Disorganized Retinal Lamellar Structures in Nonperfused ...€¦ · To investigate morphologic changes on spectral-domain optical coherence tomography (SD-OCT) images in nonperfused

Retina

Disorganized Retinal Lamellar Structures in NonperfusedAreas of Diabetic Retinopathy

Yoko Dodo, Tomoaki Murakami, Akihito Uji, Shin Yoshitake, and Nagahisa Yoshimura

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

Correspondence: Tomoaki Muraka-mi, Department of Ophthalmologyand Visual Sciences, Kyoto Universi-ty Graduate School of Medicine, 54Shogoin-Kawaracho, Sakyo, Kyoto606-8507, Japan;[email protected].

Submitted: October 24, 2014Accepted: February 22, 2015

Citation: Dodo Y, Murakami T, Uji A,Yoshitake S, Yoshimura N. Disorga-nized retinal lamellar structures innonperfused areas of diabetic reti-nopathy. Invest Ophthalmol Vis Sci.2015;56:2012–2020. DOI:10.1167/iovs.14-15924

PURPOSE. To investigate morphologic changes on spectral-domain optical coherencetomography (SD-OCT) images in nonperfused areas (NPAs) in diabetic retinopathy (DR).

METHODS. One hundred eight consecutive eyes of 80 patients with diabetic ischemicmaculopathy were retrospectively reviewed. The boundary between the nerve fiber layer(NFL) and the ganglion cell layer (GCL)/inner plexiform layer (IPL) and the status of Henle’slayer were characterized on the vertical sectional images of SD-OCT. These findings werecompared with the NPAs on the FA images and the logMAR visual acuity (VA).

RESULTS. The SD-OCT images showed that most areas of capillary nonperfusion had anindistinct boundary between the NFL and GCL/IPL in DR, regardless of high or moderate OCTreflectivity. The total transverse length of the NPAs was correlated positively with that of theareas with no boundary between these layers in all 108 eyes (R ¼ 0.860, P < 0.001). Sixty-four eyes that had center-involved diabetic macular edema (DME) also had a significantassociation between them (R ¼ 0.764, P < 0.001), and the most significant correlation wasseen in eyes without DME (R ¼ 0.955, P < 0.001). The macular transverse length of the areaswith no boundary between the NFL and GCL/IPL was associated modestly with the logMARVA (R ¼ 0.334, P < 0.001). The indistinct Henle’s layer on SD-OCT images often wasdelineated specifically in the NPAs rather than in the perfused areas.

CONCLUSIONS. Nonperfused areas were associated significantly with the absence of a boundarybetween the NFL and GCL/IPL on SD-OCT images in DR.

Keywords: diabetic retinopathy, nonperfused area, spectral-domain optical coherencetomography

Diabetic retinopathy (DR), a diabetic microangiopathy, oftenleads to severe visual impairment worldwide.1,2 Diabetes

disrupts the function and structure of the retinal vasculature,which exacerbates the vascular hyperpermeability and loss ofthe capillary beds.3–5 These changes contribute clinically to thepathogenesis of diabetic macular edema (DME) and thenonperfused areas (NPAs) and concomitant neovascular com-plications, which promote neuroglial dysfunction or retinaldegeneration in patients with diabetes.6–12

In healthy eyes, the neuroglial cells in the inner retinal layersare perfused by retinal vasculature mainly in the nerve fiberlayer (NFL)/ganglion cell layer (GCL) and the inner and outerborders of the inner nuclear layer (INL), whereas the outerretinal layers are nourished by the choroidal vessels.13,14

Disappearance of the retinal capillaries results in nutrient andoxygen deficiencies or waste accumulation in the inner retinallayers, referred to as retinal ischemia. Clinical studies haveidentified visual impairment associated with NPAs, which mightbe supported by histologic studies that documented loss ofneuronal cells and gliosis in ischemic retinas with DR.7–12,15,16

However, it is unknown how ischemia exacerbates the in vivomorphologic changes in the neuroglial tissues.

Despite its invasiveness, fluorescein angiography (FA) is thegold standard for the clinical evaluation of the morphologic andpathophysiologic changes in the retinal vasculature.17,18

Fluorescein angiography enables recognition of the details ofthe vascular lesions including microaneurysms, venous bead-

ing, intraretinal microvascular abnormalities, and neovascular-ization.19 Fluorescein angiography is the only method toadequately delineate NPAs whether the circulatory disruptiondepends on emboli resulting from blood cells or apoptoticchanges in vascular cells induced by the biochemical pathwaysand cytokines.20–25 However, despite the distinct delineation ofvascular lesions, FA cannot directly show the structural changesin the neuroglial tissues of the NPAs.

Several studies have proposed noninvasive methods toassess the NPAs rather than invasive FA. Dark areas on thered-free images were reported to correspond to NPAs on FAimages in retinal vascular diseases.26 Phase-variance opticalcoherence tomography (OCT) delineates the retinal vascula-ture, which might allow us to evaluate the capillary loss.27 Inaddition to the vascular lesions, spectral-domain (SD)-OCTshowed neuroglial changes (i.e., the decreased thickness of theGCL in eyes with diabetic ischemic maculopathy).28 A fewstudies have reported changes in the thickness of the inner orouter retinal layers measured by OCT, although the relevanceremains controversial.9,11,29,30 In eyes without retinal edema,NPAs are accompanied by thinning of the inner layers andthickening of the outer layers.10 Vascular hyperpermeabilityresulting from diabetes often exacerbates edematous changesin the retinal parenchyma and modulates the thicknesses of theinner and outer retinal layers. However, qualitative OCTfindings that correspond to the pathohistologic changes inneuroglial tissues in NPAs remain largely unknown.10

Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

www.iovs.org j ISSN: 1552-5783 2012

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In the current study, we characterized the OCT findings inthe NPAs in eyes with DR, focusing on the absence of aboundary between the NFL and GCL/inner plexiform layer(IPL) and the indistinct Henle’s layer.

METHODS

Patients

We reviewed retrospectively 108 consecutive eyes of 80patients (mean age, 60.4 6 11.8 years; range, 31–85) withdiabetic ischemic maculopathy (39 eyes with moderate non-proliferative diabetic retinopathy [NPDR], 30 with severeNPDR, and 39 with proliferative diabetic retinopathy) forwhich FA and OCT images of sufficient quality were obtainedin the Department of Ophthalmology of Kyoto UniversityHospital from November 2007 to February 2014. The inclusioncriteria were ischemic maculopathy of grade 2, 3, or 4 definedby the Early Treatment Diabetic Retinopathy Study (ETDRS)Report Number 11, which was determined based on theagreement of two independent masked graders.18 The majorexclusion criteria were the presence of any other chorioretinaldiseases, the presence of a pathology in the optic nerveincluding glaucoma, severe media opacity including preretinalhemorrhage, a history of treatment of macular pathology, and ahistory of cataract surgery within 3 months or any majorsurgery other than cataract extraction within 1 year of entry

into the study. All research and measurements adhered to thetenets of the Declaration of Helsinki. The institutional reviewboard/ethics committee of our institution approved the study.Written informed consent was obtained after full explanationof the nature and possible consequences of this study.

Imaging

After comprehensive ophthalmologic examinations includingmeasurement of the best-corrected VA, color fundus photog-raphy, and slit-lamp biomicroscopy, FA images of the macula(308 3 308 centered on the fovea) were acquired using ascanning laser ophthalmoscope (Heidelberg Retina Angiograph2; Heidelberg Engineering, Heidelberg, Germany) as describedpreviously.31 We measured the transverse length of the NPAson FA images and compared them to sectional SD-OCT(Spectralis OCT; Heidelberg Engineering) images. Briefly, wedetermined the 7-mm vertical line on the FA images, whichcorresponded to the vertical sectional images of the cross-hairmode of OCT images. Two masked graders measured thetransverse lengths of the areas with no distinct retinal vessels,which contained both the pathological NPAs and the fovealavascular zone, regardless of whether or not it was enlarged.The mean length measured by two independent graders in amasked fashion (intraclass correlation coefficient [ICC], 0.872)was applied for further analyses.

FIGURE 1. Optical coherence tomographic findings in NPAs in DR (A) NPAs involving the fovea are delineated mainly in the temporal and inferiorsubfields on FA image. (B) An SD-OCT image along the arrow in (A). The bidirectional arrow indicates the NPAs. (C–F) Magnified images of (B). (C)An OCT image depicts the distinct boundary between the NFL and GCL/IPL (black arrowheads) and Henle’s layer (white arrowheads) in theperfused areas. (D) No boundary is visible between the NFL and GCL/IPL in the NPAs without retinal edema. (E) The boundary between the NFLand GCL/IPL is indistinct in NPAs accompanied by retinal edema, and enlarged cystoid spaces sometimes disrupt Henle’s layer (area between thearrows). The arrowheads indicate Henle’s layer. (F) The boundary between the NFL and GCL/IPL (black arrowhead) is observed in the NPAsaround the arteriole (green bidirectional arrow). The red bidirectional arrow indicates the NPAs.

Morphologic Changes on SD-OCT Images in NPAs in DR IOVS j March 2015 j Vol. 56 j No. 3 j 2013


Retinal sectional images of the macula were obtained usingSD-OCT, and the vertical sections in the cross-hair mode (308)were evaluated further. We first determined the presumedfoveal center where the inner retinal layers from the NFL toINL were absent as described previously.31 It was sometimesdifficult to determine the individual retinal layers in eyes withsevere ischemic maculopathy, in which the INL or Henle’s layerwas unidentifiable. In such cases, we determined that the pointon the horizontal line dissecting the center of the optic discwas the foveal center. The sectional images within 3.5 mm ofthe (presumed) foveal center were evaluated qualitatively andquantitatively. The mean retinal thickness in the central 1-mmsubfield of the ETDRS grid was assessed on a two-dimensionalOCT map constructed by raster scans, as described previously,followed by diagnosis of center-involved DME according to thecriteria in a recent publication.32,33

We especially evaluated the boundary between the retinallayers, from the NFL to the IPL, and the status of Henle’s layer.The GCL often had the same OCT reflectivity as the IPL, whichprompted us to compare the reflectivity levels of the NFL tothose of the combined layers of the GCL and IPL, referred to asthe GCL/IPL. Since the OCT reflectivity of the NFL is muchhigher than that of the GCL/IPL in healthy eyes, we candetermine the boundary between these layers (SupplementaryFig. S1). In contrast, OCT images showed that the boundary was

indistinct in the NPAs with and without edematous changes inthe retinal parenchyma (Figs. 1–3), which was confirmed usingthe Plotprofile function of the ImageJ software (NIH, Bethesda,MD, USA). Cotton-wool spots presenting as NPAs on FA imagesdid not have boundaries between the NFL and GCL/IPL, whichagreed with histologic studies (Fig. 3).34 Two masked gradersmeasured the transverse length of the areas with no boundarybetween the NFL and GCL/IPL, which contained the foveawhere the NFL was absent and the boundary between theselayers was not seen (Fig. 4). The mean length measured by twomasked graders was analyzed further (ICC, 0.980).

We also assessed the status of Henle’s layer on the verticalsection of the OCT images. OCT showed Henle’s layer as a line ofhigh reflectivity between the INL and outer nuclear layer (ONL),both of which had moderate OCT reflectivity in healthy eyes.This layer sometimes was not identifiable because of increasedlevels of OCT reflectivity in the INL or enlarged cystoid spacesfrom the INL to the outer plexiform layer (OPL)/ONL (Figs. 1, 5).Henle’s layer was often indistinct at the presumed foveal center,whether the eyes were healthy or not. We included areas withboth of these findings into those without a distinct Henle’s layer;two masked graders measured the transverse length (ICC,0.992), and the average was analyzed further.

The total transverse length of the areas with no boundarybetween the NFL and GCL/IPL or those with an indistinct

FIGURE 2. No differences in the OCT reflectivity of the NFL and GCL/IPL in NPAs of DR (B, C) In the perfused areas, the OCT reflectivity levels arehigher in the NFL compared with the moderate levels in the GCL/IPL. (E) Optical coherence tomography shows the boundary between the NFL andGCL/IPL in the perfused areas; the boundary is indistinct in most areas of capillary nonperfusion without retinal edema (bidirectional arrow). (F)The OCT reflectivity levels along the left arrow in ([E]; perfused areas). The levels are higher in the NFL than those in the GCL/IPL. (G) Thereflectivity along the right arrow in ([E]; NPAs). There is a single peak of reflectivity levels corresponding to the NFL and GCL/IPL. (I, J) The OCTreflectivity is higher and homogeneous in the inner layers compared with the INL, resulting in the absence of a boundary between the NFL andGCL/IPL in NPAs with retinal edema. (A, D, H) FA images. (B, E, I) Optical coherence tomography images along the arrows in FA images. (C, F, G, J)Optical coherence tomography reflectivity levels along the arrows on OCT images measured by the Plotprofile function of the ImageJ software.



Henle’s layer on the OCT images, whether continuous or not,was compared with that of the NPAs on the FA images. Thelength of one continuous area with such OCT findingscontaining the (presumed) foveal center was measured anddefined as the macular transverse length. We further evaluatedits association with the logMAR VA.

Statistical Analysis

The results were expressed as the mean 6 SD. Linearregression analysis was performed to determine a statisticalcorrelation. P less than 0.05 was considered significant.

RESULTS

Indistinct Boundary Between the Nerve Fiber Layerand Ganglion Cell Layer/Inner Plexiform Layer inNonperfused Areas

Individual retinal layers have individual levels of OCT reflectivityin healthy eyes, which enables us to identify the boundariesbetween the different layers. In contrast, the boundariesbetween the retinal layers including the NFL, GCL/IPL, INL,and Henle’s layer were often indistinct in the NPAs (Figs. 1, 2).The boundary between the NFL and GCL/IPL especially was

FIGURE 3. Higher OCT reflectivity in CWS. (A) Nonperfused areas around the arrow on a FA image correspond to the CWS on the color photograph(B). (C) A retinal sectional image shows swelling of the inner retinal parenchyma with no boundary between the NFL and GCL/IPL. (D) Thereflectivity levels are higher and homogeneous in the CWS compared with the different levels of OCT reflectivity between the NFL and GCL/IPL inperfused areas (E).

FIGURE 4. Measurements of the transverse length of the areas with no boundary between the NFL and GCL/IPL. (A) An FA image shows ischemicmaculopathy accompanied by NPAs in the parafovea. (B) An OCT image along the arrow in (A). There are three areas with no boundary betweenthe NFL and GCL/IPL (bidirectional arrows). The total (both green and red arrows) or macular (red arrows alone) transverse length of the areaswith no boundary between these layers was quantified. (C) A magnified image in the parafovea. The boundary between the NFL and GCL/IPL isindistinct in the areas between the two white arrows. The black arrowheads indicate the boundary between the NFL and GCL/IPL. (D) A magnifiedimage around the fovea. There is no boundary between the NFL and GCL/IPL in the areas between the two white arrows. The inner layers (from theGCL to the INL) and Henle’s layer are absent in the areas between the two white arrowheads and the two black arrows, respectively.



indistinct and the INL was delineated in most areas of capillarynonperfusion, whether the areas were accompanied by retinaledema or not (Figs. 1, 2). In addition, cotton-wool spots, seen asNPAs on the FA images, also appeared as highly reflective lesionswith an indistinct boundary between the layers (Fig. 3).However, the OCT images often showed the boundary betweenthe NFL and GCL/IPL in the NPAs near the major vessels (Fig. 1).

We then focused on the OCT reflectivity levels of the retinalparenchyma in which the boundary between the NFL andGCL/IPL disappeared. Such parenchymal lesions around thefovea tended to have the same levels of OCT reflectivity as theGCL/IPL in the adjacent perfused areas and a gradual decreasein the NFL thickness (Fig. 4). In contrast, the typical NPAs inthe parafovea or perifovea often had higher levels of OCTreflectivity, similar to those in the NFL (Fig. 4).

We measured the total transverse length of the areas with anindistinct boundary between the NFL and GCL/IPL andevaluated the association with the NPAs (Fig. 4). The boundarywas indistinct in 88.9 6 16.7% of the transverse length of theNPAs on FA images, and 88.9 6 16.2% of the areas with noboundary between these layers corresponded to NPAs on theFA images. This may be compatible to the finding that the totaltransverse length of the areas with an indistinct boundarybetween the NFL and GCL/IPL was correlated with that of theNPAs on the FA images in all 108 eyes (R¼ 0.860, P < 0.001;Fig. 6). The association was more significant in 44 eyes withoutcenter-involved DME (R¼ 0.955, P < 0.001; Fig. 6) rather thanthose with center-involved DME. We further evaluated themacular transverse length of this finding and found a modestassociation with logMAR VA in all 108 eyes and 64 eyescombined with center-involved DME (R¼0.334, P < 0.001 andR ¼ 0.406, P ¼ 0.001, respectively; Fig. 7).

Status of Henle’s Layer in Nonperfusion Areas

No differences were sometimes seen in the OCT reflectivitybetween the INL and Henle’s layer in the NPAs in diabetic eyes,

compared with those in healthy eyes (Figs. 1, 5). The enlargedcystoid spaces extended from the INL to the OPL/ONL inlimited areas of the NPAs, indicating discontinuity of Henle’slayer (Fig. 5).35 Most areas (94.5 6 15.4%) with these findings,referred to as indistinct Henle’s layer, were delineated withinthe NPAs on the FA images, suggesting higher specificity.However, the total transverse length of the areas withoutdistinct Henle’s layer was not related to that of the NPAs on FAimages in all 108 eyes and in 44 eyes without DME (Fig. 8). Themacular transverse length of the areas with indistinct Henle’slayer was correlated modestly with the logMAR VA (Fig. 9).

DISCUSSION

Diabetes exacerbates the damage in the retinal vasculature,which leads to retinal ischemia and concomitant visualimpairment in DR8,11,12 However, it remains largely unknownhow loss of the retinal capillary beds exacerbates thepathogenesis in the neuroglial components and vice versa.10

The current study found that OCT showed the indistinctboundary between the NFL and GCL/IPL and the absence ofHenle’s layer in the NPAs. The absence of a boundary betweenthe NFL and GCL/IPL on OCT images was related significantly tothe NPAs on the FA images, suggesting that OCT has potentialuse for evaluating the NPAs in eyes with DR. In contrast, theindistinct Henle’s layer was located specifically in the NPAs,although no correlation was found between the transverselength of the indistinct Henle’s layer and that of the NPAs.

A few studies have investigated the relationship betweenthe NPAs on FA images and thinning of the inner retinal layerson OCT images in DR.28–30,36 We also observed atrophicchanges in the inner retinal layers in eyes without retinaledema, although the retinal thickness can change in responseto edema, axial length, age, and so on.37,38 Thinning of theinner retinal layers especially might not be useful for evaluatingNPAs with retinal edema, which is often exacerbated by

FIGURE 5. Indistinct Henle’s layer in NPAs in two representative cases with ischemic maculopathy. (B) An OCT image along an arrow on a FA image(A) in an eye that also has center-involved DME. The black arrowheads indicate Henle’s layer. The white arrowhead indicates Henle’s layerdisrupted by an enlarged cystoid space. The area between the two arrows indicates an indistinct Henle’s layer around the fovea. (D) A retinalsectional image along an arrow on a FA image (C) in an eye without center-involved DME. The white arrowheads indicate Henle’s layer. The areabetween the black arrows indicates the indistinct Henle’s layer at the fovea.



diabetes-induced vascular permeability. In the current study,OCT delineated the indistinct boundary between the NFL andGCL/IPL in the NPAs with and without retinal edema. Inaddition, the transverse length of the NPAs was associated

significantly with that of the areas without a boundary betweenthese layers on SD-OCT images in 64 eyes with center-involvedDME. These data may recommend clinicians to observe theabsence of a boundary between the NFL and GCL/IPL forpredicting NPAs, whether the retinal parenchyma is edematousor not. In contrast, the association between the VA and thisOCT finding was modest, suggesting that other factors alsoaffect visual impairment.

FIGURE 6. A significant association is seen between the totaltransverse length of the areas with no boundary between the NFLand GCL/IPL and that of the NPAs on FA images in 108 eyes withischemic maculopathy (A), in 64 eyes with center-involved DME (B),and in 44 eyes without center-involved DME (C).

FIGURE 7. A modest correlation between logMAR VA and the maculartransverse length with no boundary between the NFL and GCL/IPL in108 eyes with ischemic maculopathy (A), in 64 eyes with center-involved DME (B), and in 44 eyes without center-involved DME (C).



We documented the various levels of OCT reflectivity in theretinal parenchyma with no boundary between the NFL andGCL/IPL, which prompted us to hypothesize the severalhistologic changes in this lesion.10 The different levels ofOCT reflectivity in the NFL and GCL/IPL allowed us torecognize the boundary between these layers in healthy eyes.In contrast, the increased levels of reflectivity in the GCL/IPL

or the decreased levels in the NFL may result in thedisappearance of the boundary between these layers, whichmay represent the processes of neuroglial cell death and gliosisas reported in a histologic study.10 Other possible explanationsmay be that loss of the ganglion cells and accompanying axons(nerve fibers) corresponds to the OCT findings showingthinning of the inner retinal layers and decreased OCT

FIGURE 8. The relationship between the total transverse length of theareas with no distinct Henle’s layer and that of the NPAs on FA imagesin 108 eyes with ischemic maculopathy (A), in 64 eyes that also havecenter-involved DME (B), and in 44 eyes without DME (C).

FIGURE 9. A modest correlation between logMAR VA and the maculartransverse length of the areas without a distinct Henle’s layer in 108eyes with ischemic maculopathy (A), in 64 eyes that also have center-involved DME (B), and in 44 eyes without DME (C).



reflectivity around the fovea. This may agree with previousstudies that reported apoptotic changes in the ganglion cells inDR or thinning of the GCL in ischemic maculopathy.28,39 Incontrast, we often observed that the NPAs in the parafoveawere accompanied by increased levels of OCT reflectivity inthe inner retinal layers. Loss of ganglion cells may berepresented by absence of the GCL/IPL, whereas the nervefibers derived from the distal areas were observed as the innerlayers with higher OCT reflectivity.

Diabetes exacerbates the pathogenesis in the neurovascularunits (i.e., the degenerative processes in the vascular cells andneuroglial components).3,40 It remains ill-defined whether lossof the capillary beds in the NPAs is the primary process or asecondary response after neuroglial atrophy. Since themicrocirculation is disturbed in diabetic retinas, vasculardamage may precede neuroglial changes.20–22 This may becompatible with the OCT findings that the NPAs adjacent tolarge vessels were accompanied by a boundary between theNFL and GCL/IPL (Fig. 1). In contrast, several clinical andbiomedical studies have suggested that the primary processesin the diabetic retinas may be neuroglial dysfunction ordegeneration.39,41,42 We thus speculated that neuronal degen-eration resulting from diabetes induces a deficiency invasculogenic factors and concomitant disappearance of vascu-lar cells.43 These changes in vasculature and neuronal tissuesmay promote degenerative processes reciprocally in diabeticretinas.

Although the indistinct Henle’s layer was observed specif-ically in the NPAs of DR, we did not find an associationbetween the transverse length of the NPAs and that of the areaswith the indistinct Henle’s layer, suggesting that this OCTfinding is less useful for predicting NPAs. We also consideredthe possible morphologic changes (i.e., increased OCTreflectivity in the INL, disappearance of the INL, or disruptedHenle’s layer due to enlarged cystoid spaces).35 In addition toretinal ischemia, inflammation and extravasated blood compo-nents also may promote the chronic neurodegeneration orgliosis in the INL or Henle’s layer, resulting in indistinct Henle’slayer on SD-OCT images.3,10 Another mechanism may be thatenlarged cystoid spaces extending from the INL to the OPL/ONL disrupt Henle’s layer. The capillary plexus layer in theouter INL may provide structural integrity and separate thecystoid spaces in the INL from those in the OPL/ONL, althoughloss of capillaries in the NPAs may allow the cystoid spaces toextend between these layers.35,44,45 These possible patholog-ical mechanisms in the transduction system may contribute tovisual impairment, which was supported by the modestcorrelation between the VA and the indistinct Henle’s layerin the macula (Fig. 9).

Although these OCT findings have potential use fornoninvasive evaluation of NPAs and for understanding thepathogenesis, the current study had a few limitations. Weassessed the boundary between the NFL and GCL/IPLsubjectively, and further objective and automatic methodsshould be developed. In this study, we measured the transverselength of the areas with an indistinct boundary between theNFL and GCL/IPL on the vertical SD-OCT images dissecting thefovea. We considered that two-dimensional information mayprovide a better understanding, although the NFL is absent inthe temporal raphe, which did not allow us to identify theboundary between the NFL and GCL/IPL.

In summary, the current study documented two OCTfindings, that is, the absence of a boundary between the NFLand GCL/IPL and the indistinct Henle’s layer in the NPAs ofeyes with DR, suggesting their clinical use in the noninvasiveevaluation of NPAs and the pathogenesis in the neurovascularunits.

Acknowledgments

Disclosure: Y. Dodo, None; T. Murakami, None; A. Uji, None; S.Yoshitake, None; N. Yoshimura, None

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