS: The technique described in this paper for the primary culture of meningothelial cells from the subarachnoid space of the optic nerve and using magnetic beads for the removal of fibroblasts is effective in obtaining a highly enriched meningothelial cell culture.