Pathomechanisms and Treatment Implications for Stroke in COVID-19: A Review of the Literature

Abstract

Stroke in patients with COVID-19 has received increasing attention throughout the global COVID-19 pandemic, perhaps due to the substantial disability and mortality that can result when the two conditions co-occur. We reviewed the existing literature and found that the proposed pathomechanism underlying COVID-19-associated ischemic stroke is broadly divided into the following three categories: vasculitis, endothelialitis, and endothelial dysfunction; hypercoagulable state; and cardioembolism secondary to cardiac dysfunction. There has been substantial debate as to whether there is a causal link between stroke and COVID-19. However, the distinct phenotype of COVID-19-associated strokes, with multivessel territory infarcts, higher proportion of large vessel occlusions, and cryptogenic stroke mechanism, that emerged in pooled analytic comparisons with non-COVID-19 strokes is compelling. Further, in this article, we review the various treatment approaches that have emerged as they relate to the proposed pathomechanisms. Finally, we briefly cover the logistical challenges, such as delays in treatment, faced by providers and health systems; the innovative approaches utilized, including the role of tele-stroke; and the future directions in COVID-19-associated stroke research and healthcare delivery.

Keywords: COVID-19; SARS-CoV-2; acute ischemic stroke; cryptogenic stroke; intracerebral hemorrhage; management of stroke; pathomechanism stroke; pathomechanisms; pathophysiology; treatments.

Figure 1

Proposed pathomechanisms of acute ischemic stroke in COVID-19 infection. (A) Hypercoagulability in COVID-19 is presumed to be caused by an increase in inflammatory and procoagulant markers that lead to VTE and/or platelet-fibrin thrombotic deposits. (B) Endothelial dysfunction/endothelialitis involves SARS-CoV-2 interaction with the ACE2 receptor on the endothelial cells. This interaction leads to an inflammatory response, upregulation of the coagulation cascade, and dysregulation of the renin–angiotensin system (RAS), which may cause thrombosis, fibrin clot formation, and vasoconstriction. (C) Similarly, SARS-CoV-2 infection via ACE2 receptor on the cardiomyocytes leads to dysregulation of the RAS and inflammation. This mechanism in conjunction with hypoxemia may lead to stress cardiomyopathies, cardiac arrhythmias, and heart failure, increasing the possibility of an intracardiac thrombus. All three of these proposed mechanisms increase the possibility of vessel obstruction that may lead to brain ischemia. Created with BioRender.com (accessed on 20 January 2022).

Figure 2

Proposed pathomechanisms of intracerebral hemorrhage (ICH) in COVID-19 infection: direct and indirect pathways involving endothelial dysfunction. (A) Direct pathway: SARS-CoV-2 invasion of endothelial cells through ACE2 receptors may lead to endothelial cell death, vessel dysfunction, and rupture. Downregulation of ACE2 receptors may increase angiotensin II levels, resulting in hypertension and increased ICH risk. (B) Indirect pathway: SARS-CoV-2 interaction with endothelial ACE2 receptors leads to cytokine and chemokine release. This inflammatory response can interrupt tight junctions within the blood–brain barrier, increasing ICH risk. In addition to the direct and indirect pathways, ICH risk is increased by other risk factors such as anticoagulation, ICU admission, consumptive coagulopathy, and preexisting comorbidities. Created with BioRender.com (accessed on 20 January 2022).

Figure 3

Representative neuroimaging from a patient with recent SARS-CoV-2 infection, new-onset atrial fibrillation, and proximal right MCA occlusion. (A) Non-contrast head CT reveals areas of hypoattenuation within the right MCA vascular territory. (B) Conventional angiography revealing persistent proximal M1 occlusion. Adapted with permission from Batra, A.; Clark, J.R.; LaHaye, K.; Shlobin, N.A.; Hoffman, S.C.; Orban, Z.S.; et al. (2021) [57].