Using OCTA, quantitative analysis with automatic binarization methods 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 and 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 of CC flow after the treatment of PDT7,13,14,16, which was consistent with our results of the reduced value of FSV at 6-m follow-up compared to 1-m follow-up. However, in this study, the value of FSA in affected eyes retained higher at 6-m follow-up comparing with healthy controls, which indicated that CC attenuation might remain long after the treatment of half-dose PDT, contrary to previous OCTA studies suggesting that CC flow return to normal after half-dose/influence PDT treatment13,14,16. A series of other follow-up investigations have also showed that reduced SFCT on EDI-OCT in affected eyes remain higher than healthy controls1, and choroidal vascular hypermeability on ICGA persisted in some cases even after the SRF had resolved completely17,18. While, these 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 the unaffected eyes 11,19-21. Similarly, our study demonstrated that FSV in unaffected eyes of CCSC were higher than those in healthy individuals, and remained statistically 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 have 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 of reduced choriocapillaris flow on OCTA have been found to be anatomically correlated with pathologically dilated Haller layer vessels on EDI-OCT2. Compared to unaffected eyes, FSV in affected eyes, in this study, was significantly higher at 1-/3-m follow-up, but not at 6-m follow-up. We speculated that abnormal vascular situation in the CC layer in affected eyes of CCSC might recover to a subclinical condition similar to that of the contralateral 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 1 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 worsen 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 even occur at as early as 3 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 were 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 repairing mechanisms of surviving endothelial cells and the recanalization processes of novel channels within previously occluded capillaries after PDT treatment remains unclear1. In addition to the possibility that CC flow recovered from the released pressure of decreased SFCT owing to the therapeutic effect of PDT2,11, one could speculate 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, 2 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 on 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. Besides, 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 over time to better understand how they behave.
There are certain limitations in our study including its retrospective nature, the small number of subjects, and the shortage of quantitative method for binarization that limit our ability to assess FSV in early stage and reflect CC alterations of exaggerated flow and dilated CC7. Our results may underestimate the occurrence of these transient alterations of ischemia and neovascularization occur 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 CC in these patients is certainly abnormal. Although the value of FSV 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 when comparing results to those of the contralateral eyes. Besides, correlation between SFCT and FSV has not been established in this cohort, nor in other reports31. It might be related 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 could further evaluate the correlation of FSV with other more specific indicators such as choroidal vascularity index (CVI)3.