In this pilot study, we evaluated the long-term effects of mineralocorticoid antagonists on eyes with chronic CSC associated with pachychoroid spectrum disease. We described the impact of EPL on quantitative and qualitative parameters in both eyes using structural OCT and OCTA. In detail, in exudative cCSC eyes, we found a statistically significant improvement in mean BCVA and a decrease in mean SRF height and choroidal thickness at follow-up examinations (6,12, and 48 months). In the non-affected fellow eyes, we analyzed CT and CC FD% before and during EPL treatment. We found a significant reduction in CT and CC ischemia already after 6 months. Importantly, EPL was well tolerated with minimal side effects, none of which required therapy discontinuation.
At present, verteporfin PDT is the most studied treatment option for acute and chronic CSC.17–19 Although infrequent, adverse events reported with PDT use include RPE atrophy, development of CNV, and choroidal ischemia.20,21 In addition, therapy success may be limited in cases with RPE atrophy.20,21 For this reason, oral MR antagonists may provide an important alternative for cCSC treatment.
MR antagonists are well-known drugs in the treatment of cardiovascular diseases.22 EPL is primarily used to treat heart failure and systemic hypertension through its competitive aldosterone-blocking abilities.23 Endogenous mineralocorticoid dysfunction has been described in cCSC patients.24 Moreover, prolonged exposure to increased levels of exogenous and endogenous glucocorticoids plays a role in the pathogenesis of CSC.25 In rats, the administration of corticosteroids causes choroidal thickening and increased expression of MRs, thus suggesting that MR antagonists may be used to treat cCSC.26
Recent reports have described groups of CSC patients treated with EPL.4,27 These studies have frequently been limited in size and follow-up duration. Using MR antagonists (EPL and spironolactone), Bousquets et al.28 have yielded promising results during the 3 months of treatment in terms of BCVA, central macular thickness, and SRF. In a study assessing 28 eyes followed up for 6 months, Gergely et al.29 concluded that patients with cCSC can safely be treated with EPL, because it reduces choroidal permeability with an accompanying SRF resolution and BCVA improvement. In a larger retrospective study analyzing 100 eyes treated with EPL for a mean follow-up of 20.6 months,30 the authors found complete SRF resolution within the first year of treatment, which appeared to be maintained over subsequent years. In agreement with the latter investigation, our study found similar improvements in BCVA and SF resorption within the first year of follow-up. In the patients with total SRF resolution, this effect was maintained at 4 years. Likewise, SFCT did show significant anatomical improvement over 12 months of follow-up. Overall, these findings suggest that maintenance of continuous therapy may be beneficial on anatomical outcomes.
Based on the recent vision of pachychoroid pigment epitheliopathy,31 we also evaluated the non-affected fellow eye of cCSC patients to assess the effects of EPL therapy on CC flow and SFCT. Results on choroidal thickness of non-affected fellow eyes of cCSC patients are still controversial. Ghadialy et al.32 did not find significant SFCT changes in patients treated with MR antagonists; however, only two patients were exclusively treated with EPL. By contrast, Gergely et al.29 showed significantly SFCT reduction in non-affected fellow eyes during the treatment that returned to initial values after therapy discontinuation. Our findings disclosed a significant decrease in mean SFCT as early as 6 months of EPL treatment. Importantly, the significant SFCT decrease was also persisted during the follow-up period. Furthermore, following the theory that the abnormally dilated choroidal vessels cause direct compression of the overlying choriocapillaris, we also analyzed the CC FD % changes in non-affected fellow eyes. We demonstrated that CC perfusion remodels after 6 months of EPL treatment, and it was maintained in the follow up period. Previous papers have focused on the signal changes in CC flow in patients with unilateral CSC following different therapies. Ho et al.33 suggested that both PDT and MLT promote CC flow recovery, confirming that the barrier function of the CC-RPE complex can be impaired, leading to fluid accumulation in CSC cases. Nevertheless, we did not analyze the CC flow of the exudative cCSC eyes to avoid possible OCTA artifacts from SRF and masking effects.
Considering this, we speculate that the significant improvement in OCT and OCTA parameters and that none of the eyes developed SRF during treatment might be due to the reverse effect induced by EPL on choroidal vasodilatation in cCSC patients. Furthermore, we hypothesize that SRF resolution and, maybe, the normalization of choroidal circulation may have a beneficial impact on photoreceptor regeneration, causing BCVA improvement. Based on our long-term results, EPL given continuously may represent a valid approach to avoid further functional/anatomical damage.
As this was a pilot study, the patient numbers were small and sample size planning to ensure an adequate power was not necessary. The most important limitation of the present study is that it was not a randomized prospective investigation in which the patients were randomly distributed between a study group and a control group not receiving EPL. A control group would be necessary to differentiate EPL impact on the natural history of the disease and identify the exact therapeutic regimen.
In conclusion, we examined the long-term anatomical and visual outcomes in both eyes of patients continuously treated with EPL for unilateral exudative cCSC. OCT and OCTA results suggest that the beneficial effects of EPL on cCSC occur within the first year. In addition, in patients with complete SRF resolution, this effect was maintained after 4 years. Future randomized prospective case-control trials are necessary to confirm our findings.