Reversible Cerebral Vasoconstriction Syndrome in Patients with Coronavirus Disease: A Multicenter Case Series.

BACKGROUND AND OBJECTIVES: RCVS (Reversible Cerebral Vasoconstrictive Syndrome) is a condition associated with vasoactive agents that alter endothelial function. There is growing evidence that endothelial inflammation contributes to cerebrovascular disease in patients with coronavirus disease 2019 (COVID-19). In our study, we describe the clinical features, risk factors, and outcomes of RCVS in a multicenter case series of patients with COVID-19. MATERIALS AND METHODS: Multicenter retrospective case series. We collected clinical characteristics, imaging, and outcomes of patients with RCVS and COVID-19 identified at each participating site. RESULTS: Ten patients were identified, 7 women, ages 21 - 62 years. Risk factors included use of vasoconstrictive agents in 7 and history of migraine in 2. Presenting symptoms included thunderclap headache in 5 patients with recurrent headaches in 4. Eight were hypertensive on arrival to the hospital. Symptoms of COVID-19 included fever in 2, respiratory symptoms in 8, and gastrointestinal symptoms in 1. One patient did not have systemic COVID-19 symptoms. MRI showed subarachnoid hemorrhage in 3 cases, intraparenchymal hemorrhage in 2, acute ischemic stroke in 4, FLAIR hyperintensities in 2, and no abnormalities in 1 case. Neurovascular imaging showed focal segment irregularity and narrowing concerning for vasospasm of the left MCA in 4 cases and diffuse, multifocal narrowing of the intracranial vasculature in 6 cases. Outcomes varied, with 2 deaths, 2 remaining in the ICU, and 6 surviving to discharge with modified Rankin scale (mRS) scores of 0 (n=3), 2 (n=2), and 3 (n=1). CONCLUSIONS: Our series suggests that patients with COVID-19 may be at risk for RCVS, particularly in the setting of additional risk factors such as exposure to vasoactive agents. There was variability in the symptoms and severity of COVID-19, clinical characteristics, abnormalities on imaging, and mRS scores. However, a larger study is needed to validate a causal relationship between RCVS and COVID-19.

COVID-19 Related Acute Hemorrhagic Necrotizing Encephalitis: A Report of Two Cases and Literature Review.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, has proven neurotropism and causes a multitude of neurologic manifestations. Acute hemorrhagic necrotizing encephalitis (AHNE), though rare, can be seen in patients with severe infection and is associated with devastating neurologic outcomes. The true prevalence of this syndrome is unknown due to underrecognition, difficulty in timely acquisition of neuroimaging, and high mortality in this subset of patients escaping detection. It is a distinct clinicoradiological syndrome, with patients suffering from rapidly worsening encephalopathy and coma within the first two weeks of severe illness and hemorrhagic necrotizing parenchymal changes on neuroimaging. The pathophysiology of this syndrome is unclear but hypothesized to occur due to cytokine storm, blood-brain-barrier dysfunction, and direct viral-mediated endotheliopathy. Diagnosis requires a high index of suspicion in patients who have unexplained persistent severe encephalopathy associated with COVID-19 infection. Most patients have elevated systemic inflammatory markers and severe lung disease with hypoxic respiratory failure requiring mechanical ventilation. MRI is the imaging modality of choice, with a distinct neuroimaging pattern. CSF (cerebrospinal fluid) studies have a low yield for viral particle detection with currently available testing. While long-term outcomes are unclear, early immunomodulatory treatment with intravenous immunoglobulin, plasma exchange, and steroids may portend a favorable outcome. We discuss two cases of COVID-19 related AHNE and also include a pertinent literature search of similar cases in PubMed to consolidate the AHNE clinical syndrome, neuroimaging characteristics, management strategies, and reported short-term prognosis.

Regional Intervention of Stroke Care to Increase Thrombolytic Therapy for Acute Ischemic Stroke.

Background and Purpose- The aims of this study were to investigate the effect of an intervention to unblind data on r-tPA (recombinant tissue-type plasminogen activator) administration and sharing data with chief executive officers of participating hospitals, on r-tPA administration rates postintervention and on potential healthcare cost savings implemented at 26 Southeast Texas Regional Advisory Council hospitals. Methods- Retrospective analysis of prospective data on thrombolytic therapy from 26 Southeast Texas Regional Advisory Council hospitals, collected between April 2014 and June 2016. The control (blinded) period (Q2-2014 to Q2-2015) was followed by unblinding (Q3-2015). Results- Intervention was associated with 21.1% increase in r-tPA administration rates, with 38.5% increase in r-tPA administration with door-to-needle time ≤60 minutes. An absolute increase in r-tPA administration of 2.1% was seen with an average lifetime cost savings of $3.6 million. Conclusions- Transparent regional data sharing was associated with improved r-tPA administration and healthcare cost savings.

Characterization of the interaction between heterodimeric αvß6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics.

Urokinase plasminogen activator receptor (uPAR) and the epithelial integrin αvß6 are thought to individually play critical roles in cancer metastasis. These observations have been highlighted by the recent discovery (by proteomics) of an interaction between these two molecules, which are also both implicated in the epithelial-mesenchymal transition (EMT) that facilitates escape of cells from tissue barriers and is a common signature of cancer metastases. In this study, orthogonal in cellulo and in vitro functional proteomic approaches were used to better characterize the uPAR·αvß6 interaction. Proximity ligation assays (PLA) confirmed the uPAR·αvß6 interaction on OVCA429 (ovarian cancer line) and four different colon cancer cell lines including positive controls in cells with de novo ß6 subunit expression. PLA studies were then validated using peptide arrays, which also identified potential physical sites of uPAR interaction with αvß6, as well as verifying interactions with other known uPAR ligands (e.g., uPA, vitronectin) and individual integrin subunits (i.e., αv, ß1, ß3, and ß6 alone). Our data suggest that interaction with uPAR requires expression of the complete αß heterodimer (e.g., αvß6), not individual subunits (i.e., αv, ß1, ß3, or ß6). Finally, using in silico structural analyses in concert with these functional proteomics studies, we propose and demonstrate that the most likely unique sites of interaction between αvß6 and uPAR are located in uPAR domains II and III.

A site for direct integrin αvß6·uPAR interaction from structural modelling and docking.

Integrin αvß6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvß6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvß6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the ß-propeller region of integrin α-chain interacting with uPAR. Interaction of αvß6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvß6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvß6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.