Eur J Ophthalmol 2013; 23 ( 4 ): 558-563

DOI: 10.5301/ejo.5000261

ORIGINAL ARTICLE

Treatment of macular edema associated with retinal vein occlusion using sustained-release dexamethasone implants in a clinical setting
Nikolaos Merkoudis, Elisabet Granstam
Department of Neuroscience/Ophthalmology, Uppsala University Hospital, Uppsala - Sweden
D e p m a t re N o n f t e u o r s e c n ic e O /p h t m a lo U g l, y p p s U a lH y v n t e U s ir o , s a p t lp iS s a w le d e n D e p m a t re N o n f t e u o r s e c n ic e O /p h t m a lo U g l, y p p s U a lH y v n t e U s ir o , s a p t lp iS s a w le d e n

Purpose: To evaluate the clinical effect, safety, and administration procedure of slow-release dexamethasone implants (Ozurdex) for macular edema secondary to retinal vein occlusion in clinical praxis. Methods: Data from 11 patients (4 eyes with central vein occlusion and 7 eyes with branch vein oc clusion) were reviewed. Data were compiled and analyzed with respect to best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), and adverse events. Follow-up was 10 months. Changes in BCVA logMAR 0.2, IOP 5 mm Hg, and CMT 100 m were considered clinically relevant. Results: Two months after the first dexamethasone implant, BCVA improved from logMAR 0.65 0.2 to logMAR 0.34 0.1. All patients demonstrated a decrease in CMT from an initial average value of 632 178 m to 229 34 m. However, in 10 out of 11 eyes, macular edema recurred by month 4 through 5 and a second dexamethasone implant was administered. Two and 4 months after the second implant, BCVA was logMAR 0.36 0.2 and logMAR 0.40 0.2 and the CMT was 254 61 m and 357 81 m, respectively. The IOP increased 5.1 1.5 mm Hg 1 month after the first implant compared to baseline. In eyes with an IOP above 25 mm Hg (4 out of 11), pressure-lowering eyedrops were administered. Conclusions: Administration of dexamethasone implants induced a clinically relevant increase in visual acuity and a decrease in central macular thickness. In 91% of patients, macular edema recurred within 5 months and a second implant was administered. Adverse events, primarily increased IOP, were manageable. The injection procedure was relatively simple and uncomplicated. Keywords: Dexamethasone implant, Intraocular pressure, Ischemia, Ozurdex, Steroids, Vascular endothelial growth factor
Accepted: January 31, 2013

INTRODUCTION
Retinal vein occlusion (RVO) is the second most common type of retinal vascular disease after diabetic retinopathy, and is a common cause of visual morbidity and blindness. Meta-analysis of epidemiologic data has estimated the prevalence of RVO in the general population to be 5.2 cases per 1,000 adults (1). The prevalence of RVO increases with 558

age, and a majority of the affected patients are 65 years and older (2). The etiology and pathophysiology of RVO are not fully understood, though the risk factors include cardiovascular disease, hypertension, hypercholesterolemia, and diabetes mellitus (3). Two main types of RVO are commonly recognized: central RVO (CRVO) and branch RVO (BRVO). Macular edema (ME) is the major cause of vision loss in patients with CRVO and BRVO. Increased intravascular

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Merkoudis and Granstam

pressure in the retinal capillaries induces transudation of fluid from the blood vessels into the tissue. Hypoxia-induced activation of multiple inflammatory mediators such as cytokines, chemokines, and growth factors causes breakdown of the bloodretina barrier, further facilitating leakage of fluid from the blood to the retina (4). Increased levels of inflammatory mediators such as interleukin-6, interleukin-8, monocyte chemoattractant protein1, and soluble intercellular adhesion molecule 1 as well as vascular endothelial growth factor (VEGF) have been found in vitreous fluid from patients with RVO (5, 6). The leakage of fluids from the capillaries leads to thickening of the macula through accumulation of fluid in cystoid spaces within the retina and in the subretinal space (7). In the porcine experimental model of BRVO, intravitreal triamcinolone has been shown to downregulate VEGF (8). In diabetic rats, both intravitreal triamcinolone and dexamethasone have been shown to reduce VEGF expression and inhibit breakdown of the bloodretinal barrier (9). Following intravitreal administration of triamcinolone in humans, reduced aqueous levels of various cytokines have been found (10). These findings imply that reduction of intraocular inflammatory mediators by intravitreal administration of dexamethasone may decrease vascular leakage, resulting in reduced ME. Until recently, the only widely accepted treatment for ME associated with BRVO has been grid laser photocoagulation. There has been no effective treatment for ME associated with CRVO. Recently, dexamethasone intravitreal implants (Ozurdex, Allergan Pharmaceuticals, Ireland) have become available in the clinic. Additionally, one anti-VEGF drug (ranibizumab, Lucentis, Novartis Europharm Ltd., UK) has been approved. Data from pivotal studies with Ozurdex (11, 12) and Lucentis (13, 14) demonstrate absorption of ME and recovery of vision following treatment. Treatment must be repeated to maintain stable vision. The objective of the present study was to evaluate the effect, safety, and administration procedure of slow-release dexamethasone implant (Ozurdex) for ME secondary to RVO as used in clinical praxis at Uppsala University Hospital.

from December 2010 to December 2011. All patients displayed reduction in visual acuity (VA) and ME, defined as central macular thickness (CMT) of at least 320 m at the 1 mm central subfield of a spectral-domain optical coherence tomograph (Cirrus HD-OCT, Humphrey Zeiss, Inc., San Leandro, California, USA). Eyes with more than 10 months of follow-up after the initial treatment with DEX were included in the study. Patients with retinal or iris neovascularization, laser treatment within the past 6 months, previous vitrectomy, concomitant uveitis, or vitreous hemorrhage were excluded from the study. In this retrospective case series, 11 eyes of 11 patients were included: 4 eyes with CRVO and 7 eyes with BRVO. This study was approved by the institutional ethics committee, and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from each patient.

Baseline
Prior to treatment, patients were evaluated with respect to general health and ocular status. Ocular status assessment included best-corrected VA (BCVA) using a Snellen chart and converted to the logarithm of the minimum angle of resolution (logMAR), intraocular pressure (IOP) measured with Goldmann applanation tonometry, slit-lamp biomicroscopy, and optical coherence tomography. Fluorescein angiography (FA) was performed in all but 2 patients, and the degree of macular perfusion was evaluated according to the criteria of the Early Treatment Diabetic Retinopathy Study (15) and the Bevacizumab or Laser Therapy study (16). Topcon IMAGEnet software (Topcon Medical Systems Inc., Paramus, New Jersey, USA) was used to view images and measure the perifoveal capillary loss, the greatest linear dimension (GLD) of the foveal avascular zone (FAZ), and the total area of the FAZ under 100% magnification. Macular ischemia was defined as GLD of FAZ 1.000 m or a broken perifoveal capillary ring at the border of the FAZ with a distinct area of capillary nonperfusion within a 1-disc diameter of the foveal center. Changes in VA 0.2 logMAR, IOP 5 mm Hg, and CMT 100 m were considered clinically relevant.

METHODS
We reviewed the medical charts of all patients with a diagnosis of BRVO or CRVO who received treatment with dexamethasone implant (DEX) at Uppsala University Hospital

Intravitreal administration of Ozurdex

Topical anesthesia was obtained by instilling tetracaine eyedrops (Tetrakain Chauvin 1%, 10 mg/mL, Chauvin 559

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Treatment of macular edema with intravitreal implants

Pharmaceuticals Ltd., England) in the conjunctival sac. The pupil was not routinely dilated. After disinfection and draping, a lid speculum was placed into the eye and a cotton swab soaked in tetracaine solution applied gently at the injection site for about 1 minute. The injection site was defined using calipers to measure 3.5 mm from the limbus in pseudophakic eyes and 4.0 mm in phakic eyes. The eye was stabilized with the cotton swab while the tip of the Ozurdex applicator was advanced in the sclera, parallel to the limbus, for about 1mm. The applicator was then redirected towards the center of the eye and advanced until penetration of the sclera was completed. The DEX implant was released into the vitreous cavity by slowly depressing the activator button. Once injection was completed and the applicator removed, the cotton swab was immediately placed against the injection site to ensure there was no leak. Finally, a drop of fusidic acid (Fucithalmic 1%, LEO Pharma AB, Malm, Sweden) was applied in the conjunctival sac. All administration procedures were performed by the same surgeon (N.M.).

Fig. 1 - Best-corrected visual acuity (BCVA) during the follow-up period (mean and standard deviation). The lowest logMAR value (best visual acuity) was registered 2 months after each treatment with dexamethasone intravitreal implant.

pressure-lowering medication, were not given a second injection.

Statistical analysis
The BCVA was converted to logMAR equivalents for statistical analysis. Student t test was applied for paired comparisons. A p value of <0.05 was considered significant.

Follow-up
All patients were examined 1, 2, 4, and 5 months after the initial treatment with DEX. At month 1, examinations were handled by a nurse and focused primarily on monitoring changes in IOP. Eyes with IOP greater than 24 mm Hg received pressure-lowering medication. Patients were also asked for any new symptoms, or if they had noted any visual deterioration since the injection. Thorough examinations, performed by a doctor, were carried out at months 2, 4, and 5. These included biomicroscopy and measurement of BCVA, IOP, and CMT. Treatment for elevated IOP at any of these visits was administered at the physicians discretion. Laser photocoagulation was available as complementary treatment throughout the study.

RESULTS
The study included a series of 11 eyes (4 with CRVO, 7 with BRVO) of 11 patients (mean age 65 7 years, range 53-74). All eyes showed cystoid ME at the initial visit. None of the eyes were pseudophakic. Fluorescein angiography was performed in all but 2 patients. Mean time from presentation until FLA was 3.4 2.2 (range 1-7) months. The FA was delayed in some cases due to the abundance of retinal hemorrhages at the macula. The extent of macular ischemia was analyzed from the FAs. Three eyes were graded as ischemic according to the criteria for macular ischemia, whereas 6 eyes were nonischemic. Mean BCVA at the time of diagnosis was 0.40 0.2 logMAR. The first DEX implant was administered 7.4 3.7 months after diagnosis. At baseline (just prior to the treatment), the mean BCVA was 0.65 0.21logMAR and the mean CMT was 632 178 m. All patients described the administration procedure as painless, although a feeling of slight pressure on the eye was constantly experienced. Mean BCVA at 2 months after the treatment improved to 0.34 0.1logMAR (p = 0.002 compared to baseline; Fig. 1). Clinically relevant improvement in BCVA (0.2logMAR, i.e., 2 lines) occurred in 8 participants (73%). Six

Retreatment
Decisions on retreatment with DEX were based on the results from the examinations at months 4 and 5. Criteria for retreatment were worsening of BCVA by 0.2 logMAR and/or increase of CMT by 100 m compared to the findings at the 2-month visit. Patients eligible for retreatment received a new DEX within 2 weeks of their last visit. Eyes that did not respond well to the first implant in terms of CMT decrease, or were unresponsive to 560

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TABLE I -  BEST-CORRECTED VISUAL ACUITY DURING THE FOLLOW-UP PERIOD IN ISCHEMIC AND NONISCHEMIC GROUP ACCORDING TO FLUORESCEIN ANGIOGRAMS OBTAINED AT BASELINE
Baseline Month 2 Month 4 Month 8 Month 10
0.31 0.1 0.47 0.1

Ischemic (n = 3)

0.63 0.1

0.30 0.2 0.36 0.1

Nonischemic 0.66 0.2 0.36 0.1 0.45 0.2 0.36 0.2 0.38 0.2 (n = 6)
The difference in best-corrected visual acuity between groups was not clinically relevant at any visit, suggesting that the effect of intravitreal dexamethasone implant on visual acuity was not affected by the extent of macular ischemia.

Fig. 2 - Central macular thickness (CMT) during the follow-up period (mean and standard deviation). The lowest CMT value was registered 2 months after each treatment with dexamethasone intravitreal implant.

participants (55%) demonstrated improvement by 0.3logMAR (3 lines). The mean time elapsed from diagnosis of ME until treatment with DEX was 10.3 months in the 3 patients with a BCVA improvement of <0.2logMAR, and 6.1 months in the 8 patients with a BCVA improvement of 0.2logMAR. Changes in VA at all visits were not affected by the extent of macular ischemia at baseline (Tab. I). A decrease in BCVA was noticed at 4 months (0.42 0.2logMAR) compared to 2 months, and VA decreased further to nearly baseline values (0.62 0.2logMAR) at 5 months. The CMT was 229 34 m at 2 months posttreatment. At 4 months from baseline, an increase in CMT was observed in 10 out of 11 eyes (423 122 m), and further increase was observed at the 5-month visit (571 149 m) (Fig. 2). Ten out of 11 eyes (91%) received a second DEX implant after 160 15 days. One patient was not subjected to retreatment, as there was no relapse of ME. Two months after the second implant, an increase in BCVA was observed (0.36 0.2logMAR, p = 0.005 compared to baseline) and CMT was reduced (254 61 m). The difference in mean CMT at 2 months after the administration of the first and second implant respectively was 30 114 m. Clinically relevant improvement in BCVA by 0.2logMAR occurred in 7 participants (64%). Four months after administration of the second DEX, a slight decrease in BCVA (0.40 0.2logMAR) was observed, while CMT increased (357 81 m). A lasting improvement was seen in 3 participants; the remaining 8 (73%) received a third DEX. The IOP increased by 5.1 1.5 mm Hg 1 month after the first DEX (21.8 7.1 mm Hg at month 1 compared to 16.7 3.3 mm Hg at baseline; p = 0.007). Elevation of IOP above 25mm Hg was observed in 3 of 11 eyes (27%) at the 1-month visit and 4 of 11 eyes (36%) at the 2-month visit. These patients

received pressure-lowering eyedrops, and presented with acceptable IOP at all subsequent visits. Among patients who did not receive pressure-lowering medication after the first implant, one patient showed an increase in IOP above 25 mm Hg after the second implant. Additionally, in 2 of 4 patients who were already on pressure-lowering eyedrops after the first DEX implant, further increase in IOP after the second implant was observed and additional medication was prescribed. During follow-up, no patient received laser treatment. None of the patients showed any severe local adverse events such as retinal detachment, retinal tears, endophthalmitis, or uveitis. No patient developed cataract for which surgery was required. No patient experienced any adverse systemic event.

DISCUSSION
This study presents 11 cases of ME associated with BRVO or CRVO treated with dexamethasone intravitreal implants. In all but one eye, treatment induced an improvement in VA and a reduction in ME at 2 months. The results are well in line with the findings in the pivotal GENEVA study as well as those from an Ozurdex compassionate-use program (17). In our case series, clinically relevant improvement in VA of at least 0.2logMAR was observed in 73% of eyes and improvement in VA of at least 3 lines (0.3logMAR) in 55% of eyes. In the GENEVA study, the proportion of eyes achieving at least a 15-letter (3-line) improvement from baseline BCVA at month 2 was 29% in the 0.7 mg group. The effect on VA and CMT declined over the following months, and by months 4 to 5, recurrence of ME was observed in 10 out of 11 eyes. No patient displayed increase in ME compared to baseline levels, which has been observed in other case 561

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series (18). In a recent study (19), mean time to recurrence of ME was 3.8 and 3.5 months in CRVO and BRVO patients, respectively. In our case series, retreatment was administered in 91% of eyes within 5.5 months from the first injection. In the GENEVA study, retreatment was allowed no earlier than 6 months after the first DEX administration. In a study (17) of 10 patients with CRVO, with retreatment carried out on an as-needed basis starting from the fourth month, the mean number of DEX treatments during the first year was 1.7 0.4 (range 1-2). Furthermore, in the SCORE studies evaluating intravitreal triamcinolone for the treatment of ME secondary to RVO, the effect on VA and central retinal thickness was transient and the mean number of injections was 2.0-2.2 during the first year (20, 21). The second DEX injection in eyes with nonpersistent CMT reduction resulted in a comparable ratio of BCVA improvement, whereas CMT at the end of the follow-up period was found to be lower compared to baseline, which is consistent with findings in the GENEVA study. Findings in our study suggest that close monitoring is important to identify early signs of ME recurrence, and that retreatment can be considered from month 4 and onwards. In our study, FA was performed in order to evaluate the extent of macular ischemia. In some patients, obtaining of FAs was delayed due to abundance of retinal hemorrhages, which was expected to interfere with the interpretation of the FA. As a consequence, treatment with DEX was delayed. Analysis of the FAs indicates that the effect of DEX on VA was not affected by the extent of macular ischemia. However, BCVA improved more in patients with shorter elapsed time between diagnosis and treatment. A previous study of ischemic ME associated with BRVO reported a favorable effect on VA of eyes treated with intravitreal triamcinolone (22). A post hoc analysis of data from the GENEVA study revealed that increased duration of ME was associated with a lower likelihood of achieving an improvement of BCVA of 15 letters of more (23). The FAs were not performed in the GENEVA study. The findings suggest that if FA is to be performed, it should not delay administration of DEX. In the recently published clinical guidelines for the management of RVO (24), FA is recommended only for evaluation of extent of ischemia in the retinal periphery. An average IOP increase of 5 mm Hg was evident 1 month after the administration of DEX. One of 3 patients received pressure-lowering medication and demonstrated adequate reduction of IOP. Two patients received additional medication after the second implant. No patient 562

required any surgical procedure to reduce the IOP. In the GENEVA study, the IOP was 25 mm Hg in 16% of patients at day 60, and an additional 10% of patients initiated IOP-lowering medication after the second DEX administration. In the same study, a few patients required IOP-lowering surgery. Increase in IOP was also observed following intravitreal triamcinolone injections for the treatment of ME secondary to RVO (20, 21). In these studies, IOP-lowering medication was initiated during the first year in 35% and 41% of eyes in the triamcinolone 4 mg groups of CRVO and BRVO, respectively, which is in the same range as in our patients. Close monitoring of IOP and treatment with IOP-lowering medication in case of increase in IOP is necessary in patients treated with DEX. In our case series, no other adverse event occurred either locally in the eye or systemically. The lens status was not graded in this study by a formalized method such as the Lens Opacities Classification System version II; however, no patient exhibited development of posterior subcapsular cataract for which surgery was required during follow-up. Progression of steroid-induced cataract has been observed both in the GENEVA study and in the SCORE studies. The technique for implant administration was easily acquired, and implantation was performed without complications in all patients, although a slight feeling of pressure on the eye was constantly perceived. We conclude that the administration of DEX was safe and well-accepted by the patients. The findings in our patients suggest that DEX implant is a valuable tool in the treatment of ME secondary to RVO. However, this study has the limitations of being a retrospective review in a small number of patients without a control group. Prospective studies in larger number of patients are needed to further evaluate the effect and safety of DEX implants in clinical praxis.
Financial Support: None. Conflict of Interest Statement: The authors report no proprietary interest.

Address for correspondence: Nikolaos Merkoudis Department of Neuroscience/Ophthalmology Uppsala University Hospital SE-751 85 Uppsala Sweden nikolaos.merkoudis@akademiska.se

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