Key Features

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  Retinal hemorrhages in all four quadrants.

  
  
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  Dilated, tortuous veins in all four quadrants.

Associated Features

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  Optic disc edema.

  
  
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  Macular edema.

  
  
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  Submacular fluid.

  
  
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  Cotton–wool spots.

  
  
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  Capillary nonperfusion.

  
  
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  Neovascularization of the iris, retina, or optic disc.

  
  
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  Vitreous hemorrhage.

  
  
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  Neovascular glaucoma.

  
  
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  Optic disc venous – venous collateral vessels (opticociliary collateral vessels).

Key Features

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  Retinal hemorrhages in the distribution of the obstructed branch retinal vein.

  
  
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  Dilated, tortuous retinal vein in the distribution of the obstructed branch.

Associated Features

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  Optic disc edema.

  
  
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  Macular edema.

  
  
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  Submacular fluid.

  
  
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  Cotton–wool spots.

  
  
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  Capillary nonperfusion.

  
  
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  Retinal neovascularization.

  
  
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  Vitreous hemorrhage.

  
  
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  Sheathing of vasculature.

  
  
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  Lipid exudates.

  
  
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  Microvascular changes including microaneurysms and collateral vessels.

  
  
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  Pigmentary macular disturbances.

  
  
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  Subretinal fibrosis.

Introduction

Venous occlusive disease of the retina is the second most common retinal vascular disorder, behind diabetic retinopathy. It is believed to be caused by external compression of the vein by an atherosclerotic artery, intraluminal thrombosis, or inflammation of the vein and typically affects patients 50 years of age or older. Retinal vein occlusions are usually recognized by their characteristic clinical appearance, and treatment options have been investigated thoroughly with large, multicenter, randomized clinical trials.

Retinal vein occlusions are classified according to whether the central retinal vein or one of its branches is obstructed. Central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) differ with respect to pathophysiology, underlying systemic associations, clinical course, and therapy. Branch retinal vein occlusions occur more frequently than CRVO.

Epidemiology

The global impact of RVOs is significant, with an estimated 16.4 million adults affected worldwide—2.5 million affected by CRVO and 13.9 affected by BRVO. Large, population-based studies have shown that the cumulative incidence of RVO over a 9–15 year period is 1.6%–3.0% in the elderly population, with a 9–15 year cumulative incidence of CRVO at 0.3%–0.5% and BRVO at 1.6%–2.7%. Using pooled data from populations in the United States, Europe, Asia, and Australia, the estimated prevalence of BRVO is 4.42 per 1000 people and CRVO is 0.8 per 1000 people, increasing with age. Additionally, CRVO is associated with an increase in mortality because of its statistical association with comorbid diabetes or cardiovascular disease. The presence of glaucoma is frequently found to be a risk factor for the development of both CRVO and BRVO, with an odds ratio of 2.53 and 9.28, respectively ; however, the Beijing Eye Study did not find such an association. Variations in the population-based studies are likely due to significant variations in sample ethnicity as well as differences in age eligibility for subjects. Bilaterality is uncommon in both CRVO and BRVO, with a coincident second RVO occurring in 6.3% eyes in the 15-year Beaver Dam Eye Study cohort, in 6.4% of eyes after 5 years in the Blue Mountains Eye Study. The risk of any vascular occlusion in an unaffected fellow eye has also been estimated to be 0.9% per year.

Data on the economic burden of vein occlusions is limited. Using the Beaver Dam Eye Study estimates of prevalence in conjunction with a study on the Medicare cost per CRVO diagnosis based on 2006 dollars, the total costs to the U.S. Medicare population are estimated to be $1.3 billion annually for CRVO.

Pathogenesis

The occlusion is believed to be the result of a thrombus in the central retinal vein at or posterior to the lamina cribrosa. Arteriosclerosis of the neighboring central retinal artery that causes turbulent venous flow and then endothelial damage often is implicated. Endothelial cell proliferation has been suggested also. An alternative theory is that thrombosis of the central retinal vein is an end-stage phenomenon, induced by a variety of primary insults such as compressive or inflammatory optic nerve or orbital problems, structural abnormalities in the lamina cribrosa, or hemodynamic changes.

Ocular Manifestations

The diagnosis of a CRVO is based on the characteristic fundus findings of dilated and tortuous retinal veins in all four quadrants of the retina in association with intraretinal hemorrhages, cotton–wool spots, retinal exudations, disc edema, and/or concurrent signs of hypertensive retinopathy ( Fig. 6.20.1 ). Macular edema and ischemia are the most common causes of vision loss; however, the presence of intraretinal hemorrhage and exudates in the fovea can also affect vision. Patients generally present with acute onset painless blurry vision although an incidental finding of a mild CRVO is possible. Rarely, patients can present with a combined retinal vein and artery occlusion, which typically lead to a poor visual prognosis.

Central Retinal Vein Occlusion.

Fluorescein angiogram with peripheral sweeps showing dilated and tortuous retinal veins with widespread blocking defects from intraretinal hemorrhage (see color fundus photograph inset) and far peripheral nonperfusion.

The severity of CRVOs often corresponds to the amount of retinal nonperfusion, which can easily be appreciated on fluorescein angiography. Vision for minimally nonperfused CRVOs can be mild to moderate, whereas highly nonperfused eyes can have an afferent pupillary defect with significant vision loss. Traditionally, CRVOs were categorized as nonischemic CRVOs, which is defined as less than 10 disc areas of ischemia as seen on the traditional seven standard field fluorescein angiography, versus ischemic CRVOs, which encompasses all other eyes. This distinction between the two types of CRVOs remains somewhat arbitrary, representing a continuum of disease severity but has been an important separation in literature describing CRVO outcomes. Of all patients with CRVO, 75%–80% can be considered classically nonischemic ( Fig. 6.20.2 ), whereas classic ischemic CRVOs account for 20%–25% of all CRVOs ( Fig. 6.20.3 ). The Central Vein Occlusion Study (CVOS) Group found that 34% of nonischemic CRVOs progressed to become ischemic within 3 years.

Nonischemic Central Retinal Vein Occlusion.

(A) Fundus photograph and (B) fluorescein angiogram showing scattered intraretinal hemorrhages, mild optic nerve head edema and hyperemia, and dilated and tortuous veins. (C) Optical coherence tomography showing no significant macular edema.

Ischemic Central Retinal Vein Occlusion.

(A) Fundus photograph and (B) fluorescein angiogram showing extensive intraretinal hemorrhages. The vasculature is barely discernable. (C) Optical coherence tomography showing cystoid macular edema with subretinal fluid.

Ischemic CRVOs tend to have higher rates of neovascularization of the iris and/or angle, which typically occur within 3 months of disease onset (90-day glaucoma), and the subsequent rate of neovascular glaucoma ranges from 20%–63% (compared to 0% in nonischemic CRVOs). In the absence of neovascularization, the pathological clinical features of CRVOs may decrease or resolve 6–12 months after diagnosis. During the resolution phase, the optic nerve can show pallor and develop optociliary collateral vessels. Permanent macular changes can develop that include pigmentary changes, epiretinal membrane formation, and subretinal fibrosis. Macular ischemia or sequelae from persistent macular edema may ultimately limit final visual acuity, especially if there is significant peripheral nonperfusion.

In about 20% of eyes, the central retinal vein enters the optic nerve as two separate branches (superior and inferior) before merging as a single trunk posterior to the lamina cribrosa. In these eyes, occlusion of one of the dual trunks within the substance of the optic nerve results in a hemispheric CRVO. Although only one half of the retina is involved, these occlusions act like CRVOs in terms of visual outcome, risk of neovascularization, and response to treatment.

Some mild CRVOs in patients younger than 50 years are classified as papillophlebitis, a term that suggests a benign course. An inflammatory optic neuritis or vasculitis is hypothesized as the cause. These eyes tend to have optic disc edema out of proportion to the retinal findings, cotton–wool spots that ring the optic disc, and occasionally cilioretinal artery occlusions or even partial central retinal artery occlusions. Although spontaneous improvement is common, the course is not always benign. Up to 30% of these patients may develop the ischemic type of occlusion with a final visual acuity of 20/200 (6/60) or worse.

Ancillary Testing

Fluorescein angiography for CRVOs show a delayed filling of the retinal veins and is the most useful ancillary test for the evaluation of nonperfusion and neovascularization. The risk of a neovascular event increases with the extent of nonperfusion, particularly above 5.5 disc areas. The CVOS Group reported that 35% of ischemic and 10% of nonischemic CRVOs demonstrated anterior segment (iris or angle or both) neovascularization at or before the 4-month follow-up. They found the greatest predictors of anterior segment neovascularization were visual acuity and degree of nonperfusion on fluorescein angiography, the worst prognostic groups being patients with visual acuity worse than 20/200 (6/60) or 30 or more disc areas of nonperfusion.

Fluorescein angiography in ischemic CRVOs may show marked hypofluorescence (see Fig. 6.20.3 ), which is secondary to either blockage from intraretinal hemorrhages or to retinal capillary nonperfusion. When extensive hemorrhages are present, grading the degree of ischemia can be difficult. However, as the hemorrhages clear, the degree of capillary nonperfusion typically becomes more apparent. A greater amount of initial hemorrhages is associated with a higher level of ischemia. Angiography can also reveal optic nerve head leakage and perivenous staining, and in the late stages of the disease, collateral vessels and microaneurysms can be seen. The macular region may also show persistent edema or pigmentary degeneration. With nonischemic CRVOs, fluorescein angiography can reveal staining along the retinal veins, microaneurysms, and dilated optic nerve head capillaries. Retinal capillary nonperfusion (see Fig. 6.20.2 ) is minimal or absent. As the nonischemic CRVO resolves, angiography may become normal. The appearance of atypical findings on fluorescein angiography, such as choroidal nonperfusion, should prompt consideration of other diagnoses.

The original definitions of ischemic and nonischemic CRVOs in the CVOS study relied on fluorescein angiography from the seven standard field images as defined by the Early Treatment of Diabetic Treatment Study. With the advent of ultra-wide field imaging that can image up to 200° in one capture, a growing number of studies are looking at the utility of assessing nonperfusion on a continuum. Different measurements of nonperfusion, including the ischemic index, total area of nonperfusion, and radial extent of nonperfusion, have all been proposed.

Macular edema is the most common cause of visual loss in RVOs and can occur more severely in ischemic cases. Macular edema is best imaged by optical coherence tomography (OCT), which is useful in quantifying and monitoring macular edema in patients with RVOs. OCT commonly shows subclinical serous detachments of the macula in up to 80% of patients. ERM is also a common feature on OCT testing in the setting of an RVO.

Differential Diagnosis

The differential diagnosis for CRVOs includes ocular ischemic syndrome, diabetic retinopathy, radiation retinopathy, hyperviscosity retinopathy, and hypertensive retinopathy with possible multiple contributing factors. Ocular ischemic syndrome often presents with attenuated vessels rather than dilated and tortuous veins, can have choroidal in addition to retinal nonperfusion, and can be associated with hypotony from ciliary body ischemia. Additionally, the retinal hemorrhages seen in ocular ischemic syndrome tend to localize to the midperiphery instead of the posterior pole as seen in CRVO. Diabetic retinopathy requires the concurrent diagnosis of diabetes and is generally a bilateral disease. Radiation retinopathy requires an antecedent history of radiation affecting the periorbital region.

Hyperviscosity syndromes may produce a retinopathy similar to CRVO or BRVO. Simultaneous bilateral disease is an unusual finding in RVOs but occurs more commonly in hyperviscosity states seen in diseases like Waldenström’s macroglobulinemia, polycythemia vera, leukemia, and multiple myeloma. Additionally, vasculitis that may be associated with systemic inflammatory disease, such as sarcoidosis, Behçet’s, and polyarteritis nodosa, can also masquerade as a CRVO.

When a patient presents with a CRVO in the absence of clear risk factors or presents with bilateral disease, the medical and laboratory evaluation should include a targeted search for evidence of diabetes, hyperviscosity syndromes, or inflammatory disease. Treatment of the primary disease can help improve the course of the retinopathy. For instance, plasmapheresis can be effective in reversing the retinopathy seen in cases of acute hyperviscosity syndrome. Severe anemia with thrombocytopenia can also cause a retinopathy that resembles CRVO, which can be treated with transfusions. Lastly, acute hypertensive retinopathy with disc edema may resemble bilateral CRVO and require immediate lowering of blood pressure to present end-organ damage throughout the body.

Systemic Associations and Laboratory Evaluation

CRVO has been clearly associated with age greater than 50 years and hypertension. The association with hyperlipidemia, diabetes mellitus, and cardiovascular disease has been demonstrated in some studies but not others. These are the most common associations of CRVO, and in a patient over the age of 50 known to have one of these conditions, no further workup is necessary.

The absence of the above known risk factors, especially in a young patient, should prompt a general medical evaluation, which can include a medical history and physical examination with blood pressure evaluation ( Box 6.20.1 ). Basic laboratory evaluation may include a complete blood count, chemistry profile, coagulation factors, hemoglobin A1C, and lipid profile. If a systemic clotting diathesis, blood dyscrasia, or hyperviscosity is suspected based on medical history and concurrent signs, further hematological work up is required. The workup should be driven by medical history and may need to be done in conjunction with a hematologist or rheumatologist. Relevant labs may include lupus anticoagulant, antiphospholipid antibody, anticardiolipin antibody, antithrombin III, factor V Leiden, serum protein electrophoresis, complement factors, and protein S and protein C levels. Elevated levels of homocysteine have also been associated with the development of retinal vascular occlusive disease. If there are signs of inflammation, an autoimmune vasculitis must be ruled out with laboratory work and/or imaging. Oral contraceptive use in women has also been associated with CRVO.

Pathology

Green et al. evaluated histological sections of 29 eyes in 28 patients who had CRVO. All 29 eyes had the formation of a fresh or recanalized thrombus at or just posterior to the lamina cribrosa. There was a mild lymphocytic infiltration with prominent endothelial cells within the thrombi. Further, there was loss of the inner retinal layers consistent with inner retinal ischemia. Alterations in blood flow, hyperviscosity, and vessel wall abnormalities may produce CRVOs by enabling a thrombus of the central retinal vein to form. It has been hypothesized that glaucoma, a risk factor for CRVO, causes stretching and compression of the lamina cribrosa, which results in vessel distortion, increased resistance to flow, and, ultimately, thrombosis.

Treatment

No known treatment reverses the pathology seen in CRVO. It is prudent to advise risk factor reduction along with a healthy diet and exercise. Several therapies have been proposed but none have proven efficacious, including aspirin; systemic anticoagulation with warfarin, heparin, and recombinant tissue plasminogen activator; local anticoagulation with intravitreal recombinant tissue plasminogen activator; corticosteroids; anti-inflammatory agents; isovolemic hemodilution; plasmapheresis; and optic nerve sheath decompression. However, certain complications of CRVO, such as macular edema and neovascularization may be treatable ( Box 6.20.2 ).

Course and Outcome

The prognosis for visual recovery is dependent on the subtype of CRVO. In general, the visual prognosis can be predicted from the visual acuity during initial evaluation. Patients who have nonischemic CRVOs may experience a complete recovery of vision, although this occurs in less than 10% of cases. In the CVOS, which established natural history data on CRVO, baseline visual acuity tended to (but did not always) predict eventual visual acuity outcome, which in turn reflected the perfusion status of the retina. For example, for eyes with presenting visual acuity of 20/40 or more, 65% maintained this range of visual acuity, whereas for eyes with presenting visual acuity of less than 20/200, 80% had visual acuity remaining this poor at the conclusion of the study. With newer treatment modalities (particularly anti-VEGF agents), the natural course of CRVO is being curtailed, and better visual acuity outcomes are now possible compared to the era of the CVOS, as evidenced by the SCORE and CRUISE studies.

In the era of the CVOS study, recommended follow-up examination intervals depended on the presenting visual acuity and degree of ischemia. With the advent of anti-VEGF therapy, most patients with CRVO are followed monthly, at least initially, while undergoing monitoring and treatment for CME.