In this small retrospective study, we did not find a consistent or statistically significant reduction in CME of fellow eyes of patients with bilateral CME receiving only unilateral extended release corticosteroid intravitreal implants. Most patients enrolled in the study received the dexamethasone intravitreal implant; however, two patients received the fluocinolone acetonide intravitreal implant.
There are case reports suggesting that the injection of dexamethasone intravitreal implant in one eye may result in effects in the other contralateral eye, a phenomenon seen with the intraocular injection of other medications. 9–13 Additionally, the pharmacokinetics of the dexamethasone implant support a possible bilateral effect as the drug can be detected at a low concentration in plasma for up to 90 days.14 Indeed, we found that some study eyes showed a reduction in CST and macular volume after the contralateral eye received an intravitreal corticosteroid implant; however, this improvement was minimal and did not reach an arbitrary cutoff of 10% reduction in CST.
Patients with macular edema may show fluctuations in their level of CME, both improvement and worsening, spontaneously over time. Looking at the sham treatment group of several studies, both CST and visual acuity in DME and RVO may improve in up to 18% of patients.8,15,16 For this reason, we included a control group in the present study. We did not find a statistically significant difference in the changes to either CST or macular volume between the treatment and control groups. The control group has a lower baseline macular volume than the treatment group. However, this is unlikely to have affected our results as it creates a ceiling effect for the controls which would actually increase the chance of finding a statistically significant result, not reduce that chance.
To the best of our knowledge, there are no large studies that compare the effect of corticosteroid implants in fellow eyes. Currie et. al. compared the injected and fellow eyes of patients receiving the fluocinolone acetonide intravitreal implant unilaterally for DME.17 However, the fellow eyes were eligible to receive other intravitreal therapeutics, in contrast to this study. Nonetheless, there was only a minimal reduction of 3 µm in the central foveal thickness at 3 months and a 13 µm reduction at 1 year in the fellow eyes. These results fall within a similar range to our results, which showed a 6.3 µm increase in CST in the full cohort and an 8.1 µm reduction in CST in the cohort with the extended washout period. The pharmacokinetics of the fluocinolone acetonide intravitreal implant also would predict little to no effect on the contralateral eye as systemic detection is below the lower limit of quantitation in plasma (200 pg/mL)18
It is possible that we did not see an effect of these corticosteroids in the fellow eye due to an inadequate washout period. The period chosen for this study was selected as a balance between the duration of action of each medication and the desire for a larger cohort of patients. It is possible that an increase in CME from ongoing washout masked the positive effect of some contralateral injections. We explored this through a post-hoc analysis with an extended washout period. While both CST and macular volume fared slightly better in this cohort, the mean reduction in CST (8.1 µm) and macular volume (0.18 mm3) were both quite modest and not statistically significantly different from the control group.
It is also possible we did not see an effect for other reasons. First, our patients had a relatively small amounts of CME at the beginning of the observation period with a mean starting CST in the study eye of 341 µm. However, some patients had CME away from the foveal center, and therefore macular volume was also included in the analysis. Limiting the study to patients with a larger CST would have further limited the number of patients as most patients with large amounts of CME undergo treatment. In the present study, even the patients with larger CST values did not show any substantial reduction in their CST values. It remains a possibility that some patients’ conditions may not have been responsive to corticosteroids, however this is less likely. One should also note that systemic absorption of intravitreal medications may vary from patient to patient or cohort to cohort. This may be altered by various effects such as disruption of the blood-retinal barrier, which is seen in diabetes, uveitis, and RVO1–3,19−21 and was hypothesized to be a factor in the bilateral effect of unilateral intravitreal dexamethasone implant in at least 1 case report.11 It is difficult to control for the degree of blood-retinal barrier disruption and it remains possible that patients with substantial compromise may show differing effects of corticosteroids in a fellow eye. Lastly, this cohort included a small study group.
The limitations of our study have been touched upon and include a small study group, retrospective design, and a modest initial degree of CME. However, this is a very unique and limited subgroup of patients who have bilateral edema with treatment in only one eye. Despite these limitations, this study remains valuable, having a larger collection of such patients than has been previously published and including a control group.
In conclusion, we found that extended release intravitreal corticosteroids did not have a statistically significant effect on the CME of contralateral eyes. While a fellow eye response may occur in some patients, as is evidenced by prior case reports, the effect should not be expected routinely and there are several factors that may be more important in the evolution of CME. Larger scale prospective studies are needed to better characterize this phenomenon.