Retinal vein occlusion (RVO) is the second most common cause of retinal vascular disease after diabetic retinopathy.1,2 Branch retinal vein occlusion (BRVO) is the more common of the two presentations, accounting for approximately 80% of RVO.3 Macular edema (ME) is the most frequent cause of vision loss in BRVO.4 One study reports the prevalence of ME in BRVO to be as high as 60%.5
Grid laser photocoagulation has been considered the gold standard for treatment of macular edema in BRVO.4 However, the clinical outcomes are sometimes disappointing, as the average improvement after laser may leave significant visual disability in many patients, visual improvement occurs very slowly, and laser has the risk of potential complications like enlargement of laser scar, choroidal neovascularization (CNV), subretinal fibrosis, and visual sensitivity deterioration.6
The development of macular edema (ME) following BRVO has been hypothesized to be caused by tissue damage and ischemia, resulting in the release of various inflammatory mediators.7–9 Due to the limitations with laser treatment, many intravitreal pharmacotherapies targeting these inflammatory mediators are now being used as adjuncts or alternative treatment to laser. Intravitreal corticosteroid and anti-vascular growth factor (VEGF) injections have both been studied and found to be efficacious in ME secondary to BRVO.10,11 However, intravitreal steroids have a high risk of developing glaucoma and cataract, whereas intravitreal anti-VEGF agents are expensive and also have a risk of causing cerebrovascular accidents and hypertension.
Diclofenac is a nonsteroidal anti-inflammatory agent that inhibits both the cyclooxygenase and lipoxygenase pathways and has been primarily used as a topical agent in the eye. It was first used intravitreally for macular edema due to various etiologies in 2010.7 Since then, its effect has been studied in diabetic macular edema and uveitic cystoid macular edema and has been found to be efficacious and safe.12–15 However, its role in ME due to BRVO has yet not been studied. To the best of our knowledge, there has been only a single case of ME in BRVO reported where intravitreal diclofenac was used.7 Therefore, we studied the effect of intravitreal diclofenac (IVD) in ME due to BRVO.
Patients and Methods
This was a prospective interventional case study that was performed on 15 eyes of 15 patients with ME due to BRVO who presented to the outpatient department of a tertiary care center in India. The study was performed in accordance with the tenets of the Declaration of Helsinki. After local ethical committee approval, a written informed consent was obtained from each study participant. All patients underwent detailed history taking and clinical examination. A complete ocular evaluation, including measurement of best-corrected visual acuity (BCVA) with the Snellen chart, slit-lamp biomicroscopy, intraocular pressure (IOP) using applanation tonometry, fundus photography, fundus fluorescein angiography (FFA) (Zeiss Visucam NM/FA; Carl Zeiss Meditec AG, Germany), and spectral-domain optical coherence tomography (SD-OCT) (RTVue; Optovue, Fremont, CA) were performed at baseline.
Patients were included in the study if there was presence of macular edema due to BRVO on fundus biomicroscopy and confirmed on FFA; baseline Snellen's BCVA in the study eye less than 6/12, central macular thickness (CMT) on optical coherence tomography (OCT) greater than 250 µm.
Patients were excluded if they had any additional eye disease that could compromise visual acuity, ocular inflammation, intraocular surgery in the last 3 months before presentation, uncontrolled glaucoma, prior treatments with laser photocoagulation or other intervention for macular edema due to BRVO, neovascularization of retina/iris due to BRVO, or any media opacities.
Technique of Injection
Qualified patients were given a single intravitreal injection of 500 µg/0.1 mL of commercially available diclofenac preparation. Treatment was performed as an outpatient procedure. Topical anesthesia was obtained with 0.5% proparacaine eye drops, followed by standard perioperative cleaning and draping. Povidone iodine 5% solution was applied to the periocular areas, eyelids, eyelashes, and conjunctival sac. Diclofenac was injected into the vitreous with a 27-gauge needle 3.5 mm posterior to limbus in pseudophakic and 4 mm posterior to limbus in phakic eyes in inferotemporal quadrant. Tamponade was applied with sterile cotton-tipped applicator to the needle track as it was withdrawn. Indirect ophthalmoscopy was done to confirm intravitreal location of the suspension and perfusion of the optic nerve head.
All patients were examined next day for evaluation of visual acuity, IOP, and evidence of any intraocular inflammation/infection and any other complication. Topical antibiotics were prescribed for 1 week.
Subjects were followed up monthly for 3 months for BCVA, IOP, slit lamp examination for lens status assessment, and fundus examination. FA and OCT were performed at 1 and 3 months.
Main outcome measures were change in BCVA and central macular thickness (CMT). Statistical analysis was done using SPSS (version 22, SPSS, Chicago). Wilcoxon signed rank test was used for pre- and post-treatment comparison. A value of less than or equal to 0.05 was considered statistically significant.
The BRVO study (BVOS) demonstrated a benefit with grid photocoagulation in eyes with BRVO of 3 to 18 months' duration and visual acuity 20/40 to 20/200. It was seen that treated eyes were more likely to gain 2 lines of visual acuity (65%) compared to untreated eyes (37%). Furthermore, treated eyes were more likely to have 20/40 or better vision at 3 years of follow-up (60% vs. 34% untreated).4 Thus, grid laser photocoagulation is considered the gold standard for treatment of macular edema in BRVO.
However, 40% of treated eyes in BVOS had worse than 20/40 visual acuity at 3 years, and 12% of treated eyes had 20/200 or worse visual acuity at 3 years.4 Hence, a large group of patients show only a modest improvement after laser photocoagulation. Also, laser treatment cannot be performed on patients with fresh venous occlusions owing to retinal hemorrhages, and it takes several months for the hemorrhages to clear. During this time, severe retinal edema could compromise retinal cells leading to permanent photoreceptor damage.16 Laser photocoagulation also has potential risks like scar enlargement and CNV formation.6
Intravitreal steroids have been studied and found to be efficacious in ME due to BRVO. Krepler et al. and Tewari et al. found that a single injection of intravitreal triamcinolone (IVTA) produced significant improvement in vision; however, the effect was short-lasting.17,18 The SCORE study also concluded that there was no significant difference in terms of visual acuity outcomes among the groups treated with standard care, 1 mg of IVTA, or 4 mg of IVTA for vision loss associated with ME secondary to BRVO at 12 months.19 However, the risk of cataract formation and glaucoma was very high, especially in the 4 mg group.19 Dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) has also been used for ME secondary to BRVO and has been found to reduce the risk of vision loss and improve the incidence and speed of visual improvement.20
The other class of drugs that has become popular for intravitreal pharmacotherapy for ME in BRVO is anti-VEGF agents. Both bevacizumab and ranibizumab have been found to be effective and safe. In a large, multicenter prospective study, Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion (BRAVO), monthly 0.3 mg and 0.5 mg intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, CA) injections were found to be superior to sham injections in the first 6 months.21 Intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) injections were also found to be effective in ME secondary to BRVO by Prager et al. In their study, they reported that, after 12 months of follow-up time, BCVA was found to be increased by 18 letters and the mean decrease in CRT was 241 µm in the treated eyes.22 Aflibercept (Eylea; Regeneron, Tarrytown, NY) is an anti-VEGF drug that targets all isoforms of VEGF as well as placental growth factor. The VIBRANT study is an ongoing phase 3 trial that has found intravitreal aflibercept to be more efficacious than grid laser in ME due to BRVO.23 However, there is a small but definite risk of systemic adverse effects like acute hypertension, cerebrovascular accidents, myocardial infarctions, iliac artery aneurysms, toe amputations, and, very rarely, deaths with this group of drugs.24 Theoretically, this risk is higher in patients with retinal vascular occlusions, as these patients already have associated systemic risk factors. Thus, none of the intravitreal pharmacotherapies currently used for ME in BRVO are completely risk-free.
Diclofenac is nonsteroidal anti-inflammatory agent that can block both cyclooxygenase and lipoxygenase pathways similar to corticosteroids and thus decrease the production of various prostaglandins, thromboxanes, and leukotrienes.25 It has recently been used intravitreally in various types of macular edema. The initial studies in rabbit eyes found IVD less than 300 µg to be nontoxic to rabbit retina.26 Thereafter, Soheilian et al. did the first pilot study using IVD in macular edema of various etiologies (diabetic macular edema, pseudophakic cystoid macular edema, cystoid macular edema secondary to uveitis, age-related macular degeneration, and a single case of old branch vein occlusion) and found it to be safe and effective in all types of macular edema. The visual acuity improved in seven out of 10 eyes, did not change in two eyes, and decreased in one eye.7 The CMT also decreased in seven eyes, did not change in one eye, and increased in two eyes. None of the patients showed any ocular or systemic side effects, rise in IOP, cataract progression, or changes in electroretinogram. The total follow-up of the study was 8 weeks, and the effect of the drug was seen by as early as 2 weeks.7
Elbendary et al. compared IVD with IVTA (4 mg/0.1 mL) in 32 eyes with diabetic macula edema with a follow-up of 3 months. They found IVD to be as effective as IVTA in reduction of macular edema, although the improvement in visual acuity and incidence of glaucoma was higher in the IVTA group.12 Soheilian et al. recently compared IVD to IVB in 57 eyes with diabetic macular edema and found significantly more visual acuity improvement in the IVD group.15 Studies have also been conducted to evaluate the effect of IVD in uveitic macular edema. Ramezani et al. studied the role of IVD in eight eyes with refractory uveitic macular edema with a follow-up of 36 weeks. Although the mean visual acuity improved and the mean CMT decreased till the end of follow-up, it failed to reach statistical significance. Also, the beneficial effect of IVD was seen to wear off after 12 weeks.14 Soheilian et al. compared IVD with IVTA (2 mg/0.1 mL) in 15 eyes with refractory uveitic ME and did not find any improvement in the IVD group with respect to either visual acuity or CMT. They attributed the inferior response of IVD to a short half-life of 2.87 hours. They also recommended use of slow-release formulations or repeat injections.13
We evaluated the effect of IVD in ME in BRVO and found visual improvement in 80% of eyes at the end of our follow-up of 3 months. As seen in the previous studies, maximum change in vision and CMT was seen in the first month. Five eyes showed complete resolution of edema and four eyes reached a vision of 20/40 or more. None of the eyes had a decrease in visual acuity. Twelve eyes responded with decrease in ME. However, as the group consisted of BRVO of all durations, the vision improvement was not significant in old BRVO cases, despite resolution/decrease in macular edema.
Costagliola et al. have studied the effect of diclofenac on IOP. Endogenous prostaglandins can modulate IOP by synergistic or antagonistic effect on prostaglandin receptors. Hence, they can both increase and decrease IOP. Diclofenac may preferentially inhibit the action of prostaglandins on a particular subtype of receptors, hence decreasing the IOP.27 In our study, there was no significant change in the IOP at 3 months. No other ocular/systemic complications were seen in our study. None of the patients developed neovascularization of retina or iris during the follow-up, which might be due to the downregulation of prostaglandin E2 by diclofenac. Prostaglandin E2, the major prostaglandin in the retina, induces both VEGF and basic fibroblast growth factor mRNA expression.28 Thus, diclofenac causes a decrease in VEGF expression in the eye, as well.
To the best of our knowledge, our study is the first to evaluate the effect of IVD on ME in BRVO. We found IVD to be effective and safe in ME in BRVO with regard to improving visual acuity, as well as decreasing CMT during the course of our short follow-up. However, further studies with longer follow-up and a control group, on a larger subset of patients, is required to investigate the role of IVD in ME in BRVO. Additionally, studies with repeat injections of diclofenac, IVD in combination with IVTA/IVB in lower doses, IVD followed by grid photocoagulation, and sustained-release formulations of diclofenac can be tried in the future.
To conclude, intravitreal diclofenac is a promising new pharmacotherapy for macular edema in BRVO.