Original Article

Optic Nerve Head Optical Coherence Tomography
Angiography Findings after Coronavirus Disease

Mojtaba Abrishami1, MD, MS; Ramin Daneshvar1, MD, MS; Zahra Emamverdian1, MSc; Nasser Shoeibi1, MD, MS
Shima Sedighi2, MD; Talieh Saeidi Rezvani3, PhD; Neda Saeedian4, MD; Saeid Eslami5, 6, 7, PharmD, PhD

1Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, Jacksonville, FL, USA

3Department of Education and Psychology, Ferdowsi University of Mashhad, Mashhad, Iran
4Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
6Department of Medical Informatics, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The

Netherlands
7Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

ORCID:
Mojtaba Abrishami: http://orcid.org/0000-0003-2001-7929
Ramin Daneshvar: http://orcid.org/0000-0002-0884-0907
Zahra Emamverdian: http://orcid.org/0000-0002-1659-1488

Nasser Shoeibi: http://orcid.org/0000-0003-3544-0105
Talieh Saeidi Rezvani: http://orcid.org/0000-0003-0460-8454

Neda Saeedian: http://orcid.org/0000-0003-2128-0315
Saeid Eslami: http://orcid.org/0000-0003-3755-1212

This study has been presented at the 8th International Congress on OCT and OCT Angiography (ICOOR 2020 - Virtual) as an
oral presentation.

Abstract
Purpose: To quantify the microvasculature density of the optic nerve head (ONH) using optical
coherence tomography angiography (OCTA) analysis in patients recovered from Coronavirus
Disease 2019 (COVID-19).
Methods: In a comparative cross-sectional, observational study, patients recovered from COVID-
19 whose initial diagnosis was confirmed by a rRT-PCR of a nasopharyngeal sample were included
in this study. OCTA of ONH was performed in included patients and normal controls. Vascular
density (VD) of the all vessels (AV) and small vessels (SV) inside the disc and radial peripapillary
capillary (RPC) network density were measured in COVID-19 recovered patients and compared
with similar parameters in an age-matched group of normal controls.
Results: Twenty-five COVID-19 patients and twenty-two age-matched normal controls were
enrolled in the study and one eye per participant was evaluated. The mean whole image SV
VD in the COVID-19 group (49.31 ± 1.93) was not statistically significantly different from that in
the control group (49.94 ±. 2.22; P = 0.308). A decrease in RPC VD was found in all AV and SV
VD measured, which became statistically significant in whole peripapillary SV VD, peripapillary
inferior nasal SV VD, peripapillary inferior temporal SV VD, peripapillary superior nasal SV VD,
and grid-based AV VD inferior sector (P < 0.05). Inside disc SV VD in the COVID-19 group (49.43
± 4.96) was higher than in the control group (45.46 ± 6.22) which was statistically significant (P
= 0.021).
Conclusion: Unremarkable decrease was found in ONH microvasculature in patients who had
recovered from COVID-19. These patients may be at risk of ONH vascular complications. Increase
in inner disc SV VD may be an indicator of ONH hyperemia and edema.

Keywords: Coronavirus Disease 2019 (COVID-19); Optic Nerve Head; Optical Coherence Tomography
Angiography (OCTA); Radial Peripapillary Capillary Network; Severe Acute Respiratory Syndrome Corona
Virus 2 (SARS-CoV-2)

J Ophthalmic Vis Res 2021; 16 (4): 592–601

592 © 2021 ABRISHAMI ET AL. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY KNOWLEDGE E

http://crossmark.crossref.org/dialog/?doi=10.18502/jovr.v16i4.9749&domain=pdf&date_stamp=2019-07-17


Disc OCTA Findings in COVID-19; Abrishami et al

INTRODUCTION

Severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) is a new member of the
Coronaviridae family of viruses, which can
cause serious life-threatening respiratory illness,
severe pneumonia,[1] and even multiorgan
failure.[2, 3] Various clinical presentations and
fatal consequences of the associated disease,
Coronavirus Disease 2019 (COVID-19), have been
reported, but scarce reports regarding ocular
manifestations are available.[4, 5]

Angiotensin-converting enzyme (ACE)-2 is
considered as the main receptor for SARS-CoV-2
infection.[6] ACE2 as a member of the renin-
angiotensin-aldosterone system (RAAS) is present
in different cell types including type II alveolar
cells in the lung, arterial and venous endothelial
cells, enterocytes of the small intestine, and
smooth muscle cells of arterial vasculature of
most organs.[7] Its homologous enzyme is ACE,
which is the main effector in the RAAS and
ACE2 counterbalances and regulates its activity
by reducing the amount of angiotensin-II and
increasing Ang (1-7).[8] ACE and ACE2 have been
presented in the choroid and different cell types
of the retina including retinal vascular endothelial
cell, photoreceptor cells, Müller cells, and ganglion
cells.[9] Moreover, their expression in neurons and
glial cells in the central nervous system (CNS) have
been reported.[10] Hence, it seems reasonable to
expect ocular, and specifically optic nerve head
(ONH) and CNS manifestations of the SARS-CoV-2
infection.

The majority of reports on the ocular
involvement in COVID-19 describe ocular
surface manifestations including conjunctival
congestion, chemosis, and conjunctivitis.[11]
Reports of the retinal findings are numerable.
Marinho and colleagues described various retinal

Correspondence to:

Mojtaba Abrishami, MD. Eye Research Center,
Khatam-al-Anbia Eye Hospital, Qarani Blvd, Mashhad
9195965919, Iran.
E-mail: mojtaba_abrishami@yahoo.com
Received: 18-02-2021 Accepted: 23-07-2021

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i4.9749

manifestations of COVID-19 like cotton wool
spots and hemorrhages.[12] In our previous report,
we found decrease in macular vessel density
in superficial and deep capillary peluxuses of
the retina, using optical coherence tomography
angiography (OCTA) in otherwise healthy relatively
young patients.[13] However, no similar report
on ONH microvascular findings was avaiable in
patients infected with SARS-CoV-2.

As the choroid, retina and nervous tissues could
be targets of infection, because of binding of
the virus to ACE2 receptor, and previous reports
on ocular posterior segment lesions in COVID-19
individuals include nonspecific findings, like retinal
hemorrhages or cotton wool spots, we aimed to
evaluate the ONH microvasculature in relatively
young and otherwise healthy patients recovered
from COVID-19 and compare it with a normal group.

METHODS

Study Participants

A cross-sectional study was conducted at the Imam
Reza General Hospital, Mashhad, Iran. Nurses
and physicians working at Mashhad University
of Medical Sciences (MUMS) with a definite
diagnosis of COVID-19, confirmed by a positive test
result of a nasopharyngeal swab sample real-time,
reverse transcription-polymerase chain reaction,
who recovered from the systemic symptoms at
least two weeks prior to the enrolment, were
included.

Detailed ocular and systemic histories were
obtained from each participant and those with a
history of autoimmune disease, migraine, diabetes
mellitus, current pregnancy and breastfeeding, or
any history of intraocular surgery were excluded.
Additional exclusion criteria included absolute
spherical refractive error >5 diopters and
cylindrical refractive error >2 diopters, best-
corrected visual acuity <20/20, and evidence of
glaucoma or clinically apparent retinal disease.

This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which
allows others to remix, tweak, and build upon the work non-commercially, as
long as appropriate credit is given and the new creations are licensed under the
identical terms.

How to cite this article: Abrishami M, Daneshvar R, Emamverdian Z, Shoeibi
N, Sedighi S, Rezvani TS, Saeedian N, Eslami S. Optic Nerve Head Optical
Coherence Tomography Angiography Findings after Coronavirus Disease. J
Ophthalmic Vis Res 2021;16:592–601.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021 593

https://knepublishing.com/index.php/JOVR


Disc OCTA Findings in COVID-19; Abrishami et al

Those with ocular media opacity, like cataract or
corneal haziness, preventing high-quality imaging
or reduced OCTA scan quality (i.e., quality scan
index <7/10) were also excluded from the analysis.

The age-matched control groups were healthy
nurses and physicians employed by the MUMS
who were imaged on the same OCTA machine at
the Imam Reza Hospital in 2019; this group was
recruited as part of an ongoing, longitudinal cohort
study, PERSIAN Organizational Cohort study in
MUMS.

Complete medical systemic history regarding
the patients’ COVID-19 symptoms, hospitalization,
and disease course were recorded. Oxygen
saturation at the time of examination was measured
by a portable pulse oximeter.

Image Acquisition and Analysis

OCTA scans were performed with the AngioVue
(RTVue XR Avanti, Optovue, Fremont, CA, USA;
Software version 2018.0.0.14), an OCTA machine
with A-scan-rate of 70,000 scans/sec. Each B
scan line is repeated to evaluate the image
decorrelation. Optic disc cubes, AngioDisc 4.5
× 4.5 mm HD scan (400 lines × 400 A-scans)
protocols, were scanned in the horizontal and
vertical orthogonal directions. All measurements
were primarily acquired using the automated
default segmentation with the preset settings for
the radial peripapillary capillary (RPC) network. The
3D Projection Artifact Removal by OCT 3D volume
set were utilized.

All images were centered on the optic disc
and displayed a scan quality index of at least
7/10. Images with undesirable quality or image
artifact were discarded and reacquired. All images
in the study, mostly segmentation accuracy, were
carefully reviewed by two authors (MA, RD) to
ensure sufficient quality and resolution and any
images with artifact significant enough to interfere
with vessel density analysis were also excluded.
For all subjects, cases or controls, only the data
of the eye with better image quality was used for
analysis.

To evaluate the RPC layer, a slab between
the outer limit of the retinal nerve fiber layer
(RNFL) and the internal limiting membrane were
used. All images were checked for segmentation
errors and manually adjusted before testing the
vessel density. All vessels (AV), including both

large and small vessels (SV), and SV vascular
density (VD) were evaluated separately in the
RPC layer. The whole image, inside disc area,
in peripapillary whole, peripapillary superior and
inferior hemifields, and eight segments SV RPC
VD were reported. For the evaluation of AV VD,
including both large vessels and SV, the whole
image was divided into nine (three by three)
grid-based sections, and AV VD in all sections
was reported separately. Moreover, the whole
image, inside the disc area, in peripapillary whole,
peripapillary superior and inferior hemifields AV
were reported.

Statistical Analysis

The normal distribution of variables was examined
using the Shapiro–Wilk test and normality plots
and homogeneity of variances were ascertained
by Levene’s test. Based on data distribution and
type, either the independent-samples t-test, paired
t-tests, or Mann–Whitney U test were used for
comparisons. Chi-square test and Fisher’s exact
test were used for categorical variables. The
level of statistical significance was set at 0.05.
All statistical analyses were performed using the
SPSS program for Windows, version 20 (IBM SPSS
Statistics, IBM Corporation, Chicago, IL, USA).

Ethical Considerations

The study protocol adhered to the tenets of the
Declaration of Helsinki. All participants provided
written informed consent before enrollment and
the ethical aspects of the study were approved
by the Regional Committee on Medical Ethics at
Mashhad University of Medical Sciences, Mashhad,
Iran (IR.MUMS.REC.1399.104).

RESULTS

Twenty-five recovered COVID-19 patients (10
females, 40%) with a mean age of 41.5 ± 10.5 years
and 22 healthy normal controls (10 females, 45.4%)
with a mean age of 36.7 ± 7.3 years were enrolled
in the study. Age (P = 0.086) and gender (P = 0.706)
were not significantly different between the two
groups. ONH parameters like cup–disc ratio and
rim area were not different between the groups
[Table 1]. None of the patients or controls had other
systemic comorbidity except recent COVID-19 in
last six months.

594 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021



Disc OCTA Findings in COVID-19; Abrishami et al

Table 1. Comparison of optic nerve head parameters and age of COVID-19 patients eyes versus normal eyes

Normal eyes (n = 22) Mean ±±±
SD (Range)

COVID-19 patients eyes (n =
25) Mean ±±± SD (Range)

P-value
(Compare to

normal)

Age (yr) 41.5 ± 10.5 (24.00–53.00) 36.7 ± 7.3 (25.00–61.00) 0.086
Cup/Disc Area Ratio 0.14 ± 0.09 (0.00–0.33) 0.12 ± 0.10 (0.00–0.35) 0.415
Cup/Disc Vertical Ratio 0.37 ± 0.18 (0.00–0.60) 0.30 ± 0.21 (0.00–0.61) 0.283
Cup/Disc Horizontal Ratio 0.32 ± 0.16 (0.00–0.55) 0.27 ± 0.19 (0.00–0.59) 0.356
Rim Area 1.67 ± 0.27 (1.18–2.29) 1.58 ± 0.32 (1.09–2.40) 0.313
Disc Area 1.97 ± 0.31 (1.47–2.74) 1.81 ± 0.30 (1.22–2.40) 0.076
Cup Volume 0.09 ± 0.18 (0.00–0.87) 0.06 ± 0.08 (0.00–0.34) 0.469
Peripapillary RNFL 108 ± 10.77 (101.00–129.00) 112.04 ± 7.69 (83.00–133.00) 0.151

RNFL, retinal nerve fiber layer; COVID-19, Coronavirus Disease 2019; SD, Standard Deviation

Table 2. Comparison of small vessels (SV) vessel density (VD) of COVID-19 patients eyes versus normal eyes

COVID-19 patients eyes Mean
±±± SD (Range)

Normal eyes Mean ±±± SD
(Range)

P-value

Whole Image – SV VD 49.31 ± 1.93 (44.90–53.40) 49.94 ± 2.22 (44.50–53.20) 0.308
Inside Disc – SV VD S (37.70–56.40) 45.46 ± 6.22 (24.80–53.00) 0.021
Whole PeriPapillary – SV VD 51.76 ± 1.92 (47.00–55.20) 53.14 ± 2.31 (46.00–56.70) 0.032
PeriPapillary Superior Hemi – SV VD 52.01 ± 2.16 (46.90–55.70) 53.12 ± 2.90 (44.40–57.10) 0.148
PeriPapillary Inferior Hemi – SV VD 51.79 ± 3.31 (44.90–62.00) 53.16 ± 2.13 (47.70–57.90) 0.095
PeriPapillary Nasal Superior – SV VD 49.37 ± 2.96 (42.40–53.70) 49.99 ± 3.84 ( 37.90–56.10) 0.547
PeriPapillary Nasal Inferior – SV VD 48.20 ± 4.63 (39.00–57.90) 49.52 ± 4.71 (38.00–64.50) 0.337
PeriPapillary Inferior Nasal – SV VD 48.54 ± 2.94 (42.30–52.90) 53.21 ± 4.12 (45.40–59.50) <0.001
PeriPapillary Inferior Temporal – SV VD 56.93 ± 3.14 (46.60–61.50) 59.78 ± 3.25 (53.60–65.20) 0.004
PeriPapillary Temporal Inferior – SV VD 52.15 ± 3.57 (47.30–60.40) 53.69 ± 3 (45.40–58.20) 0.632
PeriPapillary Temporal Superior – SV VD 55.86 ± 4.02 (44.20–61.30) 55.96 ± 4.50 (44.50–63.80) 0.889
PeriPapillary Superior Temporal – SV VD 55.24 ± 2.76 (50.50–60.20) 57.0 ± 3.92 (49.50–63.30) 0.087
PeriPapillary Superior Nasal – SV VD 49.03 ± 3.39 43.60–55.50) 51.14 ± 3.72 (41.20–58.70) 0.049

SV, small vessels; VD, vessel density; SD, Standard Deviation; COVID-19, Coronavirus Disease 2019

All patients were symptom-free for at least
two weeks, and the mean recovery time interval
between becoming symptom free and OCTA image
acquisition was 20.3 ± 2.9 days (median: 18 days;
authors range: 13–29 days). Past medical history
was otherwise unremarkable for almost all of
the patients and controls. None of the included
subjects, COVID-19 cases or controls, endorsed a
history of diabetes mellitus. Two COVID-19 patients
had a history of grade 1 hypertension which was
well controlled with medications or diet. Nine
patients (36%) had a history of hospitalization for

COVID-19. O2 saturation was in the normal range
(94–99%) in these patients and was not different
from non-hospitalized patients (P = 0.513). The
mean scan quality was 8.28 ± 0.73 in the COVID
cases and 8.50 ± 0.67 in the normal controls (P =
0.293). Right eye OCTA was analyzed for 11 patients
and left eye for 14 patients.

The 4.5 × 4.5 mm mean whole image SV VD
in the COVID-19 group (49.31 ± 1.93) was not
statistically different from that in the normal control
group (49.94 ± 2.22) (P = 0.308) although it seems
to be lower in the COVID-19 recovered patients

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021 595



Disc OCTA Findings in COVID-19; Abrishami et al

Table 3. Comparison of all vessels (AV), including both small and large vessels, vessel density (VD) of COVID-19 patients eyes
versus normal eyes

COVID-19 patients eyes Mean
±±± SD (Range)

Normal eyes Mean ±±± SD
(Range)

P-value

Whole Image – AV VD 56.08 ± 1.89 (52.50–60.20) 56.44 ± 2.29 (51.40–59.10) 0.566
Inside Disc – AV VD 56.05 ± 4.14 (49.50–63.90) 57.25 ± 5.46 (40.40–63.80) 0.057
Whole Peripapillary – AV VD 58.31 ± 1.65 (55.00–61.80) 59.33 ± 2.34 (52.90–62.60) 0.110
Peripapillary Superior Half – AV VD 58.75 ± 1.64 (56.10–61.50) 59.50 ± 2.63 (52.00–63.70) 0.257
Peripapillary Inferior Half – AV VD 57.90 ± 2.08 (53.20–62.60) 59.11 ± 2.30 (53.90–63.60) 0.066
Grid Based AV VD Supero temporal 57.63 ± 4.21 (43.30–63.10) 59.14 ± 3.02 (52.60–64.00) 0.161
Grid Based AV VD Temporal 56.46 ± 3.08 (46.60–62.00) 57.01 ± 3.37 (50.40–61.50) 0.565
Grid Based AV VD Infero temporal 58.49 ± 4.47 (42.60–64.40) 58.67 ± 3.43 (49.20–64.10) 0.879
Grid Based AV VD Superior 56.85 ± 2.77 (52.50–62.10) 58.68 ± 3.36 (50.80–63.40) 0.051
Grid Based AV VD Central 58.10 ± 4.56 (50.00–64.60) 60.35 ± 3.23 (49.00–64.40) 0.061
Grid Based AV VD Inferior 60.68 ± 2.14 (55.30–64.50) 62.56 ± 3.15 (54.10–66.90) 0.023
Grid Based AV VD Supero nasal 51.71 ± 4.19 (43.90–58.20) 52.09 ± 3.36 (43.60–59.90) 0.739
Grid Based AV VD Nasal 52.30 ± 5.48 (43.80–67.90) 52.52 ± 3.50 (44.60–62.40) 0.869
Grid Based AV VD Inferonasal 50.29 ± 3.91 (44.40–59.80) 50.35 ± 3.84 (41.60–58.10) 0.903

AV, all vessels; VD, vessel density; SD, Standard Deviation; COVID-19, Coronavirus Disease 2019

Table 4. Comparison of small vessels (SV) vessel density (VD) of hospitalized versus non-hospitalized/outpatients treated
COVID-19 patients

Outpatients (n = 16) Mean ±±± SD
(Range)

Hospitalized (n = 9) Mean ±±± SD
(Range)

P-value

Whole Image – SV VD 46.77 ± 4.74 (29.70–53.60) 46.45 ± 4.08 (40.30–54.00) 0.860
Inside Disc – SV VD 47.64 ± 4.89 (31.70–55.20) 47.05 ± 4.86 (38.50–55.60) 0.764
Whole PeriPapillary – SV VD 48.76 ± 4.26 (34.70–56.10) 47.10 ± 4.48 (41.70–53.20) 0.344
PeriPapillary Superior Hemi – SV VD 49 ± 4.45 (34.30–55.70) 47.48 ± 4.79 (41.50–54.20) 0.412
PeriPapillary Inferior Hemi – SV VD 47.96 ± 4.90 (33.20–56.90) 46.38 ± 4.49 (41.00–54.10) 0.415
PeriPapillary Nasal Superior – SV VD 48.90 ± 4.64 (34.40–55.90) 47.64 ± 5.11 (42.60–55.90) 0.512
PeriPapillary Nasal Inferior – SV VD 49.70 ± 3.60 (43.40–55.30) 49.85 ± 3.03 (45.70–55.70) 0.910
PeriPapillary Inferior Nasal – SV VD 49.59 ± 3.65 (42.80–54.90) 49.71 ± 2.86 (46.20–54.90) 0.930
PeriPapillary Inferior Temporal – SV VD 49.79 ± 3.69 (43.90–55.60) 50 ± 3.30 (45.20–56.40) 0.884
PeriPapillary Temporal Inferior – SV VD 32.07 ± 5.11 (18.10–40.20) 34 ± 9.32 (14.10–45.40) 0.463
PeriPapillary Temporal Superior – SV VD 52.16 ± 3.61 (45.80–58.50) 52.02 ± 3.54 (46.60–58.00) 0.919
PeriPapillary Superior Temporal – SV VD 52.16 ± 3.64 (46.30–58.20) 51.82 ± 3.38 (46.70–57.50) 0.809
PeriPapillary Superior Nasal – SV VD 52.18 ± 3.74 (45.20–58.80) 52.21 ± 3.75 (46.50–58.50) 0.987

SV, small vessels; VD, vessel density; SD, Standard Deviation; COVID-19, Coronavirus Disease 2019

[Table 2]. The 4.5 × 4.5 mm mean whole image AV
VD in the COVID-19 cohort (56.08 ± 1.89) was also
not statistically significantly different with that in the
controls (56.44 ± 2.29) (P = 0.566); however, there

was a tendency for lower values in the former group
[Table 3; Figure 1].

Of note, whole peripapillary SV VD (51.76 ± 1.92
vs 53.14 ± 2.31; P = 0.032), peripapillary inferior
nasal SV VD (48.54 ± 2.94 vs 53.21 ± 4.12; P <

596 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021



Disc OCTA Findings in COVID-19; Abrishami et al

Table 5. Comparison of all vessels (AV), including both small and large vessels, vessel density (VD) of hospitalized versus non-
hospitalized/outpatients treated COVID-19 patients

Non-hospitalized (n = 16) Mean
±±± SD (Range)

Hospitalized (n = 9) Mean ±±± SD
(Range)

P-value

Whole Image – AV VD 48.58 ± 4.83 (33.40–56.30) 47.92 ± 4.28 (41.90–55.30) 0.725
Inside Disc – AV VD 49.54 ± 4.86 (31.90–56.40) 48.12 ± 3.95 (41.80–54.90) 0.444
Whole Peripapillary – AV VD 48.51 ± 4.24 (35.10–56.50) 46.68 ± 4.35 (41.60–53.00) 0.292
Peripapillary Superior Half – AV VD 45.28 ± 4.34 (30.80–53.40) 43.71 ± 4.04 (38.60–49.70) 0.362
Peripapillary Inferior Half – AV VD 52.93 ± 4.21 (40.40–59.20) 50.60 ± 4.93 (43.90–57.60) 0.197
Grid Based AV VD Superotemporal 52.41 ± 3.54 (45.30–57.80) 52.68 ± 3.02 (48.80–56.80) 0.843
Grid Based AV VD Temporal 51.53 ±4.19 (43.90–58.20) 51.16 ± 4.06 (45.30–58.60) 0.824
Grid Based AV VD Inferotemporal 52.93 ± 3.81 (46.50–59.80) 52.22 ± 3.08 (46.70–57.40) 0.622
Grid Based AV VD Superior 51.79 ± 3.91 (44.40–58.30) 51.97 ± 4.43 (45.60–59.20) 0.911
Grid Based AV VD Central 49.87 ± 6.10 (39.50–62.90) 49.52 ± 3.44 (43.00–54.00) 0.874
Grid Based AV VD Inferior 49.88 ± 6.07 (40.30–63.50) 49.07 ± 3.21 (43.90–53.70) 0.712
Grid Based AV VD Superonasal 49.77 ± 6.24 (38.60–62.20) 49.95 ± 3.81 (42.00–54.30) 0.937
Grid Based AV VD Nasal 53.35 ± 5.56 (42.10–63.60) 53.38 ± 3.78 (46.50–58.00) 0.986
Grid Based AV VD Inferonasal 48.56 ± 6.64 (39.30–62.90) 48.66 ± 3.73 (43.30–55.10) 0.967

AV, all vessels; VD, vessel density; SD, Standard Deviation; COVID-19, Coronavirus Disease 2019

Figure 1. En-face optical coherence tomography angiograms (OCTA) segmented at the level of the radial peripapillary capillary
(RPC) network from four recovered COVID-19 patients (A–D) versus four age-matched normal controls (E–H). Note the remarkable
flow deficits present in the en-face angiograms from the COVID cases.

0.001), peripapillary inferior temporal SV VD (56.93
± 3.14 vs 59.78 ± 3.25; P = 0.004), and grid-
based AV VD in inferior sector (60.68 ± 2.14 vs
62.56 ± 3.15; P = 0.023) were significantly lower in
COVID-19 patients, compared with normal controls.
In addition, in all other parameters, except inside

disc SV VD, COVID-19 patients had lower VD in AV
and SV VD, but the differences were not statistically
significant. Inside disc SV VD in COVID-19 patients
(49.43 ± 4.96) was higher than the inside disc SV
VD in the normal control group (45.46 ± 6.22),
which was statistically significant (P = 0.021).

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021 597



Disc OCTA Findings in COVID-19; Abrishami et al

Moreover, subgroup analysis between
hospitalized and outpatient treated patients
revealed no statistically significant difference
between two groups although unremarkable lower
values were observed in hospitalized patients
versus outpatients [Tables 4 and 5].

DISCUSSION

In the present study, we used OCTA to determine
the VD in the ONH and the RPC layer of optic
disc in a relatively young, mild involvement, without
other comorbidity and minority hospitalized, cohort
of recovered COVID-19 patients and compare it
with an age-matched normal control group. Except
inside disc SV VD which was higher in the COVID-
19 patients, in all RPC measured SV and AV
VD recovered COVID-19 patients showed lower
values, which became statistically significant in
whole peripapillary SV VD, peripapillary inferior
nasal SV VD, peripapillary inferior temporal SV
VD, and grid-based AV VD Inferior sector. In other
segments of peripapillary SV VD and grid-based
sectors of AV VD, vessel densities tend to be
lower in the COVID group but this did not reach
statistical significance. In a subgroup analysis, in
hospitalized patients we found in all RPC measured
SV and AV VD unremarkable lower values versus
outpatient treated COVID-19 patients which were
not statistically significant.

In an autopsy study, Casagrande and associates
detected SARS-CoV-2 viral particles in the retina
of patients who had deceased due to COVID-
19.[14] Presence of ACE2 receptors in CNS and
various layers of the retina and choroid have been
reported;[9, 10] hence, pathologic changes in the
ocular tissues, and especially in ONH and retina,
may be expected.

In a recent case series using Zeiss Cirrus 5000
HD OCT Angioplex, RPC plexus perfusion density
was lower in 80 COVID-19 recovered patients
compared to 30 controls. Moreover, patients
treated with lopinavir, ritonavir, or antiplatelet
therapy during admission had lower RPC flow index
and RPC perfusion density.[15] It indicates probable
ONH involvement in COVID-19. Moreover, Guillain-
Barré syndrome and Miller–Fisher-like syndrome
have also been reported in association with
SARS-CoV-2 infection.[16, 17] In recent studies,
SARS-CoV-2 potential for neuroinvasion has
been suggested.[18] It seems that in-line with the

previous reports of retinitis and optic neuritis
induced by coronaviruses in animal models,[19]
and the proposed neuroinvasion hypothesis,
SARS-CoV-2 can cause neuro-inflammation and
neuro-infection in humans too. Besides the
neurologic involvements, as retinal ganglion cells,
Müller cells, and blood vessels are potential
targets of the virus, the ONH and retinal findings in
COVID-19 are well anticipated. Vascular changes
can be either primary or secondary to alternations
in the hemodynamic demands of the inflamed and
damaged tissues.

Macular OCTA analysis also found similar
results. In another study by our group, using
Optovue AngioVue Imaging System, macular VD
was decreased in COVID-19 patients compared
with normal controls.[13] In another similar study
in Turkey with a same machine, parafoveal
VD in the superior and nasal quadrants of the
superficial capillary plexus and in all quadrants
of the deep capillary plexus were significantly
lower in COVID-19 patients.[20] Moreover, in a
case–control study in patients stratified to mild,
moderate, and severe COVID-19 disease activity,
and normal controls, patients with moderate and
severe disease had decreased macular VD as
compared with control subjects or even those who
were asymptomatic or paucisymptomatic.[21] It has
been proposed that SARS-CoV-2 infection, as a
systemic multi-organ infection, may affect retinal
vasculature beside other organs and marks retinal
microvasculature.[22]

OCTA analysis is an invaluable tool in the
evaluation of vascular changes in the retina and
ONH for diagnosis, staging, and monitoring in
glaucoma.[23, 24] In addition, in several neurologic
conditions, including preclinical Alzheimer’s
disease, OCTA was found to be helpful.[25] In
other neurodegenerative diseases and even mild
cognitive disorders, OCTA has been proposed as
an additional biomarker for the early diagnosis and
disease activity monitoring.[26, 27] In this study, we
found that ONH microvasculature was somewhat
decreased compared to the age-matched controls.
In all segments, VD was numerically decreased
in these comparative analyses, although the
differences were statistically significant in some
segments.

An intriguing finding in our study was the
higher SV inside disc VD, which was statistically
higher than normal controls. Previously, it has been
reported that ONH, nerve fiber layer thickness, is

598 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021



Disc OCTA Findings in COVID-19; Abrishami et al

increased in COVID 19 recovered patients.[28, 29]
In a case report, acute bilateral optic neuritis has
been reported in a 44-year-old Hispanic male
patient with no past medical history. Multimodal
ocular, orbit, and CNS imaging and paraclinic
evaluations were performed to determine the
possibility of demyelinating or other autoimmune
disease and these evaluations were negative as
well as other laboratory assessment. Therefore,
it has been concluded that his infection with
COVID-19 virus has triggered his immune system
to present ONH findings.[30] Besides our findings,
increase in SV VD inside the disc area, which
is in contrary to RPC VD findings, may be
associated with ONH edema and hyperemia,
indicating potential optic nerve involvement in
COVID-19 patients, in line with our previous
findings of nerve fiber layer thickening in COVID-
19 patients.

Essentially, the retina and optic nerve are
considered to be intraorbital extensions of
the CNS, so evaluation of the retinal, and
more specifically ONH changes, may help us
to identify the CNS disease as well. Indeed,
ONH and pRNFL changes have been already
reported in patients with CNS pathologies
like Alzheimer, multiple sclerosis, and diabetic
polyneuropathy.[31–33] In a recent review, neuro–
ophthalmic manifestations of COVID-19 was
divided to afferent and efferent manifestations.[34]
The examples of the afferent complications include
papilledema, optic neuritis, papillophlebitis, and
even vision loss due to stroke, while the efferent
complications include ocular myasthenia gravis,
cranial neuropathies, Miller Fisher syndrome, and
Adie’s pupils.[34] These presentations magnifies
the importance of ONH evaluations in COVID-
19 patients, as these presentations beyond
ophthalmic importance which may affect visual
function of patients, should be considered as CNS
involvement which may be more disabling or even
fatal.

Our control group was recruited from healthy
personnel of MUMS, as part of a longitudinal
cohort study, PERSIAN Organizational Cohort
study in MUMS.[35] The controls were evaluated
and OCTA images were acquired to build a
local normal OCTA normative database and
cohort analysis. The individuals in the control
group were examined when no COVID-19
cases were formally reported in Iran in 2019.
Therefore, there is no chance for presence of

any symptom-free patient among our control
group.

This study has several limitations. First, OCTA
images were acquired during the recovery of
the disease and not during the acute phase
when the systemic condition was active. Second,
longitudinal analysis of the patients was not
performed. Third, we had a limited sample
size, which can explain the lack of statistical
significance in some comparisons. A larger-
scale study with OCTA performed during the
symptomatic phase of the disease, followed by
repeat imaging at fixed intervals, would provide
valuable information regarding both the short
and long-term effects of COVID-19 on the ONH
vascular system.

To the best of our knowledge, it’s the first report
of ONH OCTA findings in patients with a history of
COVID-19. The clinical relevance of our finding is
unclear, as the patients were all asymptomatic with
20/20 vision at the time of this analysis. This can
indicate the acute inflammatory phase of the ocular
involvement and the associated vasodilation. It is
noteworthy that the systemic and ocular disease
phases can be unparalleled and occur at different
times. Nevertheless, our findings in a relatively
young group of COVID-19 confirmed patients who
had no other comorbidity, and the comparison with
an age-matched normal control group, similarly
imaged, is novel and may highlight the importance
of continued vigilance for the detection of nervous
tissue and ocular complications associated to
COVID-19 as the pandemic evolves.

In conclusion, our study demonstrated ONH VD
alterations in patients with a history of COVID-
19 and without other comorbidities, including a
decrease in AV and SV RPC VD. These findings
beside previous microvascular retinal findings in
these patients indicate potential retinal and ONH
ischemic changes, which may be a manifestation
of CNS potential vascular involvement. Moreover,
increase in inside disc SV VD may be an indicator
of ONH hyperemia and edema.

Acknowledgement

The authors would like to thank Abbas Saberi and
Hojjat Salmani at Mashhad PERSIAN Cohort Center,
for their kind assistance with this research project.
It is a pleasure for them to also acknowledge the
kind support of Capt. Mehdi Madadi.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021 599



Disc OCTA Findings in COVID-19; Abrishami et al

Financial Support and Sponsorship

The authors would like to acknowledge the
financial support of the Vice-Chancellor of
Research of Mashhad University of Medical
Sciences for this research project (code: 990069).
The funding organization had no role in the design
or conduct of this study.

Conflicts of Interest

The authors declare no potential conflicts of
interest for the research, authorship, and/or
publication of this article.

REFERENCES

1. Ahn DG, Shin HJ, Kim MH, 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.

2. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong J-C,
Turner AJ, 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.

3. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical
features of patients infected with 2019 novel coronavirus
in Wuhan, China. Lancet 2020;395:497–506.

4. Li JO, Lam DSC, Chen Y, Ting DSW. Novel Coronavirus
disease 2019 (COVID-19): the importance of recognising
possible early ocular manifestation and using protective
eyewear. Br J Ophthalmol 2020;104:297–298.

5. Mungmungpuntipantip R, Wiwanitkit V. Ocular
manifestation, eye protection, and COVID-19. Graefes
Arch Clin Exp Ophthalmol 2020;258:1339.

6. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor
recognition by the novel Coronavirus from Wuhan: an
analysis based on decade-long structural studies of SARS
Coronavirus. J Virol 2020;94:e00127–e00120.

7. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis
G, van Goor H. Tissue distribution of ACE2 protein,
the functional receptor for SARS coronavirus. A first
step in understanding SARS pathogenesis. J Pathol
2004;203:631–637.

8. Chamsi-Pasha MA, Shao Z, Tang WH. Angiotensin-
converting enzyme 2 as a therapeutic target for heart
failure. Curr Heart Fail Rep 2014;11:58–63.

9. Choudhary R, Kapoor MS, Singh A, Bodakhe SH.
Therapeutic targets of renin-angiotensin system in ocular
disorders. J Curr Ophthalmol 2017;29:7–16.

10. Zhou Z, Kang H, Li S, Zhao X. Understanding the
neurotropic characteristics of SARS-CoV-2: from
neurological manifestations of COVID-19 to potential
neurotropic mechanisms. J Neurol 2020;267:2179–2184.

11. Abrishami M, Tohidinezhad F, Daneshvar R, Omidtabrizi
A, Amini M, Sedaghat A, et al. Ocular manifestations of
hospitalized patients with COVID-19 in northeast of Iran.
Ocul Immunol Inflamm 2020;28:739–744.

12. Marinho PM, Marcos AAA, Romano AC, Nascimento H,
Belfort R Jr. Retinal findings in patients with COVID-19.
Lancet 2020;395:1610.

13. Abrishami M, Emamverdian Z, Shoeibi N, Omidtabrizi
A, Daneshvar R, Rezvani TS, 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.

14. Casagrande M, Fitzek A, Puschel K, Aleshcheva G,
Schultheiss H-P, Berneking L, et al. Detection of SARS-
CoV-2 in human retinal biopsies of deceased COVID-19
patients. Ocul Immunol Inflamm 2020;28:721–725.

15. Savastano A, Crincoli E, Savastano MC, Younis S,
Gambini G, De Vico U, et al. Peripapillary retinal vascular
involvement in early post-COVID-19 patients. J Clin Med
2020;9:2895.

16. Su XW, Palka SV, Rao RR, Chen FS, Brackney CR, Cambi
F. SARS-CoV-2-associated Guillain-Barre syndrome with
dysautonomia. Muscle Nerve 2020;62:E48–E49.

17. Fernandez-Dominguez J, Ameijide-Sanluis E, Garcia-
Cabo C, Garcia-Rodriguez R, Mateos V. Miller–Fisher-like
syndrome related to SARS-CoV-2 infection (COVID 19). J
Neurol 2020;267:2495–2496.

18. DosSantos MF, Devalle S, Aran V, Capra D, Roque NR, de
Mattos Coelho-Aguiar J, et al. Neuromechanisms of SARS-
CoV-2: a review. Front Neuroanat 2020;14:37.

19. Seah I, Agrawal R. Can the Coronavirus disease 2019
(COVID-19) affect the eyes? A review of Coronaviruses and
ocular implications in humans and animals. Ocul Immunol
Inflamm 2020;28:391–395.

20. Turker IC, Dogan CU, Guven D, Kutucu OK, Gul C. Optical
coherence tomography angiography findings in patients
with COVID-19. Can J Ophthalmol 2021;56:83–87.

21. Zapata MÁ, Banderas García S, Sánchez-Moltalvá A, et
al. Retinal microvascular abnormalities in patients after
COVID-19 depending on disease severity [published
online ahead of print, 2020 Dec 16]. Br J Ophthalmol
2020;bjophthalmol-2020-317953.

22. Sim SS, Cheung CMG. Does COVID-19 infection leave
a mark on the retinal vasculature? Can J Ophthalmol
2021;56:4–5.

23. Ma ZW, Qiu WH, Zhou DN, Yang WH, Pan XF, Chen
H. Changes in vessel density of the patients with
narrow antenior chamber after an acute intraocular
pressure elevation observed by OCT angiography. BMC
Ophthalmol 2019;19:132.

24. Lommatzsch C, Rothaus K, Koch JM, Heinz C, Grisanti S.
Vessel density in OCT angiography permits differentiation
between normal and glaucomatous optic nerve heads. Int
J Ophthalmol 2018;11:835–843.

25. van de Kreeke JA, Nguyen HT, Konijnenberg E, Tomassen
J, den Braber A, Kate MT, et al. Optical coherence
tomography angiography in preclinical Alzheimer’s
disease. Br J Ophthalmol 2020;104:157–161.

26. Pellegrini M, Vagge A, Ferro Desideri LF, Bernabei F, Triolo
G, Mastropasqua R, et al. Optical coherence tomography
angiography in neurodegenerative disorders. J Clin Med
2020;9:1706.

27. Criscuolo C, Cennamo G, Montorio D, Carotenuto A,
Strianese A, Salvatore E, et al. Assessment of retinal
vascular network in amnestic mild cognitive impairment

600 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021



Disc OCTA Findings in COVID-19; Abrishami et al

by optical coherence tomography angiography. PLoS One
2020;15:e0233975.

28. Abrishami M, Daneshvar R, Emamverdian Z, Tohidinezhad
F, Eslami S. Optic nerve head parameters and peripapillary
retinal nerve fiber layer thickness in patients with
Coronavirus disease 2019. Ocul Immunol Inflamm 2021
Feb:1–4.

29. Burgos-Blasco B, Guemes-Villahoz N, Donate-Lopez J,
Vidal-Villegas B, Garcia-Feijoo J. Optic nerve analysis in
COVID-19 patients. J Med Virol 2020;93:190–191.

30. Sawalha K, Adeodokun S, Kamoga GR. COVID-19-induced
acute bilateral optic neuritis. J Investig Med High Impact
Case Rep 2020;8:2324709620976018.

31. Cabrera DeBuc D, Gaca-Wysocka M, Grzybowski
A, Kanclerz P. Identification of retinal biomarkers in
Alzheimer’s disease using optical coherence tomography:
recent insights, challenges, and opportunities. J Clin Med
2019;8:996.

32. Pietroboni AM, Carandini T, Dell’Arti L, Bovis F, Colombi
A, De Riz MA, et al. Evidence of retinal anterograde

neurodegeneration in the very early stages of
multiple sclerosis: a longitudinal OCT study. Neurol
Sci 2020;41:3175–3183.

33. Salvi L, Plateroti P, Balducci S, Bollanti L, Conti FG,
Vitale M, et al. Abnormalities of retinal ganglion cell
complex at optical coherence tomography in patients with
type 2 diabetes: a sign of diabetic polyneuropathy, not
retinopathy. J Diabetes Complications 2016;30:469–476.

34. Tisdale AK, Dinkin M, Chwalisz BK. Afferent and efferent
neuro-ophthalmic complications of Coronavirus disease
19. J Neuroophthalmol 2021;41:154–165.

35. Tohidinezhad F, Khorsand A, Zakavi SR, Rezvani R,
Zarei-Ghanavati S, Abrishami M, et al. The burden and
predisposing factors of non-communicable diseases
in Mashhad University of Medical Sciences personnel:
a prospective 15-year organizational cohort study
protocol and baseline assessment. BMC Public Health
2020;20:1637.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 4, OCTOBER-DECEMBER 2021 601