Original research article

European Journal of Ophthalmology

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optical coherence tomography

angiography in diabetic maculopathy

Anadi Khatri1 , Eli Pradhan2, Bal Kumar KC1, Muna Kharel3,

Roshija Khanal Rijal4, Satish Timalsena1, Jeena Gurung1,
Sudhir Gautam1 and Ashma KC1

Abstract
Introduction: Diabetic maculopathy is a leading retinal cause of blindness. This study was conducted using optical
coherence tomography angiography and noninvasive imaging modalities. Microaneurysms were evaluated for location,
flow, and adjacent retinal tissue changes to establish knowledge of possible vision-threatening features.
Methodology: This is a hospital-based, cross-sectional observational study. Eighteen patients with diabetic maculopathy
were included in the study. Fundus photo, red-free filter image, infrared images with shadowgrams, optical coherence
tomography cross sections, and optical coherence tomography angiography were analyzed. Mean, standard deviation,
odds ratio, and 95% confidence interval were used for statistical analysis, and p-value of <0.05 was considered statis-
tically significant where applicable.
Results: A total of 64 microaneurysms were evaluated. Forty-six (71.8%) microaneurysms were identifiable in
all imaging modalities. In total, 53 (82.8%) were high-flow microaneurysms and 11 (17.2%) were low-flow micro-
aneurysms. Thirty-eight of the high-flow microaneurysms (71.6% of the high-flow microaneurysms) were found
in the deep capillary plexus, while only 15 (28.4% of the high-flow microaneurysms) were found in the superficial
capillary plexus. Twenty-seven (71%) of the high-flow microaneurysms in deep capillary plexus were present in the
areas of retinal thickening (odds ratio: 4.5, 95% confidence interval: 1.26–16.0, p ¼ 0.02). A total of 11 micro-
aneurysms were classified as low-flow microaneurysms and identified using fundus photo, red-free filter image,
infrared images with shadowgrams, and optical coherence tomography—cross sections. They had a tendency
to be present in the areas of decreased capillary plexus density (odds ratio: 25.6, 95% confidence interval:
5.09–128.7, p ¼ 0.001).
Conclusion: Noninvasive imaging modalities combined with optical coherence tomography angiography can provide
valuable information regarding microaneurysms. Certain features such as location and flow may help in predicting
impending macular edema or ischemia.

Keywords
Diabetic retinopathy, tomography, optical coherence, macular edema, non-invasive, optical coherence tomography
angiography, microaneurysms, vision threatening, blindness, ischemia
Date received: 25 June 2019; accepted: 14 April 2020
1
Birat Eye Hospital, Biratnagar, Nepal
2
Tilganga Institute of Ophthalmology, Kathmandu, Nepal
3
Department of Ophthalmology, Nepalese Army Institute of Health
Introduction Sciences, Kathmandu, Nepal
4
Diabetic maculopathy is one of the leading retinal ASG Hospitals, Kathmandu, Nepal
causes of blindness.1,2 It occurs either due to the accu-
Corresponding author:
mulation of fluid secondary to leaking vessels or ische- Anadi Khatri, Department of Vitreo-Retina Services, Birat Eye Hospital,
mia due to sluggish blood flow or capillary nonperfusion Biratnagar 55613, Nepal..
near, around, or in the macular area. Email: anadikc@gmail.com
2 European Journal of Ophthalmology 0(0)
Microaneurysms (MAs) have established themselves
as the first clue for ophthalmologists and general physi-
cians to hint that the visibly evident diabetic retinopa-
thy (DR) has initiated.3–5 The process and the damage,
however, actually begin long before these “retinal
lesions” become visible. In microscopic terms, these
lesions are the result of a continued insult to the
pericytes of the retinal vasculature.6,7
Pericytes mainly govern the retinal hemodynamics
via two mechanisms. They provide the inner blood-
retinal barrier via tight junctions. They are also
contractile in nature. The latter property is thought
to provide both the supportive and autoregulatory
function of these unique cells.8
Due to continuous loss of these cells, the loss of tight
junctions tends to make the vessel prone to leakage
and promote endothelial proliferation9 and result in
clinically significant macular edema (CSME).10 This
ultimately leads to beadings or outpunching which
become clinically evident as MA. The blood flow in
some of these MA also tends to become turbulent
and sluggish in nature.11 This, on the other hand,
could lead to microvascular stasis, a decrease in perfu-
sion and development of ischemia.
The presence of MAs is thought to provide critical
information regarding the course of the disease.
Various studies have been done regarding its distribu-
tion, progression, turn over, shapes, and sizes to predict
the prognosis.4,12–15
Various methods of visualizing the retinal vascular
system are currently available. They range from the
old yet gold standard—fundus fluorescein angiography
(FFA)—to the more recent noninvasive technique such
as optical coherence tomography angiography (OCTA).
FFA can detect the smallest of MAs, leakages, and
nonperfusion. On the other hand, OCTA is a noninva-
sive method and also has the advantage that retina and
its vasculature can be visualized in sections or slabs.
However, as OCTA is dependent on the flow of
blood, areas of sluggish blood flow may not be prop-
erly visualized.12,16
This has led to the MAs being classified as low-flow
microaneurysms (LF-MAs) or high-flow microaneur-
ysms (HF-MAs).16 By concept, if the flow of the
MAs meets the threshold for detection and is registered
by the OCTA, they are termed as high flow. Those
MAs which are present in the FFA, fundus picture,
or other imaging modalities but fail up to show in
OCTA are termed as LF-MAs.12,14–16
The debate on whether OCTA can surpass or
replace FFA continues.17 Despite FFA being the gold
standard, there are situations in which it cannot be
used due to the risk of allergies, anaphylaxis, or renal
function status of the patient.18 It is also an impractical
choice if the pathology needs to be followed in a more
frequent basis.
In such scenarios, whatever information that is avail-
able from the OCTA might be helpful as an alternative
for diagnosis and management of such patients. With
this in mind, this study was conducted using OCTA
and noninvasive imaging to evaluate the MAs of DR
with CSME in terms of their location, flow, and adja-
cent retinal tissue changes. By doing so, we aim to estab-
lish a knowledge of possible vision-threatening OCTA
features of MAs in terms of edema and ischemia.
Methodology
This is a hospital-based, cross-sectional observational
study conducted at the retina department of Birat Eye
Hospital, Biratnagar, Nepal. The study was approved
by the local ethical committee and adheres with the
tenets of the Declaration of Helsinki. Both written
and oral consent were given by the patients. Patients
assessed between January and June 2019 were included
in this study. No sample size calculations were made as
this is an exploratory study.
Patients with diabetic maculopathy—clinically
diagnosed as CSME who were contraindicated for
FFA—were included in the study. Fundus photos
(FPs), red-free filter images (RFIs), infrared images
with shadowgrams (IRIS), optical coherence tomogra-
phy (OCT) cross sections, and OCTA were analyzed.
The eyes were then classified according to the early
treatment diabetic retinopathy study (ETDRS).
Eyes with other retinal or choroidal vasculopathies,
prior laser therapy, prior intravitreal injections, or
media opacities were excluded. The sample was classi-
fied into four different levels as per ETDRS grading
(Level: 20, 35,43, and 47). Mean, standard deviation,
odds ratio, and 95% confidence interval were used for
statistical analysis, and a p-value of <0.05 was consid-
ered statistically significant where applicable.
Image acquisition and analysis
FP, RFI, IRIS, and swept source (SS)-OCT cross sec-
tions along with 3  3 mm OCTA images were obtained
using an SS-OCTA device (DRI Triton PLUS OCT,
Topcon, Tokyo, Japan). The images were segmented
automatically into superficial and deep retinal capillary
plexi via IMAGEnetTM and OCTARATM (Topcon)
software. FP and RFI images were analyzed first to
locate the MAs and tagged. IRIS was used to detect
any missed MAs clinically. This was further confirmed,
and other similar artifacts such as blot hemorrhages
were excluded using OCT cross sections, retinal thick-
ness mapping, and B-scan from OCTA.
Khatri et al.
The image analysis conducted then included identify-
ing the location and nature of flow in the MAs. A cross
wire tracker was used to first identify the MAs using the
FP which would simultaneously correlate with the loca-
tion in the OCTA superficial and deep layers, cross sec-
tions of the OCT, FP, RFI, and IRIS (Figure 1).
Superficial capillary plexus (SCP) slab was automatically
differentiated by the inbuilt software and represented
the capillary network, which are present between the
internal limiting membrane and posterior most elements
of the inner plexiform layer (IPL). Similarly, the deep
capillary plexus (DCP) slab was demarcated between the
posterior boundary of the SCP and the posterior most
retinal elements of the outer plexiform layer (OPL).
MAs that were present in the FP, RFI, IRIS, OCT
cross sections and also showed up in the OCTA were
classified as the HF-MAs. Those which did not appear
on OCTA while showed up on other imaging modalities
were classified as LF-MAs. The second step included
analyzing the location of HF and LF-MAs. For HF-
MAs, a direct flagging of the MAs was done as they
were clearly visible in the OCTA. LF-Mas were identi-
fied with the help of FP, RFI, IRIS, and cross sections
of OCT (Figure 1).
These areas were evaluated for any leakages grossly
via OCT cross sections and retinal thickness map.
Figure 1. Image analysis of low-flow microaneurysm. A fundus photo with microaneurysms becomes more distinct with infrared
imaging and shadowgrams. The same area of these microaneurysms is evaluated on OCTA which fails to register a signal but still can
be detected when evaluated on an OCT cross section.
SCP: superficial capillary plexus; DCP: deep capillary plexus; OCT: optical coherence tomography; OCTA: optical coherence
tomography angiography.
3
Retinal capillary density measurements provided by
the inbuilt software were used to identify ischemic
areas. All locations were checked throughout the rasters
of the macula to avoid false negative results by segmen-
tation errors. If MAs were detected in more than one
capillary plexus, the HF signal in the uppermost layer
where the signal was first noticed was regarded as the
location to minimize projection artifacts.
Results
Thirty-four eyes of 18 patients with CSME were
analyzed. We excluded four eyes due to artifacts.
Thirty eyes of 18 patients were eligible for evaluation.
The demographics of these patients are summarized
in Table 1.
Seventy-four lesions were flagged from the FP, RFI,
and IRIS. Seventeen of such lesions (23%) were exclud-
ed as the corresponding spots were not found in the
cross sections of the OCT as either hyper/hypo reflec-
tive elements, not detected by OCTA and did not fall in
the areas of retinal thickening.
Similarly, there were 11 (15%) lesions which were
present in the FP, RFI, and IRIS and also detected
by the cross sections of the OCT but not detected by
the OCTA. These were presumed as LF-MAs that had
4 European Journal of Ophthalmology 0(0)

Table 1. Demographics, duration of diabetes, and glycemic status of the patients.

Level 20 Level 35 Level 43 Level 47

Age (in years  SD) 53.9  11.3 59.2  13.7 61.4  9.8 65.8  7.3
Gender (male) 3/5 2/3 2/5 3/5
Duration of diabetes (in years  SD) 12.2  9.1 14.7  7.3 15.1  8.7 15.8  5.6
HbA1C (in gm%  SD) 7.2  0.87 7.47  0.63 7.9  0.92 8.5  0.71
Number of eyes evaluated 8 6 8 8
SD: standard deviation.

Table 2. Microaneurysm distribution in diabetic retinopathy of various grades.

Level 20 Level 35 Level 43 Level 47 Sub-total Total

HF-MA
SCP 2 þ 2* 3 þ 1* 4 3 12 þ 3* 53
DCP 3 6 þ 1* 8 þ 2* 17 34 þ 4*
LF-MA
SCP 1# 2# – 1# 4# 11
DCP – 3# 2# 2# 7#
HF-MA: high-flow microaneurysm; SCP: superficial capillary plexus; DCP: deep capillary plexus; LF-MA: low-flow microaneur-
ysm; OCTA: optical coherence tomography angiography.
The asterisk (*) in HF-MA represents the number of microaneurysms detected by OCTA but missed by other imaging modalities.
The hash (#) in the LF-MA represents the microaneurysms not detected by OCTA but detected with other imaging modalities.

Table 3. Microaneurysm detection by various modalities, their distribution along with their association with retinal thickening or
decreased capillary plexuses density.

Not detected
by OCTA
but via fundus Decreased
Detected photo/OCT/ capillary
by all infrared with Only detected Retinal Cystoid plexuses
Flow Location imaging shadow grams by OCTA thickening changes density

HF-MA SCP 12 – 3 5/15 3/15 1/15

DCP 34 – 4 27/38 19/38 4/38
LF-MA SCP – 4 –
DCP – 7 – 4/11 – 8/11

OCTA: optical coherence tomography angiography; HF-MA: high-flow microaneurysm; SCP: superficial capillary plexus; DCP: deep capillary plexus;
LF-MA: low-flow microaneurysm.

blood flows below the registering threshold of the
OCTA machine. OCTA was superior in identifying
seven (13%) of the MAs that were not flagged in the
FP, RFI, or IRIS. Four of such lesions were present in
the DCP and three in SCP (Table 2). Only one such
MA was present in the area of the thickened retina.
These were included in the study (Table 3).
A total of 64 MAs were evaluated, only 46 (71.8%)
of which were identifiable on all imaging modalities
(Table 2). Of the 64 MAs analyzed, 53 (82.8%) were
HF-MAs and 11 (17.2%) were LF-MAs. Thirty-eight
of the HF-MAs (71.6% of the HF-MAs) were found in
the DCP, while only 15 (28.4% of the HF-MAs) were
found in the SCP. A total of 32 (60.3%) HF-MAs were
found to be in the area of retinal thickening (Figure 2)
and 22 (34%) of them were associated with perilesional
cystoid changes in the retina (Table 2).
Twenty-seven (71%) of the HF-MAs in DCP were
present in the areas of retinal thickening (odds ratio:
4.5, 95% confidence interval (CI): 1.26–16.0, p ¼ 0.02).
Nineteen (50%) of such lesions in the DCP were direct-
ly related to perilesional cystoid lesions (Figure 3).
In comparison to DCP, 15 MAs were found to be HF
in SCP and only 5 of them were in the areas of retinal
thickening. Only three of such lesions were directly relat-
ed to perilesional cystoid changes (Table 3).
Khatri et al. 5

Figure 2. A patient with localized macular edema with hard exudates. Microaneurysms (arrows) were predominantly found in the
deep capillary plexuses in areas of thickened retina (area inside green boundary in thickness map).
SCP: superficial capillary plexus; DCP: deep capillary plexus; OR: outer retina; CCP: choriocapillary plexus.

Figure 3. Fundus photo, retinal thickness map, and optical coherence tomography (OCT) angiography along with denoting micro-
aneurysms in the DCP (arrows) in areas of thickened retina (area inside green boundary in thickness map). Note the paralesional
cystoid spaces in the cross sections of OCT cross section.
SCP: superficial capillary plexus; DCP: deep capillary plexus; OR: outer retina; CCP: choriocapillary plexus.

A total of 11 MAs were classified as LF-MAs and structures on OCT cross sections. They had a tendency
identified using FP, RFI, IRIS, and OCT—cross to be present in the areas of decreased capillary plexus
sections. More than half of these MAs were hypore- density (odds ratio: 25.6, 95% CI: 5.09–128.7,
flective and 63.3% were found in deeper retinal p ¼ 0.001) (Table 3) (Figure 4).
6 European Journal of Ophthalmology 0(0)
Figure 4. Decreased summated capillary plexus density in OCTA in areas of undetected microaneurysms (MAs). There are low-flow
microaneurysms (LF-MAs), and decrease in capillary density could denote ischemic changes. The fundus picture on right clearly shows
the image of the scanned macular area with many MAs which were not detected by OCTA.
Discussion
OCTA has been used for analysis for shapes, location,
flow, and progression and regression of MAs.12,13,16,17
Various studies have also been done to compare its
sensitivity and specificity with FFA.11,18 Using all of
this information, we conducted this study to note fea-
tures of MAs in diabetic maculopathy using OCTA,
FP, RFI, and IRIS.
There are always a group of patients who are contra-
indicated for FFA given the history of allergy or their
renal function status.18 We have here described our
method of imaging technique using multimodal imag-
ing and OCTA for such patients.
The ability of one imaging modality or another to
identify all MAs is beyond the scope of this study.
This investigation, however, highlights certain signifi-
cant findings from MAs that are analyzed which
could be valuable to predict both the disease pathology
and prognosis.
We investigated MAs in diabetic maculopathy
in terms of flow, location, and retinal thickening.
Our study found that using multimodal imaging and
OCTA, the location and possible vision-threatening
characteristics of MAs can be studied well. It illustrated
that the MAs were well distributed in the macular area
but with a higher preponderance to DCP.
Our study found that nearly three-fourths of the
HF-MAs were present in the DCP and were prone
to leakage. They were often found in the areas of
the retinal thickening and had cystoid changes when
analyzed with OCT. Various studies have been done
in diabetic eyes both with and without macular
edemas, and most of them agree that most of the
MAs were mainly found in the deep layers—mainly
in the inner nuclear layers in histological slides and
in DCP in OCTA.4,13,19,20 Hasegawa et al.14 have
mentioned a similar finding where they found 77%
of the MAs to be present in the DCP and nearly
91.3% were found to be in areas of retinal thickening.
They have also discussed on the density of the MAs
and its association with levels of macular thickness
and volume.
We have only evaluated the direct correlation of
the HF-MAs with the areas of edema. Parravano
et al.12 in their recent study mentioned a similar find-
ing—mentioning that nearly two-thirds of the MAs
were present in the DCP. It is well known that the
blood flow starts changing from the laminar to tur-
bulent with a decrease in speed when transiting sud-
denly though a lumen of a different dimension.21,22
The fact that these are termed as HF-MAs as they
are still able to register as a signal by OCTA, we
hypothesize that their transit speed is maintained
despite the presence of turbulence. For this to
occur, the perfusion pressure gradient increases.
The increased perfusion pressure, the turbulence,
and the weak walls of the MAs may be accountable
for making the vessels leaky.
While HF-MAs were easily distinguished by OCTA,
identifying the LF-MAs needs aid with multimodal
imaging techniques. We adopted the technique men-
tioned by Parravano et al.,12 where they have described
using the OCT-cross sections to identify the areas of
MAs and improvised using reflectivity patterns along
with FP, RFI, and IRIS. The MAs “like” lesions that
were present in the FP, RFI, and IRIS were compared
“point to point” as mentioned by the authors. We used
the inbuilt IMAGEnet software of Topcon. By doing
so, we were able to identify 11 (15%) additional MAs
that were not caught by the OCTA. We classified such
lesions as LF-MAs. Our study found that these
Khatri et al.
LF-MAs were more likely to be found in the areas of
decreased capillary plexus density. There have been
various studies on the parafoveal capillary density
and foveal avascular zone (FAZ), and many have
concluded that both of these can be an important
biomarker for monitoring the status of the disease.
We hypothesize that the areas of LF-MAs may indicate
the areas of intraluminal turbulence but with dropped
perfusion pressure gradient. This could explain the
decreased blood flow and the inability for an OCTA
to register it due to sub threshold signal. Such areas
may be prone to ischemic maculopathy. This, however,
needs to be confirmed with follow-ups with FFA
images and with a combination of retinal velocimetry
and Oxymap at resource-rich centers.
Conclusion
Noninvasive imaging modalities combined with OCTA
can provide valuable information regarding MAs.
Certain characterizing features such as its location
and flow when used along with OCT cross sections
and OCTA based capillary density measurement may
help in predicting impending macular edema or
ischemia.
Limitation
Since the gold standard FA could not be done in these
patients, accurate MA figures could not be established.
A comparative study with a larger sample size can help
add values to the new findings from this study.
Acknowledgements
The authors would like to thank our technical staff Mr Sabin
K C for multimodal imaging investigations performed. The
authors would also like to thank Dr Rupesh Agrawal for his
technical advice and linguistic support for the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article.
Ethical approval
The research protocol has been reviewed and approved by the
ethical committee along with the institutional review board of
Birat Eye Hospital, Biratnagar, Nepal. It strongly adheres to
the tenets of the Declaration of Helsinki.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
7
ORCID iD
Anadi Khatri https://orcid.org/0000-0002-0444-224X
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