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[Purpose] To investigate the distribution of clinically significant nonperfusion areas (NPAs) on widefield OCT angiography (OCTA) images in patients with diabetes. [Design] Prospective, cross-sectional, observational study. [Participants] One hundred and forty-four eyes of 114 patients with diabetes. [Methods] Nominal 20 × 23 mm OCTA images were obtained using a swept-source OCTA device (Xephilio OCT-S1), followed by the creation of en face images 20-mm (1614 pixels) in diameter centering on the fovea. The nonperfusion squares (NPSs) were defined as the 10 × 10 pixel squares without retinal vessels, and the ratio of eyes with the NPSs to all eyes in each square was referred to as the NPS ratio. The areas with probabilistic differences (APD) for proliferative diabetic retinopathy (PDR) and nonproliferative diabetic retinopathy (NPDR) (APD[PDR] and APD[NPDR]) were defined as sets of squares with higher NPS ratios in eyes with PDR and NPDR, respectively. The P ratio (NPSs within APD[PDR] but not APD[NPDR]/all NPSs) was also calculated. [Main Outcome Measures] The probabilistic distribution of the NPSs and the association with diabetic retinopathy (DR) severity. [Results] The NPSs developed randomly in eyes with mild and moderate NPDR and were more prevalent in the extramacular areas and the temporal quadrant in eyes with severe NPDR and PDR. The APD(PDR) was distributed mainly in the extramacular areas, sparing the areas around the vascular arcades and radially peripapillary capillaries. The APD(PDR) contained retinal neovascularization more frequently than the non-APD(PDR) (P = 0.023). The P ratio was higher in eyes with PDR than in those with NPDR (P < 0.001). The multivariate analysis designated the P ratio (odds ratio, 8.293 × 107; 95% confidence interval, 6.529 × 102–1.053 × 1013; P = 0.002) and the total NPSs (odds ratio, 1.002; 95% confidence interval, 1.001–1.003; P < 0.001) as independent risk factors of PDR. Most eyes with NPDR and 4-2-1 rule findings of DR severity had higher P ratios but not necessarily greater NPS numbers. [Conclusions] The APD(PDR) is uniquely distributed on widefield OCTA images, and the NPA location patterns are associated with DR severity, independent of the entire area of NPAs. [Financial Disclosure(s)] Proprietary or commercial disclosure may be found after the references.

Diabetic macular edema (DME) refractory to anti-VEGF drugs is a socioeconomic burden. In this retrospective study, we investigated the relationship between DME remission and hyperreflective walls in foveal cystoid spaces, a novel finding on spectral domain optical coherence tomography (SD-OCT) images in DME. In a cross-sectional study, we assessed the relationship between hyperreflective walls in foveal cystoid spaces and other OCT findings in 110 eyes of 110 DME patients. Hyperreflective walls were delineated in 27 of 171 foveal cystoid spaces. Eyes with hyperreflective walls in foveal cystoid spaces had poorer visual acuity and more severe photoreceptor disruption than did those without such findings (P = 0.008 and P P = 0.025). We characterized hyperreflective walls in foveal cystoid spaces and designated them as a predictor of no DME remission under ranibizumab injections.

Anti-VEGF drugs are as the first-line therapies for diabetic macular edema (DME). In this study, we investigated the association between hyperreflective foci in the outer retinal layers and functional efficacy in DME patients who received intravitreal ranibizumab (IVR) injections. We retrospectively reviewed 77 eyes of 71 patients with DME treated with pro re nata IVR injections for at least 12 months. We evaluated how baseline hyperreflective foci in the outer retinal layers on spectral domain optical coherence tomography images were associated with an improvement in logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 12 months. Forty-three eyes with hyperreflective foci in the outer retinal layers had greater VA improvement than 34 eyes without such foci at 12 months. Multivariate analyses demonstrated that both logMAR VA and hyperreflective foci in the outer retinal layers at baseline were associated with VA improvement. Structural analyses revealed that the central subfield thickness was decreased and that the ellipsoid zone of photoreceptors was improved more significantly in eyes with hyperreflective foci in the outer layers than eyes without such lesions. Baseline hyperreflective foci in the outer retinal layers predict the functional efficacy of IVR injections for DME.

To investigate the clinical significance of intercapillary spaces on swept source optical coherence tomography angiography images in diabetic retinopathy.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.Total counts (ρ = -0.419; Plt; 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; Plt; 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 (Plt; 0.001) and poorer logMAR (Plt; 0.001) than the other, with a wide range of the foveal avascular zone area.Decreased intercapillary spaces contribute to visual impairment in diabetic retinopathy and suggest one possible criterion of objective diagnosis of diabetic macular ischemia.

The early remission of diabetic macular edema (DME) often occurs in eyes treated with anti-vascular endothelial growth factor (VEGF) treatment. We retrospectively reviewed and characterized eyes with early remission of DME at six months in 80 eyes under pro re nata (PRN) intravitreal ranibizumab (IVR) injections. The number of eyes without center-involved DME gradually increased and 14 and 20 eyes achieved remission of DME at 3 or 6 months, respectively, under the PRN regimen following three monthly loading doses. In particular, eyes with early remission at 6 months had smaller CSF thickness than those without the remission before and after the treatment except at the 1-month visit (P P = 0.008). These data elucidate the clinical characteristics of early remission of DME under PRN IVR injections and suggest that smaller CSF thickness at baseline is a novel predictor of early remission under PRN IVR injections for DME.

PURPOSE To investigate the effect of denoise processing by artificial intelligence (AI) on the optical coherence tomography angiography (OCTA) images in eyes with retinal lesions. METHODS Prospective, observational, cross-sectional study. Optical coherence tomography angiography imaging of a 3 × 3-mm area involving the lesions (neovascularization, intraretinal microvascular abnormality, and nonperfusion area) was performed five times using OCT-HS100 (Canon, Tokyo, Japan). We acquired AI-denoised OCTA images and averaging OCTA images generated from five cube scan data through built-in software. Main outcomes were image acquisition time and the subjective assessment by graders and quantitative measurements of original OCTA images, averaging OCTA images, and AI-denoised OCTA images. The parameters of quantitative measurements were contrast-to-noise ratio, vessel density, vessel length density, and fractal dimension. RESULTS We studied 56 eyes from 43 patients. The image acquisition times for the original, averaging, and AI-denoised images were 31.87 ± 12.02, 165.34 ± 41.91, and 34.37 ± 12.02 seconds, respectively. We found significant differences in vessel density, vessel length density, fractal dimension, and contrast-to-noise ratio (P < 0.001) between original, averaging, and AI-denoised images. Both subjective and quantitative evaluations showed that AI-denoised OCTA images had less background noise and depicted vessels clearly. In AI-denoised images, the presence of fictional vessels was suspected in 2 of the 35 cases of nonperfusion area. CONCLUSION Denoise processing by AI improved the image quality of OCTA in a shorter time and allowed more accurate quantitative evaluation.

AIMS/HYPOTHESIS: In diabetic macular oedema (DMO), blood components passing through the disrupted blood-retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries. METHODS: Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries. RESULTS: After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p

OBJECTIVES: To document and characterise hyper- and hypo-reflective lesions, which we describe as ‘granular’ on short-wavelength autofluorescence (SW-AF) and near-infrared (NIR)-AF images in diabetic macular oedema (DMO). METHODS: Consecutive 103 eyes of 78 patients suffering from centre-involving DMO were reviewed retrospectively. Mosaics of hyper- and hypo-fluorescent dots on both SW-AF and NIR-AF signals were delineated and defined as granular lesions in the macula. We evaluated the association of such lesions with the logarithm of the minimum angle of resolution visual acuity (logMAR VA) and spectral-domain optical coherence tomography (SD-OCT) images. RESULTS: Diffuse mosaics of hyper- and hypo-fluorescent dots were delineated in 36 and 45 eyes on SW-AF and NIR-AF images, respectively, and both AF images defined granular lesions in 33 eyes. These lesions were delineated in both the fovea and extrafoveal areas on NIR-AF images but were limited to the parafoveal and perifoveal subfields on SW-AF images. There was a significant difference in logMAR VA between eyes with and without granular lesions (0.358 ± 0.269 vs. 0.185 ± 0.234; P = 0.001). Granular lesions were associated with the mosaic pattern on NIR-AF images (P

Diabetic retinopathy (DR) induces the breakdown of the blood-retinal barrier and promotes neuroinflammation, although autoimmune responses to sequestered retinal antigens remain poorly understood. In this study, we investigated the autoantibodies for retinal antigens in sera from diabetic macular edema (DME) patients. Screening by immunoblotting demonstrated that IgG from 7 of 10 DME sera samples reacted to an ~102-kDa autoantigen from porcine retinas. Immunoprecipitation with autoantibodies from DME sera and subsequent mass spectrometry enabled us to identify hexokinase 1 as an autoantigen reactive to IgG from DME sera. IgG in 7 of 10 DME sera partially colocalized to hexokinase 1 in the outer plexiform layer of rodent retinas. Quantitative analyses using enzyme-linked immunosorbent assays revealed that the serum titers of this autoantibody were significantly higher in the DME sera than those in the sera from diabetic patients without DME, and 20 (24.1%) of the 83 DME serum samples had higher IgG titers than the cutoff value (mean + 2 standard deviations of the sera from diabetic patients without DR). Multivariate logistic regression analysis confirmed that the higher titer of anti-hexokinase 1 IgG was clinically feasible for the diagnosis of DME. These data identify anti-hexokinase 1 antibody as a serum biomarker of a subset of DME.

PurposeTo characterise the non-perfused areas (NPAs) in the superficial and deep capillary layers (sNPAs and dNPAs, respectively) in the posterior pole in proliferative diabetic retinopathy (PDR) on wide-field optical coherence tomography angiography (OCTA) images.MethodsWe retrospectively reviewed 104 eyes of 70 patients with PDR from whom wide-field swept source OCTA images were acquired. sNPAs and dNPAs were manually measured in each quadrant of the inner (1–3 mm diameter), intermediate (3–6 mm), and outer (6–10 mm) rings centred on the fovea. Two qualitative findings, that is,segmented NPAsandperiarteriolar NPAs, were also compared.ResultsThe dNPAs were greater than the sNPAs (pρ=0.341, p=0.026) and outer (ρ=0324, p=0.032) rings, whereas sNPAs exhibited no associations.Segmented NPAswere delineated more frequently in the superficial layer than in the deep layer (pPeriarteriolar NPAswere more frequent in the deep layer (pConclusionsThree-dimensional assessment of wide-field OCTA promotes a better understanding of the enigmatic disproportion of lamellar NPAs in the posterior pole in PDR.

Purpose: The effect of the enhanced-resolution imaging (ERI) technique on optical coherence tomography (OCT) images was evaluated. Methods: A total of 5 healthy subjects and 20 patients diagnosed with various eye diseases were recruited into the study. ERI, a novel image processing technique, was accomplished by using super-resolution technology, and was assessed by objectively and subjectively comparing the image quality among three different image groups: images enlarged without bicubic interpolation (NONE), with bicubic interpolation (IP), and with ERI. Results: ERI showed a higher ratio of the detailed variance to the background variance than NONE, whereas no significant difference was detected between NONE and IP. The mean opinion score of 5 experienced retinal specialists for ERI was significantly higher than that for IP. Conclusions: ERI generated a sharper image and clearly visualized small objects. Additionally, it is effective in enhancing OCT image quality.

Diabetic hyperreflective foci in the outer retinal layers are a clinically relevant finding on optical coherence tomography (OCT) images, although their characteristics remain to be elucidated. Here we investigated the decorrelation signal around hyperreflective foci on OCT angiography (OCTA) images in diabetic retinopathy (DR). We retrospectively reviewed sufficient quality OCTA images from 102 eyes of 66 patients that were obtained using split-spectrum amplitude-decorrelation angiography algorithm. Most confluent hyperreflective foci were randomly deposited or appeared in a radiating array on the en-face structural OCT images in the inner nuclear layer (INL) or Henle’s fiber layer (HFL), respectively. Within the INL, hyperreflective foci were not accompanied by decorrelation signals and attached to capillaries on OCTA images. Decorrelation signals were sometimes delineated in hyperreflective foci in the HFL and other times appeared to be pseudopod-like or wrapping around hyperreflective foci, referred to as reflectance-decorrelated foci. The decorrelation signal intensity of hyperreflective foci in the HFL was associated with logMAR VA (R = 0.553, P R = 0.408, P reflectance-decorrelated foci on OCTA images are clinically relevant as well as shed lights on the properties in diabetic hyperreflective foci.

To quantify the signal intensity of fundus autofluorescence (FAF) and evaluate its association with visual function and optical coherence tomography (OCT) findings in diabetic macular oedema (DMO). We reviewed 103 eyes of 78 patients with DMO and 30 eyes of 22 patients without DMO. FAF images were acquired using Heidelberg Retina Angiograph 2, and the signal levels of FAF in the individual subfields of the Early Treatment Diabetic Retinopathy Study grid were measured. We evaluated the association between quantified FAF and the logMAR VA and OCT findings. One hundred and three eyes with DMO had lower FAF signal intensity levels in the parafoveal subfields compared with 30 eyes without DMO. The autofluorescence intensity in the parafoveal subfields was associated negatively with logMAR VA and the retinal thickness in the corresponding subfields. The autofluorescence levels in the parafoveal subfield, except the nasal subfield, were lower in eyes with autofluorescent cystoid spaces in the corresponding subfield than in those without autofluorescent cystoid spaces. The autofluorescence level in the central subfield was related to foveal cystoid spaces but not logMAR VA or retinal thickness in the corresponding area. Quantified FAF in the parafovea has diagnostic significance and is clinically relevant in DMO.

Diabetes induces lesions of the retinal and choroidal capillaries, which promote the pathogenesis of diabetic retinopathy (DR). The decorrelation signals in optical coherence tomography angiography (OCTA) represent the blood flow and vascular structure, and three-dimensional OCTA images enable individual capillary layers to be evaluated separately. The current study documented that en-face OCTA images revealed spots of flow void in the choriocapillaris layer in eyes with DR. Quantitative investigation demonstrated that non-flow areas within the central subfield (CSF) increased in eyes with more severe DR grades. The non-flow areas in the choriocapillaris layer were also associated with poorer visual acuity (VA) in all 108 eyes. A modest correlation was noted between the areas of flow void and poorer VA in 69 eyes without DME, whereas the non-flow areas were not related to VA or to CSF thickness measured by OCT in 39 eyes with DME. In 12 eyes with ischemic maculopathy, the choriocapillaris layer beneath the disrupted ellipsoid zone of the photoreceptor (EZ) had greater areas of flow void than did the area beneath an intact EZ. These data suggested that disrupted choroidal circulation has clinical relevance and contributes to the pathogenesis of DR.

To investigate the association between the characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab treatment for diabetic macular edema (DME) at 3 months from the initial injection. We retrospectively reviewed 66 eyes of 61 patients with center-involved DME who received three consecutive ranibizumab injections and following as-needed administrations. We evaluated the relationship between visual improvement at 3 months and the preoperative optical coherence tomography (OCT) parameters including hyperreflective foci, heterogeneous OCT reflectivity, mean levels of OCT reflectivity and height of foveal cystoid spaces. Twenty-three eyes without preoperative hyperreflective foci in the foveal cystoid spaces had significantly greater improvement in the logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 3 months than 43 eyes with foci (P = 0.006). That was similar to the greater reduction in CSF thickness in eyes without lesions after treatment at the same time point (P

Purpose To investigate whether baseline optical coherence tomography (OCT) parameters can predict the treatment frequency of intravitreal ranibizumab (IVR) injections during the first year in patients with diabetic macular edema (DME) treated with pro re nata (PRN) IVR injections. Methods We retrospectively reviewed 68 eyes of 63 patients with center-involved DME who received IVR injections for 12 months or longer according to three monthly IVR injections followed by the PRN dosing. We measured the mean retinal thicknesses in the individual subfields of the Early Treatment Diabetic Retinopathy Study grid and evaluated the qualitative and quantitative parameters on OCT sectional images. We investigated the relationship between these OCT parameters at baseline and the number of IVR injections during the 12-month follow-up. Results Three loading doses were administered to 10 eyes; four to seven annualized IVR injections were administered to 34 eyes. The number of eyes that received IVR injections decreased gradually until month 6 and was almost constant from months 7 to 11. No relationships were seen between the treatment frequency and baseline systemic factors and the ophthalmic examination findings. Univariate analyses showed that the number of IVR injections during the first year was associated with the mean retinal thickness in the individual subfields and the transverse length of the disrupted external limiting membrane (ELM) and ellipsoid zone of the photoreceptors. Multivariate analysis showed a significant association with the thickness in the inferior subfield alone. The treatment frequency during the 12-month follow-up was not correlated with improved visual acuity but was associated with the decrease in the central subfield thickness and disrupted ELM. Conclusion The retinal thickness in the inferior subfield predicts the treatment frequency during the first year in eyes with DME treated with PRN IVR injections.

PURPOSE Adaptive optics scanning laser ophthalmoscopy (AO-SLO) is a noninvasive technique that allows for the direct monitoring of erythrocyte aggregates in retinal capillaries. We analyzed the retinal hemorheologic characteristics in normal subjects, diabetic patients without diabetic retinopathy (NDR), and diabetic patients with nonproliferative diabetic retinopathy (NPDR), using spatiotemporal (ST) blood flow images to visualize blood corpuscle trajectory. METHODS AO-SLO images of the parafoveal capillary network were acquired for three groups: 20 healthy volunteers, 17 diabetic patients with NDR (8 type 1 and 9 type 2 patients), and 10 diabetic patients with NPDR (4 type 1 and 6 type 2). The erythrocyte aggregate velocity assigned to a relative cardiac cycle and the elongation rate of the erythrocyte aggregate were calculated. RESULTS Careful observation revealed that flow velocity fluctuations were found with higher frequency in diabetic patients than in normal subjects. The total average velocities were 1.26 ± 0.22 mm/s in the normal group, 1.31 ± 0.21 mm/s in the NDR group, and 1.63 ± 0.35 mm/s in the NPDR group. The average velocities of the NPDR group were higher than those in the normal (P = 0.001) and NDR (P = 0.009) groups. The average elongation rates of the 3 groups were 0.67 ± 0.20, 0.39 ± 0.19, and 0.33 ± 0.11, respectively. Elongation rate differed significantly between the normal and NDR (P = 0.003) groups as well as the normal and NPDR (P = 0.001) groups. CONCLUSIONS AO-SLO can be used to detect retinal hemorheologic changes in the early stages of diabetic retinopathy.

Purpose To compare the characteristics of macular and extramacular white spots on wide-field swept-source optical coherence tomography angiography (SS-OCTA) and optical coherence tomography (OCT) images in diabetic retinopathy (DR). Methods We retrospectively reviewed 107 eyes of 64 patients with DR, of whom nominal 12 × 12 mm SS-OCTA images centered on the optic disc and ultrawide field photographs were acquired. White spots on fundus photographs corresponded to hyperreflective lesions in the superficial en-face OCT images, and the characteristics of these white spots were investigated. We compared such OCT findings with the vertical and horizontal extents of nonperfused areas (NPAs) on OCTA images. Results We observed 136 white spots and corresponding hyperreflective lesions in 49 eyes. The hyperreflective lesions in the extramacular areas had greater areas (P < 0.001) and more frequently spanned from the nerve fiber layer to the outer plexiform layer (P < 0.001), while those in the macula were superficial. All of macular hyperreflective lesions were accompanied with nerve fiber layer defects, whereas only 18 (15.4%) of 117 extramacular lesions had them (P < 0.001). Comparative studies showed that most extramacular hyperreflective lesions corresponded to the NPAs in the whole layers on OCTA images, compared to the lamellar NPAs of the superficial layer in most of the macular lesions (P < 0.001). The NPAs extended to the peripheral side more frequently in the extramacular hyperreflective lesions compared with macular lesions (P < 0.001). Conclusions This study proposed that most of the extramacular white spots may be discriminated from macular spots with respect to diabetic NPAs on OCTA images.

To evaluate whether baseline titers of anti-fumarase antibody are associated with visual prognosis after anti-VEGF treatment for diabetic macular edema (DME).In this retrospective study, we investigated 52 eyes of 52 DME patients who received intravitreal injections of anti-VEGF drugs (ranibizumab or aflibercept) after blood sampling at baseline. Optical coherence tomography (OCT) images were obtained at every monthly visit. The serum titer of anti-fumarase antibody at baseline was measured using ELISA. We evaluated the relationship between the titer of anti-fumarase antibody at baseline and visual acuity (VA) improvement at 12 months.The serum titer of anti-fumarase IgG was related to the logMAR visual acuity (VA; R = 0.329, P = 0.017) and the disrupted ellipsoid zone (EZ; R = 0.364, P = 0.008) at baseline. The titer of this autoantibody was not associated with logMAR VA (R = -0.007, P = 0.980) but was associated with VA improvement (R = 0.465, P0.001) at 12 months upon anti-VEGF treatment. The transverse length of the disrupted EZ line was shortened at 12 months (P0.001), and restoration of the EZ line was correlated to the autoantibody titer (R = 0.396, P = 0.004) compared with the decrease in central subfield (CSF) thickness. Multivariate analysis showed that pretreatment logMAR VA (β = 0.296, P = 0.045) and the autoantibody titer (β = 0.328, P = 0.017) were associated with VA improvement after anti-VEGF treatment. In contrast, the titer was not associated with logMAR VA at 12 months.Anti-fumarase antibody is a novel serum biomarker predicting better functional efficacy of anti-VEGF treatment for DME.

Diabetes induces microvascular diseases including diabetic retinopathy and choroidopathy which reciprocally promote the pathogenesis, although optical coherence tomography images of diabetic choroidopathy remains to be documented. Here we evaluated the qualitative characteristics of choroidal vascular lesions in patients with diabetes and their association with diabetic retinopathy on swept-source optical coherence tomography (SS-OCT) images. We retrospectively reviewed 110 consecutive eyes of 110 patients with diabetes and 35 eyes of 35 healthy subjects for whom SS-OCT images (6x6-mm scans centered on the fovea) of sufficient quality were acquired. The curve of chorioretinal sections was flattened using Bruch's membrane as a reference surface, followed by generation of en-face images. We characterized choroidal vascular lesions and evaluated their association with the logarithm of the minimum angle of resolution visual acuity (logMAR VA), retinal and choroidal thicknesses, and diabetic retinopathy severity. En-face SS-OCT images showed unvisualized vessels in Sattler's layer in 33 eyes (30.0%). Focal narrowing was seen in choroidal vessels in Haller's layer in 56 eyes (50.9%). The choroidal vessels ended in the superficial or middle portion of Haller's layer, referred to as vascular stumps, in 20 eyes (18.2%). Diabetic eyes had these findings more frequently than nondiabetic eyes. The subfoveal choroid was thicker in eyes with focal vascular narrowing and vascular stumps than in eyes without such lesions. Vascular stumps in Haller's layer were significantly related to diabetic retinopathy severity, logMAR VA, and central retinal and choroidal thicknesses. These novel findings on SS-OCT images would promote the better understanding of complicated pathogenesis in diabetic retinopathy and choroidopathy.

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 × 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 ± 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.

Purpose: To characterize white dots in diabetic retinopathy (DR) and their association with disease severity using ultra-wide-field scanning laser ophthalmoscopy. Methods: We randomly selected 125 eyes of 77 patients (25 eyes from individual categories of the international classification of DR severity) for which ultrawide field photographs were obtained. We characterized white dots, which were delineated by higher signal levels on green but not red laser images, and evaluated the relationship between the number of white dots and the international severity scale of DR. Results: Most white dots were located in nonperfused areas, and the number of total white dots was significantly correlated to that of dots in nonperfused areas. White dots corresponded to microaneurysms around the boundary between nonperfused areas and perfused areas or unknown lesions in nonperfused areas. Eyes with DR had significantly more white dots than those with no apparent retinopathy. The numbers of white dots in moderate nonproliferative diabetic retinopathy (NPDR) or more severe grades were significantly higher than in mild NPDR. The area under the receiver operating characteristics curve (AROC) analyses demonstrated that the number of white dots had the significance in the diagnosis of DR (0.908-0.986) and moderate NPDR or more severe grades (0.888-0.974). Conclusions: These data suggest the clinical relevance of white dots seen on ultrawide field images in the diagnosis of the severity of DR.

PURPOSE To investigate morphologic changes on spectral-domain optical coherence tomography (SD-OCT) images in nonperfused areas (NPAs) in diabetic retinopathy (DR). METHODS One hundred eight consecutive eyes of 80 patients with diabetic ischemic maculopathy 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's layer were characterized on the vertical sectional images of SD-OCT. These findings were compared 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 an indistinct boundary between the NFL and GCL/IPL in DR, regardless of high or moderate OCT reflectivity. The total transverse length of the NPAs was correlated positively with that of the areas with no boundary between these layers in all 108 eyes (R = 0.860, P < 0.001). Sixty-four eyes that had center-involved diabetic macular edema (DME) also had a significant association between them (R = 0.764, P < 0.001), and the most significant correlation was seen in eyes without DME (R = 0.955, P < 0.001). The macular transverse length of the areas with no boundary between the NFL and GCL/IPL was associated modestly with the logMAR VA (R = 0.334, P < 0.001). The indistinct Henle's layer on SD-OCT images often was delineated specifically in the NPAs rather than in the perfused areas. CONCLUSIONS Nonperfused areas were associated significantly with the absence of a boundary between the NFL and GCL/IPL on SD-OCT images in DR.

Purpose To evaluate the relationship between lamellar capillary nonperfusion on optical coherence tomography angiography (OCTA) images and neuroglial changes on structural optical coherence tomography (OCT) images in diabetic retinopathy (DR). Methods We retrospectively reviewed 101 consecutive eyes of 69 patients with DR. OCTA and OCT images within a 3 × 3-mm square centered on the fovea were acquired simultaneously. The nonperfused areas (NPAs) in the superficial capillary layer (sNPA) (from the nerve fiber layer [NFL] to the inner plexiform layer [IPL]), the deep layer (dNPA) (corresponding mainly to the inner nuclear layer [INL]), or both layers (bNPA) were measured individually along 10 transverse lines. The corresponding lamellar neuroglial changes also were evaluated on OCT images. Results The transverse lengths of the sNPA, dNPA, and bNPA were 2.34% (interquartile range, 0.81-5.55), 0.61% (0-1.99), and 5.96% (4.02-10.88), respectively. The length of the sNPA was correlated significantly with the lengths of no boundary between the NFL and ganglion cell layer (GCL)/IPL and the spots with inverted OCT reflectivity in the sNPA. The transverse length of the dNPA was associated with the length of cystoid spaces in the INL or Henle's fiber layer (HFL) in the dNPA. There was a significant correlation between the transverse lengths of the bNPA and no boundary between the NFL and GCL/IPL within the bNPA. Conclusions Systematic evaluation of the OCTA-OCT association showed structural changes in the neuroglial tissues corresponding to the lamellar NPAs and suggested the feasibility of layer-by-layer evaluation of the capillary nonperfusion in DR.

To investigate macular morphology on spectral-domain optical coherence tomography (SD-OCT) images after microincision vitrectomy for vitreous hemorrhage associated with proliferative diabetic retinopathy (PDR). In this retrospective case series, 69 eyes (57 consecutive patients) that underwent 23-gauge microincision vitrectomy for vitreous hemorrhage due to PDR were investigated. Qualitative and quantitative characteristics on SD-OCT images [central retinal thickness, external limiting membrane (ELM), and the ellipsoid zone, epiretinal membranes involving the fovea, and hyperreflective foci at the fovea] were assessed 6 months postoperatively. Their association with the logarithm of the minimum angle of resolution visual acuity (logMAR VA) was evaluated. The ELM was disrupted in 15 and the ellipsoid zone in 27 eyes, and associated significantly (P

PURPOSE. To propose a new method to quantitatively and comprehensively evaluate photoreceptor-RPE complex alterations on spectral-domain optical coherence tomography (SD-OCT) imaging in eyes with diabetic macular edema (DME). METHODS. Spectral-domain OCT images from a consecutive series of 90 eyes in 79 patients with DME and 30 healthy eyes in 30 volunteers were analyzed retrospectively. The subfoveal area covering the photoreceptor layers was skeletonized and the orientation of the segmented lines was termed ‘‘parallelism,’’ which reflects image complexity. Photoreceptor layer status at the fovea was categorized by graders, including continuity of the external limiting membrane (ELM) line, inner segment ellipsoid line, and the presence of hyperreflective foci in the outer retinal layers. The relationships among parallelism, visual acuity, and photoreceptor layer status were evaluated. RESULTS. Parallelism was significantly lower in eyes with DME than in normal eyes (P < 0.0001), and correlated strongly with visual acuity in eyes with DME (R ¼� 0.592; P < 0.0001). Eyes with an intact inner segment ellipsoid line or ELM line had significantly better visual acuity (VA) and higher parallelism than eyes with a discontinuous or absent inner segment ellipsoid line or ELM line. Parallelism was significantly higher (P < 0.0001) and logMAR VA significantly better (P < 0.0001) in the group without hyperreflective foci in the outer retinal layers than in the group with hyperreflective foci in the outer retinal layers. CONCLUSIONS. Parallelism has the potential to reflect structural changes of the photoreceptor layers in DME.

The effect of interpolation and super-resolution (SR) algorithms on quantitative and qualitative assessments of enlarged optical coherence tomography (OCT) images was investigated in this report. Spectral-domain OCT images from 30 eyes in 30 consecutive patients with diabetic macular edema (DME) and 20 healthy eyes in 20 consecutive volunteers were analyzed. Original image (OR) resolution was reduced by a factor of four. Images were then magnified by a factor of four with and without application of one of the following algorithms: bilinear (BL), bicubic (BC), Lanczos3 (LA), and SR. Differences in peak signal-to-noise ratio (PSNR), retinal nerve fiber layer (RNFL) thickness, photoreceptor layer status, and parallelism (reflects the complexity of photoreceptor layer alterations) were analyzed in each image type. The order of PSNRs from highest to lowest was SR > LA > BC > BL > non-processed enlarged images (NONE). The PSNR was statistically different in all groups. The NONE, BC, and LA images resulted in significantly thicker RNFL measurements than the OR image. In eyes with DME, the photoreceptor layer, which was hardly identifiable in NONE images, became detectable with algorithm application. However, OCT photoreceptor parameters were still assessed as more undetectable than in OR images. Parallelism was not statistically different in OR and NONE images, but other image groups had significantly higher parallelism than OR images. Our results indicated that interpolation and SR algorithms increased OCT image resolution. However, qualitative and quantitative assessments were influenced by algorithm use. Additionally, each algorithm affected the assessments differently.

To propose a new parameter, "Parallelism," to evaluate retinal layer integrity on spectral-domain optical coherence tomography (SDOCT), and to investigate the association between parallelism and visual function in eyes with idiopathic epiretinal membrane (ERM).Retrospective, observational evaluation of a diagnostic test.We evaluated a consecutive series of 57 eyes of 57 patients with ERM and 30 healthy eyes of 30 volunteers for whom M-CHARTS testing and SDOCT were performed on the same day. OCT images were skeletonized, and the orientation of segmented lines in the image was termed "Parallelism" and was expressed as a value ranging from 0-1 and increasing as the retinal layers ran more parallel with each other. The relationships between parallelism and visual acuity and between parallelism and metamorphopsia score were evaluated.In normal eyes, parallelism was nearly homogeneous and varied slightly with the location. Parallelism in eyes with ERM was significantly lower than that in normal eyes. In the horizontal and vertical scans, parallelism was significantly correlated with visual acuity, horizontal metamorphopsia score, and vertical metamorphopsia score. Parallelism of the center (1 mm) in the horizontal scan was strongly correlated with horizontal metamorphopsia score (R = -0.632; P.0001). Significant negative correlation was found between parallelism and retinal thickness both in horizontal and vertical scans.Parallelism was significantly lower in eyes with ERM than in normal eyes, and correlated strongly with metamorphopsia and visual acuity in eyes with ERM.