Retina
Characterization of Inner Retinal Spots With Inverted
Reflectivity on En Face Optical Coherence Tomography in
Diabetic Retinopathy
Rina Yoza, Tomoaki Murakami, Akihito Uji, Kiyoshi Suzuma, Shin Yoshitake, Yoko Dodo,
Rima Ghashut, Masahiro Fujimoto, Yuko Miwa, and Nagahisa Yoshimura
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
Correspondence: Tomoaki Murakami, Department of Ophthalmology
and Visual Sciences, Kyoto University Graduate School of Medicine, 54
Shogoin-Kawaracho, Sakyo, Kyoto
606-8507, Japan;
[email protected].
Submitted: January 18, 2016
Accepted: March 9, 2016
Citation: Yoza R, Murakami T, Uji A, et
al. Characterization of inner retinal
spots with inverted reflectivity on en
face optical coherence tomography in
diabetic retinopathy. Invest Ophthalmol Vis Sci. 2016;57:1862–1870.
DOI:10.1167/iovs.16-19171
PURPOSE. The purpose of this study was to characterize inner retinal spots with inverted
reflectivity on en face images of swept-source optical coherence tomography (SS-OCT) in
diabetic retinopathy (DR).
METHODS. We retrospectively reviewed seventy-five eyes of 75 patients with DR (15 eyes with
individual grades of DR severity). We obtained three-dimensional images (6 3 6 mm) centered
on the fovea, followed by the generation of en face images. We investigated the morphologic
characteristics of spots with inverted reflectivity, which had lower reflectivity than the
surrounding areas in the nerve fiber layer (NFL) and higher reflectivity in the ganglion cell
layer (GCL).
RESULTS. Thirty-seven of 45 eyes (82.2%) with moderate nonproliferative diabetic retinopathy
(NPDR) or more severe grades were accompanied with well-defined spots with inverted
reflectivity, whereas 30 eyes with no apparent retinopathy or mild NPDR had no such lesions.
These spots had various shapes in the NFL and GCL on en face OCT images; the mean area
was 0.126 6 0.052 mm2 at the NFL level. In all 75 eyes, 153 of 184 spots (83.2%) were
localized in the NFL and GCL, whereas 31 spots (16.8%) extended to retinal layers deeper
than the GCL. One-hundred sixty-nine spots (91.8%) were not visible on color fundus
photographs, and 15 spots (8.2%) were accompanied by whitish-yellow lesions in the
corresponding areas. In 45 eyes for which fluorescein angiography images were obtained,
mild hypofluorescence was seen in 156 spots (84.8%) and focal nonperfused areas in 17 spots
(9.2%).
CONCLUSIONS. En face images of SS-OCT showed spots with inverted reflectivity in the NFL and
GCL in DR.
Keywords: diabetic retinopathy, optical coherence tomography, reflectivity
D
iabetic retinopathy (DR) often leads to severe visual
impairment, worldwide, because of neovascular complications and diabetic macular edema (DME).1–3 Diabetes
disrupts neurovascular units in the retina and leads to
development of nonperfused areas and subsequent proliferation of fibrovascular tissues.4 Despite definite clinical findings
on fluorescein angiography (FA) and optical coherence
tomography (OCT) images, the pathophysiologic and histologic
mechanisms should be elucidated in DR.
Four laminar plexuses in the retinal vasculature, which
reside in the nerve fiber layer (NFL), ganglion cell layer (GCL),
and the deep portions of the superficial nuclear layer (SINL)
and those of the deep portions of the inner nuclear layer
(DINL), respectively, perfuse and nourish neuroglial tissues in
the inner retinal layers in healthy eyes.5,6 All capillary beds
disappear in typical nonperfused areas, and concomitantly
reduced metabolism or hypoxia leads to degenerative or
atrophic processes in the inner retinal layers, or vice versa,
before neurodegeneration by diabetes decreases the expression
of angiogenic factors and subsequently leads to capillary
loss.7–11 Cotton wool spots appear to be grayish-white lesions
with fluffy margins and appear as focal nonperfused areas on FA
images. Generally, microinfarctions or focal ischemia in the NFL
is thought to disturb axoplasmic transport with concomitant
deposition of axonal cargoes.12–14 Recent publications have
reported that obstruction of the deep capillary layers including
the SINL and DINL induces deep capillary ischemia and a
concomitant increase in OCT reflectivity in the middle layers
alone, referred to as paracentral acute middle maculopathy.15,16
Compared to these findings, the kinds of clinical findings that
represent laminar ischemia in GCL remain unclear.
Advanced OCT technology facilitates an appreciation of the
retinal parenchymal lesions in DR and objective evaluation of
the edematous changes in DME.17,18 Neurodegenerative changes have been reported in DR and were confirmed by basic
research.19,20 In vivo OCT imaging showed that the inner
retinal thickness decreases in DR, although it remains ill
defined whether the pathogenesis is mediated via diabetesinduced biochemical pathways or ischemic changes.21–23
Despite the feasibility of OCT, clinicians cannot discriminate
the inner retinal thinning in DR from mild loss of the ganglion
cell complex in glaucoma.24 In addition to morphologic
findings, the changes in OCT reflectivity levels also represent
the pathogenesis. For example, the reflectivity levels were
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Spots With Inverted OCT Reflectivity in DR
increased in the middle retinal layers in eyes with paracentral
acute middle maculopathy, and DME eyes have cystoid spaces
with the various reflectivity levels.15,16,25 However, OCT
reflectivity of the diabetic lesions in the NFL and GCL remains
ill-defined.
In the current study, we identified the three-dimensional
(3D) characteristics of a novel OCT finding, that is, spots with
inverted reflectivity in the NFL and GCL in eyes with moderate
nonproliferative diabetic retinopathy (NPDR) and more severe
disease grades.
METHODS
Patients
We retrospectively reviewed 75 eyes of 75 patients with
diabetes for whom swept-source OCT (SS-OCT) images and
color fundus photographs of sufficient quality were acquired.
In eyes with moderate NPDR or more severe grades, FA and
optical coherence tomography angiography (OCTA) images
were also obtained. Exclusion criteria were the presence of any
other chorioretinal disease, abnormalities in the vitreoretinal
interface on SS-OCT images, optic nerve diseases including
glaucoma and ischemic optic neuropathy, a history of
treatment of DME, cataract surgery within 3 months, or any
intraocular surgery other than cataract extraction. We also
evaluated 30 unaffected fellow eyes of retinal vein occlusion
patients which did not meet the exclusion criteria described
above (mean age was 62.1 6 12.4 years old) as nondiabetic
control subjects. All research and measurements adhered to
the tenets of the Declaration of Helsinki. The ethics committee
of our institution approved the study protocol and all
participants provided written informed consent.
Swept-Source Optical Coherence Tomography
After patients were given a comprehensive ophthalmic
examination, we obtained retinal volumetric images in a 6- 3
6-mm square centered on the fovea, using SS-OCT (DRI OCT-1;
Topcon, Tokyo, Japan), followed by construction of 3D images.
This OCT system operates at higher scan speed of 100,000 Ascans/second, using a light source with longer wavelength
(central wavelength of 1050 nm). In addition, invisible scan
lines and an eye-tracking system further improve the continuity
between B-scan images and reduce lateral displacement in
volumetric images. We first input the axial length quantified by
partial coherence interferometry (IOLMaster; Carl Zeiss AG,
Oberkochen, Germany) to correct the horizontal scan length
and acquired 256 horizontal B-scans generated from 512 Ascans using the 3D scan mode.
Several publications have reported neurodegenerative
changes in the NFL and GCL in DR, which prompted us to
investigate the structural changes on en face images in these
layers.19–23 The raw data of volumetric images were exported
through the OCT Viewer (Topcon), followed by image
processing using EnView software (Topcon). The moving
average of individual B-scan images provided reduced speckle
noises and improved the resolution of sectional images and the
continuity between B-scan images. The NFL and GCL were
flattened by the flattening function, using the NFL/GCL
boundary as a reference surface, and subsequent seven pixels
(18.2 lm) were averaged along the z-axis led to generation of
the slab images at the levels of the NFL or GCL (4 pixels inner
or outer than the NFL/GCL boundary). One pixel Gaussian blur
was further applied using ImageJ software (National Institutes
of Health, Bethesda, MD, USA) followed by further analyses of
the lesions in these layers (Fig. 1).
To manually measure the size of spots with inverted
reflectivity at the NFL level, we traced the boundary of the
lesions using the freehand line selection function of the ImageJ
software, followed by pixel quantification in the areas. Lesions
were delineated in at least the NFL and GCL, and some lesions
extended to the outer retinal layers. Lesion depth was
determined on the B-scan images after application of the
moving average function by using EnView software.
Color Fundus Photography
Color fundus photographs of 458 were centered on the fovea
and obtained using a fundus camera (TRC-NW8F; Topcon). We
evaluated the fundus findings corresponding to the spots with
inverted reflectivity in the central 6- 3 6-mm areas.
Fluorescein Angiography
We acquired 308 3 308 FA images centered on the fovea (1536
3 1536 pixels), using Heidelberg retinal angiography 2 unit
(HRA2; Heidelberg Engineering, Heidelberg, Germany). We
evaluated and categorized the perfusion status (i.e., typical
nonperfused areas, perfused areas, and mild hypofluorescence). The well-demarcated areas with homogeneous and
significant reduction of fluorescence levels were defined as
typical nonperfused areas, after the exclusion of blocked
fluorescence by retinal hemorrhages and hard exudates. We
further defined focal and mild hypofluorescent areas with
vague border as mild hypofluorescence in this study.
Optical Coherence Tomographic Angiography
Optical coherence tomographic angiography images centered
on the fovea (3 3 3 mm) were obtained using spectral-domain
(SD)-OCT (RTVue XR Avanti; Optovue, Inc.), which allowed us
to evaluate the structural changes in capillaries in 4 capillary
layers (i.e., NFL, GCL, SINL, and DINL).26,27 Thin slices (30-lm
thickness) using inner border of the INL as a reference surface
were constructed. We screened slab images from the vitreous
cavity to the retinal pigment epithelium, comparing to the
decorrelation signals around the lesions on the B-scan images.
The first capillary layer was delineated in the NFL around the
optic disc or vascular arcades. Capillary layers in the GCL,
SINL, and DINL were in order depicted around the lesions. The
status of the decorrelation signals was evaluated in these four
layers. Capillary plexus in the NFL was not definite in the
macula, which led us to assess three capillary layers (i.e., GCL,
SINL, and DINL).
We further investigated en face SD-OCT images in the NFL
and GCL. We selected the inner plexiform layer (IPL/INL)
boundary as a reference surface, and generated the slab images
with 18 lm thickness using the manufacturer’s software. The
position was shifted to the inner retinal layers along z-axis, and
created the en face images in the NFL and GCL. We evaluated
10 lm inner and outer en face images than the NFL/GCL
boundary which was manually determined on the B-scan
images around the lesions.
Statistical Analysis
Two masked retinal specialists evaluated all qualitative and
quantitative parameters in all modalities, followed by the
decision of a third specialist if there was a disagreement. En
face SS-OCT images in the NFL and GCL were objectively
generated. Two masked specialists then assessed the characteristics of the spots with inverted reflectivity in the same
datasets. Once the spots were determined on SS-OCT images,
the corresponding lesions on fundus photography, FA, and
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Spots With Inverted OCT Reflectivity in DR
FIGURE 1. En face OCT images after flattening of the NFL/GCL boundary in a nondiabetic or diabetic eye. Horizontal B-scan images and en face
images before (A, D, G) and after (B, C, E, F, H, I) flattening. (B, C) The line indicates the NFL/GCL boundary. In a nondiabetic eye, en face images
after flattening (E, H) clearly show arcuate retinal nerve fibers in the NFL and retinal vasculature in the GCL compared to the unprocessed images
(D, G). In a representative eye with severe NPDR, spots with inverted OCT reflectivity (arrowheads) are delineated in en face images in the NFL and
GCL (F, I).
OCTA were further evaluated. To assess the interevaluator
agreements, we calculated the intraclass correlation coefficient
(ICC). The results are expressed as the mean 6 standard
deviation for the parameters with normal distributions and
equal variance or otherwise the median (interquartile range
[IQR]). Significant differences in sampling distributions were
determined using the Fisher exact test or chi-square test.
Spearman rank correlation coefficients were used to determine
statistical correlation of the number of the spots to age,
hemoglobin A1c, or the logarithm of the minimum angle of
resolution visual acuity (logMAR VA). Areas under the receiver
operating characteristic (ROC) curve (AROC) were calculated
to evaluate the DR-discriminating power of the total number of
spots with inverted reflectivity. Briefly, we determined the
sensitivity and specificity for moderate NPDR or more severe
grades, severe NPDR, or more severe grades, or proliferative
diabetic retinopathy (PDR) according to the number of the
spots, and the ROC curve was generated. The AROC was
calculated and presented as a mean value and 95% confidence
interval (CI). A P value of <0.05 was considered significant.
RESULTS
Three-Dimensional Characterization of Spots With
Inverted OCT Reflectivity
We evaluated SS-OCT images in 75 eyes of 75 patients (mean
62.4 6 14.3 years of age) in this study. Eyes with individual
grades of DR severity ranging from no apparent retinopathy, to
mild NPDR, moderate NPDR, severe NPDR, and PDR were
selected randomly (n ¼ 15 for each grade).
En face images at the levels of the NFL and the GCL
delineated arcuate retinal nerve fibers and larger retinal vessels
respectively but no other structural findings were seen in
either layer in 30 nondiabetic control eyes (Figs. 1E, 1H). In
contrast, we found a novel finding, inner retinal spots with
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Spots With Inverted OCT Reflectivity in DR
on the en face images. The spot size in the GCL was almost the
same or smaller than that at the NFL level. Most spots were
seen in the same two-dimensional positions in the NFL and
GCL, whereas some lesions were slightly shifted to the distal
side at the GCL level (Figs. 2A–D). We investigated the twodimensional morphologies but failed to identify the specific
shapes in either the NFL or GCL level. Spectral-domain optical
coherence tomography also delineated the similar lesions in
the GCL, whereas the boundary of the spots was frequently
indistinct at the level of the NFL (Figs. 3C, 3D, 3K, 3L).
Comparison of OCT Images With Color
Photography and Fluorescein Angiography
FIGURE 2. Three-dimensional images of the inner retinal spots with
inverted OCT reflectivity in DR. En face images in the NFL (A) and GCL
(B) show several inner retinal spots with inverted reflectivity. (C, D)
Representative spots in B-scan images show that the areas with
reduced reflectivity in the NFL (black arrowheads) are adjacent to
smaller areas with higher reflectivity in the GCL (white arrowheads).
The quantified reflectivity levels along the arrows (C, D [in A]) show
the trough in the NFL (arrowheads [E, F]) and the peak in the GCL
(arrowheads [G, H]).
inverted OCT reflectivity, delineated on en face OCT images.
Margins of the lesions were well defined by the lower
reflectivity compared with the surrounding areas of the NFL
and higher reflectivity of the corresponding areas of the GCL
(Fig. 2). A total of 184 spots were delineated in eyes with
moderate NPDR or more severe grades on en face images of SSOCT (Figs. 1F, 1I). Investigation of their depth on B-scan images
showed that 153 lesions (83.2%) were limited to the NFL and
GCL along the z-axis (Figs. 2C, 2D), although some reached to
the deeper layers (i.e., the IPL, INL, outer plexiform layer, and
outer nuclear layer; 9.8%, 3.3%, 2.2%, and 1.6%, respectively).
En face OCT images showed the relatively clear border of
the spots at the level of the NFL, whereas their boundaries
were not as distinct at the level of the GCL. The manual
measurements showed that the mean size of the spots with
inverted reflectivity was 0.126 6 0.052 mm2 at the NFL level
Of all spots with inverted reflectivity delineated on en face
OCT images, 169 spots (91.8%) did not have corresponding
findings on the color fundus photographs (Fig. 4A, arrowheads). In contrast, 15 spots (8.2%) were accompanied by
whitish-yellow spots with shapes similar but not identical to
those on the en face SS-OCT images (Fig. 4A, arrows).
Boundaries were indistinct and did not appear to be fluffy in
contrast to typical cotton wool spots. Comparison with B-scan
images showed a trend that 6 (40.0%) of the 15 spots with a
corresponding finding on the color fundus images reached
retinal layers deeper than the GCL, whereas only 25 of 169
lesions (14.8%) without any finding on the color fundus images
extended into deeper layers (P ¼ 0.023; Table).
We then investigated the association of these spots with FA
in 45 eyes, for which both SS-OCT and FA images were
obtained. A total of 156 spots (84.8%) were accompanied by
mild hypofluorescence in the corresponding areas (Fig. 5B),
and 17 spots (9.2%) with typical nonperfused areas (Fig. 5C).
All spots in perfused areas or 140 of 156 spots (89.7%) with
mild hypofluorescence were in the NFL and GCL alone,
whereas 15 of 17 spots (88.2%) accompanied by focal
nonperfused areas extended to retinal layers deeper than the
GCL (P < 0.001) (Table).
Optical coherence tomographic angiography images were
compared to SS-OCT images in 45 eyes with moderate NPDR or
more severe grades (Fig. 3). Vascular plexus in the GCL was
reduced or absent in 69 of 71 spots (97.2%) with inverted
reflectivity in the central 3- 3 3-mm areas (Figs. 5M–P), and
capillaries in the NFL were also absent around the optic disc or
vascular arcades (Figs. 5E–H). In contrast, capillaries in the
SINL or DINL were delineated in the corresponding areas of 67
spots (94.4%). Four spots especially with focal nonperfused
areas were noted to not have any capillary plexuses.
Relationship to Diabetic Retinopathy Severity
Scale
Spots with inverted OCT reflectivity were quantified by two
independent retinal specialists, with higher interevaluator
agreements (ICC ¼ 0.992; P < 0.001). Further investigation
demonstrated that spots with inverted reflectivity were seen in
eyes with moderate NPDR, severe NPDR, and PDR, 3 (IQR: 1–
7), 5 (IQR: 2–9), and 5 (IQR: 2–11.75), respectively, compared
with no lesions in eyes with no apparent retinopathy or mild
NPDR (Fig. 6A). The AROC for moderate NPDR or more severe
grades of the number of spots with inverted OCT reflectivity
was 0.911 (95% CI: 0.842–0.980), suggesting the diagnostic
significance of the severity of DR (Fig. 6B). The AROC for
severe NPDR or more severe grades or PDR was not as
significant (0.829 [95% CI: 0.730–0.927] or 0.735 [95% CI:
0.590–0.880], respectively) (Figs. 6C, 6D). We further investigated but did not find the association between the number of
the spots with age (q ¼0.089; P ¼ 0.446), hemoglobin A1c (q
¼ 0.042; P ¼ 0.803), or logMAR VA (q ¼ 0.226; P ¼ 0.052).
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Spots With Inverted OCT Reflectivity in DR
FIGURE 3. Focal and laminar nonperfused areas corresponding to spots with inverted OCT reflectivity in the areas with and without capillary
plesuxes in the NFL (A–H and I–P). En face SS-OCT images in the NFL (A, I) and GCL (B, J) delineate such spots (arrowheads). Spectral-domain
optical coherence tomography images in the NFL (C, K) and GCL (D, L). These spots have capillary plexuses in the SINL and DINL (G, H) but not in
GCL (F) in the areas without the NFL capillary layer (E). In areas with capillaries in the NFL (I–P), spots are accompanied with the focal capillary loss
in the NFL (M) and GCL (N) but not in the SINL or DINL (O, P).
DISCUSSION
In this study, we have reported for the first time detecting
spots with inverted OCT reflectivity in the NFL and GCL in DR
and investigated the 3D morphologic characteristics of the
spots and compared them to findings on fundus photographs
and FA images. Most such spots were accompanied by mild
hypofluorescence, suggesting a novel pathologic mechanism
regarding disruption of the neurovascular units in diabetic
retinas. Among many fundus findings, microaneurysms,
intraretinal hemorrhages, and venous beading, intraretinal
microvascular abnormalities are considered important predictors of development of PDR.28 En face images of SS-OCT also
showed the diagnostic relevance of spots with inverted
reflectivity, because they were seen in eyes with moderate
NPDR and more severe grades alone, with higher sensitivity
and specificity.
To the best of our knowledge, no previous publications
have provided a reasonable interpretation of the kinds of
histologic lesions corresponding to this novel OCT finding.
Considering the morphologic and reflective characteristics of
spots with inverted reflectivity, we propose a few possible
cellular mechanisms (i.e., apoptotic or necrotic changes in
ganglion cells or gliosis in the inner retinal layers). Several basic
and clinical research reports have supported cellular damage in
ganglion cells in DR.19–23 During the process of cell death, the
reflective properties were modulated by changes in the
organelles, which might be compatible with the reflectivity
levels of the NFL and GCL seen in the current OCT
findings.29,30 Another possibility is that spots with inverted
reflectivity correspond to the gliotic mass after neurodegenerative changes in the ganglion cells, regardless of whether the
glial cells are derived from astrocytes or Müller cells. Several
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Spots With Inverted OCT Reflectivity in DR
TABLE. Relationship Between Depth of Inner Retinal Spots Using
Inverted OCT Reflectivity and Findings on Color Fundus Photography
and Fluorescein Angiography in Diabetic Retinopathy
Location of Spots With
Inverted Reflectivity
NFL and
NFL to Deeper
GCL Alone Layers Than GCL
P
Value
Whitish-yellow spot
Present
Absent
9
144
6
25
0.023
2
140
11
15
16
0
<0.001
FA finding
Focal nonperfused area
Mild hypofluorescence
Perfused area
FA, fluorescein angiography; GCL, ganglion cell layer; NFL, nerve
fiber layer.
FIGURE 4. Color fundus findings of inner retinal spots with inverted
reflectivity in DR. (A) Color fundus photographs show no definite
findings (arrowheads) or whitish-yellow spots (arrows) in areas
corresponding to the inner retinal spots delineated on en face images
of the NFL (B) and the GCL (C).
publications have speculated that moderately or highly
reflective lesions at the fovea may correspond to gliosis in
some eyes with surgically closed macular holes, which would
support the second hypothesis.31,32 Further longitudinal
studies and clinicopathologic analyses would clarify the
cellular or histologic components of this OCT finding.
Most spots with inverted reflectivity were accompanied by
mild hypofluorescence in corresponding areas, suggesting
either blocked fluorescence or nonperfusion in some but not
all capillary plexus layers. Optical coherence tomographic
angiography found that most spots with inverted reflectivity
were accompanied by laminar nonperfusion in the capillary
plexuses in the NFL and/or GCL, although two spots with
capillaries in the NFL and/or GCL suggest the possibility of
blocked fluorescence.5,6 It is well established that focal
ischemia in the NFL alone induces cotton-wool spots on
fundus examination, which correspond to hyperreflective
masses in the NFL on OCT images.12–14,33,34 Characteristics
of cotton wool spots on fundus photography and SS-OCT
images were different from spots with inverted reflectivity,
whereas both lesions showed laminar ischemia. We therefore
speculate that these individual lesions to some extent share the
same spectra of pathologic changes.
Recent comparative studies are focusing on the association
between capillaries on FA and OCTA images. Fluorescence in
retinal vessels may correspond to the decorrelation signals in
the superficial layers on OCTA images.35 Nonperfused areas on
FA images are not necessarily identical to the absence of
decorrelation signals in the superficial or deep layers in
OCTA.27 Other studies have reported that in paracentral acute
middle maculopathy, a subtype of retinal artery occlusion,
capillary plexuses in the SINL and DINL are obstructed, and
subsequently the OCT reflectivity increases in the middle
portion of the sensory retina.15,16 Taken together, we
hypothesized that spots with inverted OCT reflectivity was
associated with a novel laminar ischemia in GCL and NFL.
Chronic changes in neurovascular units promote neurodegeneration and vascular lesions in DR, although it is unclear
whether the neuroglial component or vasculature is damaged
primarily. The morphologic characteristics of spots with
inverted reflectivity, such as the histologic size, various shapes,
and well-defined borders, encouraged us to speculate that
disrupted blood flow might induce neuroglial damage, because
such spots were present between but not on larger vessels.
However, we could not completely exclude the possibility that
ganglion cell death may lead to loss of the vascular plexus in
the GCL via reduced angiogenic factors from the neuroglial
components, which may be compatible with the eleven spots
with inverted reflectivity in the perfused areas. In addition, the
31 spots extending to layers deeper than the GCL also may
support the precedent neurodegeneration. Because capillaries
in the NFL, SINL, and DINL branch off from proximal larger
vessels in the GCL, laminar ischemic changes, such as cotton
wool spots or paracentral acute middle maculopathy, can
emerge in individual retinal layers rather than in vertical
columnar units in the neuroglial components.36
Investigation of the relationship to ocular characteristics
showed that spots with inverted OCT reflectivity were present
only in eyes with moderate NPDR and more severe grades,
whereas there were no associations with age or logMAR VA.
Although the number of spots tended to increase with the
severity of the DR, a longitudinal study should be undertaken
to elucidate whether this OCT finding can predict progression
to PDR, as shown by the 4-2-1 rule in fundus findings.28 In
addition, intraretinal hemorrhages and cotton-wool spots
develop in other retinal vascular diseases including hypertensive retinopathy, retinal vein occlusion, or interferon-associated
retinopathy, although it remains to be determined whether
spots with inverted reflectivity are specific to DR rather than
other retinal vascular diseases.
We compared the SD-OCT images to the en face SS-OCT
images and found that the reflectivity changes were similar in
both instruments, although the boundary was frequently
indistinct in the NFL on SD-OCT images. The different
appearances might depend on the different methods of image
acquisition including the wavelength of light source or
different image processing procedures including registration,
segmentation, and the reference surfaces for slab images. We
might speculate that several technologies in SS-OCT might
provide the better continuity between scanning lines in en face
images and contribute to the clearer boundary of spots with
inverted OCT reflectivity in this study.
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Spots With Inverted OCT Reflectivity in DR
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FIGURE 5. Fluorescein angiography findings of inner retinal spots with inverted reflectivity in DR. Perfused areas (A), mild hypofluorescence (B),
and typical nonperfused areas (C) are seen in the areas corresponding to the inner retinal spots (arrowheads).
FIGURE 6. Relationship between the number of inner retinal spots with inverted OCT reflectivity with DR severity grades. (A) The number of spots
in individual DR grades. The ROC curve for DR severity (moderate NPDR or more severe grades [B], severe NPDR or more severe grades [C], or PDR
[D]) of the number of spots with inverted reflectivity.
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IOVS j April 2016 j Vol. 57 j No. 4 j 1869
Spots With Inverted OCT Reflectivity in DR
In the current study, we identified the morphologic
characteristics of a novel OCT finding, that is, spots with
inverted OCT reflectivity in eyes with moderate NPDR and
more severe grades, suggesting the diagnostic relevance and
pathogenesis of the disruption of the neurovascular units.
Acknowledgments
Supported by Grant-in-Aid for Scientific Research of Japan Society
for the Promotion of Science (26462637) (TM).
Disclosure: R. Yoza, None; T. Murakami, None; A. Uji, None; K.
Suzuma, None; S. Yoshitake, None; Y. Dodo, None; R.
Ghashut, None; M. Fujimoto, None; Y. Miwa, None; N.
Yoshimura, None
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