RETINAL VENOUS OCCLUSIVE DISEASE

BRANCH RETINAL VEIN OCCLUSION

1.What are the symptoms of a branch retinal vein occlusion?

Patients may notice an acute, painless loss of vision if there is macular edema, ischemic maculopathy, or intraretinal hemorrhage involving the fovea. A branch retinal vein occlusion (BRVO) in a nasal quadrant may be asymptomatic. A long-standing BRVO can present with floaters or an abrupt decrease in vision from vitreous hemorrhage secondary to retinal neovascularization.

2.What are the clinical signs of a branch retinal vein occlusion?

The acute funduscopic findings of BRVO include a wedge-shaped segmental pattern of intraretinal hemorrhages with its apex near the site of occlusion, tortuous and dilated veins, cotton-wool spots, and macular edema (Fig. 47-1). In a chronic BRVO, collateral vessels on the disc or bridging the horizontal raphe, macular retinal pigment epithelium changes, or neovascularization of the retina (NVE) or disc can develop.

3.Are there systemic associations in patients with a branch retinal vein occlusion?

The Eye Disease Case–Control Study Group identified a number of risk factors for BRVO: hypertension, cardiovascular disease, increased body mass index, and glaucoma. Interestingly, diabetes mellitus was not found to be a major independent risk factor for BRVO. Bilaterality, young age, or other atypical features should prompt further investigation for an underlying systemic disease (hypercoagulable state, autoimmune/inflammatory condition, or infectious disease).1

4.Where does a branch retinal vein occlusion most commonly occur?

The superotemporal quadrant is the most common location for a BRVO, representing approximately 60% of observed cases. Inferotemporal BRVOs account for an additional 30% of cases, while nasally distributed ones represent the remaining 10%. However, these numbers may be misrepresented, because most patients with nasal BRVOs do not have visual complaints and are often found only incidentally. Approximately 10% of patients with a BRVO will develop a retinal vein occlusion in the fellow eye.

KEY POINTS: COMMON CHARACTERISTICS OF A BRANCH RETINAL VEIN OCCLUSION

1. Occurs at arteriovenous crossing

2. Segmental pattern of intraretinal hemorrhages

3. Macular edema

4. Majority occur in the superotemporal quadrant

5.How is a branch retinal vein occlusion categorized?

A BRVO is classified as either ischemic or nonischemic. A nonischemic BRVO is defined as having fewer than five disc areas of retinal capillary nonperfusion, as documented by fluorescein angiography. An ischemic BRVO is defined as having more than five disc areas of retinal capillary nonperfusion.

6.What are the complications of a branch retinal vein occlusion?

Patients with a nonischemic BRVO may lose vision secondary to macular edema, which may be appreciated clinically and confirmed with ancillary imaging studies, such as fluorescein angiography

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Figure 47-1.  Superotemporal branch retinal vein occlusion with intraretinal hemorrhages, cotton-wool spots, hard exudates, and macular edema.

or, more commonly, optical coherence tomography. Patients with an ischemic BRVO most commonly lose vision from macular edema, ischemic maculopathy, or vitreous hemorrhage (VH). Fluorescein angiography is useful in detecting macular ischemia, revealing an enlarged and irregular foveal avascular zone. Depending on the degree of macular ischemia present, permanent visual loss is common. Additional sequelae of BRVO include retinal neovascularization (25%), which can result in vitreous hemorrhage from traction on the neovascular fronds, and epiretinal membrane formation (20%).

7.What is the treatment for an uncomplicated branch retinal vein occlusion?

Patients with a nonischemic BRVO without macular edema are followed clinically for the development of macular edema and for potential progression into an ischemic BRVO and its complications, which include ischemic maculopathy, NVE, and VH.

8.What is the first-line treatment for macular edema secondary to branch retinal vein occlusion?

The introduction of anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the management of macular edema associated with retinal vascular disease. The BRAVO study was a large, multicenter, phase 3, randomized study that evaluated monthly ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA) versus sham injections in treating acute macular edema secondary to BRVO. After 6 months, patients who received 0.3 mg ranibizumab had a mean gain from baseline of 16.6 letters, those who received 0.5 mg ranibizumab gained 18.3 letters, and the sham group gained 7.3 letters. Many clinicians have extrapolated these results to bevacizumab (Avastin, Genentech),

a cheaper off-label alternative, which has been shown to substantially reduce macular edema in a number of smaller uncontrolled studies.2

9.What is the role of intravitreal steroids in the treatment of macular edema ­secondary to branch retinal vein occlusion?

The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) BRVO study compared the safety and efficacy of macular grid laser treatment versus intravitreal triamcinolone corticosteroid injections (1 and 4 mg doses) to treat vision loss from macular edema associated with BRVO. After 1 year, a comparable percentage of patients experienced a substantial gain of three or more lines of vision across all three groups (29% in the laser group, 26% in the 1 mg triamcinolone group, and 27% in the 4 mg triamcinolone group). However, patients who received either dose of steroid were more likely to develop a cataract or elevated intraocular pressure than those who received laser treatment. In the GENEVA study, a biodegradable dexamethasone intravitreal implant (Ozurdex, Allergan, Irvine, CA, USA) demonstrated efficacy in treating macular edema from BRVO with much less intraocular pressure elevation or cataract progression than was reported with triamcinolone.3,4

10.What is the role of macular grid laser in the treatment of macular edema ­secondary to branch retinal vein occlusion?

The Branch Vein Occlusion Study was a historic multicenter, randomized, controlled clinical trial designed to answer whether argon macular grid laser photocoagulation is useful in improving visual acuity in eyes with a BRVO and macular edema that reduced vision to 20/40 or worse. The study found 65% of eyes treated with macular grid laser compared to 37% of control eyes gained two or

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more lines of vision. The investigators recommended macular grid laser for patients with a BRVO of at least 3 months’ duration and vision 20/40 or worse secondary to macular edema. Although the results of this study may seem outdated in the modern era of anti-VEGF pharmacotherapy, there

is still a distinct role for macular grid laser treatment, either alone or as an adjunct to intravitreal therapy.3,5

11.What is the treatment for a patient with an ischemic branch retinal vein occlusion before the development of neovascularization?

A second arm of the Branch Vein Occlusion Study was designed to determine whether peripheral sectoral scatter argon laser photocoagulation in the distribution of the vein occlusion can prevent the development of retinal neovascularization and vitreous hemorrhage. Significantly less neovascularization developed in patients treated with laser (19%) than in control patients (31%). Although the Branch Vein Occlusion Study was not designed to determine whether peripheral scatter laser treatment should be applied before rather than after the development of neovascularization, data accumulated in the study suggested there was minimal risk for severe vision loss if laser treatment was performed after the development of neovascularization. Thus, the authors did not advocate for prophylactic laser.6

12.What is the treatment for a patient with an ischemic branch retinal vein occlusion after the development of neovascularization?

The Branch Vein Occlusion Study determined that peripheral sectoral scatter argon laser photocoagulation in the distribution of the vein occlusion can prevent vitreous hemorrhage in patients who have already developed neovascularization (Fig. 47-2). Patients treated with laser developed vitreous hemorrhage significantly less often (29%) compared to the control patients (61%).6

KEY POINTS: WORKUP TO CONSIDER IN PATIENTS WITH BRVO

1. Blood pressure

2. Hemoglobin A1c, fasting blood glucose

3. Lipid profile

4. Prothrombin time/partial thromboplastin time

5. Hypercoagulable panel (e.g., protein C activity, protein S activity, homocysteine, antiphospholipid antibody, antithrombin III, factor V Leiden)

CENTRAL RETINAL VEIN OCCLUSION

13.What are the symptoms of a central retinal vein occlusion?

Patients may complain of sudden, painless loss of vision. A patient who has developed neovascular glaucoma secondary to ischemic central retinal vein occlusion (CRVO) may present with complaints of a painful red eye.

Figure 47-2.  Fluorescein angiogram of a superotemporal branch retinal vein occlusion after receiving sectoral scatter argon laser photocoagulation after developing neovascularization of the retina.

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14.What are the clinical signs of a central retinal vein occlusion?

In an acute CRVO, dilated fundus examination reveals certain characteristic findings: tortuosity and dilation of the central retinal vein, intraretinal hemorrhages throughout all four quadrants, cotton-wool spots, optic disc edema, and/or macular edema (Figs 47-3 and 47-4). Increased intraocular pressure or even frank open-angle glaucoma may be noted in a patient presenting with an acute CRVO. Cases of ischemic CRVO can develop anterior-segment or posterior-segment neovascularization, which manifests as proliferating new vessels on the iris, angle, disc, or retina. In a long-standing CRVO, patients may develop disc or retinal venous collaterals (Fig. 47-5).

KEY POINTS: COMMON CHARACTERISTICS OF A CENTRAL RETINAL VEIN OCCLUSION

1. Intraretinal hemorrhages in all four quadrants

2. Dilated tortuous retinal veins

3.Cotton-wool spots

4.Disc edema

5.Macular edema

15.What are the risk factors for a central retinal vein occlusion?

The Eye Disease Case–Control Study Group identified a number of risk factors for CRVO: hypertension, diabetes mellitus, and glaucoma. Oral contraceptives and diuretics have also been

Figure 47-3.  Nonischemic central retinal vein occlusion with dilated tortuous veins, prominent disc edema, intraretinal hemorrhages in four quadrants, and macular edema.

Figure 47-4.  Ischemic central retinal vein occlusion with dilated tortuous veins, extensive intraretinal hemorrhages in four quadrants, and macular edema.

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Figure 47-5.  Disc and retinal collaterals that have formed in the setting of a long-standing central retinal vein occlusion.

Figure 47-6.  Fluorescein angiogram of an ischemic central retinal vein occlusion demonstrating extensive retinal nonperfusion involving the macula.

implicated in causing CRVO. Other systemic conditions that affect the retinal vasculature or clotting mechanisms may also be associated with CRVO: blood dyscrasias (i.e., polycythemia vera), hypercoagulable states (i.e., protein C/S deficiencies), or autoimmune/inflammatory diseases.

Notably, hyperviscosity retinopathy is a bilateral condition that can mimic CRVO; however, it is due to an underlying systemic dysproteinemia, such as Waldenstrom macroglobulinemia or multiple myeloma.7

16.How is a central retinal vein occlusion categorized?

A CRVO is classified as either ischemic or nonischemic. A nonischemic CRVO is defined as having fewer than 10 disc areas of capillary nonperfusion as demonstrated by fluorescein angiography, whereas an ischemic CRVO is defined as having more than 10 disc areas of capillary nonperfusion (Fig. 47-6). Clinically, ischemic CRVO tends to be associated with poor vision, an afferent pupillary defect, and dense central scotoma.8

17.What are the complications of a central retinal vein occlusion?

Patients with a nonischemic CRVO can lose vision secondary to macular edema (Fig. 47-7). Patients with an ischemic CRVO can lose vision from macular edema, ischemic maculopathy, neovascular glaucoma (NVG), and vitreous hemorrhage. If ischemia occurs in the macula, the patient complains of central vision loss, and a fluorescein angiogram will demonstrate an enlarged and irregular foveal avascular zone. The most feared complication of an ischemic CRVO is anterior-segment neovascu-

larization, which can lead to NVG. Approximately 15% of patients with an ischemic CRVO develop neovascularization of the retina or disc. Traction from the vitreous may cause these new vessels to bleed, leading to VH and decreased vision (Fig. 47-8).9

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Figure 47-7.  Spectral-domain optical coherence tomography scan demonstrating macular and disc edema associated with central retinal vein occlusion.

Figure 47-8.  Ischemic central retinal vein occlusion that has developed secondary neovascular membranes superiorly with associated traction and early vitreous hemorrhage.

18.What is the most important risk factor for development of iris neovascularization in central retinal vein occlusion?

The Central Vein Occlusion Study (CVOS) determined that poor presenting visual acuity is the most important risk factor predictive of iris neovascularization.10

19.What is the proposed pathophysiologic basis for development of a combined cilioretinal artery occlusion and central retinal vein occlusion?

In an acute CRVO, increased venous intraluminal pressure is transmitted upstream to the feeding capillary bed. This increase in pressure carries over to the typically low-pressure cilioretinal artery system (which is unable to autoregulate), resulting in a transient blockage and thus a cilioretinal artery occlusion (Fig. 47-9).

20.What is the treatment for an uncomplicated central retinal vein occlusion?

Patients with a nonischemic CRVO without macular edema are followed clinically for the development of macular edema and for progression into an ischemic CRVO and its complications, including ischemic maculopathy, NVG, and VH. These patients should be monitored at monthly intervals for potential progression and for at least 6 months for the development of anterior-segment neovascularization/ neovascular glaucoma.

21.What is the first-line treatment for a patient with a central retinal vein occlusion and macular edema?

Like with BRVO, intravitreal anti-VEGF injections are the mainstay treatment for macular edema secondary to CRVO. In the CRUISE study (counterpart to the BRAVO study), patients were randomized to receive monthly injections of either 0.3 or 0.5 mg ranibizumab for 6 months versus sham injections. After 6 months, patients who received 0.3 mg ranibizumab had a mean gain from baseline of 12.7 letters, those who received 0.5 mg ranibizumab gained 14.9 letters, and the sham group gained

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Figure 47-9.  Combined central retinal vein occlusion and cilioretinal artery occlusion.

0.8 letters. Ophthalmologists have extrapolated these results to bevacizumab (Avastin, Genentech), a cheaper off-label alternative, which has been demonstrated to reduce macular edema in a number of smaller uncontrolled studies. More recently, a third anti-VEGF drug, aflibercept (Eylea, Regeneron, Tarrytown, NY, USA), has been approved for the indication of macular edema secondary to CRVO.

In the nearly identical COPERNICUS and GALILEO studies, patients received 6-monthly injections of aflibercept at a dose of 2 mg versus sham injections. In the COPERNICUS trial, 56.1% of patients receiving aflibercept gained at least 15 letters of vision from baseline, compared with 12.3% of patients receiving sham injections. In the GALILEO study, 60.2% of patients receiving aflibercept gained at least 15 letters of vision from baseline, compared with 22.1% of patients receiving sham injections.11-13

22.What is the role of intravitreal steroids in the treatment of macular edema secondary to central retinal vein occlusion?

In the SCORE-CRVO study, more patients experienced an improvement of 15 ETDRS letters or more after 1 year in the 1 mg triamcinolone (27% of patients) and 4 mg triamcinolone (26%) groups compared to only 7% of patients in the observation group, In the GENEVA study, a biodegradable dexamethasone intravitreal implant (Ozurdex, Allergan) demonstrated efficacy in improving visual acuity outcomes and reducing macular edema from CRVO with a lower incidence of elevated intraocular pressure or cataract progression than was previously reported with triamcinolone.4,14

23.What is the role of macular grid laser in the treatment of macular edema secondary to central retinal vein occlusion?

The CVOS was a multicentered, randomized, controlled clinical trial designed to answer whether argon macular grid laser photocoagulation was useful in improving visual acuity in eyes with a CRVO and macular edema that reduced vision to 20/50 or worse. Patients were randomized to macular grid photocoagulation or no treatment. Although the grid laser treatment reduced angiographic evidence of macular edema, there was no improvement in final visual acuity compared to untreated eyes. However, a trend was observed that revealed that grid laser treatment may be beneficial in younger patients. Taking the results together, the study investigators did not recommend routine macular grid photocoagulation for patients with macular edema secondary to CRVO.15

KEY POINTS: WORKUP TO CONSIDER IN PATIENTS WITH CRVO

1. Blood pressure

2. Hemoglobin A1c, fasting blood glucose

3. Lipid profile

4. Prothrombin time/partial thromboplastin time

5. Hypercoagulable panel (e.g., protein C activity, protein S activity, homocysteine, antiphospholipid antibody, lupus anticoagulant, antithrombin III, factor V Leiden)

6. Consider hemoglobin electrophoresis, cryoglobulins, and serum protein electrophoresis if clinically indicated