The results of the current study showed that the DEX implant Ozurdex® significantly reduce the CRT in patients with RVO-ME, whit no differences between eyes with BRVO-ME and those with CRVO-ME or between treatment naïve and previously treated eyes.
Regarding function, there was a BCVA mean gain of + 5.4 letters at month-2, and at month-6, 20 (35.1%) eyes had achieved a BCVA improvement ≥ 15 letters. Although there was no difference in mean change in BCVA between eyes with CRVO-ME and those with BRVO-ME, the man change in BCVA was significantly greater in the treatment naïve eyes than in the previously treated ones.
Additionally, 40 (70.2%) eyes were classified as success at month-6 (CRT ≤ 250 µm or CRT reduction > 10%, at the end of the follow-up period), with no differences between CRVO/BRVO (mean difference 4.7%, p = 0.7350) and between naïve/previously treated (men difference 1.8%, p = 0.8834) groups.
DEX implant was the first medical therapy approved for treatment of RVO-ME. Different studies have shown clinically significant functional and anatomic improvements after the administration of the DEX implant in patients with RVO [10, 11, 25–29].
However, these studies did not provide information about potential biomarkers that can predict clinical outcomes in RVO-ME patients.
In a previous study published by our group we found a significant improvement of ELM integrity after DEX implant administration in patients with ME secondary to retinal vascular disease (diabetic macular edema or RVO-ME) . However, this study failed to confirm that finding. It may be partially explained by the fact that our previous study included eyes with diabetic macular edema, while the current study only included eyes with RVO. Additionally, in our previous study  we assessed the changes in ELM from a quantitative point of view, while in the current one the changes in ELM have been qualitatively evaluated.
In patients with ME secondary to diabetic retinopathy, ELM integrity was associated with the final BCVA improvement [30, 31], which may suggest a relationship between ELM status and photoreceptor damage.
In agreement with this assumption, we found a significantly lower baseline BCVA in those eyes with disrupted ELM than in those with non-disrupted or partially disrupted ELM, and lower baseline BCVA in eyes with partially disrupted ELM than in those with non-disrupted ELM. However, in the current study, the enhance of ELM integrity was not associated with a better functional outcome. This may be due to the fact that even though there was an anatomical improvement, there is a tipping point from which photoreceptor damage cannot be recovered, which would highlight the relevance of an early therapeutic approach.
Regarding the effect of DEX implant on cysts, as compare to baseline (0/57 eyes), we found a greater proportion of eyes without cysts at month 2 (31/57, p < 0.0001), month 4 (10/57, p = 0.0005), and month 6 (20/57, p < 0.0001). However, no significant changes were observed in DRIL and/or HRF.
It is no easy to compare our studies with the currently available scientific evidence, since most of the evidence evaluated ME secondary to diabetic retinopathy (DME).
The presence of DRIL  or integrity of the ellipsoid zone  have been associated with better clinical outcomes in DME patients who underwent DEX implant. Additionally, DEX treatment was also capable to ameliorate DRIL status .
However, despite the association between OCT biomarkers and BCVA at baseline, the current study did not observe any relationship between the different OCT biomarkers (DRIL, HRF, cyst, and ELM status) evaluated at baseline and the clinical outcomes.
We found worse baseline BCVA in those eyes with thicker SRF, presence of DRIL, disrupted ELM, or HRF > 20. However, due probably to the limited sample, we did not find significant associations between these OCT biomarkers and the changes in BCVA.
Evidence regarding the importance of HRF is eluding. Several studies have shown that the presence of HRF in various retinal layers was positively associated with final BCVA [13, 34] while, on the other hand, other studies showed that the presence of HRF was not associated with final BCVA . In our study a significant association between HRF and final visual acuity has not been established; however, we found worse baseline BCVA in eyes with over 20 HRF, and also in eyes with more disrupted ELM. Although we do not localize the HRF within the retinal layers, it is known that a disrupted ELM cannot block the migration of extravasated lipoproteins in the inner retinal layers to the outer retinal layers of the ELM, and makes it possible to pass these extravasated blood constituents of the HRF through the outer retinal layer . Murakami et al  reported that HRF in the outer retinal layers were associated with either a disrupted ELM or EZ and poor prognoses in diabetic ME.
The relationship between SRF and visual function is controversial.
According to CATT (Comparison of Age-related Macular Degeneration Treatments Trials) study results, in eyes with age-related macular degeneration, SRF was associated with better visual acuity, whereas eyes with subfoveal intraretinal fluid had worst visual acuity .
Conversely, in patients with ME secondary to uveitis, SRF was associated with thicker retinas and worse baseline BCVA . This finding agrees with our results. However, unlike what happened in our study, where the presence of SRF was not associated with better anatomic or functional outcomes throughout the study, they found better BCVA improvement in eyes with SRF at baseline .
Additionally, larger intraretinal cysts, thicker SRF, higher percentage of DRIL, and percentage of ELM disruption have been associated with worse baseline BCVA in patients with RVO-ME. However, only percentage of ELM disruption independently impacted baseline BCVA .
The results of the current study are in agreement with a previous study conducted by our group that found no differences in BCVA improvements between the eyes with severe ELM disruptions at baseline and those with no or less severe ELM disruption at baseline .
Since we found significant associations between different OCT biomarkers (DRIL, ELM status, SRF thicknesses, or HRF) and the baseline BCVA, the lack of relationship between these biomarkers and clinical outcomes needs to be further investigated.
CRT was significantly reduced at all the different time-point measures, not only in the overall study populations, but also in the CRVO and BRVO eyes, and in the treatment naïve and previously treated ones. We did not find any differences at any of the different time-points according to the diagnosis (CRVO vs BRVO) or to the treatment status (treatment naïve vs previously treated).
This study did not find any relationship between the time elapsed from RVO diagnosis to the first intravitreal DEX implant and the changes in CRT or BCVA. Conversely, the LOUVRE study found that the mean gain in BCVA was greater in patients with recent-onset ME . Such a difference may be explained by the fact that in our study the median time from diagnosis to treatment was 32 days, while in the LOUVRE study the cut-off point was established in 3 months. In our study 13 (22.8%) eyes had duration of ME at baseline ≥ 90 days. Although CRT reduction and BCVA improvement were lower in those eyes with ME duration ≥ 90 days (163.5 ± 261.6 µm and 7.0 ± 27.6 letters, respectively) than in those with ME duration < 90 days (263.5 ± 300.6 µm and 4.6 ± 29.2 letters, respectively), such differences were no statistically significant (p = 0.3816 and p = 0.1558, respectively, Mann-Whitney U test).
Several limitations should be taken into consideration when interpreting the results of this study. The main one is its retrospective design, which entail potential bias and confounding factors. In order to minimize its impact, we applied strict inclusion/exclusion criteria. The second limitation is the lack of sample size calculation. In fact, the power for detecting the observed differences in BCVA change, between baseline and month-6, was 13% in CRVO vs BRVO eyes and 97% between treatment naïve and previously treated eyes. Additionally, the power for detecting the observed differences in CRT reduction at month 6, between CRVO vs BRVO and between treatment naïve vs previously treated eyes, was 13% each, respectively.
An additional limitation is the fact that we have measured the presence or absence of DRIL, but not whether their extension changed over the course of the study. This fact, therefore, may explain the lack of significant changes after treatment. Finally, we did not evaluate the safety profile of DEX, but treatment related adverse events associated with DEX are well known and have been exhaustively reported .