"Idiopathic" intracranial hypertension: An update from neurointerventional research for clinicians.

BACKGROUND: The recognition of venous sinus stenosis as a contributing factor in the majority of patients with idiopathic intracranial hypertension coupled with increasing cerebral venography and venous sinus stenting experience have dramatically improved our understanding of the pathophysiologic mechanisms driving this disease. There is now a dense, growing body of research in the neurointerventional literature detailing anatomical and physiological mechanisms of disease which has not been widely disseminated among clinicians. METHODS: A literature search was conducted, covering the most recent neurointerventional literature on idiopathic intracranial hypertension, the pathophysiology of idiopathic intracranial hypertension, and management strategies (including venous sinus stenting), and subsequently summarized to provide a comprehensive review of the most recently published studies on idiopathic intracranial hypertension pathophysiology and management. CONCLUSION: Recent studies in the neurointerventional literature have greatly improved our understanding of the pathophysiologic mechanisms causing idiopathic intracranial hypertension and its associated conditions. The ability to make individualized, patient-specific treatment approaches has been made possible by advances in our understanding of how venous sinus stenosis and cerebral venous hypertension fundamentally contribute to idiopathic intracranial hypertension.

Somatic Mosaicism in the Pathogenesis of de novo Cerebral Arteriovenous Malformations: A Paradigm Shift Implicating the RAS-MAPK Signaling Cascade.

Cerebral arteriovenous malformations (AVMs) are leading causes of lesional hemorrhagic stroke in both the pediatric and young adult population, with sporadic AVMs accounting for the majority of cases. Recent evidence has identified somatic mosaicism in key proximal components of the RAS-MAPK signaling cascade within endothelial cells collected from human sporadic cerebral AVMs, with early preclinical models supporting a potential causal role for these mutations in the pathogenesis of these malformations. Germline mutations that predispose to deregulation of the RAS-MAPK signaling axis have also been identified in hereditary vascular malformation syndromes, highlighting the key role of this signaling axis in global AVM development. Herein, we review the most recent genomic and preclinical evidence implicating somatic mosaicism in the RAS-MAPK signaling pathway in the pathogenesis of sporadic cerebral AVMs. Also, we review evidence for RAS-MAPK dysregulation in hereditary vascular malformation syndromes and present a hypothesis suggesting that this pathway is central for the development of both sporadic and syndrome-associated AVMs. Finally, we examine the clinical implications of these recent discoveries and highlight potential therapeutic targets within this signaling pathway.

Management of Acute Central Retinal Artery Occlusion, a "Retinal Stroke": An Institutional Series and Literature Review.

OBJECTIVES: Acute central retinal artery occlusion (CRAO) is an ophthalmologic emergency that often results in permanent vision loss. Over 25% are associated with acute cerebral ischemia. In the absence of existing Level I treatment options, this study aims to examine institutional practice patterns and review the literature to develop a formalized approach to the treatment of CRAO in the era of ischemic stroke protocols. MATERIALS AND METHODS: This is a retrospective review of institutional practices in the workup and treatment of patients diagnosed with acute non-arteritic (NA) CRAO at a single center from January 2017 to August 2020. RESULTS: Of 91 patients managed for acute NA-CRAO, 62.6% were male and average age was 66.4 years. Only 20.9% of patients presented within 4 h of symptom onset. 12.1% of patients had evidence of acute stroke on MRI, and 27.5% had ipsilateral internal carotid artery stenosis >50%. Half (52.7%) did not receive any acute treatment for CRAO, excluding antiplatelet/anticoagulation. 48.5% of patients undergoing acute medical treatment had improved visual acuity compared to 29.4% without treatment (p=0.14). CONCLUSIONS: There is a lack of clear protocol for the management of NA-CRAO. While not reaching statistical significance, our experience mirrors the literature with patients undergoing medical treatment demonstrating improved visual acuity over those without treatment. Given the presence of acute ischemic stroke, carotid disease, and/or stroke risk factors in over 25% of patients with CRAO, multidisciplinary involvement and modern stroke algorithms should be considered for this disease.

Haplotype structure in commercial maize breeding programs in relation to key founder lines.

KEY MESSAGE: High-density haplotype analysis revealed significant haplotype sharing between ex-PVPs registered from 1976 to 1992 and key maize founders, and uncovered similarities and differences in haplotype sharing patterns by company and heterotic group. Proprietary inbreds developed by the private seed industry have been the major source for driving genetic gain in successful North American maize hybrids for decades. Much of the history of industry germplasm can be traced back to key founder lines, some of which were pivotal in the development of prominent heterotic groups. Previous studies have summarized pedigree-based relationships, genetic diversity and population structure among commercial inbreds with expired Plant Variety Protection (ex-PVP). However, less is known about the extent of haplotype sharing between historical founders and ex-PVPs. A better understanding of the relationships between founders and ex-PVPs provides insight into the haplotype and heterotic group structure among industry germplasm. We performed high-density haplotype analysis with 11.3 million SNPs on 212 maize inbreds, which included 157 ex-PVPs registered 1976-1992 and 55 public lines relevant to PVPs. Among these lines were 12 key founders identified in literature review: 207, A632, B14, B37, B73, LH123HT, LH82, Mo17, Oh43, OH7, PHG39 and Wf9. Our results revealed that, on average, 81.6% of an ex-PVP's genome is shared with at least 1 of these 12 founder lines and more than half when limited to B73, Mo17 and 207. Quantifiable similarities and contrasts among heterotic groups and major US seed industry companies were also observed. The results from this study provide high-resolution haplotype data on ex-PVP germplasm, confirm founder relationship trends observed in previous studies, uncover region-specific haplotype structure differences and demonstrate how haplotype sharing analysis can be used as a tool to explore germplasm diversity.

A comprehensive review on the development of sporadic cerebral arteriovenous malformations: from Padget to next-generation sequencing.

Cerebral arteriovenous malformations (AVMs) are a leading cause of intracerebral hemorrhage in both children and young adults. With the continued advancement of science and technology, the understanding of the pathophysiology behind the development of these lesions has evolved. From early theory published by Harvey Cushing and Percival Bailey in 1928, Tumors Arising from the Blood-vessels of the Brain: Angiomatous Malformations and Hemangioblastoma, which regarded AVMs as tumors arising from blood vessels, to the meticulous artistry of Dorcas Padget's embryological cataloguing of the cerebral vasculature in 1948, to the proliferative capillaropathy theory of Yasargil in 1987, to Ramey's 2014 hierarchical model of vascular development, there have been multiple hypotheses of congenital, developmental, and genetic two-hit theories in the pathogenesis of AVMs. Most recent evidence implicates somatic KRAS mutations in the cerebral endothelium, producing an important understanding of the pathogenesis of this disease, which is critical to the development of targeted therapeutics. The authors present the historical progression of their understanding of AVM pathogenesis. They focus on the foundation laid by early pioneers, discussing embryological anatomy and vasculogenesis, the prominent theories of AVM development that have emerged over time, and culminate in an overview of the most current understanding of the pathogenesis of these complex vascular lesions and the clinical implications of our scientific progress.

A novel method for ex-vivo latex angiography of the mouse brain.

INTRODUCTION: Latex perfusion is an effective tool to study cerebrovascular pathology in the animal brain. It provides, low-cost, high fidelity anatomical information on ex-vivo analysis, and can be utilized to study multiple, states. However, current methods of latex casting and tissue-clearance do not allow for immunohistochemical analysis following sample processing. This results in experiments that require increased numbers of animals to attain adequate data. NEW METHOD: In this paper, we present a modified latex perfusion and tissue processing protocol for ex-vivo analysis, of the cerebral vasculature. The method consists of injection of the arterial tree with liquid latex, followed by tissue clearance with a scale solution. RESULTS: Our results demonstrate effective and reliable perfusion of the murine cerebrovascular tree, rendering the arterial morphology of the brain in high detail, while allowing for post-perfusion, immunohistochemistry of the sample. COMPARISON WITH EXISTING METHOD: Our technique bypasses the limitations of previous latex angiography protocols by allowing for postperfusion, pathologic analysis of casted cerebrovascular tissue. CONCLUSION: This protocol provides a reliable, low-cost, method of cerebrovascular perfusion that reduces the number of animals required to generate robust data from latex-casted brain tissue.

Unexpected occlusion of the contralateral transverse sinus after stenting for idiopathic intracranial hypertension.

A woman in her thirties with intracranial hypertension underwent stenting of the right transverse-sigmoid (TS) junction with resolution of the pressure gradient. Due to persisting symptoms at follow-up, she underwent a repeat study showing a patent right TS stent but the non-dominant left transverse sinus, patent on initial studies, was now completely occluded. According to the positive feedback loop hypothesis, stenting of the right transverse sinus should have resulted in a reduction in intracranial pressures (confirmed by post-stenting lumbar puncture), but also an increase in left transverse sinus diameter, opposed to the occlusion seen on venography. This unexpected finding can be explained by the positive feedback loop hypothesis if a revision is made accounting for intramural venous pressures as an opposing force of venous sinus stenosis, as venous outflow obstruction in the dominant venous sinus pathway provided an increased intramural venous pressure in the non-dominant sinus facilitating patency against extramural pressures.

The Shift of the Intestinal Microbiome in the Innate Immunity-Deficient Mutant rde-1 Strain of C. elegans upon Orsay Virus Infection.

The status of intestinal microbiota is a determinant of host health. However, the alteration of the gut microbiota caused by the innate immune response to virus infection is unclear. Caenorhabditis elegans and its natural virus Orsay provide an excellent model of host-virus interactions. We evaluated the intestinal microbial community complexity of the wild-type N2 and the innate immunity-deficient mutant rde-1 (ne219) strains of C. elegans upon Orsay virus infection. The gut microbiota diversity was decreased in rde-1 (ne219) mutant animals, and a large number of genes were associated with the difference between infected and uninfected rde-1 (ne219) mutant animals. Therefore, this study provides the first evaluation of the alterations caused by Orsay virus on intestinal microbiota in wildtype and innate immunity-deficient animals using C. elegans as the model species. Our findings indicate that virus infection may alters the microbiome in animals with defective immune response.

Caenorhabditis elegans RIG-I Homolog Mediates Antiviral RNA Interference Downstream of Dicer-Dependent Biogenesis of Viral Small Interfering RNAs.

Dicer enzymes process virus-specific double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) to initiate specific antiviral defense by related RNA interference (RNAi) pathways in plants, insects, nematodes, and mammals. Antiviral RNAi in Caenorhabditis elegans requires Dicer-related helicase 1 (DRH-1), not found in plants and insects but highly homologous to mammalian retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), intracellular viral RNA sensors that trigger innate immunity against RNA virus infection. However, it remains unclear if DRH-1 acts analogously to initiate antiviral RNAi in C. elegans Here, we performed a forward genetic screen to characterize antiviral RNAi in C. elegans Using a mapping-by-sequencing strategy, we uncovered four loss-of-function alleles of drh-1, three of which caused mutations in the helicase and C-terminal domains conserved in RLRs. Deep sequencing of small RNAs revealed an abundant population of Dicer-dependent virus-derived small interfering RNAs (vsiRNAs) in drh-1 single and double mutant animals after infection with Orsay virus, a positive-strand RNA virus. These findings provide further genetic evidence for the antiviral function of DRH-1 and illustrate that DRH-1 is not essential for the sensing and Dicer-mediated processing of the viral dsRNA replicative intermediates. Interestingly, vsiRNAs produced by drh-1 mutants were mapped overwhelmingly to the terminal regions of the viral genomic RNAs, in contrast to random distribution of vsiRNA hot spots when DRH-1 is functional. As RIG-I translocates on long dsRNA and DRH-1 exists in a complex with Dicer, we propose that DRH-1 facilitates the biogenesis of vsiRNAs in nematodes by catalyzing translocation of the Dicer complex on the viral long dsRNA precursors.IMPORTANCE The helicase and C-terminal domains of mammalian RLRs sense intracellular viral RNAs to initiate the interferon-regulated innate immunity against RNA virus infection. Both of the domains from human RIG-I can substitute for the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans, suggesting an analogous role for DRH-1 as an intracellular dsRNA sensor to initiate antiviral RNAi. Here, we developed a forward genetic screen for the identification of host factors required for antiviral RNAi in C. elegans Characterization of four distinct drh-1 mutants obtained from the screen revealed that DRH-1 did not function to initiate antiviral RNAi. We show that DRH-1 acted in a downstream step to enhance Dicer-dependent biogenesis of viral siRNAs in C. elegans As mammals produce Dicer-dependent viral siRNAs to target RNA viruses, our findings suggest a possible role for mammalian RLRs and interferon signaling in the biogenesis of viral siRNAs.