Ophthalmologica 2014;232:83–91 DOI: 10.1159/000360304
Received: January 27, 2014 Accepted: February 1, 2014 Published online: June 12, 2014
Intravitreal Dexamethasone Implant in Patients with Persistent Macular Edema of Variable Etiologies Nir Sorkin Anat Loewenstein Zohar Habot-Wilner Michaela Goldstein Department of Ophthalmology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Key Words Ozurdex · Dexamethasone · Cystoid macular edema, persistent · Intravitreal injections
Abstract Purpose: To examine the effect of an intravitreal dexamethasone drug delivery system (DEX-DDS) in the treatment of persistent cystoid macular edema (CME) of different etiologies. Methods: Thirty-seven eyes with persistent CME were treated with DEX-DDS and analyzed for changes in best-corrected visual acuity (BCVA) and optical coherence tomography. Eyes were categorized into three groups: diabetic macular edema (DME, n = 14), vein occlusion (n = 15) and uveitis (n = 7). Results: The mean follow-up was 22 ± 6.9 weeks. BCVA improved from 0.62 ± 0.38 to 0.35 ± 0.29 logMAR (p < 0.0001). Central macular thickness decreased by 184 ± 246 μm from baseline (p < 0.0001). In eyes where CME resolved and recurred, the average CME-free period was 11 weeks. The uveitis group showed faster CME resolution (2 weeks) and a longer CME-free period (20 weeks). Similar efficacy was shown for repeat DEX-DDS injections. The safety profile was good. Conclusion: DEX-DDS is beneficial in the treatment of persistent CME. In cases of uveitis, CME resolution is rapid, resulting in the longest effect duration, when compared with other CME etiologies. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0030–3755/14/2322–0083$39.50/0 E-Mail [email protected]
Cystoid macular edema (CME) is a pathology known to cause visual impairment and possible permanent macular damage. CME can develop secondary to various retinal pathologies such as diabetic macular edema (DME), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) and uveitis [1–3]. DME is the main cause of mild to moderate visual loss in diabetic retinopathy. Thirty-three percent of untreated DME patients can suffer moderate visual loss . CME caused by CRVO and BRVO leads to an annual visual impairment of less than 20/40 in 1:4,760 and 1:1,785 people in the general population, respectively . In uveitis, CME is a major cause of significant visual loss . Previously proven effective treatments for CME include laser photocoagulation [4, 6, 7] and intravitreal anti-vascular endothelial growth factor agents [8–12]. In some cases, the response to those treatments is poor. Corticosteroids exhibit anti-inflammatory properties, reduce vascular permeability, inhibit fibrin deposition, stabilize endothelial cell tight junctions, and inhibit the synthesis of vascular endothelial growth factor, prostaglandins, and other cytokines . Those mechanisms can explain their therapeutic effect in the treatment of CME. The role of intraocular steroids was evaluated; they were shown to be Nir Sorkin, MD Department of Ophthalmology Tel Aviv Medical Center 6 Weizmann Street, Tel Aviv 6423906 (Israel) E-Mail nir_sorkin @ yahoo.com
effective both for DME  and macular edema secondary to CRVO/BRVO [15, 16] and are considered nowadays as one of the treatment options for those pathologies. In uveitic CME local corticosteroid therapies such as periocular  and intravitreal  injections are commonly used. However, corticosteroids can be associated with intraocular pressure (IOP) elevation and cataract progression [14–18]. All of the above treatment options for CME share a common disadvantage – their relatively short duration and the need for continuous retreatment strategies. Retreatment can be as frequent as monthly dosing [8–12, 19]. Recently, several intraocular drug delivery systems have been developed in order to allow sustained release of intravitreal steroids over a prolonged period of time [20–23]. The dexamethasone drug delivery system (DEXDDS) Ozurdex® (Allergan, Irvine, Calif., USA) provides sustained delivery of 700 μg of dexamethasone to the retina and vitreous  and is approved by the United States Food and Drug Administration for the treatment of macular edema associated with retinal vein occlusion, as well as for noninfectious posterior uveitis. The implant has shown efficacy and a good safety profile in the treatment of CME secondary to CRVO and BRVO [21, 24], DME [25, 26] and also in the treatment of uveitic CME . There is little evidence in the published literature of the effect of DEX-DDS in the treatment of edema persisting following other treatments [28–33]. The purpose of our study was to examine the effect of DEX-DDS in patients with severely recalcitrant CME that had a poor or shortterm response to other treatment modalities. A second goal was to compare treatment results between different CME etiologic groups (BRVO, CRVO, uveitis and DME). Materials and Methods
We analyzed the patients’ follow-up data, including best-corrected visual acuity (BCVA), slit lamp examination, applanation tonometry for the measurement of IOP and fundus examination. Optical coherence tomography (OCT) images were evaluated in order to determine the number of eyes achieving complete CME resolution, the time required for this resolution to occur and timing of CME recurrence. In eyes showing CME resolution and a later recurrence, we defined a CME-free period as the period of time between CME resolution and recurrence. Quantitative measurements of central macular thickness (CMT) changes were performed. OCT images were acquired using spectral domain OCT (Spectralis®, Heidelberg Engineering, Heidelberg, Germany; Cirrus®, Carl Zeiss, Oberkochen, Germany; OTI®, OPKO Instrumentation, Miami, Fla., USA). Differences in spectral domain OCT devices were due to the fact that our affiliated clinics are using different spectral domain OCT devices. In order to minimize interdevice differences, all of the statistical analysis was performed for the changes in CMT and not for absolute values. The equivalent logarithm of the minimum angle of resolution acuity (logMAR) was calculated and used for visual acuity analysis. Etiologic Groups In addition to the analysis performed on the entire cohort, eyes were categorized into three main etiologic groups: DME, vein occlusion and uveitis. The groups were analyzed separately. An additional subgroup analysis was performed with the BRVO and CRVO as separate groups. Both inter- and intragroup analyses were performed. Statistical Analysis Data was analyzed using SAS statistical software, version 9.2 (SAS, Cary, N.C., USA). Wilcoxon signed-rank test and Student’s t test were used to check for significant changes between baseline, best-achieved and last follow-up BCVA and CMT. A clinically significant value of CMT decrease greater than 30% baseline value was chosen, based on previous data showing that a CMT decrease greater than 20% baseline value is a clinically meaningful threshold for retinal thickness change in macular edema . Kruskal-Wallis test and Fisher’s exact test were used to check for significant differences between the different CME etiologic groups (DME, CRVO, BRVO and uveitis). When making a comparison between first and second DEXDDS injection results, Wilcoxon signed-rank test was used for continuous parameters and κ coefficient was used for categorical parameters; p values of 25 mm Hg and 1 eye (3%) had an IOP >40 mm Hg (IOP = 45 mm Hg). In all eyes IOP normalized with topical antihypertensive treatment. None of the eyes showed evidence of glaucomatous damage progression or required a surgical IOP-lowering procedure. Adverse Events No ocular or systemic adverse events were recorded.
In this study we examined the effect of DEX-DDS in a group of patients with recalcitrant CME, lasting an average of 20 months prior to DEX-DDS treatment. All eyes were treated with at least one other treatment modality prior to DEX-DDS and the majority (more than 60%) received two or more different treatment modalities prior Sorkin/Loewenstein/Habot-Wilner/ Goldstein
to DEX-DDS, showing either no resolution of CME or only a short-lasting/partial response following multiple injection attempts. Previously published data shows that the effect of DEX-DDS is inversely correlated with preinjection CME duration . Despite the fact that our patient cohort included eyes with prolonged CME, injections of DEXDDS led to a statistically significant improvement in BCVA, with 68% of the eyes reaching BCVA better than 20/40, this in comparison with only 30% of the eyes having BCVA better than 20/40 prior to DEX-DDS injection. In more than 30% of the eyes, BCVA improved by 3 ETDRS lines or more. These results are slightly inferior to the results of the GENEVA trial, which evaluated the safety and efficacy of DEX-DDS treatment in eyes with BRVO and CRVO. In the GENEVA trial, a cumulative 41% of the study eyes improved by 3 ETDRS lines or more [21, 36]. The difference between our results and the GENEVA results is understandable given the duration of CME prior to treatment in our patient cohort and the absence of exclusion criteria in our study for patients with severely reduced baseline BCVA. CMT showed a statistically significant decrease of 40% from baseline, at 10 weeks after the injection. Two thirds (65%) of the eyes achieved a CMT reduction greater than 30%. CMT gradually redeteriorated following peak effect. In the literature, the peak effect of DEX-DDS on CMT was observed 8 weeks after the injection in vitrectomized eyes with DME . In a study performed on 9 eyes with persistent DME peak effect was seen at 12 weeks after the injection . A retrospective analysis of 58 patients with persistent DME treated with a single DEX-DDS injection and followed up for 6 months showed improvement in BCVA (from 0.66 ± 0.36 logMAR at baseline to 0.44 ± 0.27 logMAR at month 3) and CMT (from 543.24 ± 156.51 μm at baseline to 341.12 ± 129.64 μm at month 3) . These results are consistent with our findings. Two small (9 and 17 eyes) series of patients with persistent DME demonstrated an improvement in BCVA and CMT following DEX-DDS injection [28, 30]. The improvement in BCVA shown in both studies was smaller than the BCVA improvement in our DME group. The improvement in CMT in one of those studies was comparable to our own  while in the other, CMT improved much less . The difference in results can be explained by the retrospective nature of all studies and a probable large variance in patient characteristics. All studies showed a redeterioration of BCVA and CMT values at 6 months after the injection, similar to what was shown here. In all studies
persistent DME was defined as DME persisting longer than 90 days despite treatment. A study evaluating DEXDDS treatment in 10 eyes with recalcitrant uveitic CME showed good response to DEX-DDS with improvement in retinal thickness and visual acuity. However, the duration of CME prior to treatment was not reported and the authors do not give any data on edema relapse in this study . Another study evaluated DEX-DDS effect in vitrectomized eyes with persistent uveitic CME. Average CME duration prior to injection was 12 months. Changes in CMT were comparable to our study . Our study did not include vitrectomized eyes. One retrospective study evaluated DEX-DDS in 18 eyes with CRVO or BRVO and persistent CME. The improvement in BCVA and CMT in this study was comparable to our own. It is important to point out that persistent CME in this study was defined as CME nonresponsive or partially responsive to a minimum of 2 bevacizumab injections and that the average duration of CME prior to injection was 11.08 ± 8.82 weeks. The persistence of CME in this study is therefore relatively short compared to our study and the other studies described above . We also evaluated CME status according to the presence or change in intraretinal cysts. Despite the fact that the majority of our patients (62%) had complete CME resolution following DEX-DDS injection, in 51% CME recurred. In those patients, having CME resolution and a later recurrence, the average period with no evidence of CME was 11 weeks. This reflects a more clinically relevant estimate of the effect of DEX-DDS for the management of our difficult-to-treat CME patients. In our study, CME resolved faster in the uveitis group (2 weeks). The DME and vein occlusion groups showed slower CME resolution (8 weeks in both). A fast reduction of CMT in uveitic CME, occurring 2 weeks after DEX-DDS injection, was also demonstrated by Miserocchi et al. . However, this study did not present data regarding CME resolution, only data regarding CMT reduction. Our uveitis group showed a substantially longer duration effect of DEX-DDS, manifested by an extended period with no evidence of CME (20 weeks). This was in comparison with shorter CME-free periods in the DME and vein occlusion groups (13 and 11 weeks, respectively). A similar trend for better response of uveitic CME patients to DEX-DDS was shown in the Dexamethasone DDS Phase II Study Group [26, 37]. The reason for the faster and more prolonged response of uveitic CME may be the additive effect of DEX-DDS’s steroidal anti-inflammatory properties on the inflammatory uveitic process responsible for the CME.
Intravitreal Dexamethasone Implant for Persistent CME
Ophthalmologica 2014;232:83–91 DOI: 10.1159/000360304
We observed that 86% of the early retreated eyes were in the vein occlusion group. They constitute 40% of the entire vein occlusion group. The vein occlusion group also appeared to have a slightly lessened decrease in CMT compared with the other two etiologic groups (DME and uveitis). This could indicate a less favorable response of retinal vein occlusion-induced persistent CME to DEXDDS. A previous comparison of the efficacy of DEX-DDS between different CME etiologic groups did not demonstrate a similar diminished response . One third of the eyes in our cohort (32%) received a second DEX-DDS injection. Repeated DEX-DDS injections were as effective as the first injections. This coincides with previous reports investigating retreatment with DEX-DDS [21, 38]. The safety profile demonstrated IOP elevation rates comparable to previously published data [21, 25]. The rate of cataract progression requiring surgery following the first injection in our study was 9% – similar to the GENEVA trial showing 7.6% cataract progression requiring
surgery. The rate of surgery-requiring cataract progression following DEX-DDS reinjections was 4.5% in our study – much lower than the 29.8% found in the GENEVA trial [21, 36]. Our study is limited by its retrospective nature and the relatively small sample size. Nevertheless, we were able to show the beneficial effect of DEX-DDS in the treatment of persistent CME, as well as a good response to repeated injections with a high safety profile. Some differences in the efficacy of the drug were observed between different etiologic groups. This emphasizes the need for further large prospective studies examining its effect among different etiologic groups while comparing it with today’s standard of care for each of these groups.
Disclosure Statement The authors of this study received no financial support. Anat Loewenstein is a consultant for Allergan.
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Ophthalmologica 2014;232:83–91 DOI: 10.1159/000360304
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.