The emerging association between COVID-19 and acute stroke
Authors: Laura K. Stein, Naomi A. Mayman, Mandip S. Dhamoon, Johanna T. Fifi
Journal: Trends in Neurosciences (2021)

Growing comparisons of COVID-19 positive and COVID-19 negative stroke cohorts support an association between COVID-19 and stroke.COVID-19-related stroke can be severe and has impacted young patients and minimally symptomatic individuals, as well as patients with traditional cerebrovascular risk factors and severe disease.When compared with stroke patients without COVID-19, morbidity and mortality are much worse in patients with stroke and COVID-19.Etiology of COVID-19-related stroke is frequently unknown and the pathogenesis may be related to coagulopathy, inflammation, endotheliopathy, and platelet activation.Anticoagulation may benefit those hospitalized with severe COVID-19, including those diagnosed with stroke. Prior to COVID-19, only two human-tropic coronaviruses resulted in epidemics and cerebrovascular disease was rarely reported. Evidence now suggests that 1–6% of hospitalized COVID-19 patients develop stroke. According to some reports, stroke risk is more than sevenfold greater in patients with COVID-19 than influenza. Concerningly, outcomes of COVID-19-related stroke are often worse than in stroke patients without COVID-19 from the same cohorts. In this review, we highlight the emerging association between COVID-19 and stroke and discuss putative pathogenetic mechanisms. Etiology of stroke in COVID-19 patients is likely multifactorial, related to coagulopathy, inflammation, platelet activation, and alterations to the vascular endothelium. Significant work remains to be done to better understand the pathogenesis of COVID-19-related stroke and for designing optimal primary and secondary prevention strategies. Prior to COVID-19, only two human-tropic coronaviruses resulted in epidemics and cerebrovascular disease was rarely reported. Evidence now suggests that 1–6% of hospitalized COVID-19 patients develop stroke. According to some reports, stroke risk is more than sevenfold greater in patients with COVID-19 than influenza. Concerningly, outcomes of COVID-19-related stroke are often worse than in stroke patients without COVID-19 from the same cohorts. In this review, we highlight the emerging association between COVID-19 and stroke and discuss putative pathogenetic mechanisms. Etiology of stroke in COVID-19 patients is likely multifactorial, related to coagulopathy, inflammation, platelet activation, and alterations to the vascular endothelium. Significant work remains to be done to better understand the pathogenesis of COVID-19-related stroke and for designing optimal primary and secondary prevention strategies. On 11 March 2020, the World Health Organization declared COVID-19 a global pandemic. Previously, only two of the coronaviruses known to infect humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), resulted in epidemics [1.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33298) Google Scholar, 2.Ksiazek T.G. et al.A novel coronavirus associated with severe acute respiratory syndrome.N. Engl. J. Med. 2003; 348: 1953-1966Crossref PubMed Scopus (3571) Google Scholar, 3.Saad M. et al.Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia.Int. J. Infect. Dis. 2014; 29: 301-306Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar]. 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In a review of over 230 000 patients who received advanced stroke imaging with automated processing in more than 850 hospitals in the United States, the number of patients who underwent acute stroke imaging decreased by 39% during a 14-day period from 26 March 2020 through 8 April 2020 compared with a 29-day period from 1 February 2020 through 29 February 2020 [20.Kansagra A.P. et al.Collateral effect of covid-19 on stroke evaluation in the United States.N. Engl. J. Med. 2020; 383: 400-401Crossref PubMed Scopus (351) Google Scholar]. Concerningly, this decrease was seen across all ages, sex, and stroke severity, as well as throughout the country. Meanwhile, the World Stroke Organization reported that nearly 90% of members surveyed from 100 countries worldwide had seen a decrease in stroke admissions, with median decrease in stroke admissions of 50–70% [21.World Stroke Organization The Global Impact of COVID-19 on Stroke - Survey Report from Prof. Marc Fischer, WSO President-Elect. WSO, 2020Google Scholar]. Reasons for the decline in observed stroke volumes are not entirely clear, but may be related to fewer patients seeking care, mortality due to COVID-19, or a true decrease in incidence perhaps resulting from changes in lifestyle during pandemic conditions. We suspect that fewer patients seeking care for mild stroke, as well as perhaps greater mortality in patients with traditional cerebrovascular risk factors, contribute significantly to the observed decline. A true decrease seems unlikely, we would argue, as stay at home orders, psychosocial stress, and poor utilization of routine medical care likely worsen traditional stroke risk factors. In fact, a recent study demonstrated that the decrease in stroke-related emergency medical service calls was associated with excess stroke deaths in 23 states and New York City [22.Sharma R. et al.Excess cerebrovascular mortality in the United States during the COVID-19 pandemic.Stroke. 2021; 52: 563-572Crossref PubMed Scopus (29) Google Scholar]. In the following sections, we discuss studies suggesting an association between COVID-19 and an enhanced risk for stroke. We also outline a number of putative pathophysiological mechanisms that could underlie the observed association (Figure 1). Of note, in addition to the morbidity of COVID-19-related stroke cases and potential excess of stroke-related deaths during the pandemic, one must worry about future impact on those with mild stroke who possibly failed to seek adequate care and may face greater long-term risk of stroke and its complications. Respiratory viruses are potential triggers of stroke, as well as other infections such as urinary tract infections and sepsis [23.Elkind M.S. et al.Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study.Stroke. 2011; 42: 1851-1856Crossref PubMed Scopus (94) Google Scholar, 24.Sebastian S. et al.Infection as a stroke trigger.Stroke. 2019; 50: 2216-2218Crossref PubMed Scopus (45) Google Scholar, 25.Smeeth L. et al.Risk of myocardial infarction and stroke after acute infection or vaccination.N. Engl. J. Med. 2004; 351: 2611-2618Crossref PubMed Scopus (1129) Google Scholar, 26.Elkind M.S.V. et al.Infection as a stroke risk factor and determinant of outcome after stroke.Stroke. 2020; 51: 3156-3168Crossref PubMed Scopus (122) Google Scholar]. Many viral infections, including varicella zoster, herpes simplex virus, human immunodeficiency virus, cytomegalovirus, and parvovirus B19, have also been implicated in the pathogenesis of stroke through arteriopathy, inflammation, and atherosclerosis [27.Miller E.C. Elkind M.S. Infection and stroke: an update on recent progress.Curr. Neurol. Neurosci. Rep. 2016; 16: 2Crossref PubMed Scopus (36) Google Scholar]. As a highly prevalent respiratory virus, influenza provides an especially useful historical comparison with COVID-19 [28.Chung J.R. et al.Effects of influenza vaccination in the United States during the 2018-2019 influenza season.Clin. Infect. Dis. 2020; 71: e368-e376Crossref PubMed Scopus (78) Google Scholar]. In the United States, for instance, in 2019 influenza infected over 30 million individuals and resulted in hospitalizations of over 400 000 patients. A case-crossover study of over 36 000 California patients hospitalized for ischemic stroke found that 1.5% had infection with influenza-like illness in the prior year. Odds were highest for infection within 15 days of hospitalization for stroke and the greatest odds for ischemic stroke were in patients younger than 45 years [29.Boehme A.K. et al.Influenza-like illness as a trigger for ischemic stroke.Ann. Clin. Transl. Neurol. 2018; 5: 456-463Crossref PubMed Scopus (99) Google Scholar]. A case-control study of patients admitted for stroke found an approximately 50% reduction in odds associated with influenza vaccination that year, further supporting the association between influenza and stroke [30.Lavallée P. et al.Association between influenza vaccination and reduced risk of brain infarction.Stroke. 2002; 33: 513-518Crossref PubMed Scopus (175) Google Scholar]. Recently, New York City COVID-19 patients were compared with historical influenza controls, with stroke affecting 1.6% of patients with COVID-19 versus 0.2% with influenza and more than sevenfold greater adjusted odds of ischemic stroke in patients with COVID-19 compared with influenza [31.Merkler A.E. et al.Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza.JAMA Neurol. 2020; 77: 1366-1372Crossref Scopus (428) Google Scholar]. However, the extent to which COVID-19 increases risk of stroke, and by what mechanisms, has not been fully elucidated (see Outstanding questions). In a retrospective single-center report on patients in Wuhan early in the pandemic, approximately 5.0% of hospitalized patients were reported to have stroke with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 90.9% of whom suffered ischemic stroke compared with 9.1% (n = 1) intracerebral hemorrhage [32.Li Y. et al.Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.Stroke Vasc. Neurol. 2020; 5: 279Crossref PubMed Scopus (522) Google Scholar]. In the first detailed report of neurologic manifestations in three centers in Wuhan, 5.7% of 88 patients with severe infection had stroke, four ischemic and one intracerebral hemorrhage, compared with only 0.8% of patients with nonsevere infection [33.Mao L. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (4891) Google Scholar]. Notably, one-third of patients with stroke had not yet demonstrated typical COVID-19 symptoms on presentation. Although there is no uniform case definition for COVID-19-related stroke, multiple comparisons of stroke patients with and without COVID-19 support the association between COVID-19 and cerebrovascular disease. A predominance of ischemic stroke has been reported, similar to that of the typical stroke epidemiology, but with a significant increase in a cryptogenic etiology when classified by TOAST classification [34.Kolominsky-Rabas P.L. et al.Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study.Stroke. 2001; 32: 2735-2740Crossref PubMed Scopus (1060) Google Scholar,35.Adams H.P. et al.Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.Stroke. 1993; 24: 35-41Crossref PubMed Scopus (9694) Google Scholar]. Studies have described large vessel involvement, including in younger patients without traditional risk factors or typical manifestations of COVID-19 at stroke onset, with a disproportionate impact on male and non-white individuals [36.Oxley T.J. et al.Large-vessel stroke as a presenting feature of covid-19 in the young.N. Engl. J. Med. 2020; 382e60Crossref PubMed Scopus (1558) Google Scholar, 37.de Havenon A. et al.Endovascular thrombectomy in acute ischemic stroke patients with COVID-19: prevalence, demographics, and outcomes.J. NeuroIntervention. 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Most concerningly, outcomes among COVID-19 stroke patients seem much worse than in stroke patients without COVID-19 [40.Yaghi S. et al.SARS-CoV-2 and stroke in a New York healthcare system.Stroke. 2020; 51: 2002-2011Crossref PubMed Scopus (519) Google Scholar, 41.Katz J.M. et al.Cerebrovascular complications of COVID-19.Stroke. 2020; 51: e227-e231Crossref PubMed Scopus (93) Google Scholar, 42.Benussi A. et al.Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.Neurology. 2020; 95: e910-e920Crossref PubMed Scopus (169) Google Scholar]. Now that more than 10 months have passed since official pandemic declaration, experience in caring for COVID-19 patients with stroke has grown around the world. With more than 100 million infections and 2.1 million deaths globally as of the end of January, the apparent association between COVID-19 and stroke is growing. The incidence of COVID-19-related stroke reported in the literature has ranged from 1–6% among patients hospitalized with COVID-19 [31.Merkler A.E. et al.Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza.JAMA Neurol. 2020; 77: 1366-1372Crossref Scopus (428) Google Scholar,33.Mao L. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (4891) Google Scholar,40.Yaghi S. et al.SARS-CoV-2 and stroke in a New York healthcare system.Stroke. 2020; 51: 2002-2011Crossref PubMed Scopus (519) Google Scholar], with higher incidence in the setting of more severe infection [31.Merkler A.E. et al.Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza.JAMA Neurol. 2020; 77: 1366-1372Crossref Scopus (428) Google Scholar,33.Mao L. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (4891) Google Scholar,40.Yaghi S. et al.SARS-CoV-2 and stroke in a New York healthcare system.Stroke. 2020; 51: 2002-2011Crossref PubMed Scopus (519) Google Scholar,43.Tsivgoulis G. et al.Ischemic stroke epidemiology during the COVID-19 pandemic: navigating uncharted waters with changing tides.Stroke. 2020; 51: 1924-1926Crossref PubMed Scopus (50) Google Scholar, 44.Lodigiani C. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.Thromb. Res. 2020; 191: 9-14Abstract Full Text Full Text PDF PubMed Scopus (1507) Google Scholar, 45.Klok F.A. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb. Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (3333) Google Scholar]. In the sections that follow, we focus on some of the largest-scale studies to date, both at the New York City epicenter and from other locations in the United States and around the world. As the COVID-19 surge reached the United States in March 2020, New York City (in which the authors of this article are based) became one of its primary epicenters. Several concerning early clinical observations were made. Within our New York City health system, five cases of large-vessel stroke were reported in patients under 50 years of age in the 2 week period from 23 March 2020 to 7 April 2020 [36.Oxley T.J. et al.Large-vessel stroke as a presenting feature of covid-19 in the young.N. Engl. J. Med. 2020; 382e60Crossref PubMed Scopus (1558) Google Scholar]. Compared with every 2-week period over the previous year, this was more than five times the number of patients under 50 years treated. Our group, and others, noted both occlusive and non-occlusive thrombi in the internal carotid artery in patients with and without underlying atherosclerotic risk factors [46.Fara M.G. et al.Macrothrombosis and stroke in patients with mild covid-19 infection.J. Thromb. Haemost. 2020; 18: 2031-2033Crossref PubMed Scopus (89) Google Scholar,47.Mohamud A.Y. et al.Intraluminal carotid artery thrombus in COVID-19: another danger of cytokine storm?.Am. J. Neuroradiol. 2020; 41: 1677-1682PubMed Google Scholar]. Despite many reports that thrombotic events seemed to be associated with disease severity, multiple patients with large-vessel stroke had not displayed any symptoms of COVID-19 prior to presentation with stroke [33.Mao L. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (4891) Google Scholar,36.Oxley T.J. et al.Large-vessel stroke as a presenting feature of covid-19 in the young.N. Engl. J. Med. 2020; 382e60Crossref PubMed Scopus (1558) Google Scholar,44.Lodigiani C. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.Thromb. Res. 2020; 191: 9-14Abstract Full Text Full Text PDF PubMed Scopus (1507) Google Scholar,47.Mohamud A.Y. et al.Intraluminal carotid artery thrombus in COVID-19: another danger of cytokine storm?.Am. J. Neuroradiol. 2020; 41: 1677-1682PubMed Google Scholar,48.Bilaloglu S. et al.Thrombosis in hospitalized patients with COVID-19 in a New York City health system.JAMA. 2020; 324: 799-801Crossref PubMed Scopus (568) Google Scholar]. In our retrospective series, 1.9% (n = 105) of the 5469 COVID-19 patients admitted to our health system during March and April were diagnosed with stroke [49.Dhamoon M.S. et al.Acute cerebrovascular events with COVID-19 infection.Stroke. 2021; 52: 48-56Crossref PubMed Scopus (52) Google Scholar]. The majority of COVID-19 positive stroke patients suffered ischemic stroke (79.1%) followed by 15.2% intracerebral hemorrhage, 3.8% subarachnoid hemorrhage, and 1.9% transient ischemic attack. Ischemic stroke etiology was more than twice as likely to be cryptogenic in COVID-19 positive patients compared with COVID-19 negative (51.8% versus 22.3%), and small vessel and cardioembolic strokes occurred less frequently compared with historical controls. The majority of COVID-19 stroke patients had abnormalities in peak inflammatory markers, including D-dimer, erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and interleukin-6. Additionally, ischemic stroke location was more commonly lobar in COVID-19 patients than COVID-19 negative. Most concerningly, COVID-19 positive stroke patients had longer length of stay, were more likely to require intensive care unit care, had a greater rate of neurological worsening during admission, and were more than 2.5 times more likely to experience in-hospital death compared with COVID-19 negative stroke patients. A smaller retrospective cohort study of 32 ischemic stroke patients in New York City from 15 March 2020 to 19 April 2020 compared COVID-19 stroke patients with concurrent and historical COVID-19 negative controls [40.Yaghi S. et al.SARS-CoV-2 and stroke in a New York healthcare system.Stroke. 2020; 51: 2002-2011Crossref PubMed Scopus (519) Google Scholar]. This study reported ischemic stroke in 0.9% of hospitalized patients. Cryptogenic stroke was also twice as likely in this smaller cohort of COVID-19 stroke patients (65.6% versus 30.4% COVID-19 negative, P = 0.003). Additionally, in-hospital death was even more common, occurring in 64.6% of COVID-19 stroke patients (versus 9.3% concurrent controls, P < 0.001). Another retrospective series compared 86 COVID-19 stroke patients in New York City and Long Island between 14 March 2020 and 26 April 2020 with historical controls [41.Katz J.M. et al.Cerebrovascular complications of COVID-19.Stroke. 2020; 51: e227-e231Crossref PubMed Scopus (93) Google Scholar]. Stroke subtype was comparable with typical stroke epidemiology and multivascular territory strokes occurred in 45.8%. When compared with historical controls, COVID-19 positive patients were more commonly black or multiracial minority (58.1% versus 36.9%; P = 0.001), more likely to have an in-hospital stroke (47.7% versus 5.0%; P < 0.001), and less likely to have a cerebrovascular history (10.5% versus 23.1%; P = 0.008). Mortality was also high in this COVID-19 stroke cohort, occurring in 29.1% (versus 9.0% of controls, P < 0.001). While the New York City experience is likely representative of manifestations of COVID-19 in a population with a high prevalence of disease, there are likely several factors that may be unique to the New York City experience. The data comes from the early surge in the United States, when experience in treating the disease was limited and hospitals in the region were overwhelmed. In March and April, only the sickest COVID-19 patients were admitted, patients with and without COVID-19 were often avoiding seeking healthcare unless absolutely necessary and availability of staff and testing likely impacted utilization of diagnostic testing. Furthermore, centers with high volumes of COVID-19 may have been quicker to implement treatment protocols, including around prophylactic and treatment dose anticoagulation. Outside of New York City, similar associations between COVID-19 and severe stroke have been described. A retrospective study of 111 COVID-19 patients admitted to a neurological hospital unit in Italy during the surge from 21 February 2020 to 5 April 2020 reported cerebrovascular disease in 76.8% of those COVID-19 positive compared with 58.1% of those COVID-19 negative [42.Benussi A. et al.Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.Neurology. 2020; 95: e910-e920Crossref PubMed Scopus (169) Google Scholar]. There was no significant difference in type of cerebrovascular event between the COVID-19 positive and negative stroke cohorts. Patients with COVID-19 had higher platelets, erythrocyte sedimentation rate, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, prothrombin, and fibrinogen than COVID-19 negative patients, and lower lymphocyte count. Similar to the New York City experience, in-hospital mortality among COVID-19 stroke patients was also high (34.9% versus 5.9% of COVID-19 negative, P < 0.001). Much can be learned from pooled, multicenter data. In a multinational observational study of patients with COVID-19 and stroke patients from 31 hospitals in the Society of Vascular and Interventional Neurology registry, 1.13% (n = 172) of 14 483 COVID-19 patients were diagnosed with stroke [50.Siegler J.E. et al.Cerebrovascular events and outcomes in hospitalized patients with COVID-19: the SVIN COVID-19 Multinational Registry.Int. J. Stroke. 2020; (Published online September 30, 2020. https://doi.org/10.1177/1747493020959216)Crossref Scopus (105) Google Scholar]. The majority (n = 156) experienced ischemic stroke. Interestingly, incidence ranged from 0.19% to >5% and was less common at centers that treated more COVID-19 patients. Similar to other series, cryptogenic stroke was more than twice as common than in historical controls and cardioembolism accounted for just over one-quarter of events. Additionally, slightly more than 38% of ischemic and 58% of hemorrhagic stroke patients suffered in-hospital mortality. Another multinational study of 174 consecutive patients with COVID-19 and ischemic stroke from 28 centers in 16 countries in the Global COVID-19 Stroke Registry demonstrated similarly severe stroke in patients with COVID-19 [51.Ntaios G. et al.Characteristics and outcomes in patients with COVID-19 and acute ischemic stroke.Stroke. 2020; 51: e254-e258Crossref PubMed Scopus (213) Google Scholar]. Using propensity matching to patients in the Lausanne Registry, patients with COVID-19 were found to have higher National Institutes of Health Stroke Scale score as well as greater risk of severe disability and death. One of the largest meta-analyses to date has demonstrated similar findings. Of 67 845 patients from 18 cohort studies with COVID-19, 1.1% were hospitalized with ischemic stroke and 0.2% hemorrhagic stroke [52.Katsanos A.H. et al.The impact of SARS-CoV-2 on stroke epidemiology and care: a meta-analysis.Ann. Neurol. 2021; 89: 380-388Crossref PubMed Scopus (91) Google Scholar]. When compared with COVID-19 negative controls, odds of ischemic stroke were more than 3.5 times greater and cryptogenic stroke almost four times greater. Concerningly, odds of in-hospital mortality were more than five times greater among COVID-19 stroke patients compared with COVID-19 negative controls. Epidemiologic studies suggest that large-vessel occlusion stroke typically accounts for about 38% of ischemic stroke [53.Malhotra K. et al.Ischemic strokes due to large-vessel occlusions contribute disproportionately to stroke-related dependence and death: a review.Front. Neurol. 2017; 8: 651Crossref PubMed Scopus (214) Google Scholar]. However, emergent large-vessel occlusion (ELVO) stroke is more severe and disabling, accounting for approximately 60% of post-stroke functional dependence or death [53.Malhotra K. et al.Ischemic strokes due to large-vessel occlusions contribute disproportionately to stroke-related dependence and death: a review.Front. Neurol. 2017; 8: 651Crossref PubMed Scopus (214) Google Scholar]. At one hospital outside of Philadelphia, identified cases of mild stroke declined during the lockdown period of the pandemic. However, patients with ELVO continued to present, likely because of the severity of their neurologic deficits, resulting in a greater percentage of ELVO stroke [16.Siegler J.E. et al.Falling stroke rates during COVID-19 pandemic at a comprehensive stroke center.J. Stroke Cerebrovasc. Dis. 2020; 29: 104953Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. Many COVID-19 associated stroke series have reported mean ages of thrombectomy patients younger than 60 years, which is younger than concurrent controls and the typical age of thrombectomy patients [54.Fifi J.T. Mocco J. COVID-19 related stroke in young individ