Treatment Options of Macular Edema Secondary to Retinal Vein Occlusion ( RVO ) : A Review

Retinal Vein Occlusion (RVO) is a common retinal vascular disease secondary to diabetic retinopathy resulting in permanent loss of vision despite available treatment options. Main vision impending complication of retinal vein occlusion is macular edema. Laser photocoagulation has been an established method for treating macular edema for many years but nowadays intravitreal injection of Anti-Vascular endothelial growth factors (Ranibizumab, Aflibercept Bevacizumab and Pegaptanib sodium) is the treatment of choice for macular edema from retinal vein occlusion. Intra-vitreal corticosteroids Triamcinolone Acetonide and Dexamethasone implant, are also being used to treat in some macular edema cases but with higher rates of side effects. Numerous surgical methods have been attempted for treating RVO and preventing macular edema; they include pars plana vitrectomy, radial optic neurotomy, laser induced chorioretinal anastomosis, and arteriovenous sheathotomy. Surgical methods supposedly relieve compression of the central retinal vein, altering the pathophysiology of vein occlusion at the level of the lamina cribrosa thus improving blood flow and oxygenation. But limitations result from its complications.


Introduction
Retinal Vein Occlusion (RVO) is the cause of the second most common retinal vascular disease after diabetic retinopathy resulting in potential irreversible loss of vision.Main vision impending complication of RVO is macular edema (ME).
Types of RVO are: branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO).CRVO is occlusion of central retinal vein, and BRVO occlusion in branch retinal vein [1].Hayreh divided RVO into 3 types: 1) BRVO divided into major BRVO and macular BRVO; 2) CRVO divided into ischemic (I-CRVO) and nonischemic (NI_CRVO); and 3) hemi-CRVO involving half of the retina and further divided into ischemic and nonischemic types [2].According to a pooled analysis of population-based data, RVO prevalence in the USA, Europe, Asia, and Australia containing 68,751 individuals from 31 to 101 years of age was 5.20 per 1000 for any RVO, 4.42 per 1000 for BRVO, and 0.80 per 1000 for CRVO.It is suggested around 16.4 million people are affected by RVO (BRVO = 13.9 million and CRVO = 2.5 million).BRVO is common than CRVO.
Prevalence of RVO varied by ethnicity being highest in Hispanics and Asians and increased with age, but did not differ by gender [3].Individuals with BRVO in 1 eye have a 10% risk of any RVO in the contra-lateral eye within 3 years.The estimated risk of contralateral involvement in people with CRVO is ~1% per year, which increases to 7% at 5 years [1].
RVO pathogenesis (Figure 1) is multifactorial.RVO may be due to Virchow's triad: 1) hemodynamic changes (venous stasis), 2) degenerative changes of the vessel wall, and 3) blood hypercoagulability [5].RVO may lead to fluid leak from capillaries draining into the obstructed vein, caused by secretion of VEGF and interleukin-6, and resulting in ME. [6].Atherosclerosis is associated with RVO [7].RVO can also be secondary to inflammation, vasospasm, or compression of retinal vessels [8].RVO risk factors can be systemic and ophthalmic.Systemic

Mechanism of Macular Edema from RVO (Figure 2)
Macular edema is characterized by fluid collection within the retina, due to the VEGF is proven to play crucial role in pathological process.VEGF expression is up-regulated by hypoxia and other stimuli.Intravitreal VEGF levels were noted to be elevated in patients with RVO [14] [15] [16].Main complication of retinal vein occlusion is vision loss due to macular edema (Table 1).

Treatment Options for ME Secondary to RVO
Treatment of RVO focuses on treating its outcome rather than restoring normal venous circulation.Management of RVO includes managing ME, treating risk factors and preventing occurrence of NVI, NVA, NVE.Multiple clinical trials have been done in the past (Table 2) and more ongoing in present to find most suitable treatment options for macular edema.Nowadays intravitreal injection of anti-VEGF, Triamcinolone Acetonide and dexamethasone implant, are in priority to treat ME and other RVO's complications.Surgical anastomoses [18] and laser have been tried [19] to relieve the obstruction by using thrombolytic administration [20] and by passing the congestion via optic nerve sheathotomy [21] but, limitations results from its complications.

Laser for ME
Laser has been established method for treating RVO [22] [23].Laser technique for resolving ME is macular grid photocoagulation while pan retinal (scatter) laser photocoagulation (PRPC) is used in treating retinal or disc neovascularization.Laser works by preventing secretion of chemical mediators originating from disturbed hemodynamics of retinal capillary and damaged tissue after RVO.The BVOS trial explored use of laser treatment for ME from BRVO reporting vision improvement in about 1/3 of cases in first 3 months.Grid laser was considered after an FFA after 3 months in eyes with persistent ME and VA below 20/40.At 3 years endpoint, average of 1.33 lines was gained by treated eyes compared to 0.23 lines in control group.Since then, macular grid laser Table 1.Vision loss mechanism in eyes with macular edema following retinal vein occlusion [17].[26].
Other study compared ranibizumab with standard grid laser for ME due to BRVO but found benefits in visual acuity gain and anatomic improvement with laser [27].Some study say PRPC is not needed in NI-CRVO while a review [28] of 17 RCT concluded that though prophylactic PRPC did not prevent NVA/NVI or eliminated NVG risk for patient I-CRVO, it resulted in regression NVA/NVI and reduced progression to NVG.Today, intravitreal treatment has largely replaced laser as choice of intervention for RVO.

Anti-VEGF
Currently four anti-VEGF drugs are available to treat CRVO and BRVO.Ranibizumab and aflibercept are US FDA approved, while bevacizumab and pegaptanib sodium is an off-label drug.Anti-VEGF therapy is now the treatment of choice for RVO disease.Patients with CRVO (n = 33) and BRVO (n = 55) were included.After 1 month, BCVA and OCT were recorded.If <30% improvement in BCVA and CMT, two injections were added at 1.5-month intervals.others were injected as per need.
After a year 74% had clinically significant improvement of BCVA (>0.3 log MAR) with 1.98 average number of injections.Both groups had clinically significant mean BCVA improvement from baseline vision and decrease in CMT.Pan retinal laser photocoagulation was done in 75.8% of all eyes with CRVO and sectoral photocoagulation in 49.1% of eyes with BRVO [42].
2) Ranibizumab: (Lucentis) is a monoclonal antibody fragment which binds all forms of VEGF.The BRAVO Study (Ranibizumab for the treatment of macular edema following BRVO) studied the Efficacy and Safety of Ranibizumab Injection in Patients with ME Secondary to BRVO.Study showed, 55% patient receiving 0.3 mg and 61% of patients receiving 0.5 mg ranibizumab, achieved 3-line vision improvement compared with 29% in the control group.Continued PRN treatment showed stabilizing vision, although laser was added in almost 50% of patients [43].The CRUISE Trial (Ranibizumab for the treatment of macular edema after Central Retinal Vein Occlusion Study) studied Ranibizumab for treating ME from CRVO.392 patients with ME secondary to CRVO were randomized to 0.3 mg or 0.5 mg of ranibizumab, or sham injection.At 6 months, 46% in 0.3 mg group and 48% in 0.5 mg group, showed improvement of 3 lines vision versus 17% in the control group [44].Recently a study concluded no notable difference in outcome between IVR and IVB when treating ME from RVO for a year in routine clinical practice.This information might be of use in uplifting treatment burden of patient in the developing nations [45].
3) Aflibercept: Aflibercept (VEGF Trap-Eye) Intravitreal Aflibercept binds to VEGF-A, VEGF-B and placental growth factor (PIGF) and inhibits their activity with a higher affinity than ranibizumab.The VIBRANT trial evaluated efficacy of aflibercept over grid laser in patients with BRVO and ME.Patient received either Intravitreal Aflibercept (IAI) 2 mg every 4 weeks (n = 91) from baseline to week 20 or grid laser (n = 92) at baseline with single laser treatment if needed, from weeks 12 through 20.Eyes gaining ≥15 ETDRS letters from baseline at week 24 was 52.7% in the IAI group compared with 26.7% in the laser group.At week 24 Mean improvement from baseline BCVA was 17.0 ETDRS letters in IAI group and 6.9 ETDRS letters in laser group while mean reduction in CRT was 280.5 μm in IAI group and 128.0 μm in laser group.52-week result of VIBRANT study concluded that after 6 monthly IAI, injections every 8 weeks-maintained control of ME and visual benefits through week 52.In laser group, rescue IAI given after 24 week produced solid vision improvement at week 52 [46] [47].The COPERNICUS study and The GALILEO study both evaluated safety and ef-Open Journal of Ophthalmology ficacy of IAI in treating ME from CRVO.After one year Over 50% of treated eyes gained ≥15 ETDRS letters from baseline in both studies [48] [49].A study Compared Efficacy of Intravitreal Aflibercept and Bevacizumab for ME due to BRVO.For 12 months patients (n = 27) received PRN IVB or (n = 25) PRN IAI with monthly follow-ups.Around 2/3 of the patients in both groups had final BCVA ≥ 20/40 and visual gains > 3 lines from baseline to month 12. Mean number of aflibercept and bevacizumab injection was 2.12 and 2.22 during period of 12-month.Both IAI and IVB were effective in reducing macular thickness and improving visual acuity [50].

Surgical and Other Treatments
Numerous surgical methods have been attempted for treating RVO.Treatments include pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) peeling, radial optic neurotomy (RON), and laser induced chorioretinal anastomosis (LCA), tissue plasminogen activator (tPA) and arteriovenous sheathotomy.These methods supposedly relieve compression of the central retinal vein, altering the pathophysiology of RVO at the level of the lamina cribrosa (RON) or by improving blood flow and oxygenation (PPV, LCA) [53] [54].Some studies [55] show LMWH role in the acute treatment of RVO while other study [56] shows Parnaparin to be more effective than aspirin in preventing functional worsening in RVO.Study by Hayreh [57] showed use of aspirin, other anti-platelet aggregating agents, or anticoagulants in patients with CRVO and hemi-CRVO was associated with a worse visual outcome and no credible benefit.Case reports of patients treated with clopidogrel, tPA (both intravitreal and into a vein), heparin, aspirin, LMWH, or hemodilution, have shown variable results.But none of the treatment methods has shown to prevent the vision loss from RVO and larger clinical trial allowing a guidance is required.

Summary
Today RVO is a prevalent disease of retinal vessels secondary to diabetic retino-pathy.The main complication of retinal vein occlusion is vision loss due to macular edema.Anti-VEGF therapy is the current standard of care for treating ME due to less side effect profile than intravitreal steroids which has a higher incidence of increased intraocular pressure and cataract formation.Future awaits more effective single or combined treatments for macular edema while minimizing health care cost.
either the inner nuclear layer (INL) or the ganglion cell layer (GCL) due to ischemia in the inner retina Irreversible Neuro-retinal swelling due to macular edema Light scattering resulting in a reduced amount of light received by photoreceptors at the fovea Compromised neural transduction from photoreceptors to inner retinal neurons Reversible *The disruption of the outer segment of photoreceptors might be reversible during a sufficiently long follow-up period.

4 )
Pegaptanib sodium: (Macugen) is a selective antagonist binding to 165 isoforms of VEGF.For ME from CRVO Wroblewski et al. reported, double-masked phase two trial.Patients with CRVO for ≤6 months were randomly assigned (1:1:1) to injection of pegaptanib (n = 33) 1 mg and 0.3 mg, or sham (n = 32) every 6 weeks for 24 weeks.At 30 weeks eyes gaining≥15 letters among treatment groups was not significantly different.Study concluded pegaptanib appears to provide both visual and anatomical benefits in the treating ME from CRVO.Wroblewski et al. also (level II) assessed use of pegaptanib sodium for ME from BRVO.Subjects received pegaptanib 0.3 mg (n = 15) and 1 mg (n = 5) at baseline and at weeks 6 and 12 with subsequent injections at 6-week intervals up to 48 weeks.Both groups had similar outcomes from baseline to week 54 in mean BCVA (+14 ± 13 letters) and central subfield thickness (−201 ± 153 µm) [51] [52].

Table 2 .
[25]ical trials in treating ME from RVO. Open Journal of Ophthalmology photocoagulation became gold standard for BRVO[24].The central Vein occlusion group (CVOS) was planned to use laser for CRVO induced ME.It resulted in ME reduction but, no upgrade in visual acuity and final visual outcome was found compared to control group.Thus, observation became standard care for ME from CRVO[25].Campochiaro in The RELATE Trial concluded that Scatter Photocoagulation does not reduce ME or treatment Burden in RVO eye DEX = Dexamethasone implant, IVTA = Intra Vitreal Triamcinolone, IVB = Intra Vitreal Bevacizumab, RNZ = Ranibizumab, IAI = Intra Vitreal Aflibercept, VTE = VEGF Trap Eye.
Study reported significant increase in VA from baseline in both DEX implant groups than sham from day 30 -180 with greatest response at day 60.With no statistical difference in two DEX groups at any follow-up visit.Mean decrease in CST was signifi- [37]riamcinolone Acetonide: is intermediate acting powerful steroid.It deadens the humoral and cell-mediated component of inflammatory process and decreases vessel permeability, resolving ME.It blocks breakdown of the blood ocular barrier by modulating effector proteins downstream of VEGF receptor [29].The SCORE Study (Standard Care versus Corticosteroid for Retinal VeinOcclusion) compared patients with both BRVO and CRVO using 4 and 1 mg of triamcinolone acetonide vs observation for 12 months[30][31].BRVO patient treated with 1 or 4 mg of triamcinolone versus focal laser showed that all groups achieved visual acuity score of ≥15 letters from baseline.In CRVO patient 7%, 27%, and 26% of participants achieved visual acuity score of ≥15 letters in the observation, 1-mg, and 4-mg groups.The complication rates of cataracts and increased IOP were greater in the 4 mg than 1 mg group.Despite SCORE's result anti-VEGF has replaced corticosteroid as treatment choice for RVO because of side effects.High dose 20 mg IVTA has been found to be safe and cost effective alternative to Anti-VEGF in treating ME from RVO in lower-middle-income countries despite high risk of cataract and IOP rise when weighed against the vision loss risk due to unaffordable anti-VEGF treatment[32].dexamethasone in RVO) a multicenter trials surveyed CRVO and BRVO patients treated with intravitreal DEX implant IVD (0.7 mg vs 0.35 mg) vs sham at day one and 0.7 mg at open extension on day 180[34][35].perfusionatbaseline.Adverse events were increased IOP (35%) and newly diagnosed cataract (16%).Study concluded DEX implant with interval of ≥4 months provides rapid and significantly better improvement in BCVA and CRT in BRVO-associated ME[36].A study compared 4 mg of IVTA (n = 20) and 0.7 mg IVD (n = 20) for treating ME from NI-CRVO over 6 months.Study resulted that even patient achieving ≥15 letters was 40% in both groups, IOP rise and cataract progression was 2.4 and 3.5 times higher respectively in IVTA than IVD.Thus concluding Intravitreal steroids to be effective in managing ME from RVO, while IVD being significantly safer than IVTA[37].
[41]3.3% in the (sh/bz) group.Mean decrease CRT was 435 μm and 404 μm in the bz/bz and sh/bz group respectively.Study concluded IVB given every 6 weeks for 12 months improves VA and reduce ME significantly, while delayed treatment may limit visual improvement.[40][41].A study evaluated 1-year efficacy and safety of low-frequency IVB in treating ME due RVO.