Using OCTA, quantitative analysis with automatic binarization method has been increasingly employed to analyze CC flow changes in some chorioretinal disorders, such as dry age-related macular degeneration and CSC, providing reproducible and objective data7,8,11. Excluding the masking artifacts of SRF and RPE clumping, PED could help increase the reliability of the quantitative assessment in resolved CSC 2,11. In previous studies, assessment of CC flow alterations in affected eyes showed a recovery after treatment of PDT7,13,14,16, which is consistent with our results of the reduced FSV at 6-m follow-up compared to 1-m follow-up. However, in this study, the FSA in affected eyes retained higher at 6-m follow-up compared with healthy controls, which indicated that CC attenuation might remain long after the treatment of half-dose PDT, contrary to previous OCTA studies which showed that CC flow returned to normal after half-dose PDT treatment13,14,16. A series of other follow-up investigations showed that reduced SFCT on EDI-OCT in affected eyes remained higher than healthy controls1, and choroidal vascular hypermeability on ICGA persisted in some cases even after the SRF had resolved completely17,18. The remaining choroidopathy observed after half-dose PDT could potentially be attributed to the primary pathogenesis of CSC and/or the therapeutic effects of PDT.
It has been postulated that CSC may be an ocular condition caused by a systemic disease that involves choroidal circulation1, which could be potentially supported by previous results of some systemic risk factors1 and abnormalities of CC and SFCT in self-resolved CSC eyes and unaffected fellow eyes 11,19-21. Similarly, our study demonstrated that FSV values in unaffected eyes of CCSC were higher than those in healthy individuals, and remained unchanged over time. As proposed by Nicolo, M. 19, these CC alterations in asymptomatic eyes might be in the early stage of the same condition of CSC2,11,19. Previous studies also detected punctated hyperfluorescent spots using ICGA in most contralateral eyes of CSC and PCV, which might be a subclinical manifestation of increased choroidal hypermeability and intrachoroidal hydrostatic pressure17,22. And these zones on OCTA with reduced CC flow have been found to be anatomically correlated with pathologically dilated Haller layer vessels on EDI-OCT2. In our study, compared to unaffected eyes, FSV in affected eyes was significantly higher at 1-/3-m follow-up, but not at 6-m follow-up. We speculated that the abnormal vascular situation in the CC layer in affected eyes of CCSC might recover to a subclinical condition equivalent to that of the contralateral unaffected eyes, which needs to be validated by longitudinal investigations with larger sample size.
In order to evaluate the early CC alterations in response to half-dose PDT in CCSC, qualitative observation was performed and three CC patterns at one week after PDT have been documented in the present study. Out of the affected eyes, 75.0% (21/28) showed favorable recovering signs of increased flow signals and decreased dark areas (Fig. 3), while 21.4% (6/28) exhibited worse CC ischemia (Fig. 5), which we have previously documented as transient CC ischemia in another cohort13. Demircan et al.16 showed that the transient CC ischemia may occur as early as three days after half-fluence PDT. Furthermore, 3.6% (1/28) of the eyes demonstrated transient appearance of exuberant neovascularization network within CC level (Fig. 4). Using OCTA, the direct action of PDT on the CC occlusion could be visualized in vivo during follow-up13,14,16. Post-treatment choroidal hypoperfusion was largely reported with evidence of hypoperfusion on traditional angiography23 in the treatment of neovascular age-related macular degeneration with full PDT, which might be related to the preferential aggregation of verteporfin in the lesions23.
The repair mechanisms of surviving endothelial cells and the recanalization processes of novel channels within previously occluded capillaries after PDT treatment remain unclear1. In addition to the possibility that CC flow recovers from the released pressure of decreased SFCT owing to the therapeutic effect of PDT2,11, it can be speculated that the damaged choroidal endothelial cells and RPE cells in PDT-treated areas may contribute to the release of VEGF24,25, and an imbalanced stimulatory and inhibitory condition for neovascularization formation could be compromised by PDT-related hypoxia and ischemia25,26. However, the process of recanalization could, to some extent, contribute to the formation of CNV 26. Particularly, two eyes with early CC ischemia, in this cohort, exhibited transient (Fig. 4) and persistent (Fig. 5) appearance of type I CNV, consisting with the morphologic characteristics of neovascularization networks within CC level in previous OCTA-related studies20,27,28. However, it is controversial that these suspected secondary CNV within CC level may contribute to the CC atrophy and the anterior displacement of medium-sized choroidal vessels with segmentation artifacts that masquerade as CNV24. Moreover, type I CNV has been well documented as the most common subtype of secondary CNV in the natural course of CSC1,6,29, which should also be taken into account while studying PDT-related CNV30. What makes it more controversial is that most of the previous studies of CSC related CNV were based on patients with heterogeneous treatment histories of PDT or laser photocoagulation20,28-30. Longitudinal OCTA observation would thus help to comparatively follow these lesions to better understand how they behave.
There are some limitations in our study including its retrospective nature, the relatively small number of subjects. And considering the shortage of quantitative method of binarization that limited our ability to assess FSV in affected eyes at the time point of pre-PDT and at the early stage of post-PDT owing to the shadowing artifacts of unresolved subretinal fluid7, we only compare the value of FSV between the time point of 1m and 6m after the treatment of PDT, using the related samples Wilcoxon test. And we ought to record the change terms of exact number of lines or letters in BCVA in this study, which may be more clinically relevant. Our results may underestimate the occurrence of these transient alterations of ischemia and neovascularization occurred within two intervals or outside the imaging area of OCTA. We believe that the actual value of FSV may be higher since patients with SRF were excluded in quantitative assessment, and the choriocapillaris in these patients was certainly abnormal. Although the FSV value was positively correlated with age in healthy controls in consistence with aging physiological changes of CC8,11, the dynamic nature of CC flow changes with time should also be taken into consideration in analysis. In addition, the correlation between SFCT and FSV has not been established in this cohort, nor in other reports31. It might be due to the relatively small sample size, or that SFCT generally assesses choroidal thickness and both pathologically dilated vessels and increased stromal contribute to the increase of SFCT. Future studies should further evaluate the correlation of FSV with other more specific indicators such as choroidal vascularity index (CVI)3.