Comparison of optic nerve head and macular perfusion changes before and after the development of COVID-19

Abstract

Background

COVID-19 is known to induce systemic endothelial inflammation and microvascular dysfunction, with reported implications for various tissues, including ocular structures. Optical coherence tomography angiography (OCTA) offers a non-invasive and high-resolution method to visualize and quantify retinal microcirculatory networks. While prior research has investigated ocular microvascular changes in COVID-19 patients, studies comparing these alterations in the same individuals before and after infection are limited.

Methods

Among individuals who had baseline OCTA at their previous admission to our clinic, 20 patients who later contracted and recovered from COVID-19 were included in the study. OCTA images were obtained using the AngioVue optical coherence tomography angiography system, with split-spectrum amplitude decorrelation angiography images. After resolution of COVID-19, OCTA was performed again in these patients, and the results were compared with the previous foveal avascular zone (FAZ) and vessel densities (VD) findings.

Results

After disease resolution, the optic nerve head vessel density (ONH-VD) was found to be statistically significantly decreased in all areas except the superonasal area, while the radial peripapillary capillary vessel density (RPC-VD) was found to be statistically significantly decreased in all areas, except inside the disc and superonasal and temporal areas. The superficial capillary plexus vessel density (SCP-VD) was found to be significantly decreased in the superior hemi, superior and nasal areas, and the deep capillary plexus vessel density (DCP-VD) significantly decreased in the whole image, parafovea, and inferior hemi and inferior and nasal areas.

Conclusions

After resolution of COVID-19, the ONH-VD and RPC-VD decreased generally, and in the macular region, the SCP-VD and DCP-VD decreased in certain areas. These results may be important in understanding the effects of COVID-19 on systemic vascular circulation.

Introduction

COVID-19, a novel potentially fatal respiratory illness primarily affecting the lungs and airways, is caused by severe acute respiratory syndrome coronavirus 2. The disease typically manifests with fever, cough, and fatigue and is principally transmitted through respiratory droplets [1, 2]. SARS-CoV-2, the etiologic agent of COVID-19, enters host cells via angiotensin-converting enzyme 2 receptors that are abundantly expressed across various tissues. This viral infection triggers endothelial inflammation and dysfunction across different disease stages, culminating in tissue hypoperfusion and thrombosis [3, 4].

SARS-CoV-2 enters cells expressing ACE2 receptors, which are present in various ocular tissues; moreover, viral RNA has been detected in tear fluid and retinal biopsies [5–7]. Although anterior segment manifestations such as conjunctivitis have been documented in patients with COVID-19, SARS-CoV-2 RNA has been detected in retinal and corneal biopsies from affected individuals. Furthermore, studies have reported that the virus may induce retinitis, cotton wool spots, and microhemorrhages in the retina [8, 9]. Hypercoagulability in these patients arises from the virus-induced hyperinflammatory state, which precipitates retinal vascular occlusions and ophthalmoplegia [10, 11]. Optical coherence tomography angiography (OCTA) is a non-invasive, rapid, safe, and reproducible imaging modality that enables high-resolution visualization of retinal structures, quantitative assessment of retinal capillary networks, and measurement of the foveal avascular zone (FAZ) [12–14]. This advanced imaging technique allows for the detailed examination of microvasculature in different retinal layers, such as the superficial capillary plexus (SCP) and deep capillary plexus (DCP), providing valuable insights into disease progression and treatment responses [15–17]. OCTA facilitates the detection of early microvascular alterations even before they are clinically evident, making it a crucial tool for assessing conditions such as diabetic retinopathy [18].

Although prior studies have compared optical coherence tomography angiography findings, including optic nerve head and macular vessel densities, between patients with COVID-19 and healthy controls, to our knowledge, no investigations have assessed microcirculatory changes before and after COVID-19 infection in the same individuals [19]. Accordingly, this study aimed to evaluate optic nerve head and macular perfusion alterations before and after COVID-19 development using OCTA. This approach offers a unique longitudinal perspective on the virus’s impact on ocular microvasculature, thereby enhancing our understanding of its systemic vascular implications [20].

Materials and methods

Study design and subject

Among individuals who had baseline OCTA at their previous admission to our clinic, 20 patients who later contracted and recovered from COVID-19 were included in the study. Approval for the study was obtained from the Dicle University Faculty of Medicine Ethics Committee and the Ministry of Health. The investigation was conducted in accordance with the Declaration of Helsinki, and written informed consent was secured from all participants prior to imaging.

Patients exhibiting COVID-19 symptoms—including cough, fever, sore throat, and myalgia—who were hospitalized, confirmed positive by polymerase chain reaction testing, and had recovered from the disease for at least one month were enrolled in the study.

All participants underwent comprehensive anterior and posterior segment examinations, including assessments of best-corrected visual acuity. Individuals with a history of ocular surgery, spherical equivalent exceeding 4 diopters, other ocular pathologies, or systemic diseases (diabetes, hypertension and other relevant systemic vascular conditions) were excluded from the study.

Optical coherence tomography angiography measurements

In this study, AngioVue device (Optovue, Inc, Fremont, CA), amplitude/intensity-signal-based OCTA technique [split-spectrum amplitude-decorrelation angiography (SSADA)] was used. En face images of the macula and optic nerve head were acquired with 3 × 3 mm scan protocols, restricted to the right eyes of all participants. The foveal avascular zone in the SCP and DCP was measured using the integrated non-flow detection function of the OCTA software, whereas VD was determined as the proportion of the total area occupied by vessels exhibiting perfusion. Superficial and deep macular scans enabled quantification of VD in the fovea (Fig. 1), parafovea, superior hemifield, and inferior hemifield for both Superficial capillary plexus SCP-VD and DCP-VD (Fig. 2). VD measurements of the optic nerve head and radial peripapillary capillary network were acquired using the optic nerve head scanning protocol, which permitted calculation of RPC-VD and ONH-VD across six distinct sectors. The peripapillary region was delineated as an annular ellipse extending 0.75 mm from the optic disc margin (Fig. 3). Only images with signal strength exceeding 50 and without segmentation errors were included. All images underwent meticulous review by two independent retina specialists to ensure adequate quality and resolution, with those exhibiting significant motion artifacts that interfered with VD analysis being excluded.

Fig. 1.

Superficial and deep foveal avascular zones (FAZ)

Fig. 2.

Superficial capillary plexus vessel density (SCP-VD), Deep capillary plexus vessel density (DCP-VD)

Fig. 3.

Optic nerve head vessel density (ONH-VD), Radial peripapillary capillary vessel density (RPC-VD)

Statistical analysis

Statistical analyses were performed using SPSS software. Descriptive statistics were used to characterize demographic features, expressing continuous variables as means ± standard deviations and categorical variables as frequencies/percentages. Data normality was evaluated with the Kolmogorov-Smirnov test, confirming adherence to normality assumptions (all p > 0.05). Accordingly, paired t-tests—suited to the within-subjects longitudinal design—were applied to compare optic nerve head and macular VD parameters before and after COVID-19 infection. Statistical significance was determined at a two-tailed p < 0.05, without multiple comparison adjustments due to the focused, hypothesis-driven nature of the comparisons.

Results

This study enrolled a total of 20 participants, comprising 12 females and 8 males. The elapsed time since the diagnosis of the disease was 36.6 ± 5.5 days, while the elapsed time since the negative PCR test was 21.6 ± 4.9 days (Table 1). In post-infection angio disc mode images, ONH-VD showed statistically significant reductions in the whole image, inside the disc, peripapillary, nasal, inferonasal, inferotemporal, superotemporal, and temporal areas (p < 0.001, p < 0.001, p < 0.001, p = 0.001, p = 0.004, p = 0.004, p < 0.001, and p = 0.001, respectively). Similarly, RPC-VD exhibited statistically significant decreases across all sectors except inside the disc, superonasal, and temporal regions areas (p = 0.004, p < 0.001, p = 0.001, p = 0.001, p = 0.001, and p < 0.001, respectively) (Table 2). In the retinal angiography mode, SCP-VD exhibited significant reductions in the superior hemifield, superior, and nasal areas (p = 0.002, p < 0.001, and p < 0.001respectively), whereas DCP-VD showed significant decreases across the whole image, parafovea, inferior hemifield, nasal, and inferior areas (p = 0.022, p = 0.024, p = 0.032, p = 0.04 and p = 0.004, respectively) (Table 3). Additionally, although the enlargement was not statistically significant, the foveal avascular zones of the study participants were larger following COVID-19 infection (superficial, 0.297 ± 0.066 and 0.301 ± 0.092, p = 0.811; deep, 0.338 ± 0.069 and 0.348 ± 0.068, p = 0.273).

Table 1.

Demographic characteristics of the patients included in the study

Characteristic
• Age (years), (mean ± SD)	34.50 ± 5.2
• Sex, n (%)
o Female  o Male	12 (40.0) 8 (60.0)
• Time elapsed since the diagnosis of the disease (days), (mean ± SD)	36.6 ± 5.5
• Time elapsed since the PCR test was negative (days), (mean ± SD)	21.6 ± 4.9

PCR, polymerase chain reaction; SD, standard deviation. Data are presented as mean ± standard deviation (SD) or n (%)

Table 2.

Optic nerve head (ONH-VD) and radial peripapillary capillary vessel density (RPC-VD) of the patients included in the study (%)

Characteristic	ONH-VD*			RPC-VD**
	Before Covid-19	Post Covid-19	Significant (p)	Before Covid-19	Post Covid-19	Significant (p)
Whole Image	62.03 ± 1.36	59.30 ± 2.25	< 0.001	59.70 ± 3.24	58.10 ± 2.41	0.004
o Inside disk	59.23 ± 2.53	56.04 ± 2.49	< 0.001	51.60 ± 8.82	49.88 ± 6.45	0.034
o Peripapillary	65.02± 1.54	61.06 ± 2.53	< 0.001	67.09 ± 2.66	62.47 ± 3.62	< 0.001
o Nasal	62.86 ± 1.80	58.77 ± 5.22	0.001	64.02 ± 2.74	59.23 ± 5.47	0.001
o Inferonasal	69.12 ± 6.85	64.73 ± 6.85	0.004	69.36 ± 6.20	64.31 ± 7.84	0.001
o Inferotemporal	67.44 ± 2.91	63.10 ± 6.13	0.004	71.86 ± 2.80	66.42 ± 5.39	0.001
o Superotemporal	69.08 ± 6.68	64.52 ± 6.16	< 0.001	72.36 ± 6.39	65.76 ± 5.99	< 0.001
o Superonasal	58.56 ± 8.03	59.21 ± 5.95	0.492	62.18 ± 7.20	60.41 ± 3.40	0.223
o Temporal	65.71 ± 2.46	60.59 ± 6.58	0.001	67.38 ± 3.44	63.24 ± 6.56	0.006

* ONH-VD, optic nerve head vessel density; **RPC-VD, radial peripapillary capillary vessel density. Data are presented as mean ± standard deviation (SD). P values were obtained using a two-tailed paired-samples t-test. Statistical significance was set at p < 0.05, Bold characters indicate statistical significance

Table 3.

Superficial capillary plexus (SCP-VD) and deep capillary plexus vessel density (DCP-VD) of the patients included in the study (%)

Characteristic	SCP-VD			DCP-VD
	Before Covid-19	Post Covid-19	Significant (p)	Before Covid-19	Post Covid-19	Significant (p)
Whole Image	54.61 ± 0.97	54.22 ± 1.34	0.14	60.94 ± 1.20	59.09 ± 2.46	< 0.001
o Fovea	31.64 ± 5.70	33.49 ± 3.89	0.14	31.17 ± 6.42	31.75 ± 3.58	0.65
o Parafovea	56.99 ± 0.86	56.69 ± 1.34	0.33	64.09 ± 1.76	61.76 ± 2.12	0.001
o Superior hemi	57.44 ± 0.76	56.34 ± 1.41	0.002	63.83 ± 2.47	62.90 ± 1.57	0.08
o Inferior hemi	56.96 ± 1.04	56.85 ± 1.92	0.82	64.28 ± 1.90	61.11 ± 3.77	0.002
o Temporal	55.25 ± 1.20	55.27 ± 2.41	0.97	62.45 ± 2.21	61.39 ± 2.89	0.18
o Superior	58.64 ± 0.88	56.79 ± 1.65	< 0.001	64.91 ± 2.47	64.22 ± 2.63	0.09
o Nasal	57.22 ± 1.10	55.13 ± 2.00	< 0.001	63.59 ± 1.11	59.89 ± 6.90	0.04
o Inferior	58.09 ± 2.39	58.42 ± 1.12	0.61	65.28 ± 2.41	62.70 ± 2.79	< 0.001

* SCP-VD, superficial capillary plexus vessel density; **DCP-VD, deep capillary plexus vessel density. Data are presented as mean ± standard deviation (SD). P values were obtained using a two-tailed paired-samples t-test. Statistical significance was set at p < 0.05, Bold characters indicate statistical significance

Discussion

The present study sought to evaluate alterations in optic nerve head and macular perfusion before and after COVID-19 onset using optical coherence tomography angiography. Results indicated a general decline in ONH-VD and RPC-VD, with reductions in SCP-VD and DCP-VD observed in select macular areas.

SARS-CoV-2, the etiologic agent of COVID-19, gains entry into host cells via ACE2 receptors ubiquitously expressed across diverse tissues. This viral infection has been implicated in inducing tissue hypoperfusion, thrombosis, and endotheliitis. Moreover, heightened incidences of neurovascular complications and pulmonary arterial thrombosis have been documented. Analogously, retinal vascular occlusions and cotton wool spots attributable to retinal ischemia have been observed in affected individuals [3, 21]. In addition, an increased incidence of neurovascular events and pulmonary artery thrombosis has been reported [22, 23]. These findings align with studies demonstrating reduced retinal VD in conditions associated with systemic vascular compromise, such as stroke, further underscoring the potential for COVID-19 to induce microvascular changes in the retina [24]. These microvascular alterations may manifest as decreased in the SCP-VD and DCP-VD, along with changes in the foveal avascular zone [25]. For instance, patients who have recovered from COVID-19 frequently exhibit a progressive reduction in VD over time, and some studies indicate morphological alterations and decreases in vascular density even in unaffected fellow eyes of patients with retinal vein occlusion [26, 27]. Specifically, post-COVID-19 patients exhibit reduced foveal vascular density in the DCP and choriocapillaris, suggesting impaired sub-foveal blood supply, even in the absence of visual deterioration [28].

In this study, ONH-VD exhibited significant reductions across all sectors except the superonasal region, while RPC-VD demonstrated significant decreases in all sectors excluding the interior disc, superonasal, and temporal areas. These findings align with reports of diminished radial peripapillary capillary plexus perfusion density in patients with COVID-19 compared to healthy controls [29]. Such widespread reductions in VD within the optic nerve head and radial peripapillary capillary network underscore a substantial impact of COVID-19 on ocular microcirculation [30]. The observed microvascular changes are consistent with the known vascular compromise characteristic of various optic neuropathies, where altered blood flow can lead to neuronal damage and vision impairment [31, 32].

Hypoxia may elevate circulating levels of proinflammatory cytokines, thereby promoting vascular leakage and subsequent edema [33]. In a previous study evaluating COVID 19 patients with prior OCT measurements, four out of five exhibited an increase in mean retinal nerve fiber layer thickness after recovery [34]. This increase may be attributable to inflammation and oedema secondary to hypoxia arising from the observed reduction in RPC-VD, which supplies blood to the RNFL. Furthermore, this inflammatory process may contribute to changes in retinal nerve fiber layer thickness, a phenomenon also observed in other neuroinflammatory conditions such as multiple sclerosis following optic neuritis [13, 14]. Indeed, intraocular inflammation has been identified as a key driver in various retinal pathologies, including macular edema secondary to retinal vein occlusion, where it correlates with factors such as central retinal thickness [21, 22]. This aligns with findings in quiescent posterior and panuveitis, where inflammation can lead to alterations in retinal and choroidal vascular parameters, such as fractal dimension and choroidal vascularity index [23].

Our study found that the SCP-VD (superior hemi, nasal, and inferior areas) and DCP-VD (whole image, parafovea, inferior hemi, and inferior) decreased in some areas in patients recovering from COVID-19. Consistent with our findings, a cross-sectional study comparing patients recovering from COVID-19 to healthy controls reported significant reductions in the SCP-VD and DCP-VD in the foveal and parafoveal macular regions among affected individuals. Nevertheless, that study observed no significant difference in VD between hospitalized patients and controls [35]. Another study likewise reported reduced central retinal VD in patients with moderate-to-severe COVID-19 relative to asymptomatic cases or healthy controls [36]. However, a study comparing 70 patients recovering from moderate COVID-19 with 22 healthy controls reported no significant differences in SCP-VD or DCP-VD between the groups. It has been suggested that alterations in VD may be confined to patients with severe COVID-19, with potential damage to the macular capillary plexuses resolving following the acute infection phase [37]. Thus, a plausible explanation for these discrepant findings is that measurements were performed an average of 36.1 days post-onset in the referenced study, whereas in our study, they were conducted 21.7 days after the mean recovery time.

This single-center study is constrained by its limited sample size and lack of long-term follow-up assessments. Nonetheless, the paired pre- and post-COVID-19 evaluations in the same participants functioned as an internal control, reducing inter-individual variability and enhancing the sensitivity to detect substantial microvascular alterations despite the small cohort. A primary strength is that it represents the first investigation to compare microcirculation parameters in COVID-19 patients before and after disease onset.

In conclusion, following recovery from COVID-19, ONH-VD and RPC-VD exhibited generalized reductions, with SCP-VD and DCP-VD showing decreases in select macular sectors. These findings contribute to understanding the broader vascular implications of COVID-19 on systemic circulation.

Author contributions

Study design: S.E., S.A., M.E.D., M.K.; Study intervention: S.E., M.E.D., S.A., M.K., U.K. Methodology: S.E., M.E.D., M.K., U.K., B.D.; Formal Analysis: S.E., S.A., M.K., U.K.; Writing–Original Draft Preparation: S.E., U.K., L.H., M.E.D., S.A.; Writing–Review & Editing: S.E., M.K., S.A.; Visualization: S.E, U.K., L.H., S.A.; Supervision: S.E., M.E.D., L.H., M.K., U.K.

Funding

This research received no external funding.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to concerns about patient privacy but are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Dicle University Medical Faculty (Approval No: 2021/57) Written informed consent for participation was obtained from the parents or legal guardians of all participants in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Financial disclosures

None of the authors has financial interest to disclose.

Competing interests

The authors declare no competing interests.