In this study, one possible mechanism of the decreased CVI in the eyes with BRVO and ME eyes could be VEGF-related choriocapillaris (CC) regression. Despite our efforts to exclude choroidal changes on disease duration in BRVO and ME by collecting OCT scans at the initial visit, there may be some temporal gaps between the time when an obstruction with ischemia began and when the OCT scan was initially performed. The CVI values could be measured higher if the OCT scans are taken when the obstructions first occur, or when the VEGF concentrations are not elevated enough to cause degeneration of the CC. The role of VEGF as a vasodilator in choroids could be inversely inferred from previous reports that anti-VEGFs act as vasoconstrictors for choroidal supply for one week after the injection.18,19 Therefore, we presume that when exposed to excessive VEGFs over time such as in BRVO and ME, the CC would undergo some structural changes like microaneurysms or constrictions, leading to capillary blockage from the altered hemodynamics. Tee et al.20 reported that the CC diameters, number of CC lacunae, and choroidal arterioles/venules significantly decreased in the retinal VEGF overexpressed transgenic mice model after only a few weeks. As the structural damages were prominent in small vessels, especially CC in that study, it would make sense to regard CC regression as the main reason for decreased CVI in our study rather than large choroidal vessel collapse. Even if CC was too thin layer to have a significant effect on CVI by itself, CC regression would increase the resistance of the overall choroidal vessels, resulting in decreased choroidal blood flow. Aribas et al.21 considered a pressure effect of choroidal congestion as the main cause of decreased CVI and CC flow density in BRVO. However, the supposition differs from ours in that the gradual effect of excessive VEGF on the choroid vascular structure was totally excluded in the report. Of course, the fact that the population of their study was stable patients without ME would contribute a disagreement on the underlying reason of CVI reduction in BRVO ME. Further researches are needed to elucidate a more robust theory of decreased CVI and CC flow reduction in the retinal ischemic condition.
Several optical coherence tomography angiography (OCTA) studies have shown that CC density and flow decreased in RVO and ME and improved after anti-VEGF, or dexamethasone were injected.22,23 A second possible mechanism, as these studies mentioned, could be a shadow effect of the overlapping ME. The two studies above suggested that ME-induced signal attenuation of choroids in SD-OCT results in decreased CC parameters. In our study, the univariate regression analysis showed that only CMT was significantly associated with CVI, supporting the possibility that ME-induced choroidal signal attenuation or mechanical pressure somewhat influenced the calculation of CVI. However, CC regression by lasting BRVO and ME should be highlighted, in regards of decreased CVI because our study used an SS-OCT device, which helps to clearly visualize the choroid by having a longer center wavelength and minimizing RPE-induced signal attenuation.
The increased CVI after anti-VEGF treatment in our study could also be explained by the recovered signal attenuation of choroids as ME decreased. However, we propose that the high concentration of VEGF could trigger an increase of choroidal blood flow two months after the anti-VEGF treatment. Okamoto et al.24 found that in patients with recurrent BRVO and ME, defined as macular thickness over 250 µm after anti-VEGF treatment, choroidal blood flow measured by laser speckle flowgraphy decreased significantly one week after the injection, but increased over time. As 29 patients in our study almost met the criteria of that recurrent group and all of them experienced at least one recurrent episode, our results could be due to more VEGFs impacting on the vasodilatory function in choroids two months after the injection. One possible hypothesis is that retinal VEGF and anti-VEGF compounds could alter RPE permeability, increasing the retina to choroid VEGF gradient. The influx of retinal VEGF to the choroid would increase the choroidal blood flow, resulting in an increased CVI after the anti-VEGF injection. Campa25 reported that the coadministration of anti-VEGFs with VEGF121 or VEGF165 resulted in a marked increase in macromolecular permeability. The second hypothesis is that hypoxia-induced RPE-origin VEGFs, discussed in a report by Arjamaa et al.26, accumulate in choroids over time, even though anti-VEGFs reduce active retinal VEGFs and ME. Some studies have demonstrated that even with consecutive anti-VEGF treatments, retinal ischemia could still be aggravated in patients with central RVO (CRVO).27,28 Therefore, unresolved hypoxia could lead to a high production of RPE-origin VEGF, and this newly produced VEGF might affect the choroid more than the retina two months after treatment.
The SFCT values in our study were only slightly consistent with that of previous studies in that no significant change was found between the BRVO and fellow eyes, but SFCT decreased after anti-VEGF treatment. The result of increased CVI with decreased SFCT after anti-VEGF injection could be explained by fluid shift between choroidal vessel and stroma. In condition of increased vascular resistance due to CC regression, increased choroidal inflow by VEGF would elevate hydrostatic pressure, leading to fluid shift toward stroma. In the contrary, reduced hydrostatic pressure by anti-VEGF injection could be advantageous to maintain intravascular volume, showing the result of increased CVI with decreased SFCT. We also speculate that several factors, including IOP or systemic blood pressure fluctuations, could have affected the SFCT values in our study.13 The exact region of the retinal vessel obstruction could also affect the SFCT.29
For clinical application, we performed a linear regression analysis between the choroidal parameters and logMAR VA two years post disease onset. Although the exact locations of the vein obstruction varied in BRVO, and the degree of ischemia were not necessarily consistent with the final VA, the prognosis of BRVO and ME must be related to the VA after treatment no matter how much recurrence occurs. As the CVI of the contralateral fellow eyes showed the most prominent values among the coefficients of determination, inherent choroidal vascularity could be considered as a buffer system in response to retinal ischemia. Patients with a higher vessel proportion in the choroid were more likely to have an abundant CC, which would supply oxygen and nutrients effectively to the outer retina even in the process of CC regression over the course of BRVO and ME. Khodabandeh et al.30 also reported that visual outcomes were significantly associated with OCTA CC flow in patients with CRVO.
In the additional sub-groups analysis, the most significant correlation between fellow eye CVIs and the degree of ME agreed with the hypothesis that the inherent choroidal vessel portion, the fellow eye CVI, affected the formation of the retina to the choroid VEGF gradient discussed earlier. Some articles have suggested a compartment effect.22,31 This means that if individuals originally had a large amount of vascular component in their choroids, the choroidal VEGF sensitivity might be much higher than in the lower groups, possibly reducing the severity of ME.
There were some limitations to this study. A small number of patients were included in the analysis, and only a single macular scan was used to calculate the CVI. A 3D volume image could be measured using OCTA, which would enable the choroidal vessel components to be calculated as a volume rather than an area.32 Mehta et al.33 introduced methods of OCTA image binarization thresholding and brightness/contrast adjustment. If combined with the new modalities that have enabled ophthalmologists to measure choroidal deep vessel structures beyond the CC layers, OCTA could help to provide more accurate information, such as a volumetric CVI. In addition, as the CVI was manually calculated in our study, newly invented automatic calculation software may help to improve the reproducibility of the CVI measurements. To include a wide range of the ischemic area, we selected the whole choroidal area on the macular scan. However, it might be more useful only to measure the foveal lesions. Further studies should explore a more robust method.
This study revealed the association between BRVO and CVI with SS-OCT for the first time. As it has prognostic value, the concept of using the CVI of the unaffected fellow eye could help to promote the discovery of more elaborate indexes or biomarkers for clinical application, along with the development of new modalities. Considering the choroid vascular component as one of the crucial elements in determining the final visual outcome in retinal vascular disease, we have shown that choroidal measurements could considerably support retinal biomarkers in BRVO and ME.
In conclusion, the reduced CVI in eyes with BRVO and ME suggests that retinal VEGF and ischemic condition may affect choroidal vascularity by altering the CC structure. The CVI of the unaffected fellow eye could be a useful supplementary prognostic biomarker in patients with monocular BRVO and ME.