ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–4 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.975242


Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion

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Nilufer Ilhan1, Mesut Coskun1, Ozgur Ilhan1, Esra Ayhan Tuzcu1, Mutlu Cihan Daglıoglu1, Ahmet Elbeyli2, Ugurcan Keskin1, and Huseyin Oksuz1 1

Department of Ophthalmology, Medical Faculty of the Mustafa Kemal University, Hatay, Turkey and 2Department of Ophthalmology, Antakya State Hospital, Hatay, Turkey Abstract


Objective: To evaluate the effects of dexamethasone (DEX) implant (OzurdexÕ ) on corneal endothelium in patients with retinal vein occlusion complicated with macular edema. Materials and methods: Patients (n ¼ 31) received 1–3 intravitreal DEX implants in one eye. Measurements were intraocular pressure (IOP) at baseline and 1, 3, and 6 months after the first intravitreal injection and corneal specular microscopy and central corneal thickness (CCT) at baseline and 1 and 6 months. We analyzed endothelial cell density (ECD), coefficient of variation of cell size (CV), and percentage of hexagonality. Results: Mean follow-up period was 9.7 ± 3.3 months. Mean number of injections was 1.5 ± 0.8. Mean IOP values were 15.6 ± 2.6 mm Hg at baseline, 17.7 ± 3.6 mm Hg at one month, 16.4 ± 4.1 mm Hg at three months, and 16.0 ± 2.7 mm Hg at six months. There was a significant difference in mean IOPs at one month and six months (p ¼ 0.008). There were no significant differences in mean ECD (p ¼ 0.375), CV (p ¼ 0.661), percentage of hexagonality (p ¼ 0.287), and CCT (p ¼ 0.331). Conclusion: Although intravitreal injection of 0.7 mg DEX causes moderate elevation of IOP, it does not seem to have detrimental effects on corneal endothelium at six months.

Anterior eye segment, corticosteroid, drug delivery systems

Introduction Corticosteroids have anti-inflammatory and anti-angiogenic effects that make them a preferable choice for various posterior segment diseases1. The anti-inflammatory activity of dexamethasone (DEX) is 5 times more potent than triamcinolone acetonide and 30 times more potent than cortisol, which allows higher vitreous concentrations2–5. The OzurdexÕ (Allergan Inc., Irvine, CA) DEX drug delivery system (DDS) is a biodegradable, intravitreal implant that supplies sustained release of 700 mg preservative-free DEX to vitreoretinal tissues. It has been approved by the United States Food and Drug Administration (FDA) for macular edema secondary to retinal vein occlusions (RVO) and noninfectious posterior uveitis. Corticosteroids, such as DEX, produce anti-inflammatory effects in multiple signal transduction pathways by inhibiting the production of inflammatory mediators, such as interleukin-6, prostaglandins, and vascular endothelial growth factor (VEGF)1,6–8. In addition, messenger ribonucleic acids (mRNA) encoding glucocorticoid receptors were shown in

Address for correspondence: Dr. Nilufer Ilhan, Department of Ophthalmology, Medical Faculty of the Mustafa Kemal University, Hatay, Turkey. E-mail: [email protected]

History Received 29 August 2014 Revised 16 September 2014 Accepted 3 October 2014 Published online 27 October 2014

corneal endothelium9,10. The DEX implant may affect corneal endothelial cell layer mechanisms through such mediators. In a rabbit model, researchers found that intravitreal injection of dexamethasone, up to 440 mg, was not toxic to ocular tissues, including retina, lens, and cornea4. However, there is no published data investigating the effects of DEX implants on human corneal endothelium. Therefore, the aim of our study was to evaluate the effect of the DEX implant on corneal endothelial cell layer in patients with RVO.

Methods This prospective clinical study was conducted from October 2012 to May 2014 in the Department of Ophthalmology, School of Medicine, Mustafa Kemal University. The study was approved by the ethics committee of Mustafa Kemal University. The study was conducted according to the Declaration of Helsinki. Patients were informed about the research and signed consent forms. The study included 31 patients who had RVO with macular edema. Patients were studied for at least six months. Exclusion criteria included age over 80 years, contact lens wear, or endothelial cell count less than 1000/mm2, or a history of intraocular surgery, ocular trauma, uveitis, corneal opacity, or Fuchs endothelial dystrophy.


N. Ilhan et al.

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Clinical examinations A detailed ophthalmological examination, including bestcorrected visual acuity, intraocular pressure (IOP) measurement using a Goldmann applanation tonometer, slit-lamp biomicroscopy, fundus and optical coherence tomography (OCT) examinations, and fluorescein angiography, was performed on each patient before beginning treatment (baseline). Scans of the macula were performed using a Cirrus spectral domain OCT (SD-OCT; Carl Zeiss Meditec, Dublin, CA). All patients had a central foveal thickness of at least 300 mm. In addition to baseline, IOP was measured 1, 3, and 6 months after the first injection, and specular microscopic and pachymetric analyses were performed at 1 and 6 months. A masked examiner evaluated each patient’s endothelial cells using three digital photographs of the central cornea (Topcon SP 3000P noncontact specular microscope, Topcon Corporation, Tokyo, Japan). The same examiner manually marked at least 100 neighboring cells for analysis, using a mouse and the Imagenet software program (Topcon Corporation, Tokyo, Japan). Based on the study by McCarey et al. ECD, percentage of hexagonality, and coefficient of variation in cell size (CV) measurements were carried on the photographs of good quality11. We calculated these values automatically using specular microscopy. We then applied proparacaine hydrochloride (0.5%) and, after 1 min, measured central corneal thickness (CCT) using ultrasound pachymetry (US 4000; Nidek, Japan). The subject fixated on a distant target, the pachymeter probe was localized perpendicularly and centrally to the cornea as exactly as possible. Three successive measurements were taken and then they were averaged. Subjects were examined in rooms with central air conditioning (temperature: 15–25  C; humidity: 30–50%) from 10:00 a.m. to 4:00 p.m. DEX implant injection Before an injection, the eye was anesthetized by proparacaine hydrochloride (Alcaine %0.5, Alcon Pharmaceuticals, Couver, Belgium), and the eyelids and ocular surface were disinfected with 5% povidone iodine. The DEX implant was then delivered through a 22-gauge needle, with a preloaded DEX implant applicator (OzurdexÕ ), inserted into the vitreous cavity through the pars plana (4 mm behind the limbus). Ofloxacin (ExocinÕ , Allergan Pharmaceuticals Ltd., Westport, Ireland) drops were applied four times daily for one week. Additional injections were given at follow-ups if the macular edema relapsed. Elevated IOP was noted as a

complication, and antiglaucomatous drops were given when IOP was higher than 24 mm Hg. Statistical analysis Statistical analyses were performed using SPSS for Windows (Statistical Package for Social Sciences 16.0, SPSS Inc., Chicago, IL). General linear models with repeated-measures analysis of variance (ANOVA) were used to analyze differences in IOPs and in specular microscopy and pachymetry parameters. For all analyses, p50.05 was considered statistically significant.

Results The study included 9 (29.0%) patients with central RVO and 22 (70.9%) patients with branch RVO. Patients’ mean age was 62.9 ± 11.5 years (range 35–79 years; 17 male, 14 female), and mean duration of the disease, before treatment, was 3.1 ± 2.2 months (range 1–12 months). Mean follow-up period was 9.7 ± 3.3 months (range 6–18 months), and all patients completed the six month follow-up examination. The mean number of injections was 1.5 ± 0.8 (range 1–3 injections). Mean IOPs were 15.6 ± 2.6 mm Hg (baseline), 17.7 ± 3.6 mm Hg (month one), 16.4 ± 4.1 mmHg (month three), and 16.0 ± 2.7 mm Hg (month six); there was a significant difference between month-one and month-six mean IOPs (p ¼ 0.008). However, there were no significant differences in mean ECD (P ¼ 0.375), CV (p ¼ 0.661), percentage of hexagonality (p ¼ 0.287), and CCT (p ¼ 0.331) between baseline, month one, and month six (see Table 1 for means). Similarly, there were no significant differences for these measurements in the 12 patients (38.7%) who received more than one injection. However, for six patients (19.3%), IOP became higher than 24 mm Hg. They were all successfully treated with antiglaucomatous drops. IOPs did not rise above 28 mmHg, and no patients exhibited corneal edema. No other complications, such as intraoperative lens injuries, endophthalmitis, retinal detachment, or migration of the implant to the anterior chamber, were observed.

Discussion After diabetic retinopathy, RVO is the second most frequent retinal vascular disease, and several treatment methods are available for the treatment of RVO12. Ranibizumab, DEX

Table 1. Mean values of endothelial cell density, coefficient of variation, percentage of hexagonality and central corneal thickness of patients at baseline and after dexamethasone implant therapy.

Baseline Month One Month Six *p

ECD (cells/mm2) Mean ± SD (Range)

CV (%) Mean ± SD (Range)

HEX (%) Mean ± SD (Range)

CCT (mm) Mean ± SD (Range)

2457 ± 436 (1215–3267) 2445 ± 446 (1185–3242) 2454 ± 438 (1200–3202) 0.375

36.2 ± 5.0 (28–44.8) 35.9 ± 4.8 (26–47) 36.2 ± 5.1 (25–47) 0.661

50.6 ± 7.4 (34–62) 51.0 ± 7.8 (36–66) 51.3 ± 7.4 (37–65) 0.287

513.7 ± 34.8 (450–587) 515.7 ± 37.1 (442–594) 514.5 ± 36.6 (440–596) 0.331

ECD: endothelial cell density, CV: coefficient of variation, HEX: hexagonality, CCT: central corneal thickness, mm: micrometer, SD: standard deviation, *ANOVA: Analysis of variance.

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DOI: 10.3109/15569527.2014.975242

intravitreal implant, and, recently, aflibercept have been approved for treatment of macular edema due to RVO in the UK, Europe, and the USA13. Unlike other treatments, however, DEX implant reduces the need for repeated intravitreal injections in chronic macular edema14. It is also well tolerated and maintains visual acuity up to three months after injection15,16. A pharmacokinetic animal study demonstrated that, after DEX implant injection, DEX persisted in the retina and vitreous for six months, with peak concentrations during the first two months. In the second phase, low concentrations of DEX were observed14. Despite positive results, there are some concerns about the elevation of IOP regarding the use of DEX implants. However, the results of a multicenter, prospective, doublemasked, phase 3 controlled clinical trial showed that DEX DDS was well tolerated and useful for macular edema associated with branch RVO or central RVO16. In that study, 16% of patients had IOP424 mm Hg at day 60, and 29.7% of patients received antiglaucomatous medication at day 90; baseline IOP values were achieved by day 180. Only five patients (7%) required glaucoma surgery for IOP control. Similarly, in a retrospective, multicenter study, IOP elevation developed in 20% of patients. Elevated IOP was the most common complication, and none of the patients required surgical intervention17. A recent study comparing the results of DEX intravitreal implant and macular grid laser in patients with branch RVO demonstrated 12% IOP elevation18. Finally, we found similar effects on IOP: in our study, six patients (19.3%) developed IOP424 mm Hg 1–3 months following the DEX implant injection, and all were successfully treated with IOP-lowering medication. Moreover, CCT measurements were performed by ultrasound pachymetry (still regarded as the gold standard) rather than optical method by specular microscopy to avoid underestimating CCT19. We found that CCTs did not differ significantly during followups, and no patients exhibited corneal edema. Taken together, our results indicate that, although DEX implant may cause mild IOP elevation, it does not lead to acute corneal damage. Previous immunohistochemistry studies detected mRNA encoding glucocorticoid receptor in corneal endothelium9,10, so there is some concern that DEX implants may influence the function of corneal endothelium. An in vitro study in which bovine corneal endothelial cells were cultured with different concentrations of DEX showed that DEX leads to cellular apoptosis and/or necrosis at higher concentrations20. In contrast, another study showed that DEX-loaded nanoparticles were a safe method of intravitreal application of DEX to ocular tissues21. There are some other human studies about the effect of steroids on corneal endothelium. Jamil et al. studied the effect of intracameral use of dexamethasone (0.4 mg) on corneal endothelial cells by specular microscopy. They suggested that no toxicity occurred after the use of intracameral dexamethasone at the end of cataract surgery22. Also Reinhard et al. showed that intracameral application of DEX in patients with endothelial immune reactions after penetrating keratoplasty was a safe method for corneal endothelium23. Moreover, intracameral triamcinolone as a long-acting crystalline corticosteroid was non-toxic for pediatric eyes24,25.

Dexamethasone implant and corneal endothelium


To our knowledge, however, ours is the first specular microscopy study to investigate the effects of DEX DDS on human corneal endothelium. We found no statistical variation of ECD, CV, or percentage of hexagonality during a 6-month period. DEX implants did not cause ECD reduction or alterations of endothelial cell morphology. We also observed no difference in the 12 patients who received more than one injection. Thus, in our study, the DEX implant had no harmful effect on corneal endothelium. The corneal endothelium can also be harmed by the migration of DEX implants to the anterior chamber, which can happen in aphakia or with posterior capsule defect. Khurana et al. reported 15 cases of spontaneous migration of a DEX implant26. In addition, corneal edema occurred in 14 patients (93.3%), six (40%) of whom required keratoplasty. The authors concluded that the endothelial decompensation was due to mechanical trauma rather than to chemical toxicity caused by the DEX implant. In two studies, application of a smaller form of DEX implant (60 mg) to the anterior chamber was safe and effective in controlling cataract surgery induced inflammation27,28. Consequently, these studies suggest that intravitreal DEX implants have no toxic effects on corneal endothelium, which supports our results. Other treatments for RVO have also been tested for their effects on the corneal endothelium. A study evaluating the effect of monthly intravitreal injection of ranibizumab on the corneal endothelium in patients with age-related macular degeneration demonstrated that ranibizumab had no harmful effects on the corneal endothelium29. Chiang et al. also obtained similar results for bevacizumab in patients with macular disorders30. As we mentioned above, DEX implants also do not have detrimental effects on cornea.

Conclusions There are some limitations of our study: the follow-up time was short and the sample size was small. Despite these limitations, this study is important because it provides the first evidence that the DEX implant may be safe for human corneal endothelium. However, long-term, comprehensive studies are needed to clarify the effects of DEX-loaded DDSs on human cornea.

Declaration of interest The authors report no declarations of interest.

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Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion.

To evaluate the effects of dexamethasone (DEX) implant (Ozurdex(®)) on corneal endothelium in patients with retinal vein occlusion complicated with ma...
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