ABSTRACT

Coronavirus disease 2019 (COVID-19) is a procoagulant disease that increases the risk of clinically evident thrombotic complications. Herein we present 3 cases with different retinal artery occlusions that emerged soon after the diagnosis of COVID-19. The first patient had central retinal artery occlusion (CRAO) that resulted in visual loss in one eye. The second patient had inflammatory peripheral retinal artery occlusion, vasculitis, and uveitis which did not affect vision. The third patient presented with CRAO following the progression from orbital cellulitis to orbital apex syndrome. Interestingly, CRAO progressed to internal carotid artery occlusion in this case within days and resulted in monocular visual loss. Variations in the underlying pathophysiology and the characteristics of individual immune responses in patients with COVID-19 may be factors that determine differences in clinical manifestations. This article aims to describe different presentations of COVID-19-related retinal artery occlusions and discuss possible pathophysiological aspects.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel member of the human coronaviruses and causes coronavirus disease 2019 (COVID-19).¹ It has the potential to affect various organs and systems within the body. Ocular involvement of the disease is potentially possible, though it is not known when, why, in whom, how, and to what extent SARS-CoV-2 will affect the ocular tissues.²

COVID-19 is known to be a procoagulant disease that increases the risk of clinically evident thrombotic complications.^3,4 Recently, it has been published that 42.7% of cases with SARS-CoV-2-associated neurological complications presented with ischemic stroke.^5,6 By definition, retinal artery occlusion represents end-organ ischemia and is analogous to terminal branch occlusion in cerebral stroke.⁷ Although the overall incidence of arterial thrombosis in COVID-19 has been reported to be lower than that of venous thrombosis (3.7% vs. 25%), the number of retinal artery occlusion cases in the literature is close to that of retinal vein occlusions.^8,9

However, the components involved in the ocular thromboembolism process, the mechanism of interaction, and the clinical findings have not yet been adequately defined. Herein we aim to report three cases with different types of retinal artery occlusions secondary to COVID-19 and to discuss possible pathophysiological aspects. Written informed consent for publication of the clinical details and/or clinical images have been obtained from all patients in this study.

Discussion

Growing evidence shows that macrovascular and microvascular thrombotic diseases may occur in the venous and arterial circulation of both hospitalized and ambulatory patients with COVID-19.^10,11,12 The question of whether thrombosis is specific to SARS-CoV-2 or is a pathway of the thromboinflammatory response to viral infection remains uncertain.¹³ A recent autopsy study revealed that almost no organ within the body is spared of thrombosis.¹⁴

This case series highlights that retinal artery occlusions associated with SARS-CoV-2 may present with different features. Herein, isolated microvascular occlusion was observed in the first two cases. The first case was a routine case of CRAO which seems to be of thromboembolic origin. However, the second patient had inflammatory peripheral retinal artery occlusion, vasculitis, and uveitis. The third case featured CRAO originating from the progression of orbital cellulitis to orbital apex syndrome. Interestingly, this microvascular occlusion progressed to macrovascular (ICA) occlusion within days.

In COVID-19, variations in the underlying pathophysiology and characteristics of individual immune responses may be factors that determine differences in clinical manifestations.¹⁵ Although the pathophysiological mechanism of thromboembolic complications in the ocular vasculature has not been clearly established, the coagulopathy mechanisms proposed in SARS-CoV-2 infection may be relevant.^16,17 Evidence from the literature shows that SARS-CoV-2 infects vascular endothelial cells via ACE2, which is highly expressed in endothelial cells and pneumocytes. Basically, destruction of ACE2 receptors has been associated with increased levels of reactive oxygen species, induction of fibrosis, hypertrophy, and inflammation.¹⁸ The resulting endothelial dysfunction and subsequent potentiation of the renin-angiotensin system reduces anticoagulation and fibrinolytic activity. The emergence of extensive hypercoagulation, diffuse intravascular thrombosis, and secondary fibrinolysis may lead to microvascular and macrovascular complications in COVID-19.¹⁹ Hypothetically, the clinical picture may progress to retinal artery occlusion, as in the first case, when the pathology is limited to the ocular microvasculature.

On the other hand, SARS-CoV-2 can also stimulate the innate immune system to participate in thrombosis. Essentially, immune cells, inflammatory cytokines, and pathogen-associated molecular patterns induce the formation of thrombi consisting of fibrin, monocytes, neutrophils, and platelets.^20,21,22 Although immunothrombi initially promote pathogen recognition and serve as a protective barrier against pathogen invasion, they may become maladaptive and injurious to tissue and organ perfusion in time.^20,23,24 Alveolar immunothrombosis has been proposed as a mechanism to limit dissemination of SARS-CoV-2 outside the alveoli.¹⁴ The peripheral retinal artery occlusion in our second case may have been caused by a similar mechanism or from occlusive retinal vasculitis which may have been triggered by or as a response to COVID-19. Cases of COVID-19-related uveitis of varying severity have been reported in the literature, but the presence of mild uveitis, retinal vasculitis, and peripheral retinal artery occlusion has not been reported before.²⁵

In the third case, the possible underlying pathophysiology seems somewhat complex. The arterial occlusion may have been caused by the direct thrombotic effect of COVID-19.^16,17 In this case, as in our first patient, the increase in D-dimer, fibrinogen, factor VIII, and von Willebrand factor and the decrease in antithrombin levels seem to support this suggestion. However, other mechanisms may have been involved as well. In this context, progression of orbital cellulitis to orbital apex syndrome may be the key factor. Progression of orbital cellulitis to orbital apex syndrome has been reported before in patients with COVID-19, which is congruent with our third case.²⁶ In our opinion, further invasion of inflammation may have triggered retrograde spread to the cavernous sinus and caused involvement of the vascular ICA wall. The resulting stenosis may have caused occlusion of the ICA in this third case.

In summary, all these different clinical courses depicted above emerged soon after the diagnosis of COVID-19 and had variable visual prognoses and possible mechanisms of action. In addition to one case without vision loss, two cases with devastating vision loss occurred in our series. There have been several recent reports of retinal artery occlusion associated with SARS-CoV-2, ranging from isolated CRAO to ischemic stroke with CRAO and cilioretinal artery occlusion with paracentral acute middle maculopathy.^27,28,29 To our knowledge, this is the first case series to include cases of post-COVID-19 CRAO with different presentations. While the limited number of cases, the speculative nature of the available evidence, and the individual characteristics of patients preclude any firm conclusions, this study may help gain insight into a fairly new topic that is likely to have more facets and deeper connections.

Currently, the cause of microvascular or macrovascular thromboembolism in the ocular vasculature in patients with post-COVID-19, its mechanism of development, prognostic significance, and the necessity of prophylactic measures are still unclear. Prevention of irreversible visual loss depends mainly on suspicion and timely intervention. The importance of increasing awareness of ocular thromboembolic complications and reinforcing a multidisciplinary approach is obvious. Further studies on the propagation of ocular screening in patients with COVID-19 may help solve this inadvertent complication.