In the last five years many papers showed that eplerenone is a safe and effective treatment option in chronic CSCR patients, mainly through reversing the choroidal vasodilatation that results in resolution of subretinal fluid.1, 7–13
In this study, we have chosen fluid resolution as the biomarker of good response instead of the change in visual acuity, because neuroretinal re-attachement is not always accompanied by visual acuity improvement. Besides the presence of subretinal fluid several other factors are influencing the visual prognosis, such as the disruption of ellipsoid zone, disruption of the ELM, thinning of the ON layer, hyperreflective foci in the retinal layers and the severity of RPE atrophy. 1, 15
Recent studies reported different predictors of treatment response in this new therapy. In our previous prospective study we found that in eplerenone treated CSCR patients baseline choroidal thickness was a positive predictive factor for subretinal fluid decrease, results which were recently supported by Bousquet et al. who found that a thick choroid at baseline is associated with treatment response.13,14 As for neuroretinal morphological changes Cakir and coworkers reported that CSCR patients with intact RPE and intact ellipsoid zone had better BCVA after eplerenone treatment.15 Sacconi et al. reported possible biomarkers on ICG-angiography and OCT-angiography which could predict the response to eplerenone treatment in CSCR patients.16 They found that the absence ofchoroidal neovascularization (CNV) on OCT-angiography and the presence of hot spot on ICG-angiography were associated with a good response to treatment, with 58% of the patients (17 out of 29) showing a complete resolution of the subretinal fluid at the end of the 13 week treatment.16 Interestingly patients with CNV and hotspot also showed a moderate response to eplerenone therapy.16
In our study population ellipsoid zone integrity at baseline was found to be a crucial and independent predictor of good anatomical treatment response as defined by complete and stable resolution of subretinal fluid. At the same time, hyperreflective foci in the OS and ON layer showed a significant negative correlation with subretinal fluid resolution.
Within the outer retina, a hyperreflective band—previously thought to represent the photoreceptor inner/outer segment (IS/OS) junction, more commonly referred to now as the inner segment ellipsoid—can be observed on SD-OCT. The integrity of this layer has been found to be of high clinical importance in the diagnosis and prognosis evaluation of various surgical and medical retinal diseases. The absence or disruption of this layer has been found to be associated with lower visual acuity and poor visual prognosis. An intact ellipsoid layer was identified as a significant biomarker for macular hole, epiretinal membrane, and retinal detachment surgery, as well as eyes with wet age-related macular degeneration, retinal vein occlusion or diabetic macular edema.17 Damage of ellipsoid zone integritywas described in the natural course of CSCR, which also correlates with the macular function evaluated by microperimetry.18,19 In several SD-OCT studies, the ellipsoid zone was not visible in eyes with acute serous detachment, though it did became visible after its resolution.18, 20, 21 Koo et al. suggested that the membranous stack of the photoreceptor segment is no longer perpendicular to the incoming OCT beam in acute neurosensory retinal detachment, as the highly back-reflecting signal at the IS/OS seems to be absent in the area of detachment.22 Accordingly, even if an eye with active CSCR does not show a distinct ellipsoid zone, good visual acuity is often obtained when the subretinal fluid is resorbed.22, 23 In contrast, in our study baseline ellipsoid layer damage was significantly associated with poor treatment response for mineralocorticoid antagonist therapy. We think that the reason for this incongruity is that only eyes with a chronic form of the disease were included in this study. In these cases,—as the IS/OS line is a hallmark of integrity of outer photoreceptor layer—ellipsoid integrity can show us that photoreceptors are preserved despite their long-lasting separation from retinal pigment epithelium and choroidal layers. In an experimental animal model of retinal detachment a significant decrease in the number ofphotoreceptors nuclei in the outer nuclear layer was observed at 1 month, followed by outer plexiform layer (OPL) degeneration within 50 days due to necrosis of cell processes and synaptic terminals.24 According to Piccolino et al.’s study, this is not the case in CSCR eyes where SD-OCT does not show atrophy of the OPL in detachments lasting several months, with a severe loss of the photoreceptor layer only being observed in patients with symptoms lasting more than one year.21 Our patients also had quite good baseline visual acuity despite the chronic presence of subretinal fluid, so for this reason the change in visual acuity will be smaller.
Hyperreflective foci in the OS and ON layer, as observed in all patients in the poor responder group, were the other significant biomarker predicting poor treatment response in our study population. These abnormal features of the OS and ON layer were earlier reported on the time-domain Stratus OCT images as a granulated profile of the outer border of neurosensory retina, mostly attenuated to the chronic or recurrent form of the disease.21 Later in SD-OCT studies these hyperreflective foci in the OS and ON layer were identified in as many as 65% of chronic CSCR eyes in the area of serous retinal detachment20, 25 and it co-localized with hyperautofluorescent areas on FAF images.26,27,28 The nature of these dots vary depending on their location.28 In the subretinal space these dots are thought to be macrophages and microglia activated by the photoreceptor outer segments shedding.27 Concentration of protein-like compounds, fibrin or lipids could also be identified as dots.25 Recently the observation of these hyperreflective foci in active and resolved CSCR eyes with adaptive optics scanning light ophthalmoscopy supported the hypothesis that they are cellular in nature, corresponding to activated microglia cells or macrophages.29 Their presence were found to be correlated not only to disease duration, but also to poorer final visual acuity.30,31
Interestingly, despite the fact that both biomarkers found in our study population were earlier attenuated to the chronic form of CSCR, no significant difference was found in disease duration or phenotype (recurrent or continuous, mono or multifocal) between the good and poor responder groups. One explanation for these results could be that in recurrent and chronic CSCR the duration of neurosensory detachment is often doubtful. The other important factor is that until now no consensus existed over the duration threshold that differentiates acute and chronic CSCR. In most published reports, it was arbitrarily set as being between 3 to 6 months and was used as a limit in interventional studies to determine the appropriate timing for treatment, in order to avoid self-resolution cases. As a result of which we consider that a consensual definition of the various clinical subtypes of CSCR is needed as their exact limits are critical in the determination of clinical trial design. We are of the opinion that morphologic assessment might better differentiate acute from chronic forms given that the duration of the disease seems to be an interval rather than an exact time following the appearance of the disease. These data suggests that the disease duration does not affect directly the response to eplerenone treatment. Previous study showed that the ON layer thickness positively correlates with the visual acuity in resolved CSCR and the discontinuity in the ellipsoid zone is associated with worse visual acuity.32 A recent study which reviewed clinical and multimodal imaging data of 133 patients with CSCR showed that outer retinal disruption on OCT is significantly associated with poorer visual acuity.33 These findings explains the incongruity of subretinal fluid absorbtion and visual acuity change in this disease, and shows that ellipsoid zone integrity is important in predicting the visual acuity. Nevertheless until now we had no data regarding if there is any correlation between the disruption of the ellipsoid zone and the anatomical response to eplerenone treatment in CSCR patients.
Our study’s limitations are the small sample size, the retrospective design and the absence of a placebo-treated group. Nevertheless our cohort consisted of strictly selected cases and was followed-up for a relatively long period.