RSS 1.0Neurology
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An unusual cause of cranial dural thickeningWe describe an unusual cause of cranial dural thickening in an elderly female with a chronic meningeal inflammatory process. A 70-year-old ethnically Chinese, Singaporean female presented with a history of chronic daily headache with no other meningeal signs. Serial MRI brains showed progressive pachymeningeal and leptomeningeal enhancement in the left frontal region with underlying vasogenic oedema, similar appearances in the right frontal region to a lesser extent, and persistent inflammatory changes in her bilateral paranasal sinuses. Investigative work-up showed a chronically raised ESR with a normal CRP, negative ANCA, and a chronically raised serum IgA kappa paraprotein. Bone marrow trephine biopsy was suggestive of a low level plasma cell disorder. Olfactory cleft biopsy showed no evidence of IgG4-related disease or vasculitis and no significant plasma cell infiltrate. Histopathological examination from a meningeal biopsy revealed a diagnosis of an en-plaque meningioma (the WHO, 2016; Grade I) causing an unusual granulomatous reaction. We discuss the radiological and histological relations of this rare form of meningioma. Clinicians can consider en-plaque meningioma in the differential diagnosis of linear dural thickening and enhancement. Copyright © 2020 Jing Ming Yeo et al.
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Extracellular vesicles potentiate medulloblastoma metastasis in an EMMPRIN and MMP-2 dependent mannerExtracellular vesicles (EVs) have emerged as pivotal mediators of communication in the tumour microenvironment. More specifically, nanosized extracellular vesicles termed exosomes have been shown to contribute to the establishment of a premetastatic niche. Here, we sought to determine what role exosomes play in medulloblastoma (MB) progression and elucidate the underlying mechanisms. Metastatic MB cells (D458 and CHLA-01R) were found to secrete markedly more exosomes compared to their nonmetastatic, primary counterparts (D425 and CHLA-01). In addition, metastatic cell-derived exosomes significantly enhanced the migration and invasiveness of primary MB cells in transwell migration assays. Protease microarray analysis identified that matrix metalloproteinase-2 (MMP-2) was enriched in metastatic cells, and zymography and flow cytometry assays of metastatic exosomes demonstrated higher levels of functionally active MMP-2 on their external surface. Stable genetic knockdown of MMP-2 or extracellular matrix metalloproteinase inducer (EMMPRIN) in metastatic MB cells resulted in the loss of this promigratory effect. Analysis of serial patient cerebrospinal fluid (CSF) samples showed an increase in MMP-2 activity in three out of four patients as the tumour progressed. This study demonstrates the importance of EMMPRIN and MMP-2-associated exosomes in creating a favourable environment to drive medulloblastoma metastasis via extracellular matrix signalling.Copyright © 2023 by the authors.
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EPEN-43. Targeting intra-tumour heterogeneity in paediatric ependymoma: An integrated omics study towards patient-tailored therapyEpendymoma (EPN) is the second most common malignant paediatric brain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specific biomarkers. Given the close association between gene expression, active biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant metabolic pathways, thus presenting therapeutic vulnerabilities. We first compared two distinct subgroups of EPN, PF-A and ST-RELA, identifying 115 metabolites and 1580 upregulated genes between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from the same population of cells. RNAseq identified dysregulated genes and liquid chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto the arginine and proline pathways. Integration of genes and metabolites using pathway-based network analysis revealed 124 aberrant gene-metabolite interactions between intra-tumour regions, with large numbers occurring in the glucogenesis and glycine metabolic pathways in 6/8 patients. These may represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least one unique intra-tumour genomic-metabolomic interaction, applicable for patient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicated on aberrant gene-metabolite networks will be validated in multi-region patient-derived cell lines and orthotopic models using repurposed therapeutics.
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EPEN-15. Transcriptomic and metabolic integration reveal intra-tumour heterogeneity and identify disulfiram and copper as a synergistic therapy in paediatric ependymomaBACKGROUND: Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a significant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it difficult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHOD(S): Surgical sampling of spatiallydistinct regions was performed on eight PF-A EPN patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULT(S): Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique genemetabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulfiram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ significantly sensitised cells to Disulfiram, particularly under hypoxic conditions. This synergistic combination significantly impaired invasion in both normoxia and hypoxia. CONCLUSION(S): This is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.
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A reappraisal of the pathophysiology of cushing ulcer: A narrative reviewIn 1932, Harvey Cushing described peptic ulceration secondary to raised intracranial pressure and attributed this to vagal overactivity, causing excess gastric acid secretion. Cushing ulcer remains a cause of morbidity in patients, albeit one that is preventable. This narrative review evaluates the evidence pertaining to the pathophysiology of neurogenic peptic ulceration. Review of the literature suggests that the pathophysiology of Cushing ulcer may extend beyond vagal mechanisms for several reasons: (1) clinical and experimental studies have shown only a modest increase in gastric acid secretion in head-injured patients; (2) increased vagal tone is found in only a minority of cases of intracranial hypertension, most of which are related to catastrophic, nonsurvivable brain injury; (3) direct stimulation of the vagus nerve does not cause peptic ulceration, and; (4) Cushing ulcer can occur after acute ischemic stroke, but only a minority of strokes are associated with raised intracranial pressure and/or increased vagal tone. The 2005 Nobel Prize in Medicine honored the discovery that bacteria play key roles in the pathogenesis of peptic ulcer disease. Brain injury results in widespread changes in the gut microbiome in addition to gastrointestinal inflammation, including systemic upregulation of proinflammatory cytokines. Alternations in the gut microbiome in patients with severe traumatic brain injury include colonization with commensal flora associated with peptic ulceration. The brain-gut-microbiome axis integrates the central nervous system, the enteric nervous system, and the immune system. Following the review of the literature, we propose a novel hypothesis that neurogenic peptic ulcer may be associated with alterations in the gut microbiome, resulting in gastrointestinal inflammation leading to ulceration.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
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Disproportionate expression of ATM in cerebellar cortex during human neurodevelopmentCerebellar neurodegenerationis a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of the ATM gene, a gene with multiple regulatory functions. The increased vulnerability of cerebellar neurones to degeneration compared to cerebral neuronal populations in individuals with ataxia telangiectasia implies a specific importance of intact ATM function in the cerebellum. We hypothesised that there would be elevated transcription of ATM in the cerebellar cortex relative to ATM expression in other grey matter regions during neurodevelopment in individuals without A-T. Using ATM transcription data from the BrainSpan Atlas of the Developing Human Brain, we demonstrate a rapid increase in cerebellar ATM expression relative to expression in other brain regions during gestation and remaining elevated during early childhood, a period corresponding to the emergence of cerebellar neurodegeneration in ataxia telangiectasia patients. We then used gene ontology analysis to identify the biological processes represented in the genes correlated with cerebellar ATM expression. This analysis demonstrated that multiple processes are associated with expression of ATM in the cerebellum, including cellular respiration, mitochondrial function, histone methylation, and cell-cycle regulation, alongside its canonical role in DNA double-strand break repair. Thus, the enhanced expression of ATM in the cerebellum during early development may be related to the specific energetic demands of the cerebellum and its role as a regulator of these processes.Copyright © The Author(s) 2023.
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Terson syndrome in reverse: Intraventricular haemorrhage following primary intraocular haemorrhageTerson syndrome (TS) describes the presence of intraocular haemorrhage in patients with intracranial haemorrhage or traumatic brain injury. The aetiology of TS is controversial as an anatomical conduit between the vitreous humour and subarachnoid space remains contested. We herewith present a case of primary vitreous haemorrhage with secondary intracranial extension into the ventricles. Cranial CT demonstrates blood within the left optic nerve and chiasm but not within the subarachnoid space. This unusual phenomenon, which has not been reported before, may be described as 'Terson syndrome in reverse'. We explore mechanisms by which blood within the globe may track into the ventricular system, contextualising recent advances in the understanding of ocular-intracranial fluid transport.Copyright © 2022, Fondazione Societa Italiana di Neurologia.
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P579/1741 Accumulation of iron-rim lesions correlates with change in cognition in early multiple sclerosisIntroduction: Iron rim lesions (IRLs) detected on susceptibility weighted imaging (SWI) are associated with higher disability scores in established MS and represent indicators of clinical worsening and progression of MS over the long term. It is not clear if the presence of IRL at diagnosis and detection of IRL early accumulation are clinically meaningful in early MS. Objectives/Aims: To assess whether the presence and number of IRLs detected in the first two years in newly diagnosed patients with relapsing remitting MS (RRMS) are associated with short term cognitive change. Method(s): 90 newly diagnosed RRMS patients (first symptoms =4 IRLs. IRL prevalence was higher greater in males (p=0.01). 36% pf people with MS with IRL at diagnosis developed at least an additional IRL over a mean follow up of 21 months. Of the 69% of patients who had no IRLs at diagnosis, 16 (28%) developed at least one IRL over a median follow up of 17.25 months. No significant correlation was found between IRL count at diagnosis and baseline SDMT scores, or between the IRL count at baseline and the change in SDMT scores at follow-up. In contrast, the accumulation of additional IRLs correlated with SDMT change at both the 1 year (p 0.006) and 2-year follow-up (p 0.004). Type of DMT did not influence this. . Conclusion(s): The accumulation of IRLs in early MS in the first two years after diagnosis already correlates with changes in cognitive measures. IRL accumulation may hold prognostic value for long-term cognitive impairment in MS.
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P421/1709: The neutrophil-to-lymphocyte ratio is a marker of acute inflammation but does not predict relapses or disease severity in a UK cohort of people with MOGAD and NMOSDIntroduction: Neutrophil-to-lymphocyte ratio (NLR) is a blood marker of systemic inflammation. Two studies from China have recently proposed NLR as biomarker of disease severity in people with oligodendrocyte glycoprotein associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), with higher NLR in NMOSD compared to MOGAD. Objectives/Aims: To assess if NLR predicts relapse risk and worse disability in a group of patients with MOGAD and NMOSD from the East Midlands of England. Method(s): We extracted demographic, clinical and biology data of people with MOGAD and NMOSD aquaporin4 IgG positive, attending the NMOSD/MOGAD specialist clinic at the Queen's Medical Centre in Nottingham, UK. We compared NLR in relapse and remission, and how NLR correlates with relapse rate, risk of early relapses (<6 months, considered marker of risk of recurrence in MOGAD), disease course (monophasic vs relapsing), and disability accumulation (EDSS). Two-tailed student t-test, Mann- Whitney U test, Chi-Square or Fisher's exact tests were used for detecting the differences. Receiver operator curve (ROC) analysis was used to assess the ability of NLR to distinguish between MOGAD and NMOSD aquaporin4 IgG positive. Binary logistic regression analysis was used to evaluate potential risk factors for disease recurrence. Estimates of the probability of relapse were obtained using a univariate Cox Proportional Hazards model. Result(s): We collected data of 28 patients with MOGAD (16 women; average age 33.4y; 13 relapsing MOGAD) and 37 patients with NMOSD AQP4IgG+(33 women; average age 45y) with a mean duration of follow-up of 8.6y (median 7.5y) and 9.8y (median 6.8y) respectively. NLR was higher in relapse than in remission in both MOGAD and NMOSD, but did not differentiate between the two conditions. NLR at disease onset had no predictive value in discerning the event of relapse < 6 months from onset. NLR at diagnosis (at first attack) or in remission had no association with the event of first relapse after diagnosis, number of relapses and disability accumulation for any of the two conditions, and could not differentiate between monophasic and relapsing forms of MOGAD. Conclusion(s): NLR is merely a marker of acute inflammation in MOGAD and NMOSD and cannot serve as predictor for risk of relapse or disability accumulation.
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Beta interferons as immunotherapy in multiple sclerosis: A new outlook on a classic drug during the COVID-19 pandemicBeta interferons (IFN-beta) are pleiotropic cytokines with antiviral properties. They play important roles in the pathogenesis of multiple sclerosis (MS), an incurable immune-mediated disorder of the central nervous system. The clinical expression of MS is heterogeneous, with relapses of neuroinflammation and with disability accrual in considerable part unrelated to the attacks. The injectable recombinant IFN-beta preparations are the first approved disease-modifying treatments for MS. They have moderate efficacy in reducing the frequency of relapses, but good long-term cost-efficacy and safety profiles, so are still widely used. They have some tolerability and adherence issues, partly mitigated in recent years by the introduction of a PEGylated formulation and use of 'smart' autoinjector devices. Their general impact on long-term disability is modest but could be further improved by developing accurate tools for identifying the patient profile of best responders to IFN-beta. Here, we present the IFN-beta-based immunomodulatory therapeutic approaches in MS, highlighting their place in the current coronavirus disease (COVID-19) pandemic. The potential role of IFN-beta in the treatment of COVID-19 is also briefly discussed.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Guillain–Barré syndrome variant occurring after SARS-CoV-2 vaccinationAlthough SARS-CoV-2 vaccines are very safe, we report 4 cases of the bifacial weakness with paresthesias variant of Guillain-Barre syndrome (GBS) occurring within 3 weeks of vaccination with the Oxford-AstraZeneca SARS-CoV-2 vaccine. This rare neurological syndrome has previously been reported in association with SARS-CoV-2 infection itself. Our cases were given either intravenous immunoglobulin, oral steroids, or no treatment. We suggest vigilance for cases of bifacial weakness with paresthesias variant GBS following vaccination for SARS-CoV-2 and that postvaccination surveillance programs ensure robust data capture of this outcome, to assess for causality. ANN NEUROL 2021;90:315-318.Copyright © 2021 American Neurological Association.
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Hookworm treatment for relapsing multiple sclerosis: A randomized double-blinded placebo-controlled trialImportance: Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS. Objective(s): To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS. Design, Setting, and Participant(s): This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-To-Treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-Three patients were screened; of these, 71 were recruited (2 ineligible/declined). Intervention(s): Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. Main Outcomes and Measures: The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood. Result(s): Patients (mean SD] age, 45 9.5] years; 50 women 71%]) were randomized to receive hookworm (35 49.3%]) or placebo (36 50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 51.4%] vs 10/36 27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 4.4%]; placebo, 34 3.9%]; P =.01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo. Conclusions and Relevance: Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT01470521.Copyright © 2020 American Medical Association. All rights reserved.
