Discussion
The current study adds to the existing literature by characterising the prevalence of SRF, as well as visual and anatomical outcomes of eyes with or without SRF following anti-VEGF for treatment based on real-world variable dosing. To our knowledge, this study is the first to demonstrate the effects of SRF in DME and RVO simultaneously from the same tertiary retina centre. The prevalence of baseline SRF reported in this study allows a direct comparison between two diagnostic cohorts. We also demonstrate significant differences in the change in VA and CST from baseline based on the presence of baseline SRF.
The baseline characteristics of patients with SRF were compared against the patients without SRF. A novel finding is the greater frequency of bilateral macular oedema in DME patients with SRF. Consistent with this is the significantly greater baseline CST in both the study and fellow eyes of patients with SRF compared with the respective eyes without SRF in our study. One explanation is that SRF formation is a systemic process and that the mechanisms associated with RPE dysfunction promote accumulation of fluid intraretinally in the fellow eye even in the absence of SRF.22 A previous study found associations of SRF with systemic diseases such as renal diseases, suggesting that a systemic source of VEGFs may contribute to RPE dysfunction.23
The prevalence of SRF was 23% and 43% for DME and RVO, respectively. These findings are comparable to previous reports for DME (18%–32%) and RVO (40%–57%), but no previous study has characterised SRF in both disease entities concurrently from patients attending the same retina centre.10–17 Furthermore, the resolution of SRF occurred very early in the follow-up period, as the prevalence of SRF was nearly halved in both DME and RVO at 1 month after just a single injection. The rapid resolution of SRF was also reported in previous studies and indicates that SRF responds well to initial therapy involving anti-VEGF.17 24
Eyes with SRF achieved a greater reduction in CST compared with those without SRF as early as 3 months for DME and at 1 month for RVO subcohort. Previously, Kim et al25 showed that the reduction in central foveal thickness was more evident in DME eyes with SRF at 1 month following treatment. Dogan et al14 demonstrated that BRVO eyes with SRF achieved greater reduction in central macular thickness at 1 month. Higher levels of intraocular VEGF are found in eyes with SRF compared with those without.26 It is not surprising that anti-VEGF agents would lead to significant anatomical improvements should VEGF mediate RPE dysfunction and subsequent leakage of fluid into the subretinal space.
Following the initiation of anti-VEGF therapy, DME patients with SRF demonstrated 24-month VA that was significantly greater than baseline VA. Furthermore, the improvement in logMAR VA was significantly greater compared with those without SRF at 12 and 24 months. This finding is consistent with the results of a previous study of DME patients in the RISE and RIDE trials, which demonstrated that baseline SRF predicts improvement from baseline best-corrected VA of 15 or more at 24 months.21 Even among patients receiving anti-VEGF for neovascular AMD, the presence of SRF compared with IRF was associated with excellent visual outcomes at 1 and 2 years in large scale clinical trials.27 28 The exact mechanism explaining this potentially protective role of SRF in various retinal conditions is unclear. A recent finding is that disruption in the photoreceptor integrity occurs more frequently in eyes with SRF compared with those without.13 Although not confirmed in our study, it is possible that the significant differences in vision improvement corresponded with the recovery of photoreceptor integrity in SRF eyes following long-term anti-VEGF treatment.29
Meanwhile, a larger improvement in VA may be attributed to a poorer baseline VA, which allows any improvement in vision to be more apparent. In both of our DME and RVO cohorts; however, there were no significant differences in the baseline logMAR VA between the patients with and without SRF. In addition, the differences in mean change in logMAR VA remained significant after adjusting for age, sex, lens status and baseline VA, making it less likely that the findings of our study were due to a difference in baseline VA between the groups.
In our study, no significant differences between the groups in mean VA change were observed in the earlier follow-up period prior to 12 months. This is in contrast to other studies that have observed significant differences in VA improvement in the earlier months following the initiation of DME treatment with anti-VEGF.19 20 Notably, a post hoc analysis of BRDME study participants demonstrated that baseline SRF predicted significant improvement in best-corrected VA letter score as early as 3 and 6 months.20 Although unlikely, this difference may be due to the difference in the inclusion criteria as we had strictly included patients that were anti-VEGF treatment naive who were at the earliest stages of their treatment regimen, and thus any functional improvement may have occurred later in our study period. With respect to our RVO subcohort, there were no significant differences in vision outcomes with respect to the presence of baseline SRF, consistent with the findings from a large post hoc analyses of patients from BRAVO and CRUISE studies.17 Overall, our study involving the real-world variable dosing and selection of anti-VEGF for DME and RVO patients confirm the findings of the post hoc analysis of the pivotal trials (RISE/RIDE and BRAVO/CRUISE), which were based on strict monthly injections of ranibizumab only.
It is important to note that this study was retrospective in nature and as such there was variability in follow-up intervals and the choice of anti-VEGF treatment regimen involving bevacizumab, ranibizumab or aflibercept for each patient. The variable dosing employed in our centre has the advantage of representing the practice pattern of ophthalmologists in a real-world clinical setting. The findings are also based a smaller sample size, despite being one of the largest centres with high volumes of patients presenting with retinal conditions. Future studies may help elucidate the photoreceptor integrity associated with the presence of SRF, the mechanisms underlying the development of bilateral macular oedema or bilateral SRF in patients as well as the clinical implications associated with the presence of bilateral disease at baseline. Identifying any other patient characteristics associated with faster resolution of macular oedema would be helpful for patient selection for treatment with anti-VEGF.
In conclusion, the current study evaluates the effects of baseline SRF on DME and RVO following variable treatment regimens in a real-world clinical setting. The visual improvement noted in DME eyes with SRF was greater than that of eyes without SRF, but no similar association was demonstrated in RVO patients. Significant VA improvement in the SRF compared with non-SRF patients was demonstrated only after 12 months of anti-VEGF injections and did not parallel the rapid resolution of SRF and reduction in CST. The presence of SRF at baseline may thus have significant clinical implications on patients undergoing therapy, and it may be used in clinical decision making for ophthalmologists treating DME and RVO.