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      Ischemic stroke in COVID-19: An urgent need for early identification and management

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          Abstract

          Objective

          In the setting of the Coronavirus Disease 2019 (COVID-19) global pandemic caused by SARS-CoV-2, a potential association of this disease with stroke has been suggested. We aimed to describe the characteristics of patients who were admitted with COVID-19 and had an acute ischemic stroke (AIS).

          Methods

          This is a case series of PCR-confirmed COVID-19 patients with ischemic stroke admitted to an academic health system in metropolitan Atlanta, Georgia (USA) between March 24 th, 2020 and July 17 th, 2020. Demographic, clinical, and radiographic characteristics were described.

          Results

          Of 396 ischemic stroke patients admitted during this study period, 13 (2.5%) were also diagnosed with COVID-19. The mean age of patients was 61.6 ± 10.8 years, 10 (76.9%) male, 8 (61.5%) were Black Americans, mean time from last normal was 4.97 ± 5.1 days, and only one received acute reperfusion therapy. All 13 patients had at least one stroke-associated co-morbidity. The predominant pattern of ischemic stroke was embolic with 4 explained by atrial fibrillation. COVID-19 patients had a significantly higher rate of cryptogenic stroke than non-COVID-19 patients during the study period (69% vs 17%, p = 0.0001).

          Conclusions

          In our case series, ischemic stroke affected COVID-19 patients with traditional stroke risk factors at an age typically seen in non-COVID populations, and mainly affecting males and Black Americans. We observed a predominantly embolic pattern of stroke with a higher than expected rate of cryptogenic strokes, a prolonged median time to presentation and symptom recognition limiting the use of acute reperfusion treatments. These results highlight the need for increased community awareness, early identification, and management of AIS in COVID-19 patients.

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          Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

          Ling Mao, Huijuan Jin, Mengdie Wang … (2020)
          The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations.
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            Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

            Lei Fang, George Karakiulakis, Michael Roth (2020)
            The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues 1 were cerebrovascular diseases (22%) and diabetes (22%). Another study 2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, 3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study. Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. 4 The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). 4 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. 5 ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. If this hypothesis were to be confirmed, it could lead to a conflict regarding treatment because ACE2 reduces inflammation and has been suggested as a potential new therapy for inflammatory lung diseases, cancer, diabetes, and hypertension. A further aspect that should be investigated is the genetic predisposition for an increased risk of SARS-CoV-2 infection, which might be due to ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in Asian populations. Summarising this information, the sensitivity of an individual might result from a combination of both therapy and ACE2 polymorphism. We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs. Based on a PubMed search on Feb 28, 2020, we did not find any evidence to suggest that antihypertensive calcium channel blockers increased ACE2 expression or activity, therefore these could be a suitable alternative treatment in these patients. © 2020 Juan Gaertner/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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              Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

              Thomas Oxley, J Mocco, Shahram Majidi … (2020)
              To rapidly communicate information on the global clinical effort against Covid-19, the Journal has initiated a series of case reports that offer important teaching points or novel findings. The case reports should be viewed as observations rather than as recommendations for evaluation or treatment. In the interest of timeliness, these reports are evaluated by in-house editors, with peer review reserved for key points as needed. We report five cases of large-vessel stroke in patients younger than 50 years of age who presented to our health system in New York City. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in all five patients. Cough, headache, and chills lasting 1 week developed in a previously healthy 33-year-old woman (Patient 1) (Table 1). She then had progressive dysarthria with both numbness and weakness in the left arm and left leg over a period of 28 hours. She delayed seeking emergency care because of fear of Covid-19. When she presented to the hospital, the score on the National Institutes of Health Stroke Scale (NIHSS) was 19 (scores range from 0 to 42, with higher numbers indicating greater stroke severity), and computed tomography (CT) and CT angiography showed a partial infarction of the right middle cerebral artery with a partially occlusive thrombus in the right carotid artery at the cervical bifurcation. Patchy ground-glass opacities in bilateral lung apices were seen on CT angiography, and testing to detect SARS-CoV-2 was positive. Antiplatelet therapy was initiated; it was subsequently switched to anticoagulation therapy. Stroke workup with echocardiography and magnetic resonance imaging of the head and neck did not reveal the source of the thrombus. Repeat CT angiography on hospital day 10 showed complete resolution of the thrombus, and the patient was discharged to a rehabilitation facility. Over a 2-week period from March 23 to April 7, 2020, a total of five patients (including the aforementioned patient) who were younger than 50 years of age presented with new-onset symptoms of large-vessel ischemic stroke. All five patients tested positive for Covid-19. By comparison, every 2 weeks over the previous 12 months, our service has treated, on average, 0.73 patients younger than 50 years of age with large-vessel stroke. On admission of the five patients, the mean NIHSS score was 17, consistent with severe large-vessel stroke. One patient had a history of stroke. Other pertinent clinical characteristics are summarized in Table 1. A retrospective study of data from the Covid-19 outbreak in Wuhan, China, showed that the incidence of stroke among hospitalized patients with Covid-19 was approximately 5%; the youngest patient in that series was 55 years of age. 1 Moreover, large-vessel stroke was reported in association with the 2004 SARS-CoV-1 outbreak in Singapore. 2 Coagulopathy and vascular endothelial dysfunction have been proposed as complications of Covid-19. 3 The association between large-vessel stroke and Covid-19 in young patients requires further investigation. Social distancing, isolation, and reluctance to present to the hospital may contribute to poor outcomes. Two patients in our series delayed calling an ambulance because they were concerned about going to a hospital during the pandemic.
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                Author and article information

                Contributors
                Dinesh V. Jillella:
                ORCID: http://orcid.org/0000-0002-5399-0170
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Nicholas J. Janocko: Role: ConceptualizationRole: Data curationRole: Writing – original draftRole: Writing – review & editing
                Fadi Nahab: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Karima Benameur:
                ORCID: http://orcid.org/0000-0002-4599-5705
                Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                James G. Greene: Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Wendy L. Wright: Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Mahmoud Obideen: Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Srikant Rangaraju: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Muhammad Adrish: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 18 September 2020
                Publication date Collection: 2020
                Publication date PMC-release: 18 September 2020
                Volume: 15
                Issue: 9
                Electronic Location Identifier: e0239443
                Affiliations
                [1 ] Department of Neurology, Emory University School of Medicine and Grady Memorial Hospital, Atlanta, GA, United States of America
                [2 ] Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States of America
                BronxCare Health System, Affiliated with Icahn School of Medicine at Mount Sinai, NY, USA, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5399-0170
                http://orcid.org/0000-0002-4599-5705
                Article
                Publisher ID: PONE-D-20-18864
                DOI: 10.1371/journal.pone.0239443
                PMC ID: 7500690
                PubMed ID: 32946512
                SO-VID: 22e0e83d-2c1d-4a4e-9c6a-76a860e9a33c
                Copyright © © 2020 Jillella et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 19 June 2020
                Date accepted : 4 September 2020
                Page count
                Figures: 1, Tables: 1, Pages: 8
                Funding
                The author(s) received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Ischemic Stroke
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Ischemic Stroke
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Stroke
                Subject: Ischemic Stroke
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Infectious Diseases
                Subject: Viral Diseases
                Subject: Covid 19
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cerebrovascular Diseases
                Subject: Stroke
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Stroke
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Signs and Symptoms
                Subject: Infarction
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Cardiovascular Diseases
                Subject: Cardiovascular Disease Risk
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Cardiovascular Medicine
                Subject: Cardiovascular Diseases
                Subject: Cardiovascular Disease Risk
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Arrhythmia
                Subject: Atrial Fibrillation
                Custom metadata
                Data Availability Emory University School of Medicine owns the dataset and de-identified / limited data sets could be requested via the legal/ethics committee of the University. I am giving the contact details of our legal expert - Zainab Wurie Harvey, JD, Assistant Director, Faculty Affairs Administration, Emory School of Medicine, Dean’s Office | Room 416, Ph: 404-727-3407, Email: zwurie@ 123456emory.edu . Please direct any specific queries regarding this to her.
                Outbreaks COVID-19

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