To report outer retinal structural changes associated with macular capillary nonperfusion at the level of deep capillary plexus (DCP) in diabetic patients.
Prospective observational cross-sectional study.
The study included 14 eyes of 10 patients who were diagnosed as having diabetic retinopathy. To study the outer retina and localize areas of capillary nonperfusion at the superficial (SCP) or DCP, we used the spectral-domain optical coherence tomography (SDOCT) device (RTVue-XR Avanti; Optovue Inc, Fremont, California, USA) with split-spectrum amplitude-decorrelation angiography (SSADA) software for optical coherence tomography angiography (OCTA). Two independent masked graders (F.S. and A.A.F.) qualitatively evaluated SDOCT scans as either normal or having outer retina disruption. The angiographic images were examined to define the presence and location of capillary nonperfusion.
Eight eyes showed outer retinal disruption on SDOCT that co-localized to areas of enlarged foveal avascular zone, areas of no flow between capillaries, and capillary nonperfusion of the DCP. Six eyes without outer retinal changes on SDOCT showed robust perfusion of the DCP.
Using OCTA, this study shows that macular photoreceptor disruption on SDOCT in patients with diabetic retinopathy corresponds to areas of capillary nonperfusion at the level of the DCP. This is important in highlighting the contribution of the DCP to the oxygen requirements of the photoreceptors as well as the outer retina in diabetic macular ischemia.
The human macular vascular supply is a complex system composed of 3 interconnected capillary plexuses: the superficial capillary plexus (SCP) lies in the retinal nerve fiber layer, while the middle (MCP) and deep capillary plexus (DCP) are located at the inner and outer borders of the inner nuclear layer, respectively. This complex vascular arrangement leaves the fovea (foveal avascular zone; FAZ) and the outer retina avascular, with their oxygen demand primarily dependent on diffusion from the choroidal circulation. Interestingly, experimental studies have shown that the DCP contributes to photoreceptor inner segment oxygen requirements (10%-15%), particularly during dark adaptation. More importantly, recent experimental evidence from our group suggests that during systemic hypoxia, the inner retinal vascular contribution to the metabolic needs of the outer retina become even more significant, as the choroidal vasculature fails to autoregulate its blood supply in the setting of hypoxia.
Thus, extrapolating from this finding, it is intriguing to question whether the choroidal circulation is able to compensate for retinal capillary ischemia in the setting of diabetic retinopathy (DR). In addition, given the potential for underlying diabetic choroidopathy and the generalized failure of autoregulation, it is likely that the photoreceptors are in a state of chronic, unmitigated hypoxia during diabetes. Supporting this hypothesis, we have recently shown that diabetic capillary nonperfusion can be associated with outer retinal disruption on spectral-domain optical coherence tomography (SDOCT), and proposed that nonperfusion of the DCP in these patients could explain these outer retinal structural changes. Innovative software enhancements in SDOCT have introduced OCT angiography (OCTA), which allows noninvasive visualization of the 3-dimensional blood flow within retinal capillaries including the SCP and DCP, as well as the choriocapillaris. A recent study has shown that OCTA allows depth-resolved visualization of abnormal vascular changes in DR, including neovascularization, microaneurysms, and areas of retinal capillary nonperfusion, with the added advantage of detailed information regarding the individual layers of the retinal capillaries.
In the current prospective study, using OCTA, we sought to further confirm our hypothesis that photoreceptor and outer retinal disruption on SDOCT in diabetic macular ischemia corresponds to areas of capillary nonperfusion at the level of the DCP. To confirm our hypothesis, we examined 1 eyes of 1 diabetic patients, focusing on eyes with outer retinal changes on SDOCT and diabetic macular capillary nonperfusion on OCTA at the level of the DCP.
This study was a prospective consecutive case series of patients examined at the Department of Ophthalmology, Northwestern University, Chicago, Illinois between June 12, 2015 and October 15, 2015. This study was approved by the Institutional Review Board of Northwestern University, followed the tenets of the Declaration of Helsinki, and was performed in accordance with HIPAA regulations. Written informed consent was obtained from all participants.
Inclusion criteria for this study included diabetic patients diagnosed with different stages of DR, ranging from minimal nonproliferative DR (NPDR) to high-risk and treated quiescent proliferative DR (PDR). We also included 1 eye from a healthy, age-matched individual with normal DCP perfusion for comparison with our study sample.
Exclusion criteria included patients with significant diabetic macular edema (DME), diagnosed either clinically or with SDOCT, that disrupted the contour of the segmentation on OCTA, or if the edema was diffuse and obscured the entire outer retinal changes in areas of nonperfusion. We defined DME as central subfield thickening of at least 250 μm (2 standard deviations above average normal thickness). Other exclusion criteria included eyes that had undergone surgical retinal repair or laser treatment within the past 5 years and/or any laser treatment in the area with outer retinal disruption as revealed on SDOCT, as well as eyes that had received intravitreal anti–vascular endothelial growth factor (anti-VEGF) or intravitreal corticosteroids. We also excluded patients with evidence of significant cataracts, graded above nuclear opalescence grade 3 or nuclear color grade 3, in order to avoid optical artifacts that may potentially compromise SDOCT image quality. We excluded eyes with other retinal disease that may contribute to retinal nonperfusion, including arterial branch occlusion of the retina. After image acquisition, we excluded eyes where the OCTA images had movement or shadow artifacts in the area of interest, OCTA signal strength score lower than 50, and eyes with previously undetected cystic changes and macular edema. The original study population included 28 eyes of 14 patients and, after applying the exclusion criteria, only 14 eyes of 10 patients from the original study population were found eligible and are included in the study, as well as 1 healthy (nondiabetic) control eye.
To localize the level of capillary nonperfusion at the SCP or DCP, we used the XR Avanti Optical Coherence Tomography OCTA instrument (Optovue Inc, Fremont, California, USA) with split-spectrum amplitude-decorrelation angiography (SSADA) software. SDOCT images from the same OCTA device, in the same OCT volume, were used to study outer retinal disruption. This instrument has an A-scan rate of 70 000 scans per second and uses a light source centered on 840 nm and a bandwidth of 45 nm. A 3 × 3-mm scanning area, centered on the fovea and/or area corresponding to the outer retinal disruption on SDOCT, was obtained. Two consecutive B-scans (M-B frames), each containing 304 A-scans, were captured at each sampling location and SSADA was used to extract OCTA information. The OCT signal strength score is considered “unacceptable” if the score is less than 40, “acceptable” if the score is between 40 and 50, and “good” if the score is greater than 50. We only analyzed images with a score greater than 50. En face OCT angiograms were segmented to define the SCP, DCP, and choriocapillaris, using the segmentation algorithm by the built-in software.
Two independent masked graders (F.S. and A.A.F.), masked to any associated information, analyzed SDOCT and angiographic images from the OCTA device. The SDOCT scans for each patient were qualitatively evaluated as normal or as having thinning of the inner retina and/or outer retina. Outer retinal changes were defined as focal thinning of the outer nuclear layer (ONL), disruption of the external limiting membrane, disruption of the inner segment–outer segment (IS/OS) junction, or thinning/absence of the OS–retinal pigment epithelium (RPE) junction. Scans in which the presence of macular edema was noted were not considered for the analysis. The OCTA images were examined to define the presence and location of capillary nonperfusion areas and/or reduced capillary density either in the SCP or DCP, which appeared as areas of capillary nonperfusion (nonflow areas wider than 100 μm) on the OCTA.
Incidents of disagreement between graders (3 cases in SDOCT and 1 case in OCTA) were resolved by an open discussion and review of the data to reach consensus. Medical records were reviewed to gather information about systemic renal and hypertension status, visual acuity, data regarding slit-lamp biomicroscopy, and any history of retinal laser treatment or intravitreal injection or surgery.
This study included a total of 14 eyes of 10 patients aged 34-58 years with mean duration of diabetes mellitus (DM) of 12.6 years. A healthy control eye from a 42-year-old subject (nondiabetic) was included for comparison ( Figure 1 ). Eight eyes with DR showed evidence of capillary nonperfusion (nonflow) at the level of the DCP (with or without SCP involvement) in the macula. Six additional eyes with DR and normal DCP, with or without evidence of SCP changes on OCTA, served as controls and did not show any outer retinal abnormalities on SDOCT. The demographic characteristics and ocular findings are summarized in the Table .
|Case Number||Sex/Age, y||DM Type||Duration of DM, y||HbA1c||HTN||HLD||KD||Study Eye||BCVA||DR Stage||Laser Treatment||Diabetes Medication|
|Healthy Control||M/42||–||–||–||No||No||No||Left||20/20 (OU)||–||None||–|
|1||M/41||2||10||11.3||No||No||No||Both||20/20 (OU)||Moderate NPDR||None||Metformin|
|2||F/33||1||26||9||No||No||No||Both||20/20 (OU)||PDR||PRP (OS)||Insulin|
|6||M/42||2||5||7.9||Yes||No||No||Right||20/20||PDR||PRP + focal (OU)||Insulin, liraglutide|
|8||F/52||2||1||7.0||Yes||Yes||No||Both (control)||20/30 (OD), 20/20 (OS)||NPDR||None||Metformin|
|9||F/53||2||0.25||7.2||Yes||Yes||No||Both (control)||20/30 (OD), 20/40 (OS)||NPDR||None||Metformin|
|10||F/46||2||4||6.3||No||No||No||Left (control)||20/20 (OU)||NPDR||None||Glipizide, plioglitazone|
OCTA in 8 eyes showed capillary derangements including an irregular and enlarged contour of FAZ along with reduced capillary density, appearing as areas of capillary nonperfusion (nonflow) of either SCP or DCP or both. Point-by-point correlation between areas of capillary nonperfusion on OCTA showed exact correspondence to outer retinal disruption on B-scan SDOCT.
Based on OCTA image analysis, the 8 eyes were divided into 2 groups. In the first group, 4 eyes of 3 patients ( Figures 2, 3, and 4 ) had mild reduced capillary density or areas of reduced flow intensity suggestive of low flow within the DCP. Group 2 comprised the remaining 4 eyes ( Figures 5 and 6, and Supplemental Figure ; Supplemental Material available at AJO.com ), which had larger zones of complete capillary nonflow at the level of the DCP.