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 Table of Contents  
MAJOR REVIEW
Year : 2016  |  Volume : 28  |  Issue : 1  |  Page : 4-13

Retinal vein occlusion


Department of Vitreoretinal Services, Aravind Eye Hospital, Coimbatore, Tamil Nadu, India

Date of Web Publication11-Nov-2016

Correspondence Address:
Rodney Morris
Department of Vitreoretinal Services, Aravind Eye Hospital, Coimbatore - 641 014, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-6677.193868

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  Abstract 


Retinal vein occlusion is commonly seen in the elderly.This article aims to comprehensively discuss the etiology,classification,risk factors and latest modalities of management of this condition.

Keywords: BRVO; CRVO; hypertension; macular edema


How to cite this article:
Morris R. Retinal vein occlusion. Kerala J Ophthalmol 2016;28:4-13

How to cite this URL:
Morris R. Retinal vein occlusion. Kerala J Ophthalmol [serial online] 2016 [cited 2019 Jan 21];28:4-13. Available from: http://www.kjophthal.com/text.asp?2016/28/1/4/193868




  Introduction Top


Retinal vein occlusions (RVO), a sight threatening condition in older adults is a major retinal vascular disorder. It is the second most common retinal vascular disease following diabetic retinopathy,[1],[2] with branch retinal vein occlusion (BRVO) occurring 2–6 times as frequently as central retinal vein occlusion (CRVO).[3] The prevalence of RVO ranges from 0.7–2% in persons older than 40 years of age.[4],[5],[6] No gender or racial differences in prevalence in RVO have been reported. Majority of cases have unilateral involvement, however, 5–6% of BRVO and 10% of CRVO patients present with bilateral involvement.[4] Although the exact etiology has been poorly understood, RVO is known to induce ischemic and hypoxic state that leads to visually significant sequel including macular edema, anterior segment, and retinal neovascularization.


  Terminology and Disease Classification Top


RVO is an obstruction in the retinal venous system by thrombus formation and may involve central, hemi-central, and branch retinal vein.

CRVO is due to a thrombosis of the central retinal vein when it passes through lamina cribrosa.[7]

BRVO is caused by venous thrombosis at an arteriovenous crossing where an artery and vein share a common vascular sheath.

Hemi-retinal vein occlusion (HRVO) affects either the superior or inferior part of the retina.

RVO has been classified by Hayreh [8] into the following six distinct clinical entities.



  1. CRVO


    • Non-ischemic CRVO (or venous stasis retinopathy)
    • Ischemic CRVO (or hemorrhagic retinopathy)
  2. Hemi-central retinal vein occlusion (HCRVO)


    • Non-ischemic HCRVO (or hemi-venous stasis retinopathy)
    • Ischemic HCRVO (or hemi-hemorrhagic retinopathy)
  3. BRVO


    • Major BRVO
    • Macular BRVO.
Epidemiology of retinal vein occlusion

RVO is a common cause of vision loss in United Kingdom.[3] There is no prevalence or incidence data from England or Wales. In 2008, US reported 15-year incidence of 500 new cases of CRVO per 100,000 population and 1800 BRVO cases per 100,000 population.[9] Both CRVO and BRVO have an increased rate of incidence and prevalence with age. Australian data [4] suggest that the prevalence of RVO is 0.7% for those younger than 60 years, 1.2% for 60–69 years, 2.1% for 70–79 years, and it increases to 4.6% in people aged 80 years or above.

Most patients are unilaterally affected by this condition. Under 10% of CRVO are bilateral at presentation (range: 0.4–43%). The fellow eye involvement over 1-year period is approximately 5%. Similarly, only 5–6% of patients at baseline have BRVO in both eyes at diagnosis, with 10% showing bilateral involvement over time. Major population-based studies such as the Blue Mountain Eye Study,[10] the Beaver Dam Eye Study,[6] the Beijing Eye Study,[11] and the Multiethnic Study of Atherosclerosis [12] have reported the current population-based data on the incidence of RVO in different ethnic groups.

Visual impairment is more frequent with CRVO than BRVO. Macular edema is the leading cause of visual impairment. It is estimated that approximately 11600 people with BRVO and 5700 people with CRVO suffer from visual impairment due to macular edema each year in England and Wales based on an annual incidence of BRVO of 0.12% and CRVO of 0.03% in people aged 45 years or older, and 85% of BRVO and 75% of CRVO developing macular edema within 2 months of diagnosis, with 50% of BRVO and 100% of CRVO experiencing visual impairment due to macular edema.

Pathogenesis and risk factors of retinal vein occlusion

RVO is caused due to thrombosis of retinal veins.[13],[14] The pathogenic mechanism of RVO which produces stagnation of flow in the vein resulting in a thrombus has been described by Klein and Olwin [15] and Klein.[16]

  • Occlusion of the vein externally by the sclerotic central retinal artery, enclosed by the same sheath and secondary endothelial formation
  • Occlusion due to degenerative or inflammatory nature of the primary venous wall
  • Factors that produce hemodynamic disturbances.


Risk factors associated with RVO are as follows:

  • Hypertension
  • Diabetes
  • Hyperlipidemia
  • Hyperhomocysteinemia
  • Blood coagulation disorders: High plasma viscosity such as leukemia, myeloma, Waldenstrom's macroglobulinemia, myelofibrosis, changes in protein C pathway, Factor V Leiden.
  • Systemic inflammatory disorders: Behcçets disease, polyarteritis nodosa, sarcoidoisis, Wegener's Granulomatosis and Goodpasture's Syndrome
  • Glaucoma
  • Shorter axial length
  • Retrobulbar external compression.


The most common association of RVO is atherosclerosis, and the rest of the conditions cause hyperviscosity or slow or turbulent flow through retinal veins. The Eye Disease Case Control Study [17] found association of CRVO with increased hypertension, diabetes, and glaucoma. This study was conducted between 1986 and 1990 in five centers, comparing 258 CRVO patients with 1142 age-matched controls. These associations were higher in ischemic CRVO.

The Geneva study conducted in 2010, evaluated 1267 RVO cases, and their response to Ozurdex showed that hypertension was found in 64% of patients and diabetes in 12%.[18]

Inherited or acquired thrombophilia is another condition which increases the risk of venous thromboembolism. A meta-analysis [19] conducted in 2005 did not find any statistically significant relation between RVO and inherited thrombophilia, however, suggested Factor V Leiden, F5G1691A (OR 1.5), and factor II gene, F2G20210A (OR 1.6) mutations might be weak risk factors. Acquired thrombophilia includes anti-phospholipid syndrome (APS), myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria (PNH).

Anti-phospholipid syndrome is an acquired autoimmune disorder, the diagnosis of which is the persistence of test abnormalities on repeat testing >12 weeks apart according to the guidelines on the diagnosis and management of APS in UK.[20] Antibodies may be detected as a lupus anticoagulant (LA) using coagulation based assays or solid phase enzyme-linked immunosorbent assay (ELISA) tests for IgG anti-phospholipid antibodies.

Hyperhomocysteinemia is another factor which has been independently related to the increased risk of thrombosis. Although 5–7% of normal people do have an elevated plasma homocysteine, so far it has not been proven that lower plasma homocysteine levels can reduce the risk of RVO.[21]

RVO in young adults (less than 50 years) is known to have a benign outcome, with spontaneous regression of CRVO. However, 20% of these cases tend to develop poor visual outcome with severe neovascular complictions.[22] Procoagulant states predominate the mechanism of RVO in young patients. Phlebitis of central retinal vein is the cause of thrombosis in young adults. Phlebitis such as papillophlebitis, retinal vasculitis, mild retinal and papillary vasculitis, and optic disc vasculitis type II [23] have been reported.

Clinical features

RVO presents with a sudden painless loss of vision, while some patients with BRVO complain of a visual field defect. On clinical examination, it is easy to differentiate all the three entities of RVO based on the site of retina affected. They are all characterized by engorgement and dilatation of the involved retinal veins associated with intraretinal hemorrhages, cotton wool spots, intraretinal edema, retinal exudates, and macular edema.[24],[25] CRVO is caused by an obstruction of the venous outflow probably at the site of lamina cribrosa or posterior to it. It typically presents with retinal hemorrhages, both flame-shaped and deep blot type and dilated and tortuous vessels in all the four quadrants, and have a classic “blood and thunder” appearance. In case of BRVO, only a branch of retinal venous system is affected, most common location being the superotemporal quadrant. Vision loss is due to macular ischemia, macular edema, and neovascular diseases.

Natural history of CRVO was well-studied in central vein occlusion study (CVOS)[24] with 728 eyes in 1993. The visual acuity at the time of presentation is an important prognostic factor for the final visual outcome. This study found that the baseline visual acuity was 20/40 or better in 29% of affected eyes, 20/50–20/200 in 43%, and 20/250 or worse in 28%; median baseline acuity was 20/80. Cases with very poor visual acuity at presentation had only 20% chance of improvement.[26]

Based on the fluorescein angiographic characteristics, perfusion state of RVO was classified into perfused (non-ischemic), nonperfused (ischemic) and indeterminate type [Figure 1] and [Figure 2].
Figure 1: Fundus image of a 53-year-old male diagnosed as ischemic CRVO

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Figure 2: Fundus image of a 55-year-old male diagnosed as non-ischemic CRVO

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Diagnosis

Owing to their classic characteristic features, diagnosis is not a problem; however, differentiating ischemic from non-ischemic cases is challenging. This differentiation plays a crucial role in the management of RVO because non-ischemic cases will have a benign course whereas ischemic RVO is associated with serious blinding complications.

Primary symptom is always a sudden painless loss of vision. Treatment naïve patients typically have intraretinal hemorrhages, macular edema, cotton wool spots, intraretinal edema with venous stasis. Other examination features which will help to determine the perfusion state are the baseline visual acuity, afferent pupillary defect, electroretinography (negative waveform may be seen), and Goldmann perimetry.[27] Anterior segment neovascularization is a common complication of ischemic RVO with high risk of development of neovascular glaucoma. Thus slit-lamp biomicroscopy and gonioscopy is a must for all patients. Old cases are characterized by sclerosed vessels, intraretinal hard exudates, venous-venous collaterals, and optociliary shunt vessels [Table 1].
Table 1: Difference between ischemic and non-ischemic CRVO

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Optical coherence tomography

Optical coherence tomography (OCT) enables the detection of subtle macular edema even in the presence of intraretinal hemorrhages. It shows the presence of cystoid spaces, serous retinal detachment, epiretinal membranes, and macular hole. It plays an important role in monitoring the response to various treatment modalities employed, thereby reducing the need for repeated angiograms. OCT can also indicate the visual prognosis of cases depending on the integrity of the foveal photoreceptor layer [Figure 3].[28]
Figure 3: OCT image showing the effect of pre and post-injection Ranibizumab in a 64-year-old male patient diagnosed to have non-ischemic CRVO

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Fluorescein angiography

Fluorescein angiography plays a significant role in not only diagnosing RVO but also to detect the perfusion state. The CVOS study made photographic protocols for the angiographic assessment of the perfusion status of CRVO using a wide-angle fundus camera. A non-perfused or ischemic CRVO demonstrates 10 or more disc areas of capillary non-perfusion whereas an ischemic BRVO must have greater than 5-disc diameter of capillary drop outs.[3] It also demonstrates macular edema and leakage with cystoid involvement of fovea to rule out macular ischemia. If the perifoveal capillary net is preserved and perfused with minimal macular edema, vision can be quiet good.


  Current Treatment Modalities for Central Retinal Vein Occlusion Top


Retinal photocoagulation

Efficacy of macular grid photocoagulation for macular edema secondary to CRVO was assessed by the CVO study group.[24] This study also aimed at preventing iris neovascularization by panretinal photocoagulation therapy. A total of 728 cases were enrolled in this study with a mean follow-up period of 3 years. Patients were subdivided into four groups depending on the perfusion status and the presence of reduced vision due to macular edema. They were then randomized to undergo only observation or photocoagulation therapy. In the follow-up period, patients were assessed with the help of iris photography, color fundus photographs, and fundus angiography. This study proved to have no significant improvement in the final visual outcome in treated and untreated eyes. It also showed that the effect of photocoagulation was beneficial for eyes with at least 2 clock hours of iris neovascularization.

Corticosteroids

The rationale for the use of intravitreal triamcinolone acetonide (IVTA) to treat macular edema is that corticosteroids reduce retinal capillary permeability and inhibit the expression of the vascular endothelial growth factor (VEGF) gene and the metabolic pathway of VEGF.[29] Two major clinical trials have demonstrated the efficacy of corticosteroids in the treatment of CRVO.

The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) study [30] was conducted in 2009 with 271 patients. It was a multicenter randomized clinical trial that studied and evaluated the clinical benefits of triamcinolone for treating macular edema associated with RVO. Patients diagnosed as RVO with a BCVA of 20/40–20/400 and a central foveal thickness of more than 250 microns were enrolled in this study. The study compared intravitreal injection of 1 mg and 4 mg triamcinolone treatment with the standard care. All the study eyes received IVTA at 4-month interval unless retreatment was not indicated. The primary outcome measurements and the endpoint were a gain in visual acuity letter score of 15 or more from within a 12-month period. The percentage of patients meeting the primary endpoint was 27%, 26%, and 7% for the 1 mg, 4 mg, and control groups, respectively. The central retinal thickness was similar among all three groups at 12 months. The adverse effects of IVTA, such as cataract formation and elevated intraocular pressure, were higher in the 4 mg group than 1 mg group. Thus, evidence from the SCORE study indicates that it may produce anatomical and functional improvement of macular edema, however, the effects are short lived. It also proved that repeated IVTA may not necessarily improve vision. Hence, this treatment is rarely offered to patients today.

Dexamethasone has been shown to be a more potent corticosteroid than IVTA though the rationale for the use of intravitreal dexamethasone to treat macular edema is similar to that of IVTA. Intravitreal dexamethasone, in its free form, has a short half-life, which limits its clinical usefulness. Hence a pre-filled applicator for single-use, sustained release with a biodegradable implant containing 0.7 mg of dexamethasone (OZURDEX, Allergan) was analyzed in the GENEVA study programe.[31] A dexamethasone implant is composed of a biodegradable copolymer of lactic acid and glycolic acid containing micronized dexamethasone. Results from the GENEVA study were based on the two identical multicenter 6 month trials that included 1267 patients who had BRVO or CRVO. Specifically, 437 patients had CRVO. They were randomized to receive a dexamethasone implant with either 0.7 mg (OZURDEX), 0.3 mg, or a sham implant. They were followed-up and evaluated at the end of 6 months. The percentage of eyes with ≥15 letter gain in BCVA was significantly higher in both implant groups compared with sham at 30 to 90 days with a peak effect at 60 days. Mean central foveal thickness decreased in eyes with dexamethasone compared to sham at 90 days, however, the improvement was not maintained at day 180. At 12 months, 32% of the patients had a 15-letter gain in the 0.7 mg dexamethasone group. There was a mean increase in central foveal thickness of 236 µm in both 0.3 mg and 0.7 mg implant compared to a 267 µm decrease in the sham group.[18]

Anti-vascular endothelial growth factors

VEGF plays an important role in the pathophysiology of CRVO by initiating angionesis and vascularization in ischemic conditions. VEGF-A is a key cytokine that mediates vascular leakage and causes macular edema. Thus anti-VEGF agents have become a popular choice for treatment of macular edema.

  • Ranibizumab: It is a humanized recombinant monoclonal antibody fragment which selectively binds to human VEGF-A, thus preventing it from binding to its receptors. The licensed dose of ranibizumab is 0.5 mg/0.05 ml as a single intravitreal injection. The interval between two injections is at least 4 weeks. The CRUISE study [32] was a pivotal phase III randomized controlled trial that evaluated the effect of ranibizumab (0.3 mg and 0.5 mg) in macular edema caused by CRVO. Three hundred and ninety-two patients with macular edema due to CRVO of less than 12 months' duration with a visual acuity between 20/40 to 20/230 and a central macular thickness of more than 250 µm on status OCT were enrolled. They were randomized 1:1:1 to receive a monthly injection of 0.3 mg, 0.5 mg, and sham injection. Primary outcome measurements were mean change in the baseline visual acuity, percentage of patients gaining, or losing more than 15 letters on visual acuity testing. Change in the central foveal thickness from baseline was also measured. At the end of 6 months, patients in the 0.3 mg and 0.5 mg ranibizumab treatment groups had gained a mean of 12.7 and 14.9 letters, respectively, compared to 0.8 letters in the sham group. A total of 46.2% and 47.7% of patients in the 0.3 mg and 0.5 mg ranibizumab groups had gained more than 15 letters from baseline visual acuity compared to 16.9% of cases in the sham group Campochiaro et al.[33] published an extension of the CRUISE trial for a period of 12 months. In their study, patients who were randomized to 0.3 mg, 0.5 mg, and sham injections were able to receive a dose of 0.5 mg of ranibizumab on a pro re nata (PRN) basis if the visual acuity was <20/40 or if central foveal thickness was more than 250 µm
  • Patients who completed the 12-month CRUISE trial entered into an open label, single arm, multicenter follow-up study called the HORIZON [34] extension study. According to this study, patients would continue to receive 0.5 mg ranibizumab on PRN basis. The primary outcome was the mean change in BCVA from HORIZON baseline at the end of 24 months; it also evaluated the safety and the efficacy of long-term use of ranibizumab. The HORIZON study showed that the mean letters gained at the 12 months of HORIZON from CRUISE baseline was +12 letters in the initial 0.5 mg ranibizumab group and 7.6 letters in the sham group. A key finding in the HORIZON group was that the long-term use of ranibizumab was well tolerated

    RETAIN study [35] published in 2014 by Campochiaro et al. is a prospective follow-up of a subset of patients from 2 phase 3 trails. This study determined the long-term outcome of ranibizumab treated RVO. The mean follow-up was 49.7 months for CRVO patients, where 14 of 32 patients (44%) had edema resolution, with 71% receiving their last injection within 2 years of treatment initiation. However, in unresolved patients, a mean number of 5.9 injections of ranibizumab were given in year 4. Eyes with resolved disease had greater improvement in BCVA compared to baseline (25.2 vs 4.3 letters; P = 0.002)

  • Bevacizumab: The intravitreal use of bevacizumab is off label. The lack of large randomized clinical trials limits its use, and makes it difficult to quantify theoretically the systemic risk factors such as stroke and myocardial infarction. Epstein et al.[36] in 2012 investigated the safety and efficacy of bevacizumab in treating macular edema in CRVO cases. Sixty patients were enrolled in this prospective, double-masked trial, wherein the patients were randomized to receive intravitreal bevacizumab versus sham every 6 weeks for 6 consecutive months. The primary outcome measure was the proportion of patients with 15 letter increase in BCVA. At the end of 6 months, there was statistically significant increase in BCVA in bevacizumab treated eyes. Several retrospective and prospective studies have reported the decreased retinal thickness and improved visual acuity with bevacizumab with CRVO associated with macular edema [37],[38],[39]
  • Aflibercept: The pan-VEGF-A, VEGF-B, and placental growth factor (PIGF) blocker, is the aflibercept. Its safety and efficacy in macular edema secondary to CRVO was evaluated in the COPERNICUS study.[40] One hundred and eight-nine eyes enrolled in the study were randomized to receive monthly intravitreal aflibercept and sham injections for 6 months. Primary outcome measures were the proportion of eyes with a ≥ 15 letter gain or more in BCVA at the end of 24 weeks, mean changes in BCVA, and central foveal thickness. It was noted that at the end of 24 weeks, treated eyes had a statistically significant higher percentage of patients, reaching the primary endpoint


The extended COPERNICUS study was published by Brown et al.[41] in 2013. It was a 12-month follow-up result of all patients who were eligible to receive aflibercept 2 mg every 4 weeks if they met the specific retreatment criteria. Approximately 55% of eyes treated with aflibercept gained >15 letters, with a mean change in visual acuity of + 16.2 letters. In comparison, only 30% of the sham group gained >15 letters, with a mean change in visual acuity of +3.8 letters. Thus, this study concluded that BCVA could be maintained with aflibercept PRN, with less frequent dosing and close monitoring Similarly, the safety and efficacy of aflibercept injections in the treatment of macular edema was studied by Holz et al. in the General Assessment Limiting Infiltration of Exudates in Central Retinal Vein Occlusion with aflibercept (GALILEO) study.[42] One hundred and seventy-seven patients were randomized in a 3:2 ratio to receive intravitreal aflibercept. Primary outcome measures were similar to the COPERNICUS study and included 15 letter gain of visual acuity and central foveal thickness. At the end of 6 months, percentage of patients with both 15 letter gain in visual acuity compared to baseline and reduction in central foveal thickness were significantly greater in the treated versus sham group.

Surgical techniques

Various surgical options have been studied for the treatment of CRVO. Retinal veins can be punctured via laser [43] or surgically [44] to create an anastomosis between the retina and choroid to reduce the macular edema, which subsequently improves vision.

Another technique proposed is the radial optic neurotomy, which is based on surgically relieving compression of the central retinal vein near the optic nerve and improving the blood flow. During pars plana vitrectomy, a microvitreoretinal blade is used to relax the scleral ring surrounding the optic nerve, theoretically improving blood flow through the central vein.[45],[46]

A pars plana vitrectomy [47] has also been proposed as an alternative surgical management. Few studies have reported that vitrectomy reduces the VEGF factors that may be trapped in the vitreous as well as macular traction and subsequently the incidence of macular edema.


  Current Treatment Modalities for Branch Retinal Vein Occlusion Top


Observation

Although visual improvement is more prevalent in BRVO than CRVO, few studies have reported improvement beyond Snellen 6/12. A systematic review of the natural history of BRVO shows the visual acuity is moderately poor at baseline (Snellen <6/12). The natural history and the effect of laser treatment in BRVO was reported in The Branch Vein Occlusion Study (BVOS),[48] which was a multicenter, prospective randomized clinical trial. This study demonstrated that, after three years of follow-up and based on available data of 43 participants, 28 (63%) laser treated eyes had improved ≥2 lines of vision, compared with 13 (37%) out of 35 untreated eyes that remained in the study for 36 months.

Laser photocoagulation

Macular laser has been the treatment of choice for macular edema in BRVO for the past 20 years. However, with the availability of anti-VEGF, the role of laser as the first-line treatment has to be confined to patients who are unsuitable or unwilling for anti-VEGF therapy. This recommendation has been supported by the BVOS study, which showed that the average improvement in visual acuity in the laser arm after 3 years of follow up was 1.3 lines. This study also proved that better treatment options are needed because 40% of treated eyes had worse than 20/40 visual acuity and 12% of treated eyes had 20/200 or worse at the end of three years. Thus, today the recommended treatment guidelines for macular edema in BRVO is that laser photocoagulation should be performed in eyes with macular edema in BRVO of at least 3 months' duration with a visual acuity of 6/12 or worse and without significant macular hemorrhage along with fluorescein angiogram showing capillary perfusion in the absence of blood involving the fovea. The cases with severe visual loss (<Snellen 6/60) and in those in whom symptoms have been persistent for more than 1 year are unlikely to benefit from the treatment. Laser photocoagulation using 50–100 µm spot size for macular edema requires mild photocoagulation spots only, that is, faint grey discoloration of the retina only. An average of between 20 and 100 applications are required in a grid pattern to the areas of vascular leakage by avoiding the foveal avascular zone any surrounding areas of capillary closure.

Disc or retinal neovascularization is an indication for photocoagulation to the ischemic retina, although available evidence suggests that waiting until vitreous hemorrhage occurs before laser treatment does not adversely affect the visual prognosis.[3] An adequate number of laser spots using a single spot or multispot laser should be applied in the affected sector, one shot width apart with sufficient energy to create a mild gray-white laser discoloration of the retina. A quadrant usually requires at least 500 shots of 500 µm in diameter.

Intravitreal steroids

Since studies showed that visual gains were poor with laser photocoagulation, intravitreal steroids have been tried for the treatment of macular edema. SCORE trial [49] in 2009 tested the efficacy of intravitreal steroids for macular edema and showed that there was no significant difference in visual acuity or foveal thickness outcome between the grid LASER group, 1 mg and 4 mg IVTA groups at the end of 1 year proving that IVTA is not beneficial in this condition.

As previously stated, dexamethasone implant, being a better corticosteroid, was studied in the treatment of macular edema for BRVO in the GENEVA trial.[18] Peak improvement in visual acuity and retinal thickness was noted after 60 days in the 0.7 mg group, after which the vision deteriorated. These gains were significantly higher than the sham group. A repeat injection of 0.7 mg at the end of 6 months also yielded similar results.

Based on the GENEVA study program, OZURDEX received FDA and EU approval for the 0.7 mg preparation, and is licensed in the UK for the treatment of adult patients with macular edema in RVO.

Anti-vascular endothelial growth factors

  • Ranibizumab: Elevated levels of VEGF in RVO forms the basis for the management of BRVO with macular edema with intravitreal anti-VEGF injections. The efficacy of ranibizumab in BRVO cases was evaluated by Campochiaro et al.[50] Diagnosed cases of macular edema secondary to BRVO with BCVA between 20/40–20/400, with a central foveal thickness of more than 250 µm with no history of treatment were subdivided into three groups sham, 0.3 mg ranibizumab and 0.5 mg ranibizumab. They were treated monthly for 6 months, and provision for rescue laser after 3 months if visual acuity did not improve more than 5 letters. At the mark of 6 months, there was a significant increase in the visual acuity and reduction in central foveal thickness in the ranibizumab treated group than the sham group. The benefits of these gains continued when the patients were followed-up for the next 6 months with treatment on a PRN basis in the BRAVO study.[51] At 50 months follow-up, 50% of patients with BRVO treated with ranibizumab had complete resolution of macular edema whereas the remaining half required up to 3 injections a year in order to sustain the original gains.[35] The efficacy of ranibizumab compared to bevacizumab on a PRN basis for the management of BRVO with macular edema was reported in the MARVEL study.[52] This study found that PRN administration of either bevacizumab or ranibizumab was effective in reducing macular edema with improvement in visual acuity with 2.53 letters difference between the two drugs. Both treatments also resulted in rapid restoration of anatomy and function, which was sustained by PRN treatment with rescue laser therapy
  • Bevacizumab: Hikichi et al.[53] studied the efficacy of bevacizumab as a PRN treatment. The eligible patients were followed-up every 3 months or earlier with no fixed follow-up protocol and underwent reinjection if the foveal thickness was >250 microns or for persisting or recurrent macular edema affecting visual acuity. With a 2 year follow-up, patients required an average of 3.8 ± 1.5 injections, with provision for rescue laser at the end of 3 months. The authors suggested that the decreased frequency of injections might be related to the greater intravitreal half-life of bevacizumab. A comparative study between Ozurdex and bevacizumab showed that patients treated with Ozurdex showed greater reduction in the foveal thickness at 1 month follow up, however, these differences disappeared by 3 months onward with both treatments providing similar results.[54] Moreover, by comparing the efficacy of bevacizumab to grid laser proved that bevacizumab resulted in better and faster visual recovery [55]
  • Aflibercept: The VIBRANT study,[56] was a double-masked, multicenter trial to assess the efficacy of aflibercept compared to macular laser in eyes with macular edema secondary to BRVO. A total of 183 participants with treatment-naïve macular edema were randomized to four weekly aflibercept versus macular lasers. At 6 months, 53% of the participants gained 15 letters after a mean of 5.7 injections compared to 27% in the laser arm treated with a mean of 1.7 sessions of macular laser. This was the first study to directly compare the efficacy of an anti-VEGF agent to laser therapy and show that anti-VEGF was superior.



  Treatment Algorithms of Retinal Vein Occulusion – Translation of Clinical Trials Into Clinical Practice! Top




  1. Non-Ischemic CRVOBaseline visual acuity measurement, fluorescein angiography, OCT, intraocular pressure, and gonioscopy if ischemic CRVO is suspected.

    If no angle or iris neovascularization and evidence of macular edema on OCT:



    1. If visual acuity is 6/96 or better, commence on either intravitreal anti-VEGF therapy or Ozurdex implant.
    2. If visual acuity is less than 6/96, the potential significant improvement in visual acuity is minimal and the risk of ocular neovascularization is high. However, eyes with BCVA <6/96 may be offered treatment because few of them may respond but these patients should be watched for NVI/NVA
    3. If visual acuity is better than 6/12, it is better to observe for spontaneous resolutionChoice of pharmacological agents: Although any of these drugs ranibizumab, aflibercept, or Ozurdex are recommended as the first-line therapy, anti-VEGF is preferred in eyes with previous history of glaucoma and young patients who are phakic. Ozurdex may be a better choice in patients with recent history of cardiovascular events and in those who do not favor monthly injections

      Re-treatment: At each follow-up visit, visual acuity macular thickness, intraocular pressure, and the presence of NVI/NVA was assessed

      If ranibizumab is the first-line of treatment, monthly injection should be continued until maximum visual acuity is achieved, which is defined as stable vision for three consecutive months while on ranibizumab therapy. If no improvement in visual acuity over the course of the first three injections is observed, cessation of treatment may be considered and is recommended after six injections. Patients who achieve visual acuity stability should be monitored monthly, and retreatment with ranibizumab can be started if there is loss of vision due to macular edema. Monthly injections should be resumed until stable visual acuity is reached for 3 consecutive months. Similarly, if aflibercept is chosen as the first-line of drug, it is to be given monthly until maximum vision is achieved and is stable for 3 consecutive months. If no improvement in visual acuity over the course of the first three injections is achieved, cessation of treatment may be considered and is recommended after six injections. Monthly treatment should continue until visual and anatomical outcomes are stable for 3 monthly assessments. If Ozurdex is the first-line of treatment, re-treatment may be required at 4–6 month intervals until vision is stabilized. These patients should be monitored for adverse effects such as raised intraocular pressure and cataract formation Stopping anti-VEGF therapy is recommended if after six consecutive monthly treatments, visual acuity has not improved by at least five letters and central macular thickness has not reduced from baseline.


  2. Ischemic CRVOIf iris or angle neovascularization occurs: Urgent pan retinal photocoagulation (PRP) is recommended, and reviewed at 2 weeks initially and then less frequently as regression occurs. PRP plus intravitreal bevacizumab can be repeated if NVI/NVA persist.

  3. Non-Ischemic BRVOBaseline



    1. If BCVA better than 6/12, recommended to observe progress for 3 months
    2. If BCVA is 6/12 or worse with macular edema and hemorrhages are not masking:



      1. FFA recommended to asses foveal integrity
      2. If no macular ischemia is identified, regularly observe for 3 months if macular edema is mild
      3. In mild to moderate macular edema cases consider treatment with ranibizumab or Ozurdex if spontaneous improvement is unlikely
      4. If severe macular ischemia is present no treatment is recommended and regularly observe for neovascularization


    3. If visual acuity of 6/12 or worse with macular edema and hemorrhages are masking macula



      1. Monthly ranibizumab or baseline Ozurdex for 3 months
      2. Perform FFA at 3 months to assess foveal integrity
      3. In severe macular ischemic cases, no treatment is beneficial and further treatment should be carefully considered


      At 3 months follow-up



      1. If vision is ≥6/9 or no macular edema is detected, observation is recommended
      2. Modified grid laser photocoagulation is recommended for persistent macular edema, no or minimal macular ischemia, and other treatment is unsuccessful


    4. Ischemic BRVO



      1. Careful observation for neovascularization
      2. PRP applied to all ischemic quadrants if NVE is noticed
      3. Follow up at 3 monthly intervals for up to 24 months.






Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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