The Coronavirus disease 2019 (COVID-19) sparked a widespread health crisis that is currently going into its fourth year.
This article will explore the current evidence linking COVID-19 infection (and vaccination) to diseases of the retinal vasculature in particular. The inflammatory, thromboembolic, and hypercoagulable states induced by COVID-19 create risk factors for retinal compromise, even in otherwise healthy patients.
Overview of COVID-19
COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), and it classically presents with symptoms of dyspnea, fever, cough, and anosmia (loss of smell).1
Severity of symptoms can range from asymptomatic to severe, even death secondary to respiratory distress or serious thrombotic complications. While the life-threatening complications are primary areas of concern, SARS CoV-2 viral mechanisms can potentially impact other bodily systems—including the eye.
Ocular manifestations of COVID-19
Early on in the COVID-19 pandemic, eyecare providers were alerted to look for anterior segment ocular manifestations, mainly conjunctivitis and ocular inflammation. Later, posterior segment sequelae were also identified. The posterior segment manifestations can range from retinal vascular occlusions, maculopathy, and optic neuropathy.
“The same mechanisms causing systemic disease also cause these ocular complications as well.”
The vascular changes initiated by SARS CoV-2 infection include circulatory system inflammation, endothelial dysfunction, and vessel stasis—during and after infection. The virus activates an inflammatory “cytokine storm,” inducing a hypercoagulable state.
Subsequent endothelial dysfunction disrupts the microvascular system, which can then lead to vascular occlusion. The incidence of adverse vascular events in patients with COVID-19 can be as high as 30%. While such complications are of increased incidence among those with comorbidities (e.g., obesity, diabetes, smoking, vitamin D deficiency), the properties of the SARS CoV-2 viral infection can also have significant health impacts on otherwise healthy individuals without systemic disease.2
Changes to retinal vasculature following a COVID-19 infection
Microvascular retinal changes have been observed after COVID-19 infection. The findings can range in severity from cotton wool spots and small hemorrhages to vascular occlusions. While early retinal findings may be non-sight-threatening, others (e.g., vascular occlusions) can pose a significant threat to vision and be indicative of severe systemic disease or an impending emergency.
The appearance of the retinal vasculature can be similar to that observed in diabetic or hypertensive retinopathy. This has made it more difficult to pinpoint the relationship between retinal pathology and viral infection, especially since many patients suffer from these overlapping comorbidities.
According to the American Academy of Ophthalmology, the virus causes a hypoxic insult to the middle and outer retinal layers. Paracentral acute middle maculopathy and acute macular neuroretinopathy have also been detected and thought to result from microvascular ischemia of the choriocapillaris.
In the former, optical coherence tomography (OCT) imaging shows hyperreflectivity in a band at the inner nuclear layer. In the latter, a wedge-shaped, brown-colored lesion that seems to point toward the macula can be observed coupled with new onset of paracentral scotoma.1
Retinal vascular occlusion after coronavirus infection
In more severe cases of retinal compromise, artery and vein occlusions can occur. Central retinal vein occlusion (CRVO) is more common in patients over age 60 and those with systemic hypertension, diabetes, hyperlipidemia, history of smoking, and glaucoma.1,2 In younger patients with vein occlusion, hypercoagulable state is a significant risk factor.
COVID-19 increases the propensity for endothelial cell dysfunction, inflammation, and a hypercoagulable state, which can further increase the risk in those with underlying factors and create a risk for those without.1
What patients are at risk of vascular occlusion after a COVID-19 infection?
In the report from Shiroma et al., 87% of the patients suffering from vascular occlusion after COVID-19 had no prior history of hypertension or thrombotic event. The average age was also younger than anticipated, with the average age of COVID-19-related retinal vascular occlusion reported at 48 years old.2
The severity of symptoms can vary from none to severe, depending on the vessel(s) involved. The most typical symptoms of retinal vein occlusion (RVO) are decreased or blurred vision.1 Management can include treatment for resulting macular edema with intravitreal anti-angiogenic agents or corticosteroids by a retina specialist.1,2
Central retinal artery occlusions and COVID-19
A patient with central retinal artery occlusion (CRAO) will most often present with painless, sudden, unilateral vision loss, while a patient with a branch retinal artery occlusion can present with a sectoral or hemifield loss. In those cases where cilioretinal artery sparing occurs, the patient can maintain 20/20 visual acuity. CRAO can lead to irreversible and complete vision loss.
While there is no ocular therapy of value for this condition, it is considered a medical emergency that warrants an immediate stroke evaluation. The episode could be indicative of a stroke or other life-threatening conditions (e.g., giant cell arteritis). A majority of patients suffering from CRAO, suspected as secondary to COVID-19 infection, had other, more typical risk factors as well. These include hypertension, obesity, smoker status, and coronary artery disease—already placing them at a higher risk for occurrence.1
Comparing the rates of retinal vein and artery occlusions
Modjtahedi et al. reviewed over 400,000 cases of patients with COVID-19 and found the incidence of retinal vein occlusion in the 6-month period post infection was higher than the incidence in the 6-month period before infection.
The incidence of retinal artery occlusion pre- and post-infection was very similar, but the incidence was slightly higher after infection. This suggests retinal vein occlusion may have a stronger association with COVID-19 infection than artery occlusion.3
General timeline for thromboembolic complications following a COVID-19 infection
Thromboembolic complications of COVID-19 are more common with moderate to severe cases and usually occur late in the disease or in early recovery.2 The timeline for adverse ophthalmic retinal manifestations is about 2 to 3 months post-infection.2,3
Shiroma identified 14 patient cases of retinal vascular occlusion within 3 months following laboratory-confirmed COVID-19 infection. In Modjtahedi’s study, the time to presentation for retinal vein occlusion was 6 to 8 weeks after infection, as compared to retinal artery occlusion, presenting slightly later at the 10- to 12-week mark.3
Exploring the possible link between RVO and COVID-19 vaccinations
An association between retinal vascular occlusion and COVID-19 vaccination has been suggested in the literature as well; however, the evidence is mixed. Vujosevic et al. reviewed 15 cases of retinal vascular occlusion (14 vein occlusions and one artery occlusion) and found a relationship between vaccinations and time to occlusive event. The timeline ranged from 7 to 42 days, with a median of 14 days from vaccination to symptom onset, and the patient’s best-corrected acuity ranged from 20/20 to 20/200 with a mean of 20/50.
Of the 15 cases evaluated, 6 cases occurred after an initial dose of Vaxzevria brand vaccine, 8 cases were after the second dose of the Pfizer vaccine, and the remaining case was after the Janssen vaccine. Since the vascular occlusive events are similar to those that occur as a result of COVID-19 itself, the authors attribute the findings to the same pathogenic mechanism of the viral vector or the vaccine-mediated immune response. This was a small sample of patients but suggests the need for further research.4
Further clinical studies evaluating the association of RVOs and COVID-19 vaccinations
Another study, by Feltgen et al., reviewed cases of retinal artery and vein occlusion and anterior ischemic optic neuropathy to determine vaccination status and timeline of vaccination to the vascular event. This study included over 400 patient cases of retinal vascular occlusive disease, and when compared to population-matched individuals, no association was found between COVID-19 vaccination and increased risk of occlusive event.
It was of note that the patient cases studied did have higher incidence of other known risk factors such as arterial hypertension, atrial fibrillation and diabetes. A limitation of the study is that ophthalmic complications may not have been accurately detected in patients with serious adverse reactions to the COVID-19 vaccine, such as pericarditis or deep venous thrombosis since attention was focused on life preservation and no ophthalmic exam was performed.5
Though the Feltgen study did not find an association, the authors still call for further research in this area and implore practitioners to “watch the retina” to detect microvascular changes in patients after a COVID-19 vaccine or infection.
Investigators from the study suggest utilizing multimodal high-resolution imaging to capture more subtle changes.5 OCT angiography has been identified as a useful tool in detecting reduced vascular density in patients with COVID-19. This could be the case for post-vaccination retinal complications as well.3
Why is it hard to outline the association between RVO and COVID-19?
There are several contributing factors that make it difficult to determine the link between retinal vascular occlusion and COVID-19 infection. One is that patients who are ill may be unable to exercise, and a lack of physical activity increases the risk for vascular or thrombotic events. Patients who are severely ill or hospitalized may also be poor historians or may not be capable of reporting vision loss or visual symptoms that would prompt retinal evaluation.3
In addition, the systemic conditions that increase risk for COVID-19-related retinal vascular occlusion, like diabetes or hypertension, can cause retinopathy on their own and may not warrant the clinician’s probing with COVID-19-related case history questions.
For these reasons, it has been difficult to establish a causal relationship. Most COVID-19-related posterior segment disease clinical case reports and reviews have served as the primary route of information dissemination.1
Conclusion
Though the exact incidence of vascular events as sequelae of COVID-19 is not known at this time, the abundance of case reports demonstrates the need for further attention and investigation.
In cases of retinal vascular occlusion in young, healthy patients, COVID-19 infection and vaccination status should be considered as part of the list of differentials. For older patients and those with comorbidities, COVID-19 infection and vaccination status should be considered as possible and additional risk factors for retinal vascular occlusion.
