A Case of Branch Retinal Arteriole Occlusion and Paracentral Acute Middle Maculopathy after COVID-19 Infection

Abstract

Introduction

The aim of this study was to report a case of segmental deep capillary plexus ischemic injury after COVID-19 infection in a vaccinated otherwise healthy male.

Case Presentation

A healthy 38-year-old male presented with a complaint of not being able to see above his fixation point in the left eye. He had developed a positive scotoma 2 weeks after a COVID-19 infection. Examination showed a branch retinal arteriole occlusion in the inferotemporal quadrant with an area of subtle arcuate retinal whitening inferior to the fovea. Systemic workup was unremarkable. His vision remained 20/20, with a persistent scotoma over 2 months. Severe thinning of the inner nuclear layer and marked attenuation of the outer plexiform layer in an arcuate segment inferior to the fovea were detected with optical coherence tomography (OCT). OCTA revealed a flow void in the deep capillary plexus inferior to the fovea and cessation of the blood flow distal to the occluded retinal arteriole.

Conclusion

This case highlights the deep capillary plexus’s unique vulnerability to COVID-19-related occlusion, likely due to its high autoregulatory demand and dense vascular architecture. It emphasizes the need for further investigation into retinal microvascular complications of the disease.

Introduction

COVID-19 has been associated with a broad spectrum of retinal pathologies, including retinal vein and artery occlusion, acute macular retinopathy, paracentral acute middle retinopathy, central serous chorioretinopathy, and even secondary fungal infections, like candida retinitis [1–3]. The pathophysiology underlying these retinal complications is multifaceted, involving direct viral infection of retinal endothelial cells, endothelial dysfunction, and systemic coagulopathy [4]. SARS-CoV-2 exploits the angiotensin-converting enzyme II (ACE2) receptor, which is expressed in the retina, to gain cellular entry, triggering local inflammation and vascular injury in addition to these mechanisms [5]. COVID-19 also induces a prothrombotic state characterized by elevated D-dimer and disrupted anticoagulant pathways.

Paracentral acute middle maculopathy (PAMM) is characterized by macular, reddish-brown, wedge-shaped lesions and presents with mild visual loss, scotomas, and photopsia [6]. OCT findings include a hyperreflective band at the level of the middle retina, indicating ischemia of the inner nuclear layer [7]. There are a few isolated reports of PAMM cases that developed during or after COVID-19 cases [8], indicating the vulnerability of retinal capillaries during COVID-19, although the pathogenic mechanism of how COVID-19 leads to PAMM is still unknown. Herein, we present the case of a 38-year-old male who developed PAMM and a small retinal arteriole occlusion, showing the involvement of both retinal macro- and microvessels during COVID-19.

Case Presentation

A 38-year-old Caucasian male with no significant past medical history presented to the clinic with a complaint of not seeing an area above the fixation point in the left eye. His symptoms started 2 weeks ago after he recovered from a PCR-proven COVID-19 infection. Previously, he had received three doses of the mRNA-based COVID-19 vaccinations (Pfizer-BioNTech), with the last dose administered a year ago. His visual acuity was 20/20 in both eyes, and intraocular pressure was unremarkable. The patient was describing an arcuate scotoma above the fixation point. Ophthalmological examination revealed a well-defined area of arcuate retinal whitening along the inferior arcade. A dilated fundus exam revealed a non-perfused peripheral retinal arteriole in the inferonasal quadrant with retinal hemorrhages at the occlusion site (Fig. 1).

Fig. 1.

a Color fundus photography of the left eye showing well-defined arcuate retinal whitening inferior to the fovea and a superficial retinal hemorrhage at the occlusion site of a retinal arteriole in the inferonasal quadrant. b, c A magnified view of the arteriolar occlusion and retinal hemorrhage is shown.

Optical coherence tomography (OCT) imaging showed retinal thinning due to the atrophy of the inner retina inferior to the fovea (Fig. 2). Along this arcuate area of inner retinal atrophy, inner nuclear layer and outer plexiform layers were markedly attenuated. Occasionally, a hyperreflective plaque with convoluted borders extending from the attenuated outer plexiform layer into the outer nuclear layer was observed. The ellipsoid zone and RPE bands remained intact in all OCT scans, indicating preservation of the outer retina from the vascular insult.

Fig. 2.

Optical coherence tomography (OCT) of the left eye showing inner retinal thinning inferior to the fovea (b) compared to superior to the fovea (a). c Thinning of the retina is due to the severe atrophy of the inner nuclear layer and disappearance of the outer plexiform layer (indicated by red arrow). d OCT also reveals a hyperreflective plaque with convoluted borders extending from the attenuated outer plexiform layer into the outer nuclear layer (indicated by yellow arrow). Note that the integrity of the ellipsoid zone has not been destroyed.

OCT angiography (PLEX Elite 9000; Carl Zeiss Meditec, Inc.) revealed a filling void in the deep capillary plexus along an arcuate zone inferior to the fovea (Fig. 3). No specific interventions were initiated, and the patient noted a slight improvement in the size of the scotoma over 2 months. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550630).

Fig. 3.

Optical coherence tomography angiography at the deep capillary plexus level reveals perfusion defect along an arcuate area inferior to the fovea. Please note the lack of blood flow at the occlusion site and retrograde filing of the arteriolar segment distal to the occlusion.

Discussion

A growing body of evidence links COVID-19 infections to retinal vascular occlusions and PAMM [9–11]. These vascular events may occur before clinical symptoms of COVID-19 appear or up to 2 months following the infection. A clear causative role of COVID-19 infection for retinal arterial and venous occlusions has not been established yet due to the rarity of these cases [12]; however, a significant number of PAMM cases have been associated with COVID-19 infection [13]. Although the exact pathogenesis of COVID-19-related retinal vascular occlusions remains elusive, it has been associated with the vascular endothelial disruption caused by the virus, complement system activation, or systemic inflammation, leading to a hypercoagulable state [14, 15]. Elevated D-dimer levels, prolonged prothrombin and activated partial thromboplastin times, upregulation of tissue factor expression in vascular endothelial cells, and increased fibrinogen levels during the COVID-19 infection may induce hypercoagulability [15]. All proposed pathogenic mechanisms are expected to exert similar detrimental effects on retinal vascular endothelial cells. However, COVID-19-related vascular occlusions most commonly manifest in the retinal microvascular bed rather than in retinal arterioles and venules. Cases presenting with combined retinal macro- and microvascular occlusions during or after COVID-19 are highly limited, with our case being the fourth report in the literature [16–18]. Co-occurrence of retinal macro- and microvessel closure suggests a common pathogenic pathway; however, it is not known why COVID-19-related retinal vascular occlusions preferentially affect microvessels, particularly deep capillary plexus vessels, rather than retinal veins and arteries.

SARS-CoV-2 primarily enters host cells through its spike glycoprotein by binding to ACE2 receptors and a cell-surface protease (transmembrane protease serine 2), which are more abundantly expressed in the retinal deep capillary plexus than in other retinal vascular beds [5]. Higher expression of virus binding sites in the deep capillary network may explain what makes the deep capillary plexus more vulnerable to SARS-CoV-2 infection. Meta-analyses showed that even individuals who had not developed any visual symptoms during or after COVID-19 infection displayed microvasculature alterations in the deep capillary plexus [19]. However, the retinal expression of these two genes involved in SARS-CoV-2 entry remains low compared to other organs, supplying a low vulnerability of the neuroretina during COVID-19 infection [20].

Anatomical features of the deep retinal capillary bed may also play a role in the manifestation of the deep retinal SARS-CoV-2 microangiopathy with visual symptoms. Unlike denser and multilayered superficial and intermediate retinal capillary plexuses, deep capillary plexus is uniplanar, and the capillaries run within an approximately 10-micron slab in the outer plexiform layer [21]. At this location, all the oxygen diffusing from the choroid has already been consumed by the photoreceptors, and the deep capillary plexus is required to maintain bipolar cells and synaptic transmission of the visual signal through the outer plexiform layer [22]. Due to the capillaries’ structural organization and proximity to cells with high metabolic demand, the deep capillary plexus is susceptible to ischemia [23]. The higher expression of ACE2 receptors at the deep capillary plexus has evolved as a protective role by counteracting angiotensin type 1 receptor-mediated vasoconstriction, thus providing vasodilation. The inactivation of ACE2 during SARS-CoV-2 infection disrupts its role in converting angiotensin II into vasodilatory angiotensin (I–VII) and leads to angiotensin II accumulation, which exacerbates vasoconstriction and inflammation. This ultimately compromises retinal blood flow and increases the risk of ischemia and hemorrhage [24, 25]. All these differential characteristics of the microvessels highlight the deep capillary plexus as a critical site of ischemic injury in SARS-CoV-2 infection [26].

In our case, we observed the simultaneous occlusion of a branch retinal arteriole and local retinal capillary bed during COVID-19 infection, suggesting that these vascular occlusions share a similar pathogenesis involved by SARS-CoV-2 access into vascular endothelial cells through ACE2 receptors. The extent and severity of the angiopathy seem proportional to the known ACE2 expression of these vascular beds [5].

COVID-19 can cause occlusion of different retinal vascular beds. SARS-CoV-2 virus entry to retinal vascular endothelial through ACE2 receptors plays a significant role in COVID-19-related retinal vascular occlusions. The deep retinal plexus is particularly vulnerable to SARS-CoV-2-related occlusions due to higher ACE2 expression in this vascular bed to counteract the vasoconstrictive effects of the classical ACE/angiotensin II/angiotensin type 1 receptor axis.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., NYC, NY, and Foley Research Fund, New York, NY (THT).

Author Contributions

A.S., M.G.İ., O.İ., S.P., and T.H.T. designed and conceptualized the study, critically revised the manuscript for important intellectual content, conducted the literature review, and assisted in the interpretation of clinical findings. A.S., M.G.İ., O.İ., and S.P. performed the literature review and prepared the initial draft of the manuscript. All authors approved the final version of the manuscript.

Funding Statement

This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., NYC, NY, and Foley Research Fund, New York, NY (THT).

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.