Clinical Relevance of Parafoveal Intercapillary Spaces and Foveal Avascular Zone in Diabetic Retinopathy Without Macular Edema

概要

Retina

Clinical Relevance of Parafoveal Intercapillary Spaces and
Foveal Avascular Zone in Diabetic Retinopathy Without
Macular Edema
Noriko Terada, Tomoaki Murakami, Kenji Ishihara, Yoko Dodo, Keiichi Nishikawa,
Kentaro Kawai, and Akitaka Tsujikawa
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

Correspondence: Tomoaki
Murakami, 54 Shougoin
Kawahara-cho, Sakyo-ku, Kyoto
606-8507, Japan;
mutomo@kuhp.kyoto-u.ac.jp.
Received: May 31, 2022
Accepted: October 11, 2022
Published: November 2, 2022
Citation: Terada N, Murakami T,
Ishihara K, et al. Clinical relevance
of parafoveal intercapillary spaces
and foveal avascular zone in diabetic
retinopathy without macular edema.
Invest Ophthalmol Vis Sci.
2022;63(12):4.
https://doi.org/10.1167/iovs.63.12.4

PURPOSE. To investigate the clinical significance of intercapillary spaces on swept source
optical coherence tomography angiography images in diabetic retinopathy.
METHODS. We retrospectively reviewed 110 eyes of 110 patients suffering from diabetic
retinopathy without macular edema for whom 3 × 3 mm swept source optical coherence
tomography angiography images centered on the fovea were obtained. Automatic image
processing of the superficial slab images allowed us to define the areas encircled by retinal vessels as intercapillary spaces within the central 2-mm circle. We evaluated how the
quantitative parameters of intercapillary spaces are associated with logMAR and feasible
to diagnose diabetic macular ischemia.
RESULTS. Total counts (ρ = −0.419; P < 0.001) rather than morphologic parameters of the
intercapillary spaces showed a significant correlation with logMAR. There were individual levels of correlations between logMAR and counts of intercapillary spaces in individual sectors. In particular, the summed numbers of the spaces in three highly significant
sectors were more significantly associated with logMAR (ρ = −0.515; P < 0.001). Multivariate analyses confirmed that the number of the intercapillary spaces (β = −0.266; P =
0.016) and foveal avascular zone area (β = 0.227; P = 0.042) were related to logMAR. The
clustering using the foveal avascular zone area and the number of intercapillary spaces
revealed two major clusters; one had fewer intercapillary spaces (P < 0.001) and poorer
logMAR (P < 0.001) than the other, with a wide range of the foveal avascular zone area.
CONCLUSIONS. Decreased intercapillary spaces contribute to visual impairment in diabetic
retinopathy and suggest one possible criterion of objective diagnosis of diabetic macular
ischemia.
Keywords: diabetic retinopathy, diabetic macular ischemia, intercapillary space, foveal
avascular zone, optical coherence tomography angiography

D

iabetic retinopathy (DR) is a leading cause of vision
loss in people of working ages worldwide.1,2 In addition to the morphological changes in retinal vessels, capillary nonperfusion exacerbates retinal neurodegeneration.3,4
Neuroglial cells exposed to hypoxia secrete VEGF and
concomitantly promote angiogenesis and vascular hyperpermeability, which clinically contribute to the pathogenesis in
proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). In the era of anti-VEGF therapy, therapeutic strategies against diabetic macular ischemia should be
established.5
Retinal vessels originate from the optic disc and mainly
run within the ganglion cell layer. They bifurcate into the
capillaries in the nerve fiber layer and those in the inner
and outer borders of the inner nuclear layer.6 Multiple retinal vascular plexus layers mainly nourish the neurons in
inner retinal layers which allow signal transduction. Classically, fluorescein angiography (FA) shows the feasibility of evaluating the foveal avascular zone (FAZ), which
enables us to diagnose ischemic maculopathy subjectively.7

However, multilayered vascular plexuses and the leakage
of fluorescein dye often make it difficult to evaluate threedimensional vessels in the parafovea or perifovea on FA
images. In contrast, optical coherence tomography angiography (OCTA) delineates retinal vessels three-dimensionally
and has advantages in the selective assessments of superficial and deep vascular plexuses in any areas of the macula.8,9
It allows us to quantify perfusion or nonperfusion indices to
investigate microcirculatory disturbance.5
Comparative studies between structural OCT and OCTA
images have revealed the disturbance of the neurovascular unit in DR.10,11 It has recently been reported that the
nonperfused areas (NPAs) in the superficial vascular plexus
are accompanied by no boundaries between the nerve fiber
layer and ganglion cell layer, and cystoid spaces in the inner
nuclear layer often correspond to the NPAs in the deep
vascular layer.11 Previous publications showed a modest
association between the FAZ areas and the reduction of
visual acuity (VA) in DR, which is consistent with the simultaneous neurovascular degeneration.12,13 However, there is

Copyright 2022 The Authors
iovs.arvojournals.org | ISSN: 1552-5783

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

1

Parafoveal Intercapillary Spaces and FAZ in DMI
a question of whether ischemic changes at the fovea and
in the parafovea are critical for bipolar cells and subsequent
ganglion cells from foveal cone photoreceptors, respectively,
which are centrifugally displaced.14
We have recently proposed an intercapillary space spectrum that contains both healthy intercapillary areas and
pathophysiological NPAs on OCTA images; this spectrum
can be used to evaluate the processes of capillary nonperfusion automatically and objectively.15 In this study, we investigated whether the characteristics of capillary nonperfusion
in the parafovea are associated with VA and the diagnostic significance of diabetic macular ischemia in DR without
center-involving DME.

METHODS
Participants
In this retrospective study, we reviewed 110 consecutive
eyes of 110 patients with DR for whom swept source OCTA
images of sufficient quality (signal strength index of 8 or
more) were obtained. The inclusion criteria were DR and
central 3 × 3 mm swept source OCTA images centered on
the fovea had been acquired. We excluded eyes with centerinvolved DME, severe media opacity, an axial length of less
than 22 mm or more than 26 mm, any other chorioretinal
disease, other ocular diseases that lead to visual impairment,
photocoagulation within 6 months before imaging, previous treatment for macular pathology, cataract surgery within
3 months before imaging, or any intraocular surgery other
than cataract surgery. We further excluded eyes that received
other treatments for DR or DME than panretinal photocoagulation. Additional exclusion criteria were poor image quality (signal strength index of 7 or less) or severe segmentation error in the superficial slab. If both eyes met these
criteria, we selected the right eye for this study. All research
and measurements were performed in compliance with the
tenets of the Declaration of Helsinki and with the approval
of the Kyoto University Graduate School and Faculty of
Medicine Ethics Committee. Written informed consent was
obtained from all participants.

Fundus Imaging
We measured the refraction and subsequent best-corrected
decimal VA and converted it to the logMAR. After a comprehensive ophthalmic examination, the axial length and the
central subfield thickness were measured using partial
coherence interferometry (IOL Master, Carl Zeiss Meditec,
Inc., Dublin, CA) and Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), respectively. Eyes with a central
subfield thickness of greater than 320 μm or 305 μm for male
or female patients, respectively, were diagnosed as centerinvolved DME.16
Swept source OCTA images within the nominal 3 × 3
mm square centering on the fovea were acquired using Plex
Elite 9000 (Carl Zeiss Meditec, Inc.). The nominal 3 × 3 mm
square was obtained with 300 × 300 A-scans and digitally
converted to a 1024 × 1024 pixel array for quantitative analyses.

Intercapillary Spaces
Among several perfusion or nonperfusion indices, we
selected intercapillary spaces and the FAZ, because we

IOVS | November 2022 | Vol. 63 | No. 12 | Article 4 | 2
consistently evaluated the circulation disturbance in both
the parafovea and fovea. Several publications have proposed
each method to detect NPAs on OCTA images.17–21 We
hypothesized the morphological continuum from healthy
intercapillary areas to pathological NPAs and therefore
defined areas enclosed by retinal vessels as intercapillary spaces in this study, as proposed recently.15 Because
we considered that the transient and persistent capillary
nonperfusion may affect neuronal function, we selected a
single en face image, but not the smoothened images.17,18
Additionally, we focused on the superficial layer, because
VA depends on the signals derived from the foveal photoreceptors and transmitted to the bipolar cells and ganglion
cells in the superficial slab. All intercapillary spaces were
assessed quantitatively on OCTA images according to four
steps, as described previously15 : (1) the construction of the
superficial en face OCTA images according to the default
settings of the manufacturer’s software, (2) the determination of the central 2-mm area using image processing software (Adobe Photoshop, Adobe Systems Inc, San Jose, CA),
(3) the binarization of retinal vessels by the Phansalkar adaptive local thresholding method of ImageJ (NIH, Bethesda,
MD) (Fig. 1), and (4) quantitative analyses of intercapillary
spaces. The Analyze Particles function of ImageJ allowed us
to detect each intercapillary space automatically and quantify its geometric parameters (area, perimeter, maximum
diameter, and minimum diameter) and the coordinates (x, y)
of its centroid. The space containing the foveal center was
defined as the FAZ. ...

この論文で使われている画像