Central Retinal Vein Occlusion (CRVO)

Background

Central retinal vein occlusion (CRVO) is a common retinal vascular disorder. Clinically, CRVO presents with variable visual loss; the fundus may show retinal hemorrhages, dilated tortuous retinal veins, cotton-wool spots, macular edema, and optic disc edema. Note the images below.

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Recent onset central retinal vein occlusion, showing extensive hemorrhages in the posterior pole and giving the "blood and thunder appearance."

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Peripheral fundus view of the same patient with central retinal vein occlusion as in the previous image, showing hemorrhages extending all over the fu....

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Fluorescein angiograph of same patient with central retinal vein occlusion as in previous images, showing hypofluorescence due to blockage from hemorr....

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Fundus picture of the same patient with central retinal vein occlusion as in previous images, showing resolving neovascularization of the disc and pan....

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Fluorescein angiogram of the same patient with central retinal vein occlusion as in the previous images, taken more than 1 year later, showing persist....

In view of the devastating complications associated with the severe form of CRVO, a number of classifications were described in the literature. All of these classifications take into account the area of retinal capillary nonperfusion and the development of neovascular complications.^{[1, 2, 3, 4, 5]}

Broadly, CRVO can be divided into 2 clinical types, ischemic and nonischemic. In addition, a number of patients may have an intermediate presentation with variable clinical course. On initial presentation, it may be difficult to classify a given patient into either category, since CRVO may change with time.

A number of clinical and ancillary investigative factors are taken into account for classifying CRVO, including vision at presentation, presence or absence of relative afferent pupillary defect, extent of retinal hemorrhages, cotton-wool spots, extent of retinal perfusion by fluorescein angiography, and electroretinographic changes.

Nonischemic CRVO is the milder form of the disease. It may present with good vision, few retinal hemorrhages and cotton-wool spots, no relative afferent pupillary defect, and good perfusion to the retina. Nonischemic CRVO may resolve fully with good visual outcome or may progress to the ischemic type. Note the images below.

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Patient with nonischemic central retinal vein occlusion presented with dilated, tortuous veins and superficial hemorrhages.

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Fundus picture of the same patient with central retinal vein occlusion as in previous image, showing resolved hemorrhages and pigmentary changes in th....

Ischemic CRVO is the severe form of the disease. CRVO may present initially as the ischemic type, or it may progress from nonischemic. Usually, ischemic CRVO presents with severe visual loss, extensive retinal hemorrhages and cotton-wool spots, presence of relative afferent pupillary defect, poor perfusion to retina, and presence of severe electroretinographic changes. In addition, patients may end up with neovascular glaucoma and a painful blind eye.

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Pathophysiology

The exact pathogenesis of the thrombotic occlusion of the central retinal vein is not known. Various local and systemic factors play a role in the pathological closure of the central retinal vein.^{[3, 6, 7]}

The central retinal artery and vein share a common adventitial sheath as they exit the optic nerve head and pass through a narrow opening in the lamina cribrosa. Because of this narrow entry in the lamina cribrosa, the vessels are in a tight compartment with limited space for displacement. This anatomical position predisposes to thrombus formation in the central retinal vein by various factors, including slowing of the blood stream, changes in the vessel wall, and changes in the blood.

Arteriosclerotic changes in the central retinal artery transform the artery into a rigid structure and impinge upon the pliable central retinal vein, causing hemodynamic disturbances, endothelial damage, and thrombus formation. This mechanism explains the fact that there may be an associated arterial disease with central retinal vein occlusion (CRVO). However, this association has not been proven consistently, and various authors disagree on this fact.

Thrombotic occlusion of the central retinal vein can occur as a result of various pathologic insults, including compression of the vein (mechanical pressure due to structural changes in lamina cribrosa, eg, glaucomatous cupping, inflammatory swelling in optic nerve, orbital disorders); hemodynamic disturbances (associated with hyperdynamic or sluggish circulation); vessel wall changes (eg, vasculitis); and changes in the blood (eg, deficiency of thrombolytic factors, increase in clotting factors).

Occlusion of the central retinal vein leads to the backup of the blood in the retinal venous system and increased resistance to venous blood flow. This increased resistance causes stagnation of the blood and ischemic damage to the retina. It has been postulated that ischemic damage to the retina stimulates increased production of vascular endothelial growth factor (VEGF) in the vitreous cavity. Increased levels of VEGF stimulate neovascularization of the posterior and anterior segment (responsible for secondary complications due to CRVO). Also, it has been shown that VEGF causes capillary leakage leading to macular edema (which is the leading cause of visual loss in both ischemic CRVO and nonischemic CRVO).

The prognosis of CRVO depends upon the reestablishment of patency of the venous system by recanalization, dissolution of clot, or formation of optociliary shunt vessels.

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Epidemiology

Frequency

United States

Central retinal vein occlusion (CRVO) and branch retinal vein occlusion constitute the second most common retinal vascular disorder. The nonischemic type is more common than the ischemic type.

The Beaver Dam Eye Study Group reported the 15-year cumulative incidence of CRVO to be 0.5%.^[8]

International

A large population-based study in Israel reported a 4-year incidence of retinal vein occlusion of 2.14 cases per 1000 of general population older than 40 years and 5.36 cases per 1000 of general population older than 64 years.

In Australia, the prevalence of vein occlusion ranges from 0.7% in patients aged 49-60 years to 4.6% in patients older than 80 years.^[9]

Pooled data from population studies from the United States, Europe, Asia, and Australia show that CRVO affects 0.8 per 1000 persons.^[10]

Mortality/Morbidity

CRVO is not associated directly with increased mortality.

Nonischemic CRVO may resolve completely without any complications in about 10% of cases. In about 50% of patients, vision may be 20/200 or worse. One third of patients may progress to the ischemic type, commonly in the first 6-12 months after presentation.

In more than 90% of patients with ischemic CRVO, final visual acuity may be 20/200 or worse. Anterior segment neovascularization with associated neovascular glaucoma develops in more than 60% of cases. This can happen within a few weeks and up to 1-2 years afterward.

It has been reported that the fellow eye may develop retinal vein occlusion in about 7% of cases within 2 years. In another report, the 4-year risk of developing second venous occlusion is 2.5% in the same eye and 11.9% in the fellow eye. Neovascular glaucoma may result in a painful blind eye.

Race

CRVO does not have any particular racial preference.

Sex

CRVO occurs slightly more frequently in males than in females.

Age

More than 90% of CRVO occurs in patients older than 50 years, but it has been reported in all age groups.

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Prognosis

For nonischemic CRVO, complete recovery with good visual recovery occurs only in about 10% of cases. Fifty percent of patients will have 20/200 or worse vision. About one third of patients convert to ischemic CRVO. CVOS noted that, of 547 eyes initially diagnosed to have nonischemic central retinal vein obstructions, 185 (34%) progressed to become ischemic central retinal vein obstructions within 3 years; 15% converted within the first 4 months.

For ischemic CRVO, more than 90% of patients will have 20/200 or worse vision. About 60% of patients develop ocular neovascularization with associated complications. About 10% of patients can develop CRVO or other type of vein occlusions within either the same eye or the contralateral eye within 2 years.

The long-term prognosis of CRVO has significantly improved with new anti-VEGF agents and steroids, maintaining good visual acuity for a long duration in most patients, except those with severe ischemic maculopathy. Development of neovascular complications has also decreased with continued monitoring and anti–VEGF treatment.

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Patient Education

Good control of systemic medical problems is important, as are regular medical and ophthalmologic checkups.

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History

A direct review of systems toward the various systemic and local factors predisposing the central retinal vein occlusion (CRVO) is indicated.

Significant history includes the following:

• Hypertension
• Diabetes mellitus
• Cardiovascular disorders
• Bleeding or clotting disorders
• Vasculitis
• Autoimmune disorders
• Use of oral contraceptives
• Closed-head trauma
• Alcohol consumption
• Amount of physical activity
• Primary open-angle glaucoma or angle-closure glaucoma

Ocular symptoms at initial presentation are as follows:

• Asymptomatic
• Decreased vision
• Visual loss can be sudden or gradual, over a period of days to weeks. Visual loss ranges from mild to severe. Patients can present with transient obscurations of vision initially, later progressing to constant visual loss.
• Photophobia
• Painful blind eye
• Redness of eyes

Ocular symptoms in later stages are as follows:

• Decrease of vision
• Pain in the eyes
• Discomfort
• Redness
• Watering

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Physical

Patients with central retinal vein occlusion (CRVO) should undergo a complete eye examination, including visual acuity, pupillary reactions, slit lamp examination of the anterior and posterior segments, undilated examination of the iris, gonioscopy, fundus examination with indirect ophthalmoscope, and fundus contact lens.^[11] Note the following:

• Visual acuity: Best-corrected vision always should be obtained. It is one of the important indicators of the final visual prognosis.
• Pupillary reactions may be normal and may present with relative afferent pupillary reflex. If the iris has abnormal blood vessels, the pupil may not react.
• Conjunctiva: Advanced stages may show congestion on conjunctival and ciliary vessels.
• Cornea: Advanced stages may show diffuse corneal edema obscuring the visibility of internal structures.
• The iris may be normal. Advanced stages may show neovascularization. These vessels are detected best on an undilated iris. Initially, the vessels may be seen around pupillary margins and peripheral iridectomy openings if present.
• The anterior chamber angle is examined by gonioscopy. This is examined best in an undilated iris. Initially, it may show neovascularization with open angles and later show total peripheral anterior synechia and closed angles.
• Fundus examination: Retinal hemorrhages may present in all 4 quadrants. Hemorrhages can be superficial, dot and blot, and/or deep. In some patients, hemorrhages may be seen in the peripheral fundus only. Hemorrhages can be mild to severe, covering the whole fundus and giving a "blood and thunder appearance." Note the images below.

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  Scattered retinal hemorrhages in a patient with central retinal vein occlusion.

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  Fundus of a patient with nonischemic central retinal vein occlusion, showing few scattered peripheral fundus hemorrhages.

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  Recent onset central retinal vein occlusion, showing extensive hemorrhages in the posterior pole and giving the "blood and thunder appearance."

   

  

   
• Dilated tortuous veins: Veins may be dilated and tortuous, as shown in the image below.

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  Patient with nonischemic central retinal vein occlusion presented with dilated, tortuous veins and superficial hemorrhages.

   

  

   
• Optic disc edema: The optic disc may be swollen during the early-stage disease. Note the images below.

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  Central retinal vein occlusion showing significant disc edema with dilated tortuous veins and scattered retinal hemorrhages.

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  Fluorescein angiogram of the same patient with central retinal vein occlusion in as in previous image, showing leakage from disc, staining of retinal ....

   

  

   
• Cotton-wool spots are more common with ischemic CRVO. Usually, they are concentrated around the posterior pole. Cotton-wool spots may resolve in 2-4 months.
• Neovascularization of the disc: Fine abnormal neovascularization of the disc (NVD) or within 1 disc diameter from the disc may be present. NVD indicates severe ischemia of the retina. NVD is sometimes difficult to differentiate from optociliary shunt vessels. NVD can lead to preretinal or vitreous hemorrhage.
• Neovascularization elsewhere: Neovascularization elsewhere (NVE) is not as common as NVD. NVE indicates severe ischemia of the retina. NVE can lead to preretinal or vitreous hemorrhage.
• Optociliary shunt vessels (depicted in the images below) are abnormal blood vessels on the disc, directing blood from retinal circulation to choroidal circulation, which indicate good compensatory circulation.

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  Fundus picture of a well-compensated, old central retinal vein occlusion showing optociliary shunt vessels.

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  Red-free photo of the same patient with central retinal vein occlusion as in the previous image, showing prominent optociliary shunt vessels.

   

  

   
• Preretinal or vitreous hemorrhage
• Macular edema with or without exudates
• Cystoid macular edema
• Lamellar or full-thickness macular hole
• Optic atrophy
• Pigmentary changes in the macula

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Causes

Central retinal vein obstruction has been associated with various systemic pathological conditions, although the exact cause and effect relationship has not been proven.

Some of the conditions in which CRVO has been associated include the following:

• Systemic vascular disease - Hypertension, diabetes mellitus, cardiovascular disease
• Blood dyscrasias - Polycythemia vera, lymphoma, leukemia
• Clotting disorders - Activated protein C resistance, lupus anticoagulant, anticardiolipin antibodies, protein C, protein S, antithrombin III
• Paraproteinemia and dysproteinemias - Multiple myeloma, cryoglobulinemia
• Vasculitis - Syphilis, sarcoidosis
• Autoimmune disease - Systemic lupus erythematosus
• Oral contraceptive use in women
• Obstructive sleep apnea - This affects more patients with retinal vein obstruction than other disorders; treatment of the sleep apnea may help prevent central vein obstruction.^[12]
• Other rare associations - Closed-head trauma, optic disc drusen, arteriovenous malformations of retina

The Eye Disease Case-Control Study Group reported that the risk of CRVO is decreased in men with increasing levels of physical activity and increasing levels of alcohol consumption. The same study group reported a decreased risk of CRVO with the use of postmenopausal estrogens and an increased risk with higher erythrocyte sedimentation rates in women.

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Complications

Ocular neovascularization is a potential complication.^[13]  Anterior segment neovascularization can lead to neovascular glaucoma. Posterior segment neovascularization can lead to vitreous hemorrhage.

Macular edema is another potential complication.^{[14, 15, 16]}  Macular edema is the common cause of decreased vision in CRVO, more so in the nonischemic type. It may resolve with good visual return. The patient may develop permanent degenerative changes with poor visual prognosis and may develop cystoid macular edema leading to lamellar or full-thickness macular hole.

Other potential complications include cellophane maculopathy and macular pucker, as well as optic atrophy.

Reported complications due to treatment with intravitreal injections include endophthalmitis, vitreous hemorrhage, and retinal detachment.

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Laboratory Studies

No laboratory studies are routinely indicated in the diagnosis of central retinal vein occlusion (CRVO). In older patients, laboratory testing should be directed toward identifying systemic vascular problems. In young patients, laboratory testing may be tailored depending upon individual findings, to include the following:

• Complete blood cell (CBC) count
• Glucose tolerance test
• Lipid profile
• Serum protein electrophoresis
• Chemistry profile
• Hematologic tests
• Syphilis serology
• In addition, thrombophilic screening, activated protein C resistance, lupus anticoagulant, anticardiolipin antibodies, protein C, protein S, and antithrombin III may be completed.

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Imaging Studies

Color Doppler imaging is a noninvasive quantitative method of assessing the retrobulbar circulation. Detection of low venous velocities has been used to predict the onset of iris neovascularization. At present, this is performed as an investigational procedure in large facilities.^[17]

Optical coherence tomography (OCT)^[18] scanning is a noninvasive, noncontact, transpupillary imaging technology that can image retinal structures in vivo with an axial resolution of 1-15 µm. Spectral-domain OCT is used to detect intraretinal and subretinal fluid and to measure the thickness of individual retinal layers. OCT provides information regarding the health of photoreceptors and ganglion cell layers. OCT is used exclusively to monitor macular edema over time and the response with various treatment modalities.^{[18, 19]}

In addition to providing quantitative measurements of central retinal thickness, spectral-domain OCT reveals disorganization of the retinal inner layers (DRIL) and ellipsoid zone disruptions, which are used increasingly as biomarkers for assessing visual outcomes to various therapeutic agents.^[20]

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Other Tests

Fluorescein angiography

Fluorescein angiography is the most useful test for the evaluation of retinal capillary nonperfusion, posterior segment neovascularization, and macular edema.^[2] Note the images below.

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Fluorescein angiogram of a patient with nonischemic central retinal vein occlusion, showing staining of dilated tortuous veins with leakage into macul....

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Fluorescein angiogram of the same patient as in previous image, showing perifoveal capillary leakage in a cystoid pattern in late phases of angiogram.....

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Late phase of fluorescein angiograph of the same patient as in previous image, showing cystoid pattern of leakage from perifoveal dilated leaking capi....

Fluorescein angiography is one of the tests used in the classification of CRVO. Areas of capillary nonperfusion are visualized as hypofluorescence, but hemorrhages can block fluorescence and give a similar picture. Therefore, in the early stages of the disease process, due to extensive hemorrhages, fluorescein angiography gives little information regarding the perfusion status of the retina. Once the hemorrhages clear, areas of capillary nonperfusion can be detected as hypofluorescence in the fluorescein angiography. Wide-angled fluorescein angiography is useful tool to detect areas of retinal perfusion and non-perfusion in mid and peripheral retina in early stages of disease.^[21]

Various studies have reported different criteria for defining ischemic CRVO versus nonischemic CRVO based on the extent of capillary nonperfusion of the retina. The amount of retinal nonperfusion ranges from 10-30 disc areas.

In addition, fluorescein angiography may show delayed arteriovenous transit, staining along the retinal veins, microaneurysms, arteriovenous collaterals, NVD, NVE, and dilated optic nerve head capillaries.

In a nonischemic central retinal vein obstruction, angiography may show minimal or absent retinal capillary nonperfusion, staining along the retinal veins, microaneurysms, and dilated optic nerve head capillaries. Resolved CRVO may be completely normal.

Macular edema may be detected as leakage from perifoveal capillaries (depicted in the image below), leakage from microaneurysms, or diffuse leakage on fluorescein angiography. If extensive edema is present, fluorescein angiography may show pooling of dye in large cystoid spaces. In addition, capillary nonperfusion around the fovea may indicate macular ischemia. If macular edema persists, pigmentary changes become evident.

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Arteriovenous phase of fluorescein angiograph showing perifoveal capillary leakage in a patient with nonischemic central retinal vein occlusion.

Optical coherence tomography angiography

OCT angiography (OCTA) generates high-resolution noninvasive angiograms (no dye injection required) that qualitatively illustrate most clinically relevant findings in retinal venous occlusion. Unlike standard fluorescein angiography, OCTA provides details of superficial and deep retinal capillary plexus and choroidal capillary structures, which are affected by retinal vein occlusions. OCT angiography is a useful tool in evaluating capillary nonperfusion, which can allow for more objective differentiation of ischemic CRVO from nonischemic CRVO.^{[22, 23, 21]}

Electroretinography

Electroretinography (ERG) is another useful test to evaluate the functional status of the retina and to classify CRVO.^{[18, 24, 25]} In ERG waveform, b-wave and a-wave are produced by the inner retina and the outer retina, respectively. In central retinal vein obstruction, perfusion of the inner retina is affected, so that the amplitude of the b-wave is decreased relative to the a-wave; the b-to-a ratio has been shown to be reduced. Some studies indicate that a b-to-a ratio of less than 1 suggests an ischemic central retinal vein obstruction.

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Histologic Findings

Not many histopathologic reports exist in the literature. A report of histologic sections of 29 eyes with central retinal vein obstruction showed a fresh or recanalized thrombus at or just posterior to the lamina cribrosa. Within the thrombi, a mild lymphocytic infiltration with prominent endothelial cells was seen. Loss of the inner retinal layers consistent with inner retinal ischemia also was seen.^[26]

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Approach Considerations

No known effective medical treatment is available for the prevention or treatment of central retinal vein occlusion (CRVO). Identifying and treating any systemic medical problems to reduce further complications is important. Because the exact pathogenesis of the CRVO is not known, various medical modalities of treatment have been advocated by multiple authors with varying success in preventing complications and in preserving vision.

Macular edema is one of the prominent treatable causes of decreased visual acuity in patients with CRVO. The exact mechanism of macular edema is unclear, but multiple factors involved include increased venous pressure, elevated levels of VEGF, and deregulation of multiple inflammatory mediators leading to increased capillary permeability and leakage.

Various treatment modalities have been used to counter different components of macular edema pathogenesis, with significant progress in stabilizing or improving visual acuity.

Advocated treatments are as follows:

• Aspirin
• Anti-inflammatory agents
• Isovolemic hemodilution
• Plasmapheresis
• Systemic anticoagulation with warfarin, heparin, and alteplase
• Fibrinolytic agents
• Systemic corticosteroids
• Local anticoagulation with intravitreal injection of alteplase
• Intravitreal injection of ranibizumab
• Intravitreal injection of aflibercept
• Intravitreal injection of triamcinolone
• Intravitreal injection of bevacizumab
• Dexamethasone intravitreal implant

The Ophthalmic Technology Assessment Committee Retina/Vitreous panel of the American Academy of Ophthalmology evaluated available literature regarding efficacy of available pharmacotherapies in the treatment of macular edema due to CRVO. The panel reported that intravitreal anti-VEGF therapy is safe and effective over 2 years for macular edema and that delayed treatment is associated with worse visual outcomes. Intravitreal corticosteroid therapy yielded short-term efficacy but was associated with a higher frequency of adverse events.^[27]

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Medical Care

Corticosteroid therapy

Intraocular steroid injection has been shown to be effective in decreasing macular edema. Although the exact mechanism of action is unknown, steroids work by targeting various inflammatory pathways and decreasing expression of VEGF, reducing vascular permeability, stabilizing endothelial tight junctions, and decreasing macular edema.

Currently, triamcinolone acetonide and dexamethasone are the two steroid preparations used to treat macular edema associated with central retinal vein occlusion (CRVO).

Intravitreal injection of triamcinolone

The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study is a National Eye Institute–sponsored randomized controlled trial comparing 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone acetonide versus observation for visual acuity loss due to macular edema associated with perfused CRVO.

The SCORE study reported that intravitreal triamcinolone (both 1-mg and 4-mg dose groups) yielded better visual acuity outcomes over 12 months than observation alone. Beyond 12 months, the greater likelihood of visual acuity gain with triamcinolone persists, although there is a mild attenuation of the effect of triamcinolone with respect to mean change in visual acuity.

Both triamcinolone groups had a similar change in mean visual acuity letter score compared with the observation group, but the 4-mg group had the highest rate of cataract formation, cataract surgery, and intraocular pressure (IOP) elevation. The risk factors for IOP-related events included higher treatment dose, younger age, and higher baseline IOP. IOP-related events may take several months from the time of first triamcinolone injection to occur, so it is recommended to assess the risks and benefits of triamcinolone therapy and to maintain long-term follow-up of patients at risk for this complication.

Based on safety and efficacy findings from the SCORE-CRVO trial, administering intravitreal triamcinolone in a 1-mg dose and following the retreatment criteria used in this study should be considered for up to 1 year, and possibly 2 years, in patients with vision loss associated with macular edema secondary to CRVO.^{[28, 29]}

Dexamethasone intravitreal implant

Dexamethasone is a potent, water-soluble corticosteroid that can be delivered to the vitreous cavity by the dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan; Irvine, Calif). A dexamethasone implant is composed of a biodegradable copolymer of lactic acid and glycolic acid containing micronized dexamethasone. The drug-copolymer complex gradually releases the total dose of dexamethasone over a series of months after insertion into the eye through a small pars plana puncture using a customized applicator system.

A 6-month study evaluated the safety and efficacy of dexamethasone implant 0.35 mg and 0.7 mg compared with a sham procedure in eyes with vision loss due to macular edema associated with BRVO and CRVO.^[30] In conclusion, the results of the study demonstrated that the dexamethasone implant reduced the risk of further vision loss and increased the chance of improvement in visual acuity in eyes with CRVO.

The percentage of eyes with a greater than or equal to 15-letter improvement in BCVA was significantly higher in both dexamethasone implant groups compared with sham at days 30 to 90 (P< .001). The results of this study further demonstrate that when these eyes were left untreated, a significant percentage will either fail to improve or will experience further loss of visual acuity. The dexamethasone implant was well tolerated, producing generally transient, moderate, and readily managed increases in IOP in less than 16% of eyes. Overall, this study suggests that the DEX implant could be a valuable treatment option for eyes with visual loss due to CRVO.

Antivascular endothelial growth factors

The postulated mechanism for macular edema is up-regulation of VEGF in response to retinal ischemia secondary to increased resistance to venous blood flow. The reported intravitreal levels of VEGF-A are higher in CRVO than in any other ischemic retinal vascular disease. VEGF increases vascular permeability, leading to macular edema and development of neovascularization. Multiple anti-VEGF medications have been shown to be effective in reducing edema.

Intravitreal injection of ranibizumab

Ranibizumab (Lucentis, Genentech, Inc.) is a humanized, affinity-matured VEGF antibody fragment that binds to and neutralizes all isoforms of VEGF.

The role of ranibizumab in the management of CRVO was reported in multiple studies. In the CRUISE and HORIZON studies, intravitreal injection of ranibizumab improved visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events. Results suggest that, during the second year of ranibizumab treatment, follow-up and injections should be individualized. On average, patients with CRVO may require follow-up more frequent than every 3 months.

The CRYSTAL study was a 24-month phase-3b, open-label, single-arm, multicenter study conducted in a broad patient population with visual impairment resulting from macular edema secondary to CRVO, including those with macular ischemia or greater disease duration. An individualized dosing regimen of ranibizumab 0.5 mg driven by stabilization criteria for up to 12 months resulted in significant best-corrected visual acuity gain in a broad population of patients with macular edema secondary to CRVO, including those with macular ischemia at baseline. The safety findings were consistent with those reported in previous ranibizumab studies in patients with CRVO.^{[31, 32, 33, 34, 35, 36]}

Intravitreal injection of aflibercept

Intravitreal aflibercept (VEGF Trap-Eylea; Regeneron Pharmaceuticals, Inc.) is a fusion protein comprising key domains of human VEGF receptors 1 and 2 with immunoglobulin-G Fc. Intravitreal aflibercept binds multiple isoforms of human VEGF-A and placental growth factor with high affinity.

Two parallel trials, the COPERNICUS and GALILEO studies, evaluated the efficacy and safety of intravitreal aflibercept injection for the treatment of macular edema secondary to CRVO. Aflibercept injection demonstrated a statistically significant difference in the proportion of patients who gained 15 or more letters from baseline at week 24 compared with placebo in each study. The visual and anatomic improvements were diminished after continued PRN dosing, with a reduced monitoring frequency from weeks 52 to 100.

In conclusion, the studies demonstrate that long-term anti-VEGF therapy and more frequent monitoring is necessary to control macular edema in many patients with CRVO, likely because the continued ischemia leads to continued excessive VEGF production.^{[37, 27, 38, 39, 40]}

Intravitreal Injection of bevacizumab

Bevacizumab (Avastin, Genentech, Inc.) is a recombinant, humanized monoclonal antibody that binds all isoforms of VEGF-A. Intravitreal injection of bevacizumab (0.05 mL/1.25 mg) has been shown to be effective not only in resolving the edema but also in corresponding improvement in vision. In a prospective, randomized, double-masked clinical study by Epstein et al, intravitreal injections of bevacizumab given every 6 weeks for 12 months improve visual acuity and significantly reduce edema compared with sham. Early treatment is important in these patients to optimize visual outcome, as patients in whom treatment is delayed have limited visual improvement. In addition, none of the patients developed neovascular glaucoma when treated with bevacizumab.

Bevacizumab is approved for treatment of various metastatic cancers, including metastatic colorectal cancer, non-small cell lung cancer, and glioblastoma multiforme. Intravitreal injection of bevacizumab is considered off-label use. Bevacizumab is not commercially available as an intravitreal injection. Reports of small series of eye infections due to contamination from repackaging into preservative-free single use vials have been reported.

Significant complications were reported with high doses of bevacizumab given intravenously for the treatment of cancer. There have been no significant reports of these complications when used in low dosage in eye.^{[18, 13, 41, 27, 42]}

Intravitreal anti-VEGF injections yielded better anatomical and functional improvements than did corticosteroids. After initial improvements in visual acuity with anti-VEGF injections, some of those gains were lost over time because of recurrent macular edema.^{[43, 44]}

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Surgical Care

Laser photocoagulation

Laser photocoagulation is the known treatment of choice in the treatment of various complications associated with retinal vascular diseases (eg, diabetic retinopathy, branch retinal vein occlusion). Panretinal photocoagulation (PRP) has been used in the treatment of neovascular complications of central retinal vein occlusion (CRVO) for a long time. However, no definite guidelines exist regarding exact indication and timing of PRP. A National Eye Institute (NEI) sponsored multicenter prospective study, the Central Vein Occlusion Study (CVOS), provided guidelines for the treatment and follow-up care of patients with CRVO.^{[1, 11, 45, 46, 15]}

CVOS evaluated the efficacy of prophylactic PRP in eyes with 10 or more disc areas of retinal capillary nonperfusion, confirmed by fluorescein angiography, in preventing development of 2 clock hours of iris neovascularization or any angle neovascularization or whether it is more appropriate to apply PRP only when iris neovascularization or any angle neovascularization occurs. CVOS concluded that prophylactic PRP did not prevent the development of iris neovascularization and recommended to wait for the development of early iris neovascularization and then apply PRP.

Argon green laser usually is used. Laser parameters should be about 500-µm size, 0.1-0.2 second duration, and power should be sufficient to give medium white burns. Laser spots are applied around the posterior pole, extending anterior to equator. They should be about 1 burn apart and total 1200-2500 spots.

If ocular media is hazy for laser to be applied, cryoablation of the peripheral fundus is performed. About 16-32 transscleral cryo spots are applied from ora serrata posteriorly.

CVOS evaluated the efficacy of macular grid photocoagulation in preserving or improving central visual acuity in eyes with macular edema due to central vein occlusion (CVO) and best-corrected visual acuity of 20/50 or poorer. Macular grid photocoagulation was effective in reducing angiographic evidence of macular edema, but it did not improve visual acuity in eyes with reduced vision due to macular edema from CVO. At present, the results of this study do not support a recommendation for macular grid photocoagulation for macular edema.

Chorioretinal venous anastomosis

Chorioretinal venous anastomosis^{[47, 48, 49, 50, 51]} is performed by creating an anastomosis to bypass the site of venous occlusion in the optic disc. In this procedure, retinal veins are punctured, either using laser or by surgery, through the retinal pigment epithelium and the Bruch membrane into the choroid, thereby developing anastomotic channels into the choroid.

Chorioretinal venous anastomosis reduces macular edema and may improve vision in nonischemic CRVO. The success rate is low, and the complication rate can be quite high, including vitreous hemorrhages and choroidal neovascularization at the anastomosis site.

The exact indication and timing of the procedure has not been clearly studied.

Radial optic neurotomy

Radial optic neurotomy (RON)^{[52, 53, 54, 55, 56, 57]} is a new surgical technique in which a microvitreoretinal blade is used during pars plana vitrectomy to relax the scleral ring around the optic nerve. The central retinal artery and vein passes through the narrow openings of the cribriform plate in the optic disc.

Promoters of this technique suggest that CRVO may be due to the compression of the central retinal vein at this location creating a compartment syndrome. If this procedure is successful, it decompresses the closed compartment and leads to an improvement in venous outflow and a reduction of macular edema.

In one study, RON resulted in clinically relevant improvements on a long-term basis. Patients with nonischemic CRVO may respond more favorably than patients with ischemic CRVO.

In another study, significant improvements were observed in the b-to-a ratio of the standard combined ERG after surgery in eyes with CRVO.

The benefits from surgery have not been clearly documented. One study, looking into the biomechanical effect of RON, found negligible change in the space around the central retinal vein; RON is unlikely to be a procedure that could mechanically ameliorate the clinical sequelae of a central vein occlusion. The improvement of retinal function is most likely due to improved oxygenation of the retina caused by vitrectomy and not by RON.

In addition to the regular complications of vitrectomy, RON can result in significant hemorrhage and neovascularization at the incision site.

No consensus currently exists among various researchers regarding the exact criteria for the use of RON.

Vitrectomy

A vitrectomy^[58] is a technique in which the vitreous is surgically removed along with removal of the posterior hyaloid.

Some studies have shown that a vitrectomy may be beneficial for macular edema due to CRVO. One theory is that a vitrectomy may relieve traction on the macula and, thus, reduce macular edema. According to another hypothesis, removing the vitreous will also remove cytokines and VEGF associated with a venous occlusive event; thus, the stimulus for macular edema will be reduced.

At the present time, no convincing evidence indicates that a vitrectomy is the best approach.

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Consultations

A general ophthalmologist should consult a retinal specialist for management of CRVO complications. Other consults include an internist for proper evaluation and management of any systemic medical problems. If patients develop neovascular glaucoma, a glaucoma specialist should be consulted.

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Diet

Diet should be tailored to systemic medical problems.

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Activity

No restrictions usually exist. If patients develop vitreous hemorrhage, they are advised to avoid strenuous activities, sleep with few pillows, and avoid bending and lifting heavy weights.

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Prevention

Optimal control of associated systemic diseases may reduce the incidence of similar occlusions in the fellow eye.

Even though controversial, good control of intraocular pressure in patients known to have glaucoma may prevent CRVO.

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Long-Term Monitoring

Since neovascular complications and development of second venous occlusions can develop after central retinal vein occlusion (CRVO), all of these patients need long-term follow-up care.

CVOS recommended careful observation with frequent follow-up examinations in the early months for detection of iris neovascularization and prompt treatment.

Patients with poor initial visual acuity should be monitored every month during the first few months and spaced thereafter, depending on the course of the disease. These criteria apply more for patients with ischemic CRVO than with patients with nonischemic CRVO.

With any associated complications, follow-up care should be individualized.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

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Ranibizumab (Lucentis)

• Dosing, Interactions, etc.

Clinical Context:  VEGF antibody. Indicated for macular edema following retinal vein occlusion.

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Aflibercept intravitreal (Eylea)

• Dosing, Interactions, etc.

Clinical Context:  Binds and prevents activation of vascular endothelial growth factors (VEGF-A) and placental growth factor (PIGF). Activation of VEGF-A and PIGF can result in neovascularization and vascular permeability. It is indicated for treatment of macular edema following retinal vein occlusion (branched or central retinal vein occlusion).

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Bevacizumab (Avastin)

• Dosing, Interactions, etc.

Clinical Context:  Bevacizumab (Avastin, Genentech, Inc.) is a recombinant, humanized monoclonal antibody that binds all isoforms of VEGF-A. It is used as an off-label medication in various ocular conditions associated with up-regulation of VEGF and increased vascular permeability and neovascularization.

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Class Summary

These agents bind to VEGF-A receptors to arrest macular edema and improve visual acuity associated with CVRO.

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Triamcinolone (Aristospan, Kenalog)

• Dosing, Interactions, etc.

Clinical Context:  Intraocular steroid injection has been shown to be effective in decreasing macular edema. Although the exact mechanism of action is unknown, steroids work by targeting various inflammatory pathways and decreasing expression of VEGF, reducing vascular permeability, stabilizing endothelial tight junctions, and decreasing macular edema.

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Dexamethasone intravitreal implant (Ozurdex)

• Dosing, Interactions, etc.

Clinical Context:  Intraocular steroid injection has been shown to be effective in decreasing macular edema. Although the exact mechanism of action is unknown, steroids work by targeting various inflammatory pathways and decreasing expression of VEGF, reducing vascular permeability, stabilizing endothelial tight junctions, and decreasing macular edema.

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Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

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