In this case series, we present 15 eyes (14 patients) with RVO and CRAO presenting from 1 to 6 weeks after receiving a dose of the Covid-19 vaccine, either mRNA vaccines or vector ones. The condition occurred throughout the post-vaccination period, but it had occurred more often within 2-6 weeks after the first dose of ChAdOx1, whereas within 1 week after the second dose of BNT162b2.
The clinical course of the condition had a range in the severity of findings; most patients responded well to therapy or recovered spontaneously, and visual acuity was preserved. Four eyes (26.6%) with an occlusion of either central artery or vein, and retinal vein proximal to the macula showed poor outcomes, with BCVA of 20/200 after 3 months of follow-up.
RVOs are a group of vascular disorders characterized by an impaired venous drainage from the retinal circulation. Although the exact patho-physiology of RVO remains elusive, it is well established that the retinal microvasculature impairment and the Virchow’s triad, which consists of hypercoagulability, venous stasis, endothelial injury, may predispose to the development of vein occlusions12. Advancing age and systemic vascular disorders, including HTN, HL, and metabolic disease such as T2DM are strongly associated with RVO. The most common ocular risk factor associated with RVO is glaucoma. In young patients with no obvious RVO etiology, it is recommended to consider thrombophilic factors, such as hyperhomocysteinemia12.
CRAO is an ophthalmic emergency caused by the sudden blockage of the central retinal artery. Although it shares the same cardiovascular risk factors as RVO, it is considered analogous to a cerebral stroke or transient ischemic attacks and, therefore, it requires a multidisciplinary approach with stroke expertise13.
Our cohort of patients notably included 13 patients (92.9%) older than 65 years old, except for 1 patient (7.1%) that was 40 years old. In our case series, 9 patients (64.3%) had the classic risk factors for RVO, defined as the presence of HTN, HL and/or T2DM. The 40-year-old patient had hyperhomocysteinemia, already reported as a risk factor for RVO12.
The report of ocular adverse events occurred after Covid-19 vaccines is published on a monthly basis by AIFA in Italy10 and is presented in Table 1; the incidence rates sum up to 1.716/99.797.303 doses of vaccine, i.e. an overall rate of 1.70 cases/105 vaccine doses. Therefore, the occurrence of ocular adverse events after SARS- CoV-2 immunization is rare.
In this study, we have found a statistically significant increase in new cases of VO between May and the end of October 2021 compared to the numbers of the same 6 months’ interval in 2019. Therefore, this observation could foster the temporal association between Covid-19 vaccination and VO to explain the increase in the number of patients presenting with VO in the short period of time noted above. However, we need to acknowledge that this study was not powered to examine incidences of vascular ophthalmic events after receiving Covid-19 vaccination.
Different ophthalmic manifestations after Covid-19 vaccinations have been reported, including facial nerve palsy, abducens nerve palsy, superior ophthalmic vein thrombosis, corneal graft rejection, uveitis, anterior segment inflammation, central serous chorioretinopathy, Vogt-Koyanagi-Harada disease reactivation, and onset of Graves’ disease14. A recent case series study has described different ocular adverse events, including scleritis, episcleritis and acute maculopathies, occurred 5.2 days after the inactivated Covid-19 vaccine by Sinopharm’s China National Biotec Group15. These ocular findings seem to overlap with ophthalmic manifestations induced by Covid-19 itself, implying a common pathogenetic pathway between Sars-Cov-2 virus and vaccine-mediated immune response14. It has been suggested that the pathogenesis of abnormalities in the retina subsequent to Covid-19 vaccinations, regardless they are adenovirus vector or mRNA vaccines, could be explained by molecular mimicry, where the spike antigen or other viral epitopes share structural similarities with self-antigens leading to an immunological self-tolerance break and an autoimmune response, and by type II or type IV hypersensitivity reactions16.
Retinal vascular adverse events after Covid-19 vaccinations appear to be rare12. Only, 2 single case reports have been available in the literature. One study documented a single patient with CRVO occurring immediately after the 2nd vaccination with an mRNA-based vaccine17. In the other report, a healthy 55-year-old woman presented with bilateral superior ophthalmic vein thrombosis after 10 days from her first vaccine dose against SARS-CoV-2— ChAdOx1 nCoV-19, accompanied by ischaemic stroke, and immune thrombocytopenia18.
Several studies have reported single cases or series of patients who developed unusual thrombotic systemic event after receiving Covid-19 vaccines, including ChAdOx1 nCoV-19, Ad26.COV2.S19-28. The condition is described as Covid-19 vaccine-related thrombosis and thrombocytopenia, namely thrombosis with thrombocytopenia syndrome (TTS).
Three separate case series have described patients who developed TTS after ChAdOx1 vaccination19-21. TTS, which clinically simulate heparin-induced thrombocytopenia, is mediated by platelet-activating antibodies against Platelet Factor 4 (PF4)22 and, interestingly, is more frequently observed following the first dose of ChAdOx123-26 suggesting that any underlying mechanism might be predominant after the first dose27. Furthermore, it has been noted that TTS manifest at 1 to 4 weeks period post-vaccination, which corresponds to the time for mounting a secondary antibody response22,26. Similar haematological findings have been reported after Ad26.COV2 vaccination, that is an adenoviral-based vaccine like the ChAdOx128.
To investigate the association between Covid-19 vaccines and hematological and vascular adverse events, a Scottish national population-based prospective cohort study has been conducted29. Positive associations were seen between the first-dose of ChAdOx1 and idiopathic thrombocytopenic purpura as well as venous, arterial thromboembolic and hemorrhagic events29. BNT162b2, by contrast, did not show a statistically significant association with the aforementioned adverse events29.
Interestingly, our findings of RVO occurrence after the first dose of ChAdOx1 are consistent with the results of these studies. Specifically, it has been observed that the retinal vascular adverse events occurred more often within 2-6 weeks after the first dose of ChAdOx1. Therefore, it may be tempting to suggest a common pathogenic pathway of these thromboembolic events, linking the interaction of adenoviral-based vaccine vector versus SARS-CoV-2 with PF4 and other specific host proteins and the contribution to rare adverse events like RVO.
With regards to mRNA based vaccines, it remains still unknown the pathogenic pathway underlying the observed vascular adverse events. Further studies are needed to investigate it and if there is any common pathogenic mechanism already described for ChAdOx1.
To the best of our knowledge, this is the first case series to report the temporal association between Covid-19 vaccination and VO. It presumably related to SARS-CoV-2 vaccination is an entity that apparently shares several features with the typical VO.
In this context, the pathogenic mechanism of VO after Covid-19 vaccination has not been elucidated and it is important to emphasize that no certain causality can be established from this case-series.
Finally, one important issue concerns the presumable time period of cause-effect relationship between vaccination and RVO. In this case series, this interval was set to 6 weeks, in reasonable accordance with available data and established knowledge linking vaccines with vascular or autoimmune conditions30.
Considering the massive rollout vaccination campaign and the well-established excellent safety profile related to vaccines, it is important to highlight the very low incidence of reported adverse events in the literature. Consequently, Covid-19 vaccination should be strongly encouraged, having shown to be one of the most effective means to reduce the risk of getting and spreading the virus.
In conclusion, retinal vascular occlusion can be considered a rare manifestation of the spectrum of ophthalmic complications after Covid-19 vaccination. Patients with pre-existing cardiovascular risk factors seem to be more likely to develop this complication, however further studies with more data are warranted to draw final conclusions about eventual association between RVO/CRAO and Covid-19 vaccinations.
Therefore, physicians should consider RVO/CRAO if patients present with vision loss within 6 weeks from Covid-19 vaccination. Prompt diagnosis and quick initiation of the appropriate therapy may provide patients with a better visual outcome.