In this prospective study, we found that S-NPDR eyes showed a significant decrease macular VD except fovea VD of SCP before PRP. Besides, FAZ area increased significantly. In S-NPDR eyes treated with PRP, VD only changed in fovea. Three months after PRP, the VD in fovea of DCP first increased significantly. Six months after PRP, the VD in fovea of SCP and DCP both increased. And FAZ area had a significant decrease at 6 months following PRP.
Consistent with previous studies (6, 7), our results showed whole en face VD decreased in SCP and DCP(p<0.001) in S-NPDR eyes. It should be noted, however, this change was less remarkable in fovea. In parafovea and perifovea, VD decreased both in SCP and DCP(p<0.001). In fovea, VD of SCP showed a non-significant decrease (17.6%-16.99%, p = 0.7) and VD of DCP decreased from 32.45–27.49% (P = 0.01). Perhaps it was because DR affects the peripheral retina first, and fovea is damaged in the last stage. In addition, fovea is a region which overlies photoreceptors and has a high acuity vision. (8)Another possibility is that relatively preserved fovea VD helps to maintain visual acuity and it may be a self-protective mechanism of retina. Of course, there is another possibility that fovea has fewer capillary than parafovea and perifovea, so the change of VD is not obvious. Further studies are needed to clarify the mechanism. Besides, we had an unexpected finding that fovea VD of SCP did not decreased significantly in S-NPDR eyes(p = 0.7). But fovea VD of DCP decreased significantly (P = 0.01). So far OCTA examinations have been performed on various layers of the retina of DR patients. In the early stage of DR, SCP showed high flow and DCP presented a steep decline of blood flow with increasing DR severity(6, 9, 10). Compared with SCP, blood flow of DCP decreased more steeply with the aggravation of DR. These findings coincide with our result of fovea VD decreased only in DCP. One possible explanation is the self-regulation of SCP. With the progress of DR, SCP retains a certain degree of self-regulation function compared with DCP. Another possible explanation is that the dilated capillaries of SCP, which have increased blood flow and decreased vascular resistance, may contribute a steal phenomenon at DCP.(11)
In S-NPDR eyes which received PRP, fovea VD increased. At 3 months following PRP, fovea VD in DCP increased first(p = 0.03). At 6 months following PRP, fovea VD increased both in SCP and DCP(p = 0.01,p = 0.008, respectively).The changes of VD in S-NPDR eyes which received PRP were consistent to our expectation. However, the mechanism of this observation is not fully clarified. Therefore ,we proposed several hypotheses. The first assumption we put forward is that PRP may redistribute the circulation of ocular. It is generally accepted that laser energy is mainly absorbed by retinal pigment epithelium (RPE), destroys RPE and photoreceptor cells, and injures surrounding retina and choriocapillaris. Both in retina and choroid, capillary dropout in the areas of laser scars(12). There are some studies have suggested that choroidal vessels in the untreated macular area increased after retinal peripheral photocoagulation(13, 14). For example, Takahashi reported PRP may increase choroidal blood flow in fovea in eyes with severe diabetic retinopathy (14). So, it is also possible that fovea VD in retina increased after PRP. Histological studies should be performed to prove this assumption. The second assumption is the recanalisation occurred in fovea vascular after PRP. As we all know, DR is a form of microangiopathy which accompanied by obstruction of capillaries. (15) Several ophthalmologists have demonstrated the occurrence of capillary revascularization(16, 17). Rema Mohan and Evam Kohner reported a case which demonstrated the occurrence of capillary revascularization in a previously avascular area of the retina in a patient with advanced diabetic eye disease after extensive photocoagulation. Meanwhile, the vessels are in the plane of the retina and do not have the appearance of new vessels(16). By optics scanning light ophthalmoscopy, Chui, T.Y. observed capillary recanalized and remained perfused in fovea (17). These examples illustrated macular VD is reversible and it is possible that there are partially reversible components in DR. Thus ,we hypothesized that PRP may promote the recanalization of fovea microvascular. More studies are needed to verify these assumptions.
Interestingly, both fovea VD of SCP and DCP increased ,but the enhancement of DCP was more notable and earlier. In our investigation between S-NPDR eyes and normal eyes, S-NPDR eyes showed a significant decrease in fovea VD of DCP(p = 0.01),while fovea VD of SCP had no significant change(p = 0.7). Besides, as we have mentioned, many previous studies have suggested microvascular changes occur at DCP earlier than SCP in DR (6, 9, 10). These above two points may help explaining the phenomenon that DCP is more susceptible to PRP. Previous studies together with our observations suggest a role of DCP in evaluating therapeutic effect and monitoring DR progression.
Furthermore, we found FAZ area in S-NPDR eyes increased (p = 0.05) before PRP. At 6 months following PRP, FAZ area decreased (p = 0.04). In DR, an increase in FAZ area caused by capillary alteration has already been shown and it is in line with our finding(18). The FAZ is a specialized region of the human retina which is capillary-free and approximates the region of highest cone photoreceptor density and oxygen consumption. (19) It is well known that diabetes induces microvascular diseases including not only retinopathy but also choroidopathy ,and the disrupted choroidal circulation also has clinical relevance and contributes to the pathogenesis. Cells in FAZ are principally nourished by the choroid and during physiologic conditions the choroidal circulation is able to meet the metabolic demands of the FAZ(20). And the severity of DR is associated with enlarged FAZ area(21). Our finding that FAZ area decreased after PRP suggests PRP could reverse the progression of DR. Consequently, FAZ area may be a marker for monitoring the therapeutic effect in DR.
Before our study, Fawzi et.al studied 10 DR eyes and found VD decreased only in middle capillary plexuses which is located between SCP and DCP after PRP(22). But they only studied whole en face VD of retina and ignore different change in different region of macula and FAZ area.
Of course, there are several limitations in this study. Firstly, it is impossible for OCTA machine to avoid all of artifacts and segmentation errors of retina, particularly in eyes with poor vision. To reduce the effect of artifacts and segmentation errors, manual adjustments were performed to segment retina and edge FAZ in every image. Secondly, during our follow-up period, five eyes appeared cystoid macular edema. Some previous studies reported a decrease of macular VD in patients with macular edema.(23, 24) So we supposed that macular edema will not make VD decreased. In addition, anti-VEGF therapy has been widely applied in recent years and has achieved short-term returns. However, anti-VEGF therapy needs high costs, regular follow-up and it is still to be studied whether it will relapse after anti-VEGF withdrawal. If we can combine anti-VEGF and PRP, the macular edema after PRP may be inhibited. We are also carrying out relevant research. Last but not least, the patient numbers in our study was still limited. Future studies with larger samples are needed to verify our results.
In summary, by compared with healthy eyes, we found macular VD decreased in S-NPDR eyes, and the decrease of fovea VD is not as significant as parafovea and perifovea. After PRP, only fovea VD increase, especially in DCP. It suggests us fovea VD could be a possible predictor of the effectiveness of PRP. In addition, FAZ area decreased at 6months after PRP. It suggested FAZ area may also help in the assessment of treatment efficacy. Our study provided a new angle to the study of mechanisms of PRP and further work is needed to understand the effect of PRP better.