REPEATED INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX ) FOR DIABETIC MACULAR EDEMA MATTEO SCARAMUZZI, MD,* GIUSEPPE QUERQUES, MD, PHD,*† CARLO LA SPINA, MD,* ROSANGELA LATTANZIO, MD,* FRANCESCO BANDELLO, MD, FEBO* Purpose: To evaluate the effects of repeated intravitreal dexamethasone implant. Methods: We reviewed the charts of 12 patients with diabetic macular edema, who received at least 2 intravitreal Ozurdex (0.7 mg) on an “as needed” basis. Main outcome measures included changes in best-corrected visual acuity, central macular thickness, retreatment interval, and incidence of side effects. Results: A total of 15 eyes of 12 patients (6 men, 6 women; mean age 62 ± 12 years) were included. Retreatment was judged necessary after mean of 7.8 ± 4.1 months from the first Ozurdex (median, 6 months) (15 of 15 eyes), mean of 4.8 ± 0.9 months from the second Ozurdex (median, 5 months) (7 of 15 eyes), mean of 5.3 ± 1.5 months from the third Ozurdex (median, 5 months) (3 of 15 eyes), and mean of 5.6 ± 2 months from the fourth Ozurdex (median, 5 months) (3 of 15 eyes). Mean baseline best-corrected visual acuity was 0.67 ± 0.33 logMAR in the overall diabetic macular edema population; it significantly improved to 0.53 ± 0.31 logMAR after mean of 40.9 ± 18.2 days from the first Ozurdex (peaking efficacy) (P , 0.001), to 0.53 ± 0.29 logMAR after mean of 34.4 ± 9.0 days from the second Ozurdex (peaking efficacy) (P , 0.003), and stabilized to 0.62 ± 0.26 logMAR after mean of 29.8 ± 12.1 days from the third Ozurdex (peaking efficacy) (P = 0.05), to 0.5 ± 0.26 logMAR after mean of 36.3 ± 3.2 days from the fourth Ozurdex (peaking efficacy) (P = 0.2), and to 0.50 ± 0.26 logMAR after mean of 37.0 ± 2.6 days from the fifth Ozurdex (peaking efficacy) (P = 0.2). Mean baseline central macular thickness significantly decreased from 546 ± 139 mm to 292 ± 43 mm at 39.4 ± 17.9 days from the first Ozurdex (peaking efficacy) (P , 0.001), to 297 ± 47 mm at 33 ± 9.4 days from the second Ozurdex (peaking efficacy) (P , 0.001), to 293 ± 22 mm at 29.8 ± 12.1 days from the third Ozurdex (peaking efficacy) (P = 0.01), and stabilized to 309 ± 35 mm at 36.3 ± 3.2 days from the fourth Ozurdex (peaking efficacy) (P = 0.1), and to 295 ± 7 mm at 37.0 ± 2.6 days from the fifth Ozurdex (peaking efficacy) (P = 0.1). No serious adverse events were observed; three eyes developed a transient intraocular pressure increase, and cataract was extracted in one eye. Conclusion: Repeated intravitreal Ozurdex on an “as needed” basis with a variable retreatment interval may produce long-term clinically meaningful benefits in the treatment of diabetic macular edema, without other significant side effects than expected after intraocular corticosteroid treatment. RETINA 35:1216–1222, 2015

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most eyes did not improve significantly.5 Recent investigations suggested inflammation as one of the main factors in the development of DME. Therefore, the use of steroids administered intravitreally has been introduced as a possible therapy. Intravitreal injection of triamcinolone acetonide determines a rapid decrease of macular edema and short-term gain in vision, but visual acuity decreases when this treatment is prolonged for .2 years.6,7 Dexamethasone is a strong synthetic member of the glucocorticoid class of steroid

iabetic retinopathy (DR) is a leading cause of blindness in patients among 25 years and 74 years.1 The loss of visual ability caused by DR can be a consequence of the development of macular edema, hemorrhage of new blood vessels, a detachment of the retina, or the development of neovascular glaucoma.2 Diabetic macular edema (DME) is mainly because of leakage of abnormal retinal vessels.3,4 For over 30 years, the standard therapy for DME has been laser photocoagulation; however, visual acuity of 1216

REPEATED OZURDEX IMPLANT FOR DME  SCARAMUZZI ET AL

drugs that has antiinflammatory and immunosuppressant activity 30 times more effective than cortisol and 6 times more effective than triamcinolone.8 A sustained-release dexamethasone implant (Ozurdex; Allergan, Inc, Irvine, CA) is an approved therapy for macular edema secondary to different causes. It is delivered with a solid polymer system, a poly (D,L-lactide-co-glycolide) (PLGA) matrix structure. The PLGA matrix slowly degrades to lactic acid and glycolic acid (Novadur; Allergan, Inc).9 Currently, the results of repeated administration of Ozurdex for DME and the best retreatment interval are not well known. In this study, we retrospectively evaluated the outcomes, retreatment interval, and incidence of side effects of repeated intravitreal dexamethasone implant administrated on an “as needed” basis for DME in a single-center institutional setting.

Methods We longitudinally reviewed the charts of all consecutives patients with decreased visual acuity because of DME, who underwent repeated intravitreal Ozurdex on an “as needed” basis at the Department of Ophthalmology of the University Scientific Institute San Raffaele in Milan between April 2010 and June 2013. Criteria for inclusion were: 1) adults (older than equal to 18 years) with controlled diabetes (e.g., blood HbA1c, ,9%), 2) the presence of fovea-involving ME secondary to DR in the study eye (including focal or diffuse clinically significant macular edema), 3) bestcorrected visual acuity (BCVA) between 20/200 and 20/25, 4) central macular thickness (CMT) $300 mm as measured by spectral domain optical coherence tomography (SD-OCT), 5) follow-up of at least 6 months after the last Ozurdex injection given, and 6) availability of complete medical records including From the *Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy; and †Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France. G. Querques is an advisory board member of Alimera Sciences, Inc, Allergan, Inc, and Bayer Schering Pharma. He is a consultant to Allergan, Inc, Alimera Sciences, Inc, Bayer Schering Pharma, Bausch and Lomb, Novartis Pharmaceuticals Corporation, and Ophthotech. F. Bandello is an advisory board member to Allergan, Inc, Novartis Pharmaceuticals Corporation, Farmila-Thea, Bayer Schering Pharma, Pfizer, Inc, Alcon, Inc, Bausch and Lomb, Genentech, Inc, Alimera Sciences, Inc, and Thrombogenics, Inc. The other authors have no financial/conflicting interests to disclose. Dr G. Querques and Dr F. Bandello have contributed equally to this study and should be considered as equivalent authors. Reprint requests: Giuseppe Querques, MD, PhD, Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Via Olgettina 60, Milan 20132, Italy; e-mail: [email protected]

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BCVA, SD-OCT, and fluorescein angiography throughout the follow-up. The exclusion criteria were: 1) ME secondary to other causes than DR, 2) the presence of other retinopathies/maculopathies (e.g., retinal vein occlusion (RVO), age-related macular degeneration) or visually significant media opacities (e.g., cataract or corneal opacity); 3) history of ocular trauma or surgery #6 months before the first Ozurdex injection, 4) intravitreal triamcinolone #6 months before the first Ozurdex injection, 5) intravitreal antivascular endothelial growth factor (bevacizumab, ranibizumab, or pegaptanib) ,1 month before the first Ozurdex injection, 6) marked intraocular pressure (IOP) elevation in response to any previous steroid treatment, and 7) IOP .23 mmHg without antiglaucoma medication, or IOP .21 mmHg with 1 antiglaucoma medication. Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects. Demographic data of the pooled patients, duration, subtype and grade of DME, presence of macular ischemia, glaucoma, IOP, lens status, previous and subsequent treatments were recorded. During the study period, all patients underwent repeated complete ophthalmic evaluations, including BCVA (logMAR), slit-lamp biomicroscopy, applanation tonometry, fundus biomicroscopy, SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany; Spectra OCT/SLO; OPKO-OTI, Miami, FL) with CMT measurement, and fluorescein angiography (only if considered necessary) (TRC-50DX; Topcon Corporation, Tokio, Japan). With a customized, single-use 22-gauge applicator, through the pars plana, 0.7 mg intravitreal Ozurdex was given in the vitreous cavity of all the patients. Operatory room was the site of every injection. After the treatment, we treated all the patients for 4 days with topical ophthalmic antibiotic and monitored them for adverse effect during the whole period of the study. Dexamethasone implant injections were continued with a minimum interval of 4 months until stable BCVA was reached. However, the treatment was discontinued if no further BCVA improvement was attributable to intravitreal Ozurdex. Retreatment with intravitreal dexamethasone was judged necessary by the treating physician if, at the scheduled follow-up visits, there was a decrease in BCVA because of DME progression. Judgment about the need of retreatment was driven by the following general minimum criteria: 1) fovea-involving intraretinal and/or subretinal fluid, found with fundus biomicroscopy and SD-OCT, which was increased with respect to the peaking efficacy observation; and 2) CMT was higher than 300 mm. Based on the opinion of the physician, it was

1218 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

possible to add other medical/laser treatments during the period between the loss of efficacy of dexamethasone implant and the next injection. Analysis of treatment outcomes included mean change in BCVA and CMT from baseline to each peaking efficacy, and at the time of DME recurrence; the proportion of eyes with at least 2 lines of BCVA improvement, and the proportion of eyes exhibiting $2 lines of BCVA worsening, after repeated intravitreal Ozurdex; retreatment intervals; need for, and effects of combined treatments during the study period; and the incidence of side effects after repeated intravitreal Ozurdex (e.g., marked IOP elevation and cataract progression/surgery). Comparison of BCVA converted to logMAR and CMT between baseline and each peaking efficacy, and at the time of each DME recurrence for the overall population, was performed using Student’s t-test. Comparison of BCVA and CMT between baseline and each peaking efficacy, and at the time of each DME recurrence for the population stratified according to the disease, was performed using the Mann– Whitney test: Type 1 versus Type 2 diabetic patients; older (.55 years of age) versus younger (#55 years of age) patients; proliferative DR versus nonproliferative DR eyes; eyes showing mild macular ischemia versus eyes showing no macular ischemia; or eyes with (.36 months of duration) versus without chronic DME (#36 months of duration). Statistical calculations were performed using Statistical Package for Social Sciences, for Windows version 20 (SPSS, Inc, Chicago, IL). The chosen level of statistical significance was P , 0.05.



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Table 1. Baseline Characteristics of the Study Population Characteristics

n (%)

Patients Sex Male Female Age, years Mean Range Study eyes Mean diabetes duration, years DM type 1 2 Mean HbA1C (%) DME duration before Ozurdex injection, months Mean Range Macular ischemia DME duration ,36 months .36 months Lens status in study eye Phakic Pseudophakic DR Proliferative Nonproliferative

12 6 (50) 6 (50) 62 ± 12 44–81 15 23.1 ± 15.8 7 (47) 8 (53) 7.6 ± 1.2 32 ± 23 2–60 3 (20) 11 (73) 4 (27) 9 (60) 6 (40) 8 (53) 7 (47)

time between diagnosis of DME and the first dexamethasone implant treatment was 7.7 ± 4.7 months (Table 2). Retreatment interval with intravitreal Ozurdex ranged between 4 months and 21 months; it was

Results A total of 15 eyes of 12 patients (6 men, 6 women; mean age, 62 ± 12 years) met the inclusion criteria and were included for the analysis. Four patients (33%) were treated for hypertension, 1 patient (8%) for dyslipidemia, but none had uncontrolled hypertension or hyperlipidemia. Moreover, no patients with renal disease or other comorbidities were enrolled in the study. No changes were found during the follow-up. Mean duration of DME was 32 ± 23 months (range, 2–60 months). Macular ischemia was recorded in 3 eyes (20%) (Table 1). One eye of 1 patient (7%) was treatment-naive, whereas 14 eyes of 11 patients (93%) underwent previous treatments for DME before the first administration of intravitreal Ozurdex (Table 2); 13 eyes of 10 patients (87%) have been undergoing laser photocoagulation of ischemic retina before the first administration of intravitreal Ozurdex. The mean

Table 2. Previous Treatment in the Study eyes

Previous Treatment Total previous treatment Panretinal photocoagulation Anti-VEGF Intravitreal bevacizumab Intravitreal ranibizumab Grid photocoagulation Intravitreal triamcinolone Anti-VEGF + grid photocoagulation Anti-VEGF + intravitreal triamcinolone Intravitreal triamcinolone + grid photocoagulation Anti-VEGF + intravitreal triamcinolone + grid photocoagulation Time from the last treatment to Ozurdex, months VEGF, vascular endothelial growth factor.

No. Eyes, N (%) 14 13 8 8 2 4 5 1 3 1

(93) (87) (53) (53) (13) (27) (33) (7) (20) (7)

0 (0) 7.7 ± 4.7

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REPEATED OZURDEX IMPLANT FOR DME  SCARAMUZZI ET AL

Table 3. Peaking Functional and Morphologic Characteristics of the Study Population After Each Ozurdex Injection

Characteristics BCVA, logMAR CMT, mm

Baseline

Peaking Efficacy Peaking Efficacy Peaking Efficacy Peaking Efficacy After fourth After Third After Second After First Ozurdex Ozurdex Ozurdex Ozurdex

Peaking Efficacy After fifth Ozurdex

0.67 ± 0.33

0.53 ± 0.31

0.53 ± 0.29

0.62 ± 0.26

0.5 ± 0.26

0.5 ± 0.26

546 ± 139

292 ± 43

297 ± 47

293 ± 22

309 ± 35

295 ± 7

judged necessary after 7.8 ± 4.1 months from the first Ozurdex (15 of 15 eyes), 4.8 ± 0.9 months from the second Ozurdex (7 of 15 eyes), 5.3 ± 1.5 months from the third Ozurdex (3 of 15 eyes), and 5.6 ± 2.0 months from the fourth Ozurdex (3 of 15 eyes). Mean baseline BCVA was 0.67 ± 0.33 logMAR before the first administration of intravitreal Ozurdex; it significantly improved to 0.53 ± 0.31 logMAR after a mean of 40.9 ± 18.2 days from the first Ozurdex (peaking efficacy) (P , 0.001), to 0.53 ± 0.29 logMAR after a mean of 34.4 ± 9.0 days from the second Ozurdex (peaking efficacy) (P , 0.003), and stabilized to 0.62 ± 0.26 logMAR after mean of 29.8 ± 12.1 days from the third Ozurdex (peaking efficacy) (P = 0.05), to 0.5 ± 0.26 logMAR after mean of 36.3 ± 3.2 days from the fourth Ozurdex (peaking efficacy) (P = 0.2), and to 0.50 ± 0.26 logMAR after mean of 37.0 ± 2.6 days from the fifth Ozurdex (peaking efficacy) (P = 0.2) (Table 3). Changes in BCVA after each Ozurdex implant injection measured as lines of improvement or worsening and are reported in Figures 1 and 2. Mean baseline CMT significantly decreased from 546 ± 139 mm to 292 ± 43 mm at 39.4 ± 17.9 days from the first Ozurdex (peaking efficacy) (P , 0.001), to 297 ± 47 mm at 33 ± 9.4 days from the second Ozurdex (peaking efficacy) (P , 0.001), to 293 ± 22 mm at 29.8 ± 12.1 days from the third Ozurdex (peaking efficacy) (P = 0.01), and stabilized to 309 ± 35 mm at 36.3 ± 3.2 days from the fourth Ozurdex

(peaking efficacy) (P = 0.1), and to 295 ± 7 mm at 37.0 ± 2.6 days from the fifth Ozurdex (peaking efficacy) (P = 0.1) (Table 3). Mean BCVAs and CMT at the time of each intravitreal Ozurdex readministration are reported in Table 4. A rebound effect (late increase in CMT to a higher level than baseline, after an early response to treatment) occurred in 7 eyes after the first Ozurdex (47%) (mean rebound, 660 ± 181 mm), in 3 eye after the second Ozurdex (20%) (mean rebound, 712 ± 128 mm), in 1 eye after the third Ozurdex (14%) (646 mm), in 1 eye after the fourth Ozurdex (33%) (836 mm), and in no eye after the fifth Ozurdex (0%) (Table 5). Eyes receiving variable combination of antivascular endothelial growth factor treatments and/or macular laser photocoagulation and time of administration after each intravitreal Ozurdex are reported in Table 6. There was no difference in overall outcomes (BCVA and CMT) in Type 1 versus Type 2 diabetic patients; older (.55 years old) versus younger (#55 years old) patients; proliferative DR versus nonproliferative DR eyes; eyes showing mild macular ischemia versus eyes showing no macular ischemia; or eyes with (.36 months of duration) versus without chronic DME (#36 months of duration) (data not shown). Posterior or anterior segment neovascularization did not develop during follow-up in any patient. No serious ocular and systemic adverse events were observed in eyes undergoing repeated Ozurdex. Three

Fig. 1. Percentage of patients showing $2-line improvement after each Ozurdex injection.

Fig. 2. Percentage of patients showing $2-line worsening before each Ozurdex injection.

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Table 4. BCVA and CMT Values at the Time of Retreatment With Ozurdex Injection

Time, months BCVA, logMAR CMT, mm

After First Ozurdex

After Second Ozurdex

After Third Ozurdex

After fourth Ozurdex

7.8 ± 4.1 0.69 ± 0.33 593 ± 146

4.8 ± 0.9 0.87 ± 0.12 569 ± 148

5.3 ± 1.5 0.73 ± 0.31 665 ± 103

5.6 ± 2.0 0.63 ± 0.32 553 ± 250

eyes (20%) developed an IOP increase (mean, 20 mmHg) between 1 month and 3 months after injections: 1 eye (7%) developed IOP increase after the first injection, 1 eye (7%) after the second injection, and 1 eye (7%) after the third injection. Two patients (14%) were treated with timolol maleate, and 1 patient (7%) was treated with brinzolamide–timolol. Cataract progression was observed in 1 of 9 phakic eyes (11.1%) during the study period. A laser or surgical procedure to reduce IOP was not required for any of the study eyes, whereas cataract was extract at the investigator and patient discretion after 18 months from the first Ozurdex injection. Discussion In this study, we evaluated the effects of repeated Ozurdex in the treatment of DME. Overall, we found a sustained functional (BCVA) and morphologic (CMT) improvement in eyes needing retreatment and a good response even after repeated injection, without the development of serious side effects. Zucchiatti et al10 demonstrated that in eyes with persistent DME, single intravitreal Ozurdex implant produces improvement in BCVA and CMT as soon as the first day after the injection, and such improvement is maintained until the fourth month. Recently, Zalewski et al11 reported similar results regarding BCVA increase and side effects occurrence after repeated Ozurdex injections. However, the study sample was small and the results were biased by the exclusion from analysis of the patient who developed cataract. Short-term effect and the durable action of Ozurdex retreatment facilitate combination with laser photocoagulation or intravitreal anti-vascular endothelial growth factor.12,13 Our data show that results in terms of the final BCVA, CMT, and incidence of side effects

are comparable regardless of administration of previous therapies, or combination with other treatments. Similarly, Rishi et al14 observed that after one or more treatments by macular laser photocoagulation and/or anti-vascular endothelial growth factor intravitreal injections, dexamethasone implant injection seems effective in management of recalcitrant DME. The Diabetic Retinopathy Clinical Research Network reported that visual acuity may not improve after treatment with the same time course as the macula thinning. They concluded that BCVA improvement could possibly lag behind anatomical improvement.15 Similarly, we found that after the first and second Ozurdex injections, the CMT decrease was a little faster than the gain in visual acuity. In this study, a rebound effect was recorded in 7 eyes after the first Ozurdex (47%), in 3 eyes after the second Ozurdex (20%), in 1 eye after the third Ozurdex (14%), in 1 eye after the fourth Ozurdex (33%), and in no eye after the fifth Ozurdex (0%) (Table 5). Interestingly, all eyes showing a rebound effect improved again in both BCVA and CMT after readministration of intravitreal Ozurdex. None of our patients had at the time of inclusion, or developed during the follow-up period, uncontrolled hypertension, hyperlipidemia, renal disease, or other comorbities. Therefore, a health status change does not seem to be the cause of the rebound effect. Conversely, no patients maintained glycated hemoglobin levels in the lower range (mean, 7.6 ± 1.2) (Table 1); however, we do not believe that it should be considered as the main reason because .50% of eyes, even with uncontrolled diabetes, did not present a rebound effect. Moreover, we previously demonstrated a similar rebound occurrence and response to readministration of intravitreal dexamethasone implant in patients with ME-related to retinal vein occlusion.16

Table 5. Rebound Effect, Number of Eyes, and Mean CMT After Each Ozurdex Injection Rebound Effect

After First Ozurdex

After Second Ozurdex

After Third Ozurdex

After Fourth Ozurdex

After Fifth Ozurdex

No. eyes, N (%) Mean CMT, mm

7 (47) 660 ± 181

3 (20) 712 ± 128

1 (14) 646

1 (33) 836

0 (0) —

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REPEATED OZURDEX IMPLANT FOR DME  SCARAMUZZI ET AL Table 6. Time Intervals for Treatments Administrated in Addition to Ozurdex Implant Treatments Administrated in Between Repeated Ozurdex #30 .30 to #60 .60 to #90 .90 to #120 .120 to #150 .150 to #180 After first Ozurdex PRP Grid photocoagulation Intravitreal ranibizumab After second Ozurdex PRP Grid photocoagulation Intravitreal ranibizumab After third Ozurdex PRP Grid photocoagulation Intravitreal ranibizumab After fourth Ozurdex PRP Grid photocoagulation Intravitreal ranibizumab After fifth Ozurdex PRP Grid photocoagulation Intravitreal ranibizumab

.180

— — —

— — —

— — 1 (7%)

— — —

1 (7%) — —

— — —

— — —

— — —

— — —

— — —

— 1 (7%) —

1 (7%) — —

— — —

— — 4 (14%)*

— — —

— — —

— — —

— — 2 (29%)

— — —

— — —

— — —

— — —

— — —

— — —

— — 2 (66%)†

— — 1 (33%)†

— — 1 (33%)†

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

*Three treatments on the same eye. †Three injections were administrated on the same patients in the next 3 months. PRP, panretinal photocoagulation.

Boyer et al17 recently reported the results of the MEAD trial. Although our results are consistent with those reported in the MEAD trial regarding functional and anatomical outcomes, it is noteworthy that a large number of our patients required additional injections before 6 months defined as the minimum interval time between 2 treatments by the MEAD study protocol. It is possible that there has been a selection of the more favorable cases (those who gained good results with less number of injections) in the MEAD study population. The relatively high dropout rate in both 0.7 mg and 0.35 mg treatment arms may have driven to an overestimation of the outcomes. Our study has several limitations, being uncontrolled, retrospective, and having a small study population. However, this is one of the first studies to evaluate the efficacy and side effects of intravitreal Ozurdex for DME used repeatedly in real-life conditions over a long time. In conclusion, repeated intravitreal Ozurdex implants administrated in real-life condition, according to the patient functional condition and to the presence of macular edema on SD-OCT, seem effective in the treatment of DME. It may produce long-term clinically meaningful benefits, without other significant side effects than the ones expected after intraocular corticosteroid treatment. Intravitreal Ozurdex may also be effective when used in

combination with other treatments currently available for DME. Further studies are needed to better understand which patients with DME can most benefit, both functionally and morphologically, from repeated Ozurdex treatments. Key words: central macular thickness, dexamethasone implant, macular edema, optical coherence tomography, diabetic retinopathy. References 1. Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48–58. 2. Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136:122–135. 3. Tranos PG, Wickremasinghe SS, Stangos NT, et al. Macular edema. Surv Ophthalmol 2004;49:470–490. 4. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology 1984;91:1464–1474. 5. Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806. 6. Stewart MW. Corticosteroid use for diabetic macular edema: old fad or new trend? Curr Diab Rep 2012;12:364–375. 7. Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev 2008: CD005656. 8. Katzung B, Masters S, Trevor A. Adrenocorticosteroids and Adrenocortical Antagonists. Basic & Clinical Pharmacology. London, United Kingdom: Appleton & Lange, 1995; 592–607.

1222 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 9. Ozurdex [package insert]. Irvine, CA: Allergan Inc; 2009. 10. Zucchiatti I, Lattanzio R, Querques G, et al. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica 2012;228:117–122. 11. Zalewski D, Raczynska D, Raczynska K. Five-month observation of persistent diabetic macular edema after intravitreal injection of Ozurdex implant. Mediators Inflamm 2014;2014: 364143. 12. Bandello F, Battaglia Parodi M, Tremolada G, et al. Steroids as part of combination treatment: the future for the management of macular edema? Ophthalmologica 2010;224:41–45. 13. Callanan DG, Gupta S, Boyer DS, et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013;120:1843–1851.



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14. Rishi P, Rishi E, Kuniyal L, et al. Short-term results of intravitreal dexamethasone implant (OZURDEX) in treatment of recalcitrant diabetic macular edema: a case series. Oman J Ophthalmol 2012;5:79–82. 15. Diabetic Retinopathy Clinical Research Network, Browning DJ, Glassman AR, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology 2007;114:525–536. 16. Querques L, Querques G, Lattanzio R, et al. Repeated intravitreal dexamethasone implant (Ozurdex) for retinal vein occlusion. Ophthalmologica 2013;229:21–25. 17. Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year, Randomized, Sham-Controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904–1914.

Repeated intravitreal dexamethasone implant (Ozurdex) for diabetic macular edema.

To evaluate the effects of repeated intravitreal dexamethasone implant...
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