The capillary density on 3-mm × 3-mm OCT angiograms was measured in both plexus and compared with the mean density in the 20 healthy nondiabetic eyes. The mean capillary density was reduced in both plexus in DCME eyes compared with healthy nondiabetic eyes (44.98 ± 3.32% vs. 58.43 ± 2.28%, P < 0.0001, and 51.55 ± 3.41% vs. 58.84 ± 2.43%, P < 0.0001, for the SCP and DCP, respectively). No correlation was found between the full CMT and the capillary density of the SCP or that of the DCP (P = 0.84 and 0.79, respectively). The comparison between treated and untreated eyes showed no significant difference in capillary density, CMT, and qualitative grading parameters (Figure 5).
Among the 11 eyes that experienced DCME resolution, the mean capillary density did not change significantly after edema resolution: 43.40 ± 5.1% after DCME resolution in the SCP compared with 43.89 ± 3.6% on the initial OCTA (P = 0.80), and 49.02 ± 5.8% after DCME resolution in the DCP compared with 51.14 ± 4.1% on the initial OCTA (P = 0.33). This stability of the capillary density after edema resolution was observed both in cases of spontaneous resolution and after anti-VEGF treatment. Similarly, after DCME resolution, the areas of resolved cystoid spaces and the nonperfusion areas outside the cystic spaces in all the 11 eyes remained devoid of capillaries. The few capillaries visible in the areas of resolved edema were either the projection artifact of the SCP (Figures 4 and 6) or capillaries already present at the roof of the cystoid spaces (Figure 1). This phenomenon was even more obvious in cases in which the macula became thinner than normal after treatment.
In chronic DCME, capillary changes variably combine some degree of capillary closure and leakage from perfused capillaries and microaneurysms.5 It is likely that vasoregression is the first event in the sequence of DR progression.3,4 Although the exact combination of events has not been identified in humans, animal studies have shown that pericytes first disappear followed by endothelial cells, resulting in acellular capillaries and capillary closure.3,4 As a consequence, glial cell activation and increased local VEGF release result in blood–retinal barrier breakdown of the neighboring capillaries.1 In DCME, capillary closure and leakage from perfused capillaries are thus closely linked. The OCTA technology enables to compare changes in capillary perfusion and structural retinal changes in a dataset acquisition. It was then possible to study the relationship between the capillary density, capillary dropout, and intraretinal cystic spaces induced by capillary leakage. On OCTA, both nonperfusion areas and cystoid spaces appear black without any decorrelation signal. However, cystoid spaces may easily be differentiated from nonperfusion areas by their shape,10 and because they appear identical on structural OCT and on the companion en-face image (Figures 2 and 3).
We found that cystoid spaces were colocalized within nonperfusion areas, especially in the DCP where they were surrounded by a wider area of poor capillary perfusion, suggesting a possible relationship between the capillary dropout and the occurrence of the edema. Furthermore, in this series, no reperfusion occurred in areas of cystoid spaces after DCME resolution. A decrease in capillary density was found in the SCP and DCP in all DCME eyes, without significant change after treatment. Considering these results, it seems unlikely that the cystoid spaces had only displaced laterally the capillaries or reduced their visualization in chronic DCME. It could be assumed that fluid preferentially accumulated in areas of capillary dropout. This is in agreement with findings in retinal vein occlusion showing that edema occurs in areas of poor perfusion in eyes with branch retinal vein occlusion.12,13 However, it could also be assumed that some capillaries were not detected by OCTA because their blood flow was too slow and not detected by split-spectrum amplitude–decorrelation angiography. Thus, nonperfusion areas might either be void of capillaries or show a severely decreased flow signal. In DCME, de Carlo et al10 have reported that the microvasculature reappeared in some cases in the areas of intraretinal fluid after treatment and hypothesized either a reperfusion after anti-VEGF treatment or a displacement of the vessels by the cystoid spaces. We did not find such an evolution. In our cases, we only observed some capillaries located at the roof of the cysts projecting partially into the cystoid spaces and still visible after edema resolution, or some capillaries reappearing with changes in the segmentation plane. In all cases, they were already present at the baseline pretreatment examination. However, it should be noted that our case selection mainly included chronic or recurrent DCME with already well-established areas of capillary nonperfusion. At an earlier stage of the disease, DCME could eventually develop without significant capillary dropout. This relationship between the capillary closure and the occurrence of DCME has previously been stressed in reports on the microaneurysm turnover.14,15 It is well known that microaneurysms develop in areas of acellular capillaries and are the clinical marker for capillary nonperfusion in early DR.16,17 Yet, a high microaneurysm turnover has been associated with a higher risk of DCME development in nonproliferative DR eyes, suggesting also a possible relationship between the capillary nonperfusion and the occurrence of DCME.14,15 Further long-term studies of diabetic eyes with early-onset DCME are needed to clarify the relationships between the progression of capillary dropout and the occurrence of DCME.
We also found that in patients with DCME, the capillary density was less than that found in healthy controls, confirming the findings of the report by Agemy et al18 for DR in general. However, the loss of density capillary was greater in the SCP than in the DCP, which contrasts with the results of Agemy et al. In our series, the capillary density in the DCP was obviously overestimated by AngioAnalytics software for several reasons. First, some reflective areas were falsely interpreted as a correlation signal such as the walls between cystoid spaces or the very small lipid deposits in the cystoid spaces themselves, and overestimated the flow density (Figure 6). Second, projection artifacts of the SCP on the DCP also contributed to a false increase in capillary density in the DCP (Figures 4 and 6).19 However, although until now it was not possible to correlate capillary loss and retinal tissue thinning or disorganization, the retinal capillary density may nowadays be measured, although imperfectly, by OCTA. Future improvements in density measurement software could enable to clarify the relationship between the capillary perfusion, tissue loss, and visual function. It remains to be demonstrated whether the amount of capillary dropout before treatment may have a prognostic value for the functional recovery.
This study had some limitations, including its retrospective design and small sample size. Cases were mainly chronic recurrent DCME, which might not be representative of all types of DCME. The presence of cystoid spaces could have limited the segmentation accuracy and the assessment of capillary changes. False decorrelation signal and artifactual projections of the SCP on the DCP impaired the interpretation of DCP angiograms and the measurement of capillary density. The measurement tool for the vessel density has not been validated in a large series and has no corrections for artifacts. The fact that most patients had previously received anti-VEGF therapy could also have influenced the capillary changes seen; however, the four treatment-naive eyes showed similar capillary changes on OCTA.
In summary, this OCTA study of areas of nonperfusion in chronic DCME shows that cystoid spaces were colocalized within areas of capillary nonperfusion. No capillary reperfusion occurred after DCME resolution. Further studies in early stages of untreated DCME are needed to confirm the relationship between the occurrence of edema and the capillary dropout.
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Keywords:© 2016 by Ophthalmic Communications Society, Inc.
anti-VEGF; capillary density; capillary dropout; capillary nonperfusion; capillary plexus; cystoid macular edema; diabetic macular edema; diabetic retinopathy; optical coherence tomography angiography