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.

Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.

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.

The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

PURPOSE: To predict biochemical recurrence respecting the natural course of pT2 prostate cancer with positive surgical margin (R1) and no adjuvant/neoadjuvant therapy. METHODS: A multicenter data analysis of 956 patients with pT2R1N0/Nx tumors was performed. Patients underwent radical prostatectomy between 1994 and 2009. No patients received neoadjuvant or adjuvant therapy. All prostate specimens were re-evaluated according to a well-defined protocol. The association of pathological and clinical features, in regard to BCR, was calculated using various statistical tests. RESULTS: With a mean follow-up of 48 months, BCR was found in 25.4 %. In univariate analysis, multiple parameters such as tumor volume, PSA, Gleason at positive margin were significantly associated with BCR. However, in multivariate analysis, Gleason score (GS) of the prostatectomy specimen was the only significant parameter for BCR. Median time to recurrence for GS ≤ 6 was not reached; 5-year BCR-free survival was 82 %; and they were 127 months and 72 % for GS 3+4, 56 months and 54 % for GS 4 + 3, and 27 months and 32 % for GS 8-10. The retrospective approach is a limitation of our study. CONCLUSIONS: Our study provides data on the BCR in pT2R1-PCa without adjuvant/neoadjuvant therapy and thus a rationale for an individual's risk stratification. The data support patients and physicians in estimating the individual risk and timing of BCR and thus serve to personalize the management in pT2R1-PCa.

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.

Effects of natural acids on surface properties of asbestos minerals and kaolinite.

Serpentine, and other asbestos minerals, are considered potential hazards to human respiratory health. It has been postulated that the surface characteristics of these substances, such as surface charge and adsorbed metals, notably Fe and other transition metals, may be the major agents responsible for their toxicity. There is a general consensus that the amphibole group of minerals possesses a greater health risk than serpentines dominated by chrysotile. There have been suggestions that natural processes can alter the surfaces of these minerals and reduce their potency. This study examined the effects of carbonic acid, oxalic acid and hydrochloric acid on the surface characteristics of two trioctahedral minerals, actinolite (amphibole) and chrysotile (serpentine), and compared the results to a non-asbestiform, dioctahedral mineral, kaolinite. Results confirm that the treatments alter the mineral surfaces by changing the zeta potential of the asbestiform minerals from positive to negative and by removing considerable amounts on non-crystalline Fe and other metals. X-ray analyses indicated that mineral structure was little affected by the treatments, and TOF-SIMS revealed that treatments did remove surface adsorbed metals and cations in octahedral coordination within the samples.

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.

The mutual prospective influence of child and parental post-traumatic stress symptoms in pediatric patients.

BACKGROUND: Previous studies found notable rates of post-traumatic stress symptoms (PTSS) and post-traumatic stress disorder (PTSD) in pediatric patients and their parents and suggest a significant association between child and parent PTSS. However, little is known about mutual influences between child and parental PTSS over time. This study prospectively examined the presence of PTSS and PTSD and the mutual influence of child and parental PTSS in a large sample of pediatric patients with different medical conditions. METHODS: A total of 287 children (aged 6.5-16 years) and their mothers (n = 239) and fathers (n = 221) were assessed at 5-6 weeks and 1 year after an accident or a new diagnosis of cancer or diabetes mellitus type 1 in the child. RESULTS: At the first assessment 11.1% and at the second assessment 10.2% of the children had moderate to severe PTSS. At 5-6 weeks 29.3% of mothers and 18.6% of fathers met criteria for PTSD. At 1 year the rates were 14.6% for mothers and 7.9% for fathers. There were considerable differences of PTSS among different medical diagnostic groups in children and parents. Mothers were more vulnerable than fathers. Structural equation analysis revealed that initially high PTSS in mothers and fathers were longitudinally related to poorer recovery from PTSS in the child. Cross-lagged effects from the child to the parents and from one parent to the other were not significant. CONCLUSIONS: This study highlights the long-term influence of parental PTSS on the child's recovery after trauma and calls for a family systems approach and for early interventions in the treatment of traumatized pediatric patients.