Abstract
Purpose
The goal of this study is to compare the optical coherence tomography angiography (OCTA) findings in Coronavirus (COVID-19) positive adult and pediatric patients with those of healthy volunteers with the same demographic characteristics.
Methods
The right eye of 157 adults infected with covid, 168 healthy adult volunteers, 40 children (6–18 years of age) infected with covid, and 44 healthy children (6–18 years of age) were included in this prospective study. All participants underwent ophthalmological examination and OCTA. The OCTA findings were evaluated.
Results
Deep nasal density (DND), deep inferior density (DID), and deep parafoveal density (DPD) were significantly lower in the pediatric covid-affected group (PCAG) than in the pediatric healthy control group (PHCG) (P = 0.034, P = 0.029, P = 0.022 respectively). On the other hand, radial peripapillary capillary vessel density (RPCVD) intra-disc measurements were significantly higher in the PCAG compared to the PHCG (P = 0.025). There was no significant difference between the OCTA measurements of the adult covid-affected group (ACAG) and the adult healthy control group (AHCG).
Conclusion
In our study, significant differences were found in OCTA measurements between the covid group and the healthy control group in children. Retinal microvascular changes may occur in patients with covid infection, and these patients might be followed for long-term retinal changes.
Keywords: Coronavirus, Optical coherence tomography angiography, Foveal avascular zone, Retina
Résumé
Objectif
L’objectif de cette étude est de comparer les résultats de l’angiographie par tomographie à cohérence optique (OCTA) de patients adultes et pédiatriques positifs au coronavirus (COVID-19) avec des volontaires sains présentant les mêmes caractéristiques démographiques.
Méthodes
L’œil droit de 157 adultes infectés par la covid, 168 volontaires adultes sains, 40 enfants (6–18 ans) infectés par la covid et 44 enfants sains (6–18 ans) ont été inclus dans cette étude prospective. Tous les participants ont subi un examen ophtalmologique et une OCTA a été réalisée. Les résultats de l’OCTA ont été évalués.
Résultats
La densité nasale profonde (DND), la densité inférieure profonde (DID) et la densité parafovéale profonde (DPD) étaient significativement plus faibles dans le groupe pédiatrique atteint de la covid (PCAG) que dans le groupe témoin sain (PHCG) (p = 0,034, p = 0,029, p = 0,022 respectivement). D’autre part, les mesures de la densité des vaisseaux capillaires péripapillaires radiaux (RPCVD) à l’intérieur du disque étaient significativement plus élevées dans le PCAG que dans le PHCG (p = 0,025). Il n’y avait pas de différence significative entre les mesures OCTA du groupe d’adultes atteints de la covid (ACAG) et du groupe de contrôle adulte sain (AHCG).
Conclusion
Dans notre étude, des différences significatives ont été trouvées dans les mesures OCTA entre le groupe covid et le groupe de contrôle sain chez les enfants. Des changements microvasculaires rétiniens peuvent se produire chez les patients atteints d’une infection de la covid, et ces patients peuvent être suivis pour des changements rétiniens à long terme.
Mots clés: Coronavirus, Angiographie par tomographie par cohérence optique, Zone avasculaire fovéale, Rétine
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betavirus, caused the coronavirus (COVID 19) epidemic that emerged in 2019, spreading rapidly around the world and causing a large number of deaths [1]. It is known that SARS-CoV-2 virus uses the angiotensin-converting enzyme-associated carboxypeptidase (ACE) 2 receptor to enter the cell. Angiotensin-converting enzyme 2 receptors are found on the cell membranes of type II alveolar cells in the lung and enterocytes of the small intestine, as well as on arterial and venous endothelium [2]. It is found in different cell types of the retina, including choroid and müller cells, ganglion cells, retinal vascular endothelial cells, and photoreceptor cells. It is known that the ACE 2 receptor plays a role in diabetic and hypertensive retinopathy [3]. In addition to damaging the endothelium via the ACE 2 receptor, SARS-CoV-2 virus can cause microvascular damage and coagulopathy because of complement activation and intense inflammatory response [4]. The prevalence of ocular symptoms in COVID-19 patients has been reported to range from 2 to 32% [5], [6], [7], [8]. It has been reported that COVID 19 infection causes ophthalmologic involvement such as conjunctival congestion, chemosis, conjunctivitis and enlarged vessels and increased vascular tortuosity, bleeding areas, etc. [9]. In addition, it has been reported that coronaviruses cause ocular infections in animals, including retinitis and optic neuritis [3].
In this study, our aim is to investigate the effects of COVID 19 infection on the vascular structures of the retina and optic disc in adults (19–60 years old) and children (6–18 years old) using optical coherence tomography angiography (OCTA).
Materials and methods
This prospective study was carried out at Gaziantep University Şahinbey Training and Research Hospital between January 2021 and July 2021. The principles of the Declaration of Helsinki were followed. Approval was granted by the Ethics Committee of Gaziantep University. Consent forms were obtained from patients and volunteers. Our study includes 157 adults with PCR positive covid infection referred from covid polyclinics, 168 healthy adult volunteers who applied to the eye diseases outpatient clinic for control, 40 children (6–18 years old) with PCR positive covid infection and 44 healthy children (6–18 years old). Patients were evaluated within 3 to 6 months after the positive result of covid 19 PCR test. Only right eyes were included in statistical analysis.
Inclusion criteria for the study were; ages between 6 and 60, open optic axis, adequate pupil dilation and fixation for OCTA. Exclusion criteria were: history of previous ocular surgery, an additional systemic disease, retinal and optic disc disease, history of regular drug use, and refraction values above ± 3 diopters.
OCTA assessments
Patients with covid infection and healthy volunteers included in our study were evaluated by taking 3 × 3 mm macular images centered on the fovea and 4.5 × 4.5 mm optic disc images using AngioVue® (RTVue-XR, Fremont, California, USA; software version 2017.1.0.151). Patients with image quality less than 6/10 were excluded from the study.
Foveal avascular zone (FAZ) area, flow area, foveal density (FD), vascular density were evaluated. Foveal density (FD), the ratio of the vascular image to the whole area in the images made with OCTA gives the density as a percentage. Density measurements were made automatically in two segments as superficial capillary plexus (SCP) and deep capillary plexus (DCP) with the OCTA device. The circle with a radius of 1 mm from the center of the fovea was evaluated as the density of the fovea, and the circle between 3 and 1 mm was considered as the density of the parafovea. The segments are divided by the device into 4 quadrants: temporal, superior, nasal, and inferior. Central macular thickness (CMT) measurement is made by applying the Quickvue module in OCTA. The optic disc images were taken with a 4.5 × 4.5 mm measurement. The device automatically calculates the average vessel densities in and around the optic disc. Measurement of radial peripapillary capillary vascular density (RPCVD) with OCTA and peripapillary retinal nerve fiber layer (PPRNFL) in a 3.45 mm diameter circle around the optic disc were also evaluated.
Statistical analysis
Categorical measurements were summarized as numbers and percentages, and continuous measurements as mean and standard deviation (median and minimum-maximum where necessary). Shapiro-Wilk test was used to check normal distribution. The Mann-Whitney U test was used to compare the non-normally distributed variables in the two groups. SPSS 22.0 Windows version was used in the analysis. P < 0.05 was considered significant.
Results
Comparison of findings of patients in the adult group (18–60 years)
The mean age of the adult healthy control group (AHCG) (18–60) was 36.39 ± 9.1 years, and the mean age of the adult covid-affected group (ACAG) was 36.23 ± 9.28 years. Age distributions between the groups were homogeneous (P = 0.712). No significant difference was found between the groups in macular thickness and flow field measurements made in the adult age group. It is shown in Table 1 .
Table 1.
Adult group macular thickness and flow field measurements.
| ACAG n = 157 | AHCG n = 168 | P | |
|---|---|---|---|
| CMT (μm) | 249.31 ± 19.69 | 251.67 ± 18.08 | 0.651 |
| FAZ area (mm2) | 0.28 ± 0.12 | 0.26 ± 0.09 | 0.344 |
| CC flow area (mm2) | 2.09 ± 0.16 | 2.12 ± 0.12 | 0.077 |
CMT: central macular thickness; FAZ area: foveal avascular zone area; CC: choriocapillaris. P-values were measured using Mann-Whitney U test.
When the vascular density measurements of SCP and DCP were examined, there was not significant difference between two groups in all parameters (P > 0.05) as shown Table 2 .
Table 2.
Comparison of adult group macular OCTA findings.
| ACAG n = 157 | AHCG n = 168 | P | |
|---|---|---|---|
| SFD (%) | 19.01 ± 6.35 | 19.71 ± 5.04 | 0.363 |
| SPD (%) | 50.85 ± 3.9 | 51.21 ± 2.84 | 0.619 |
| STD (%) | 49.15 ± 3.71 | 49.71 ± 3.08 | 0.134 |
| SSD (%) | 52.14 ± 4.26 | 52.23 ± 3.33 | 0.852 |
| SND (%) | 49.98 ± 4.46 | 50.48 ± 3.02 | 0.549 |
| SID (%) | 52.09 ± 4.28 | 52.58 ± 3.23 | 0.647 |
| DFD (%) | 34.7 ± 7.49 | 36.09 ± 6.28 | 0.278 |
| DPD (%) | 54.81 ± 3.72 | 54.97 ± 2.79 | 0.927 |
| DTD (%) | 54.73 ± 3.85 | 55.04 ± 3.15 | 0.579 |
| DSD (%) | 55.13 ± 3.98 | 54.9 ± 3.13 | 0.310 |
| DND (%) | 55.07 ± 3.93 | 55.31 ± 2.57 | 0.874 |
| DID (%) | 54.44 ± 4.22 | 54.52 ± 3.47 | 0.895 |
SFD: superficial foveal density; SPD: superficial parafoveal density; STD: superficial temporal density; SSD: superficial superior density; SND: superficial nasal density; SID: superficial inferior density; DFD: deep foveal density; DPD: deep parafoveal density; DTD: deep temporal density; DSD: deep superior density; DND: deep nasal density; DID: deep inferior density. P-values were measured using Mann-Whitney U test.
There was not any significant difference between two groups when comparing optic disc OCTA measurements (P > 0.05 for all parameters) as shown Table 3 .
Table 3.
Comparison of adult group optic disc OCTA findings.
| ACAG n = 157 | AHCG n = 168 | P | |
|---|---|---|---|
| PPRNFL mean (μm) | 113.7 ± 11.79 | 112.31 ± 10.63 | 0.536 |
| PPRNFL sup (μm) | 113.49 ± 12.69 | 112.31 ± 10.63 | 0.737 |
| PPRNFL inf (μm) | 113.99 ± 12.65 | 112.77 ± 13.13 | 0.290 |
| RPCVD mean (%) | 52.08 ± 2.67 | 51.97 ± 2.64 | 0.702 |
| RPCVD sup (%) | 52.07 ± 2.84 | 51.82 ± 2.95 | 0.430 |
| RPCVD inf (%) | 52.02 ± 2.77 | 52.08 ± 2.72 | 0.897 |
| RPCVD intra-disc (%) | 50.85 ± 4.66 | 50.47 ± 5.02 | 0.610 |
PPRNFL mean: peripapillary retinal nerve fiber layer average; PPRNFL sup: peripapillary retinal nerve fiber layer superior; PPRNFL inf: peripapillary retinal nerve fiber layer inferior; RPCVD mean: radial peripapillary capillary vessel density average; RPCVD sup: radial peripapillary capillary vessel density superior; RPCVD inf: radial peripapillary capillary vessel density inferior; RPCVD intra-disc: radial peripapillary capillary vessel density intra-disc. P-values were measured using Mann-Whitney U test.
Comparison of findings of patients in the pediatric group (6–18 years)
The mean age of pediatric covid-affected group (PCAG) was 10.40 ± 3.02 years, and the mean age of pediatric healthy control group (PHCG) was 11.75 ± 3.86 years. Age distributions between the groups were homogeneous (P = 0.670).
No significant difference was found between the groups in macular thickness and flow field measurements made in the pediatric age group. It is shown in Table 4 .
Table 4.
Pediatric group macular thickness and flow field measurements.
| PCAG n = 40 | PHCG n = 44 | P | |
|---|---|---|---|
| CMT μm | 238.4 ± 15.55 | 241.88 ± 18.92 | 0.515 |
| FAZ area (mm2) | 0.28 ± 0.12 | 0.28 ± 0.12 | 0.602 |
| CC flow area (mm2) | 2.25 ± 0.14 | 2.24 ± 0.1 | 0.349 |
CMT: central macular thickness; FAZ area: foveal avascular zone area; CC: choriocapillaris. P-values were measured using Mann-Whitney U test.
Table 5 shows the SCP and DCP vascular density measurements between 2 pediatric groups. Deep parafoveal density (DPD), deep nasal density (DND), deep inferior density (DID) were significantly lower in PCAG compared to PHCG (P = 0.022, P = 0.034, P = 0.029, respectively). There was not a significant difference between two groups in all other measured parameters (P > 0.05).
Table 5.
Comparison of pediatric group macular OCTA findings.
| PCAG n = 40 | PHCG n = 44 | P | |
|---|---|---|---|
| SFD (%) | 19.13 ± 5.59 | 19.69 ± 6.78 | 0.775 |
| SPD (%) | 50.86 ± 3.34 | 51.33 ± 2.28 | 0.861 |
| STD (%) | 49.69 ± 3.29 | 49.72 ± 2.42 | 0.638 |
| SSD (%) | 51.87 ± 4.28 | 52.41 ± 2.31 | 0.521 |
| SND (%) | 50.14 ± 3.72 | 50.3 ± 2.63 | 0.934 |
| SID (%) | 51.7 ± 3.63 | 52.8 ± 2.96 | 0.172 |
| DFD (%) | 35.75 ± 7.87 | 35.1 ± 8.65 | 0.481 |
| DPD (%) | 55.22 ± 4.24 | 57.04 ± 3.39 | 0.022* |
| DTD (%) | 55.47 ± 3.97 | 56.72 ± 3.71 | 0.096 |
| DSD (%) | 55.69 ± 4.98 | 57.55 ± 3.16 | 0.066 |
| DND (%) | 55.44 ± 3.93 | 57.15 ± 3.22 | 0.034* |
| DID (%) | 54.53 ± 5.41 | 56.72 ± 4.38 | 0.029* |
SFD: superficial foveal density; SPD: superficial parafoveal density; STD: superficial temporal density; SSD: superficial superior density; SND: superficial nasal density; SID: superficial inferior density; DFD: deep foveal density; DPD: deep parafoveal density; DTD: deep temporal density; DSD: deep superior density; DND: deep nasal density; DID: deep inferior density.
P < 0.05 were considered statistically significant using Mann-Whitney U test.
Radial peripapillary capillary vessel density (RPCVD) intra-disc measurements were 53.81 ± 4.75 in PCAG and 52.09 ± 3.17 in PHCG, and a statistically significant difference was found between these two measurements (P = 0.025) as shown in Table 6 .
Table 6.
Comparison of pediatric group optic disc OCTA findings.
| PCAG n = 40 | PHCG n = 44 | P | |
|---|---|---|---|
| PPRNFL mean (μm) | 111.69 ± 16.82 | 110.15 ± 10.29 | 0.691 |
| PPRNFL sup (μm) | 113.46 ± 17.18 | 110.88 ± 10.28 | 0.609 |
| PPRNFL inf (μm) | 109.63 ± 17.44 | 109.46 ± 11.06 | 0.857 |
| RPCVD mean (%) | 50.65 ± 3.01 | 50.03 ± 2.46 | 0.175 |
| RPCVD sup (%) | 50.63 ± 3 | 50.12 ± 2.61 | 0.222 |
| RPCVD inf (%) | 50.67 ± 3.45 | 50.03 ± 2.6 | 0.200 |
| RPCVD intra-disc (%) | 53.81 ± 4.75 | 52.09 ± 3.17 | 0.025* |
PPRNFL mean: peripapillary retinal nerve fiber layer average; PPRNFL sup: peripapillary retinal nerve fiber layer superior; PPRNFL inf: peripapillary retinal nerve fiber layer inferior; RPCVD mean: radial peripapillary capillary vessel density average; RPCVD sup: radial peripapillary capillary vessel density superior; RPCVD inf: radial peripapillary capillary vessel density inferior; RPCVD intra-disc: radial peripapillary capillary vessel density intra-disc.
P < 0.05 were considered statistically significant using Mann-Whitney U test.
Discussion
There is increasing evidence of impaired retinal microcirculation during SARS-CoV-2 infection due to vasculitis and coagulopathy [10]. In this study, we aimed to evaluate the microvascular changes that may be caused by COVID 19 infection in the retina using OCTA and to compare it with the findings of healthy volunteers. As a result of our study, it was found that the DPD, DID, DND values of pediatric patients with covid were statistically significantly lower and RPCVD intra-disc values were higher than the control group. No statistically significant difference was found in other findings.
COVID 19 infection is thought to cause retinal changes. Invernizzi et al. detected retinal hemorrhages (9.25%), cotton blots (7.4%), dilated vessels (27.7%), and tortuous vessels (12.9%) in 54 COVID-19 patients in scanning with fundus photography [11]. They also found that retinal vein diameter directly correlates with disease severity, suggesting that this may be a non-invasive parameter for monitoring inflammatory response and/or endothelial damage in COVID 19. Lecler et al. performed FLAIR-weighted magnetic resonance imaging in 9 patients with COVID 19 infection and found abnormal findings consisting of one or more hyperintense nodules in the macular region [12]. These lesions were thought to be either direct inflammatory infiltration of the retina or microangiopathic disease resulting from viral infection. In animal model studies, conditions such as retinal vasculitis, retinal degeneration and disruption of the integrity of the blood-retina barrier were observed [13], [14], [15]. There are studies on the retinal findings of patients with COVID-19 infection, but few of them used OCTA.
In a study conducted by Abrishami et al., it was observed that the mean SCP vascular densities and DCP vascular densities decreased in patients who did not have COVID-19 as a result of OCTA applied at least 2 weeks later in patients with COVID-19 infection [16]. In our study, in the comparison of the adult group, it was observed that the vascular densities of SCP and DCP were decreased in the group that had COVID 19 group, but there was not any significant difference. Similar studies showed that vascular densities decrease in patient groups with COVID 19 [3], [17]. In the study by Tiryaki Demir et al., SCP, DCP and choriocapillaris flow area values in pediatric patient groups were found to be lower in the COVID-19 group than in the control group [18]. In our study the pediatric age group, a significant difference was found between the study and control groups in terms of DPD, DND and DID measurements. It is thought that there are several reasons why the macular vessel densities of patients with COVID 19 infection, especially the deep plexus density, were decreased compared to the control group. Local foveal flow disturbance may occur as a result of an obstructive event in the vessel lumen caused by thrombotic events caused by SARS-COV-2 infection. Because SARS-COV-2 infection causes proinflammatory endothelial dysfunction, a decrease in vascular density may occur as a result of increased apoptosis and pyroptosis of endothelial cells [19]. It is thought that the deep plexus is more affected than the superficial plexus because of its distance to the large arterioles and its proximity to the high metabolic activity of the retina. The retina and choroid are among the tissues with the highest vascularization per unit area in the body. For this reason, the effects of the pathophysiological processes of systemic diseases that will cause inflammation and ischemia can be observed locally in these two tissues. COVID-19 is associated with diffuse microvascular changes; therefore, it has the potential to cause disruption of retinal and choriocapillary blood flow [20]. In a study by Abrishami et al., the FAZ area in patients with COVID-19 infection was found to be larger in the group with COVID-19 infection, but this was not statistically significant. In our study, the FAZ area in the adult age group was found to be larger in patients with COVID 19 infection than in healthy patients, and it was not statistically significant. In the pediatric age group, mean FAZ area values were found to be equal between the group with COVID 19 infection and the control group. Unlike other tissues with collateral blood vessels, retinal plexi consists of terminal arteries without anastomotic connections [21]. Since the boundary delimiting the FAZ area consists of these terminal vessels, an area particularly susceptible to ischemic changes occurs [22]. It has been thought that FAZ area enlargement may occur with capillary loss in various different retinal vascular diseases such as diabetic retinopathy and retinal vascular occlusions [23], [24]. Retinal macular microvascular changes caused by COVID-19 infection may also have increased the FAZ area.
There are few studies in the literature that measured retinal nerve fiber layer (RNFL) thickness in patients with COVID-19 infection. Burgos-Blasco et al. found that peripapillary RNFL thickness was increased in patients with COVID-19 infection [25]. In another study, it was defined that peripapillary RNFL thickness increased in patients with COVID-19 infection [3]. In another study with children, it was observed that the retinal nerve fiber layer thickness increased in pediatric patients who had COVID-19 [26]. In our study, the mean RNFL thickness measurement was found to be higher in the covid group in both age groups. But the difference between the measurements was not statistically significant. The radial peripapillary capillary (RPC) plexus is a branch of the retinal arterioles and runs parallel with nerve fiber axons from the optic disc to the temporal arcades [27]. The RPC plexus is thought to be crucial for the homeostasis and function of retinal ganglion cells and their axons. The RPC plexus has an important role in providing blood flow to the RNFL. Studies have shown that there is a correlation between RPC plexus density and retinal nerve fiber layer thickness [28]. In line with these findings, RPC plexus density measurement gives information about RNFL hemostasis. In our study, when the RPCVD values were examined, it was found that it was higher in ACAG compared to AHCG. This difference was not statistically significant. When the RPCVD values were examined, it was determined that it was higher in PCAG compared to PHCG, and this difference was not statistically significant except for the RPCVD intra-disc value (P = 0.025). RNFL thickening and high RPCVD measurement in our study can be thought to be related to the initial effect of inflammation due to COVID-19 infection [29].
Our study has several limitations. First of all, treatments used by adult patients for COVID-19 infection may also cause changes in retinal vascular tissues. We could not classify and evaluate our patients according to their medications. Secondly, we were unable to examine the association of disease severity or virus titer with vascular changes in patients with COVID-19.
In our study, no significant difference was observed between the OCTA values of the adult age group with COVID-19 infection and the healthy control group. However, a significant difference was observed in some OCTA values between pediatric patients and healthy volunteers. Adult patients with COVID-19 infection who participated in our study, used drugs such as favipravir or hydroxychloroquine (plaquenil), which is known to cause various changes in retinal tissue, in addition to symptomatic treatment. Patients who had COVID-19 infection in the pediatric age group received only symptomatic treatment. It can be thought that this difference may have occurred due to the effect of drugs used in the treatment of adult patients. The effects of drugs used in the treatment of covid infection on the retina can also be investigated.
Conclusion
Microvascular changes may not be noticed in the biomicroscopy examination of patients with COVID-19 infection. OCTA provides three-dimensional images of retinal capillary plexuses, measures FAZ area, blood flow areas, and vascular densities, giving us information about microvascular changes. It can be easily used to examine the retinal microvascular changes of patients with COVID-19 infection and to evaluate the short- and long-term effects of the infection on the retina. Evaluating the effects of this viral infection causing a pandemic on the retinal layer of the eye with a method such as OCTA that shows the retinal vascular plexuses with clear numerical data can provide useful information on the diagnosis, follow-up and treatment of the disease. For this reason, it would be beneficial to conduct more studies with more samples on this subject.
Funding
This work did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosure of interest
The authors declare that they have no competing interest.
References
- 1.Ahn D.G., Shin H.J., Kim M.H., Lee S., Kim H.S., Myoung J., et al. Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19) J Microbiol Biotechnol. 2020;30:313–324. doi: 10.4014/jmb.2003.03011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gheblawi M., Wang K., Viveiros A., Nguyen Q., Zhong J.C., Turner A.J., et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020;126:1456–1474. doi: 10.1161/CIRCRESAHA.120.317015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.González-Zamora J., Bilbao-Malavé V., Gándara E., Casablanca-Piñera A., Boquera-Ventosa C., Landecho M.F., et al. Retinal microvascular impairment in COVID-19 bilateral pneumonia assessed by optical coherence tomography angiography. Biomedicines. 2021;9:247. doi: 10.3390/biomedicines9030247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Magro C., Mulvey J.J., Berlin D., Nuovo G., Salvatore S., Harp J., et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13. doi: 10.1016/j.trsl.2020.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Jevnikar K., Jaki Mekjavic P., Vidovic Valentincic N., Petrovski G., Globocnik Petrovic M. An update on COVID-19 related ophthalmic manifestations. Ocul Immunol Inflamm. 2021;29:684–689. doi: 10.1080/09273948.2021.1896008. [DOI] [PubMed] [Google Scholar]
- 6.Soltani S., Tabibzadeh A., Zakeri A., Zakeri A.M., Latifi T., Shabani M., et al. COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis. Rev Neurosci. 2021;32:351–361. doi: 10.1515/revneuro-2020-0108. [DOI] [PubMed] [Google Scholar]
- 7.Domínguez-Varela I.A., Rodríguez-Gutiérrez L.A., Morales-Mancillas N.R., Barrera-Sánchez M., Macías-Rodríguez Y., Valdez-García J.E. COVID-19 and the eye: a review. Infect Dis (Lond) 2021;53:399–403. doi: 10.1080/23744235.2021.1882697. [DOI] [PubMed] [Google Scholar]
- 8.Kumar K.K., Sampritha U.C., Prakash A.A., Adappa K., Chandraprabha S., Neeraja T.G., et al. Ophthalmic manifestations in the COVID-19 clinical spectrum. Indian J Ophthalmol. 2021;69:691–694. doi: 10.4103/ijo.IJO_3037_20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hu K., Patel J., Swiston C., et al. StatPearls [Internet] StatPearls Publishing; Treasure Island (FL): 2022. Ophthalmic manifestations of coronavirus (COVID-19) [updated 2022 May 24] [PubMed] [Google Scholar]
- 10.Magro C.M., Mulvey J., Kubiak J., Mikhail S., Suster D., Crowson A.N., et al. Severe COVID-19: a multifaceted viral vasculopathy syndrome. Ann Diagn Pathol. 2021;50:151645. doi: 10.1016/j.anndiagpath.2020.151645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Invernizzi A., Torre A., Parrulli S., Zicarelli F., Schiuma M., Colombo V., et al. Retinal findings in patients with COVID-19: results from the SERPICO-19 study. EClinicalMedicine. 2020;27:100550. doi: 10.1016/j.eclinm.2020.100550. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lecler A., Cotton F., Lersy F., Kremer S., Héran F., SFNR's COVID., et al. Ocular MRI findings in Patients with Severe COVID-19: a retrospective multicenter observational study. Radiology. 2021;299:E226–E229. doi: 10.1148/radiol.2021204394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chin M.S., Hooper L.C., Hooks J.J., Detrick B. Identification of α-fodrin as an autoantigen in experimental coronavirus retinopathy (ECOR) J Neuroimmunol. 2014;272:42–50. doi: 10.1016/j.jneuroim.2014.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wang Y., Detrick B., Yu Z.X., Zhang J., Chesky L., Hooks J.J. The role of apoptosis within the retina of coronavirus-infected mice. Invest Ophthalmol Vis Sci. 2000;41:3011–3018. [PubMed] [Google Scholar]
- 15.Vinores S.A., Wang Y., Vinores M.A., Derevjanik N.L., Shi A., Klein D.A., et al. Blood-retinal barrier breakdown in experimental coronavirus retinopathy: association with viral antigen, inflammation, and VEGF in sensitive and resistant strains. J Neuroimmunol. 2001;119:175–182. doi: 10.1016/S0165-5728(01)00374-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Abrishami M., Emamverdian Z., Shoeibi N., Omidtabrizi A., Daneshvar R., Saeidi Rezvani T., et al. Optical coherence tomography angiography analysis of the retina in patients recovered from COVID-19: a case-control study. Can J Ophthalmol. 2021;56:24–30. doi: 10.1016/j.jcjo.2020.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Guemes-Villahoz N., Burgos-Blasco B., Vidal-Villegas B., Donate-López J., de la Muela M.H., López-Guajardo L., et al. Reduced macular vessel density in COVID-19 patients with and without associated thrombotic events using optical coherence tomography angiography. Graefes Arch Clin Exp Ophthalmol. 2021;259:2243–2249. doi: 10.1007/s00417-021-05186-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tiryaki Demir S., Dalgic N., Keles Yesiltas S., Akbas Ozyurek E.B., Karapapak M., Uke Uzun S., et al. OCT and OCTA evaluation of vascular and morphological structures in the retina in recovered pediatric patients with COVID-19. Photodiagnosis Photodyn Ther. 2022;40:103157. doi: 10.1016/j.pdpdt.2022.103157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lowenstein C.J., Solomon S.D. Severe COVID-19 is a microvascular disease. Circulation. 2020;142:1609–1611. doi: 10.1161/CIRCULATIONAHA.120.050354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Turker I.C., Dogan C.U., Guven D., Kutucu O.K., Gul C. Optical coherence tomography angiography findings in patients with COVID-19. Can J Ophthalmol. 2021;56:83–87. doi: 10.1016/j.jcjo.2020.12.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Patton N., Aslam T., Macgillivray T., Pattie A., Deary I.J., Dhillon B. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat. 2005;206:319–348. doi: 10.1111/j.1469-7580.2005.00395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Eldaly Z., Soliman W., Sharaf M., Reyad A.N. Morphological characteristics of normal foveal avascular zone by optical coherence tomography angiography. J Ophthalmol. 2020;2020:8281459. doi: 10.1155/2020/8281459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Murakami T., Tsujikawa A., Miyamoto K., Sakamoto A., Ota M., Ogino K., et al. Relationship between perifoveal capillaries and pathomorphology in macular oedema associated with branch retinal vein occlusion. Eye. 2012;26:771–780. doi: 10.1038/eye.2012.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Soares M., Neves C., Marques I.P., Pires I., Schwartz C., Costa MÂ, et al. Comparison of diabetic retinopathy classification using fluorescein angiography and optical coherence tomography angiography. Br J Ophthalmol. 2017;101:62–68. doi: 10.1136/bjophthalmol-2016-309424. [DOI] [PubMed] [Google Scholar]
- 25.Burgos-Blasco B., Güemes-Villahoz N., Donate-Lopez J., Vidal-Villegas B., García-Feijóo J. Optic nerve analysis in COVID-19 patients. J Med Virol. 2021;93:190–191. doi: 10.1002/jmv.26290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Akpolat C., Cetinkaya T., Kurt M.M. A pediatric COVID-19 study: retinal nerve fiber layer, ganglion cell layer, and alterations in choroidal thickness in swept-source OCT measurements. Klin Monbl Augenheilkd. 2022;239:916–922. doi: 10.1055/a-1785-3863. [DOI] [PubMed] [Google Scholar]
- 27.Yu P.K., Cringle S.J., Yu D.Y. Correlation between the radial peripapillary capillaries and the retinal nerve fibre layer in the normal human retina. Exp Eye Res. 2014;129:83–92. doi: 10.1016/j.exer.2014.10.020. [DOI] [PubMed] [Google Scholar]
- 28.Kornzweig A.L., Eliasoph I., Feldstein M. Selective atrophy of the radial peripapillary capillaries in chronic glaucoma. Arch Ophthalmol. 1968;80:696–702. doi: 10.1001/archopht.1968.00980050698002. [DOI] [PubMed] [Google Scholar]
- 29.Chen Y., Li J., Yan Y., Shen X. Diabetic macular morphology changes may occur in the early stage of diabetes. BMC Ophthalmol. 2016;16:12. doi: 10.1186/s12886-016-0186-4. [DOI] [PMC free article] [PubMed] [Google Scholar]