9 Retinal Venous Occlusive Disease
Retinal venous occlusive disease is the second most common retinal vascular disease following diabetic retinopathy. 1 There are three distinct types of retinal vein occlusion (RVO) based on the site of obstruction: branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), and hemiretinal vein occlusion. 2 Population-based studies report a prevalence rate of 0.5 to 2.0% for BRVO and 0.1 to 0.2% for CRVO. 3 The 15-year incidence rate is estimated to be 1.8% for BRVO and 0.5% for CRVO. 4 The most common cause of vision loss in RVO is macular edema (ME); other causes of vision loss include macular ischemia, intraretinal hemorrhage, and neovascularization (NV) with secondary vitreous hemorrhage, tractional retinal detachment, and/or neovascular glaucoma (NVG). 5 , 6 Many systemic diseases are risk factors for RVO. 7 , 8 The various treatment options for RVO can be categorized broadly into pharmacotherapy, laser treatment, surgical treatment, and combination therapy. 9 This chapter reviews the pathophysiology, clinical features and various treatment modalities for, RVO.
9.2 Branch Retinal Vein Occlusion
BRVO is four to six times more common than CRVO. 3 Advanced age is an important risk factor, with the prevalence of BRVO in persons older than 80 years being seven times higher than the prevalence of BRVO in people between 40 and 49 years of age. 3 Systemic vascular diseases such as hypertension (HTN), hyperlipidemia (HLD) and peripheral arterial disease (PAD), and metabolic diseases such as diabetes mellitus (DM) have been associated with BRVO. 7 A meta-analysis of risk factors in patients with BRVO reveals that the odds ratio is 3.0 (95% CI: 2.0–4.4) for HTN, 2.3 (95% CI: 1.5–3.5) for HLD, and 1.1 (95% CI: 0.8–1.5) for DM. 10
RVO risk factors
Cardiovascular risk profile of patients is more important than thrombophilic risk factors.
The role of thrombophilia in the pathogenesis of BRVO is not clear. A review of the literature reveals a lack of consensus regarding the role in RVO of currently known thrombophilic risk factors such as hyperhomocysteinemia, factor V Leiden mutation, deficiency in protein C and/or S, antithrombin III deficiency, prothrombin gene mutation, anticardiolipin antibodies, lupus anticoagulant, increased packed cell volume, hematocrit, and fibrinogen. 11 Some authors have concluded that, with respect to RVO, cardiovascular risk profile is more important than thrombophilic risk factors. 11 BRVO can also occur secondary to local or systemic vasculitis. 12 Further, BRVO can be a result of direct infiltration leading to venous obstruction such as in sarcoidosis, ocular tuberculosis, or neoplastic diseases. 12 Glaucoma and ocular HTN may predispose to RVO because increased intraocular pressure (IOP) may lead to venous stasis; these conditions are not considered as important risk factors for BRVO as compared to CRVO. 12 Moreover, medications such as oral contraceptives and anabolic steroids have been reported as risk factors for BRVO due to hypercoagulability associated with the use of these medications. 12
BRVO usually develops at arteriovenous (AV) crossing sites where the artery is situated superficially over the vein. Histological examinations have shown that arteriosclerotic changes in the retinal artery may cause compression of the underlying vein, leading to thrombus formation and vein occlusion. 13 , 14 Other theories include hemodynamic variations due to venous contouring at AV crossing sites as the inciting cause of BRVO. Diseases of the vein wall, such as vasculitis, can also cause BRVO and may not involve AV crossing sites. 15 BRVO leads to localized retinal ischemia which is associated with secretion of vasopermeability factors such as vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). These factors lead to breakdown of the blood–retinal barrier and development of ME. Release of VEGF and IL-6 at the border between perfused and nonperfused retina is also associated with formation of retinal NV, which may lead to vitreous hemorrhage and abnormal vitreoretinal adhesions.
9.2.2 Clinical Features and Diagnosis
BRVO is typically characterized by clinical findings in a segmental distribution distal to the involved AV crossing site, with the most common location being the superotemporal quadrant of the retina. 16 BRVOs are classified according to their anatomical location either as major, when one of the major branch veins draining one of the retinal quadrants is involved, or as macular, when one of the smaller venules within the macula is occluded. 12 BRVOs can also be classified according to their duration either as acute, when present for less than 6 months, or as chronic, when present for more than 6 months. 9 In an acute BRVO, the involved area is usually wedge-shaped with dilated and tortuous veins surrounded by deep and superficial retinal hemorrhages, cotton-wool spots, and retinal edema (Fig. 9-1). Visual acuity (VA) may be reduced due to retinal hemorrhage, edema, or ischemia involving the central macular region. If the venous blockage is peripheral to branches draining the macula or involves a branch in the nasal retina, VA may be unaffected unless other complications arise. Approximately 50 to 60% of untreated patients will have a final VA of 20/40 or better. However, severe vision loss is not uncommon, with 20 to 25% of patients having a VA of 20/200 or worse. 17 In a chronic BRVO, intraretinal hemorrhages have usually resolved and subtle retinal vascular changes such as capillary abnormalities (telangiectasia and microaneurysms) and collateral vessel formation may be observed. Intravenous fluorescein angiography (FA) may aid in the diagnosis in these cases by better demonstrating the segmental retinal vascular alterations. Angiographic findings reflect changes in vessel permeability, caliber, and patency, and may assist in identifying areas of ME, NV, and nonperfusion. If the area of retinal capillary nonperfusion is smaller than 5 disc diameters in size on fluorescein angiography, the occlusion is defined as perfused. 18 If the area of nonperfusion is larger than 5 disc diameters in size, the occlusion is defined as nonperfused. 18 Of eyes with a BRVO affecting at least one quadrant of the retina, approximately 50% are nonperfused. 18 It is important to recognize that perfused BRVO may progress to the nonperfused type during ensuing weeks, months, and even years. 19 Visually significant complications associated with BRVO include ME (most common) and intraocular NV, which may result in vitreous hemorrhage or tractional retinal detachment. 19
9.2.3 Macular Edema
In eyes with a BRVO, ME can be classified angiographically as perfused, nonperfused (ischemic), or mixed (perfused and nonperfused). 17 , 20 ME is perfused (Fig. 9-2) when fluorescein angiography shows a completely intact parafoveal retinal capillary network during the transit phase of the angiogram followed by the late accumulation of fluorescein dye in and around the foveal center. 20 ME is nonperfused (Fig. 9-3) when fluorescein angiography reveals an irregular parafoveal vascular network with parafoveal and perifoveal retinal capillary nonperfusion and no late accumulation of fluorescein dye in the foveal center. 20 ME is mixed when fluorescein angiography demonstrates a combination of parafoveal retinal capillary dilation with leakage and areas of capillary nonperfusion. 20 In patients with perfused ME, approximately one-third will regain some vision spontaneously. 19 However, this becomes less likely the longer the edema persists. Early in the course of BRVO, macular nonperfusion can result in permanent vision loss. 19 The presence of a significant amount of intraretinal hemorrhage in the central macula may interfere with the angiographic interpretation, and optical coherence tomography (OCT) may be useful in these cases. In fact, OCT has become a mainstay for the detection of ME and for monitoring of treatment efficacy in patients with ME due to RVO. 21 The findings from the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study revealed a modest correlation between OCT-measured center point thickness and VA in patients with BRVO or CRVO. 21
9.2.4 Intraocular Neovascularization
In the Branch Vein Occlusion Study (BVOS), retinal or disc NV developed in 36% of eyes with 5 disc diameters or more of retinal nonperfusion, 18 and 60% of these eyes developed vitreous hemorrhage if untreated. 18 The NV usually develops within the first 6 to 12 months after the onset of the occlusion but may develop anytime within the first 3 years. 19 Neovascular vessels may be confused with collateral vessels on ophthalmoscopic examination. Fluorescein angiography is useful to differentiate collateral vessels from NV as dye leakage is more prominent from the NV than from the collateral vessels (in contrast to NV, collateral vessels are associated with no or only minimal leakage on FA). 18 Iris NV and NVG are infrequent complications in eyes with BRVO. 19
Macular edema in RVO
OCT has become a mainstay for the detection of ME and for monitoring of treatment efficacy in patients with ME due to RVO.
9.2.5 Management and Course
In addition to a thorough eye examination, initial evaluation of patients with BRVO may include medical assessment to identify any underlying systemic causes. It is important to look for cardiovascular risk factors, and baseline laboratory testing may include fasting blood glucose level, complete blood count with differential and platelets, renal function tests, and lipid profile. 11
Retinal or disc NV developed in 36% of eyes with 5 disc diameters or more of retinal nonperfusion.
Further testing may be indicated in patients younger than 50 years with or without suspicion for coagulopathy (see the following list). 11
Tests for coagulopathy in the assessment of selected patients with RVO 11 :
Functional protein C and protein S levels
Antithrombin III levels
Antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies
Activated protein C resistance (factor V Leiden mutation [R506Q] polymerase chain reaction assay)
Factor XII (Hageman factor)
Prothrombin gene mutation (G20210A)
Various treatments for BRVO are aimed at minimizing visual loss from complications such as ME and NV. 9 Treatment options for ME include pharmacotherapy and laser. 9 Surgical treatments such as AV sheathotomies have been attempted with varied success, but they are not generally considered standard of care due to the associated risk of complications, unpredictable efficacy, and inability to alter the chronic effects from ischemia. 22
Intravitreal injection of pharmacological agents reduces the breakdown of the blood–retinal barrier by inhibiting factors such as VEGF, IL-6, prostaglandins, and protein kinase C. The various pharmacological preparations currently available for intraocular delivery include anti-VEGF agents and corticosteroids. 23
Intravitreal Anti-VEGF Therapy
Anti-VEGF therapy is typically the first-line treatment in patients with ME associated with BRVO. Anti-VEGF agents currently available for the treatment of ME associated with BRVO by intravitreal injection include ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea).
Ranibizumab (Lucentis, Genentech) is a humanized Fab fragment that binds and neutralizes all isoforms of VEGF-A. Ranibizumab was the first anti-VEGF agent to receive Food and Drug Administration (FDA) approval (in June 2010) for the treatment of ME secondary to BRVO.
Intravitreal pharmacotherapy for ME associated with BRVO
Anti-VEGF therapy is typically the first-line treatment in patients with ME associated with BRVO.
In the BRanch Retinal Vein Occlusion (BRAVO) study 24 (a phase III, multicenter, prospective clinical trial comparing the efficacy and safety of intravitreal injections of ranibizumab 0.3 mg, intravitreal injections of ranibizumab 0.5 mg, and sham injections), 397 patients with center-involved ME from a BRVO occurring within 12 months of study entry were randomized to receive monthly intraocular injections of 0.3 mg (n =134) or 0.5 mg (n =131) of ranibizumab or sham injections (n = 132). A gain of =15 Early Treatment Diabetic Retinopathy Study (ETDRS letters in best-corrected visual acuity (BCVA) at 6 months compared to baseline (the primary study endpoint) was achieved in 55.2% (0.3 mg) and 61.1% (0.5 mg) of patients in the ranibizumab groups and 28.8% in the sham group (p < 0.0001 for each ranibizumab group versus sham). There was greater resolution of ME in the ranibizumab groups compared to the sham group; central subfield thickness (CST) was reduced by 337.3 µm in the 0.3 mg group; 345.2 µm in the 0.5 mg group; and 157.7 µm in the sham group (p < 0.0001 for each ranibizumab group versus sham). Rescue grid laser therapy was performed in 18.7% of patients in the 0.3 mg ranibizumab group, 19.8% of patients in the 0.5 mg ranibizumab group, and 54.5% of patients in the sham group. After 6 months, all the patients were evaluated monthly and, if study eye Snellen equivalent BCVA was =20/40 or mean CST was =250 µm, patients received intravitreal ranibizumab; patients in the ranibizumab groups received their assigned dose and patients in the sham group received 0.5 mg of ranibizumab. Between 6 and 12 months, the vision was maintained in the ranibizumab groups, and there was substantial improvement in the sham group (an improvement in VA letter score of =15 compared to baseline was achieved in 28.8% of patients in the sham group at month 6 and in 43.9% of patients in the sham group at month 12). 25 In the BRAVO study, patients in the sham group showed a substantial improvement in vision after receiving ranibizumab as needed, but their vision at month 12 was not as good as that in patients in the ranibizumab groups. 25 This indicates that a delay in instituting treatment may affect the final visual gain. 25
Bevacizumab (Avastin, Genentech) is a full-length humanized monoclonal antibody to VEGF-A. Although bevacizumab is not FDA approved for intravitreal use, numerous case reports and case series have reported that intravitreal bevacizumab is associated with improvement in VA and retinal thickening in eyes with ME due to BRVO. 26 , 27 , 28 Fung et al concluded that physician reporting of adverse events after intravitreal bevacizumab injections did not show an increased rate of drug-related ocular or systemic events. 29 There are concerns about tolerance and tachyphylaxis with intravitreal bevacizumab therapy, which may be addressed by switching to other anti-VEGF agents. 30
Aflibercept (Eylea, Regeneron) is a small soluble VEGF receptor that acts as a decoy receptor binding free-VEGF. Aflibercept was approved by the FDA for treatment of ME secondary to BRVO in October 2014. 31 In the VIBRANT study 31 (a phase III, multicenter, prospective clinical trial comparing the efficacy and safety of intravitreal aflibercept with macular grid laser for treatment of ME after BRVO), 183 treatment-naive eyes with ME after BRVO of less than 12 months’ duration and BCVA between 20/40 and 20/320 Snellen equivalent were randomized to receive either intravitreal aflibercept 2 mg every 4 weeks (n = 91) from baseline to week 20 or grid laser (n = 92) at baseline with a single grid laser rescue treatment, if needed, from weeks 12 through 20. Rescue treatment criteria included (a) a >50-µm increase in central retinal thickness (CRT) compared with the lowest previous measurement; (b) presence of new or persistent cystic retinal changes, subretinal fluid, or persistent diffuse edema in the central OCT subfield; or (c) loss of =5 ETDRS letters compared with the best previous measurement because of BRVO in conjunction with any increase in CRT. If =1 rescue treatment criterion was met, eyes in the intravitreal aflibercept group received sham laser at either week 12, 16, or 20. Eyes in the laser group eligible for rescue treatment before week 24 received one additional laser treatment from week 12 to 20. A gain of =15 ETDRS letters in BCVA at 24 weeks compared to baseline (the primary study endpoint) was achieved in 52.7% of eyes in the aflibercept group compared to 26.7% in the laser group (p = 0.0003). The mean reduction in CRT at week 24 compared to baseline was 280.5 µm in the aflibercept group and 128.0 µm in the laser group (p < 0.0001). There were no cases of intraocular inflammation or endophthalmitis.
Intravitreal corticosteroids reduce the breakdown of the blood–retinal barrier by inhibiting factors such as VEGF, IL-6, prostaglandins, and protein kinase C. 32 Several case studies have shown favorable anatomical response to intravitreal injection of triamcinolone acetonide (TA) in eyes with ME associated with RVO. 33 , 34 , 35 , 36 , 37 Corticosteroid preparations currently available for intraocular use include TA and dexamethasone. Fluocinolone acetonide is a glucocorticoid that can be delivered by polymer-based non-biodegradable platforms to the posterior segment; there is currently no fluocinolone implant approved by the FDA for use in RVO. 9
Triamcinolone Acetonide (TA)
According to a pharmacokinetics study of human nonvitrectomized eyes, a single 4 mg intravitreal injection of TA has a mean half-life of 18.6 days with measurable concentrations expected to last approximately 3 months. 38 Reported side effects include cataract, increased IOP, and injection-related complications including noninfectious and infectious endophthalmitis, retinal detachment, vitreous hemorrhage, and lens injury. 33 , 34 , 35 , 36 , 37 The SCORE Study, a multicenter, randomized, phase III National Eye Institute–sponsored study, investigated the efficacy and safety of standard care versus intravitreal injection(s) of TA for ME secondary to BRVO and CRVO. 39 , 40 Individuals with BRVO or CRVO with associated ME of up to 24 months’ duration and BCVA between 19 and 73 ETDRS letters (corresponding to a Snellen VA equivalent of approximately 20/40–20/400) were eligible for participation in the SCORE Study. 39 , 40 , 41 The two primary study objectives of the SCORE-BRVO trial were (1) to determine whether intravitreal TA at 1 and 4 mg doses produces greater visual benefit, with an acceptable safety profile, than grid laser (standard care), when appropriate, for the treatment of vision loss associated with ME secondary to BRVO; and (2) to compare the efficacy and safety of the 1- and 4-mg TA doses. 40 The results of the SCORE-BRVO trial demonstrated no significant differences among the three treatment groups for a gain in VA letter score of =15 at 12 months (29, 26, and 27% in the standard care, and 1- and 4-mg TA groups, respectively). 40 An early positive treatment response of a gain in VA letter score of =15 was observed at month 4 in the 4-mg TA group compared with the 1-mg TA and standard care groups. After month 12 and through month 36, the mean improvement from baseline VA letter score was greatest in the standard care group compared with the two TA groups. With respect to OCT-measured center point thickness, all three groups showed a decrease from baseline to month 12. Analogous to the VA results, only at month 4 did the 4-mg TA group demonstrate a greater treatment effect on center point thickness than the 1-mg TA and standard care groups; at all other times investigated (months 8–36), the standard care group demonstrated the greatest overall median decrease in center point thickness from baseline. The rates of adverse events were higher in the 4-mg TA group compared with the 1-mg and standard care groups. There was a dose-dependent higher frequency of initiating IOP-lowering medications in the TA groups (41% in 4 mg and 8% in 1 mg) compared with the standard care group (2%). The proportion of phakic eyes that had new-onset lens opacity or progression of an existing opacity through 12 months based on assessment at the clinical center was greater in the two TA groups (35% in 4 mg and 25% in 1 mg) compared with the standard care group (13%). Most cataract surgeries were performed during the second year of the study and occurred with the highest frequency in the 4-mg TA group (n = 35). The rates of adverse events with respect to cataract surgery and elevated IOP were similar between the standard care and 1 mg TA groups. Thus, the SCORE Study results, at the time of publication, supported grid laser as the standard of care for patients with decreased VA attributable to ME secondary to BRVO. 40
Dexamethasone is a glucocorticoid which is three times more potent than TA. 41 However, it is cleared rapidly from the vitreous cavity (half-life of 5.5 h) in humans. Ozurdex (Allergan) is an extended delivery bioerodable dexamethasone polylactic acid polyglycolic acid (PLGA) copolymer complex. 41 A specially designed proprietary instrument is used for the intravitreal injection of the Ozurdex dexamethasone implant, thus obviating the need for surgery. The Ozurdex dexamethasone implant is approved by the FDA for ME associated with BRVO or CRVO. 42 Two identical, randomized, prospective, multicenter, masked, sham-controlled, phase 3 clinical trials investigated the efficacy of the dexamethasone implant compared with sham treatment for ME associated with BRVO or CRVO. 42 The trials enrolled 1,267 patients aged =18 years with a BCVA between 20/50 and 20/200 secondary to ME of =300 µm in the central 1-mm macular subfield associated with either BRVO or CRVO. The study consisted of a 6-month primary phase followed by a 6-month, open-label, follow-up phase. 43
SCORE BRVO trial
Grid photocoagulation recommended over intravitreal triamcinolone acetonide for patients with decreased VA associated with ME secondary to BRVO.
In the primary phase, enrolled patients were randomized 1:1:1 to receive either a 700-µg dexamethasone implant (n = 427), a 350-µg dexamethasone implant (n = 412), or a sham injection (n = 423). Ninety-four percent of patients completed the study through day 180, and 997 patients continued in the open-label phase. One-third of patients in each group had a diagnosis of CRVO, whereas the remaining two-thirds had a diagnosis of BRVO. The duration of ME was similar among groups. Patients did not receive grid laser in the control arm. All patients were examined at baseline, and at 1, 7, 30, 60, 90, and 180 days after treatment. The primary outcome for the first 6 months was the proportion of eyes achieving at least a 15-letter VA improvement from baseline. The FDA later changed the primary outcome for the second study to be the time to reach a 15-letter improvement from baseline. Following completion of the first portion of the study, patients were eligible to have open-label retreatment with the 700-µg dexamethasone implant regardless of which initial treatment group they were in (sham, 350 µg, or 700 µg), provided that they demonstrated evidence of ME >250 µm on OCT examination and VA was worse than 20/20 at 6 months.
Both dexamethasone implant groups showed significantly greater improvement in vision than the sham treatment. The cumulative response rate was 41% in the 700-µg group, 40% in the 350-µg group, and 23% in the sham group (p < 0.001). Although the proportion of eyes achieving at least a 15-letter improvement from baseline BCVA was greater in the treatment groups at month 1 (21% in the 700-µg group vs. 18% in the 350-µg group vs. 8% in the sham group; p < 0.001) and month 3 (22% in the 700-µg group vs. 23% in the 350-µg group versus 13% in the sham group; p < 0.001), this effect was not statistically significant at month 6. The reduction in mean OCT central subfield retinal thickness was greater in the 700-µg (208 ± 201 µm) and 350-µg (177 ± 197 µm) groups than in the sham group (85 ± 173 µm) at month 3 (p < 0.001), but not statistically significant at month 6. It should be noted that 21% of BRVO and 17% of CRVO eyes required only a single treatment through 12 months. The dexamethasone implant was well tolerated and most eyes had no significant increase in IOP at the 6-month follow-up. Only 0.2% of eyes in either dexamethasone group had an IOP >35 mm Hg and 1.2% had an IOP >25 at 6 months. Overall, 29.7% of eyes were treated with IOP-lowering medication at day 90 and the IOP returned to baseline by day 180 in all groups. Five eyes (0.7%) underwent surgical intervention for IOP control, and three of these were for NVG secondary to RVO. Rates of cataract progression up to 1 year did not differ significantly among the groups. The side effect profile was similar during the 6-month open-label extension, during which all eyes received a first (in the case of sham-treated eyes) or second dexamethasone implant. In the extended follow-up, 32.8% of retreated dexamethasone 700-µg/700-µg group patients had at least a 10-mm Hg increase in IOP from baseline at some point over the 12-month period. In this retreatment group, 14 eyes underwent laser or surgery to reduce IOP. Cataracts were reported in 29.8% of phakic study eyes in the retreated dexamethasone 700-µg/700-µg group, 19.8% of the dexamethasone 350-µg/700-µg group, and 10.5% of the delayed treatment (sham/700-µg) group (p = 0.001). A total of 11 patients underwent cataract surgery. The results from these two “phase 3” trials have important clinical implications. Earlier treatment was associated with a better VA outcome across subgroups. A three-line VA gain following treatment with the 700-µg implant was seen in 48% of eyes with BRVO =90 days and in 67% of eyes with baseline BCVA worse than 55 letters in the =90-day subset. In addition, there was up to a twofold greater risk of three-line VA loss in sham-treated eyes compared with the 700-µg implant group. Risk of vision loss persisted at 12 months even after the sham group was treated with a 700-µg implant at the 6-month visit. 43