Clinical features

CRVO usually presents with sudden painless loss of vision, but it may also present with a history of gradual visual decline that may correlate with a series of less severe occlusions. The typical clinical constellation in CRVO includes retinal hemorrhages (both superficial flame-shaped and deep blot type) in all four quadrants of the fundus with a dilated, tortuous retinal venous system. The hemorrhages radiate from the optic nerve head, are variable in quantity, and may result in the classic “blood and thunder” appearance (Fig. 54.1). Optic nerve head swelling, cotton-wool spots, splinter hemorrhages, and macular edema are present to varying degrees (Figs 54.2 and 54.3). Breakthrough vitreous hemorrhage may also be observed.

Fig. 54.1 Fundus photograph of a central retinal vein occlusion with extensive intraretinal hemorrhage. Extensive blocking on fluorescein angiography in such an occlusion precludes accurate determination of perfusion status.

Fig. 54.2 (A) Fundus photograph of a central retinal vein occlusion demonstrating typical features of venous tortuosity, macular thickening, and intraretinal hemorrhage in all four quadrants of the fundus. (B) Early-phase angiogram of the fundus depicted in A, demonstrating an intact parafoveal capillary network in this perfused central retinal vein occlusion.

Fig. 54.3 (A) Fundus photograph of an eye with central retinal vein occlusion demonstrating scattered retinal hemorrhages, venous engorgement, and cotton-wool spots. (B) Midphase fluorescein angiogram of the eye shown in A, demonstrating capillary nonperfusion involving the foveal center. This eye also had extensive peripheral nonperfusion and is an example of the nonperfused form of central retinal vein occlusion.

A cilioretinal artery occlusion can occur in association with CRVO. Together, these occlusions have been hypothesized to constitute a distinct clinical entity arising from a sudden increase in the intraluminal capillary pressure due to CRVO, inducing relative occlusion of the cilioretinal artery whose perfusion pressure is lower than the central retinal artery.^12,13 Rarely, a central retinal arterial occlusion may also accompany a CRVO.¹⁴

With time, the extent of retinal hemorrhage may decrease or resolve completely with variable degrees of secondary retinal pigment epithelium alterations. The time course for resolution of the hemorrhages varies and is dependent on the amount of hemorrhage produced by the occlusion. Macular edema often chronically persists despite resolution of retinal hemorrhages (Fig. 54.4). An epiretinal membrane may also form. Optociliary shunt vessels can develop on the optic nerve head, a sign of newly formed collateral channels with the choroidal circulation (Fig. 54.5). Neovascularization of the optic disc (NVD) or retinal neovascularization elsewhere (NVE) may develop as a response to secondary retinal ischemia. The vessels that comprise NVD are typically of smaller caliber than optociliary shunt vessels, branch into a vascular network resembling a net, and will leak on fluorescein angiography. Fibrovascular proliferation from NVD or NVE may result in vitreous hemorrhage or traction retinal detachment.

Fig. 54.4 Fluorescein angiogram of a chronic central retinal vein occlusion with resolution of intraretinal hemorrhage but persistence of cystoid macular edema demonstrated by petaloid leakage.

Fig. 54.5 Fundus photograph demonstrating optociliary shunt vessels (better termed collaterals) at the inferior border of the optic nerve head in this patient with a chronic central retinal vein occlusion. These vessels do not leak on fluorescein angiography.

The natural history of CRVO was examined in the Central Vein Occlusion Study (CVOS), a randomized multicenter clinical trial of 728 eyes with CRVO. In this study, visual acuity at the time of presentation was variable but an important prognostic indicator of final visual outcome. Baseline visual acuity was 20/40 or better in 29% of affected eyes, 20/50–20/200 in 43%, and 20/250 or worse in 28%; median baseline acuity was 20/80.^3,15 Of those with initial visual acuity of 20/40 or better, the majority maintained this acuity. Individuals with intermediate visual acuity (20/50–20/200) had a variable outcome: 21% improved to better than 20/50, 41% stayed in the intermediate group, and 38% were worse than 20/200. Persons with poor visual acuity at onset (less than 20/200) had only a 20% chance of improvement.⁹

Anterior-segment findings may include iris and/or angle neovascularization (NVI/NVA). NVI typically begins at the pupillary border but may extend across the iris surface. NVA is detected during undilated gonioscopy as fine branching vessels bridging the scleral spur and may develop without any NVI in 6–12% of eyes with CRVO.^3,9,16 The CVOS used an index of any 2 clock-hours of NVI or any NVA as evidence of significant anterior-segment neovascularization, which was found in 16% of eyes with 10–29 disc areas of angiographic nonperfusion and 52% of eyes with 75 disc areas or more of angiographic nonperfusion.⁹ In the CVOS, worse initial visual acuity correlated with the development of NVI/NVA: 5% in eyes with 20/40 or better, 14.8% in eyes with 20/50–20/200, and 30.8% in eyes with worse than 20/200 acuity.⁹ Long-standing NVA may lead to secondary angle closure from peripheral anterior synechiae formation. Elevated intraocular pressure associated with NVI/NVA is the hallmark of neovascular glaucoma.

Perfusion status

The CVOS classified the perfusion status of a CRVO as perfused, nonperfused, or indeterminate based on fluorescein angiographic characteristics. Angiographic assessment of perfusion status in CRVO is based on the photographic protocol from the CVOS which used a conventional wide-angle fundus camera with sweeps of the midperiphery 30 seconds after intravenous injection of sodium fluorescein.

A perfused CRVO (also termed nonischemic, incomplete, or partial) demonstrates less than 10 disc areas of retinal capillary nonperfusion on angiography (Fig. 54.2). These eyes typically have a lesser degree of intraretinal hemorrhage on presentation. Generally, eyes with perfused CRVO have better initial and final visual acuity. A nonperfused CRVO (also termed ischemic, hemorrhagic, or complete) demonstrates 10 or more disc areas of retinal capillary nonperfusion on angiography (Fig. 54.3). Acutely, these eyes demonstrate a greater degree of intraretinal hemorrhage, macular and disc edema, and capillary nonperfusion than in perfused CRVO. A CRVO is categorized as indeterminate when there is sufficient intraretinal hemorrhage to prevent angiographic determination of the perfusion status. Other examination features that may help in determining the perfusion status in the acute phase of a CRVO include baseline visual acuity, presence of an afferent pupillary defect, electroretinography (a negative waveform may be seen), and Goldmann perimetry.^5,9,17

The CVOS classification of initial perfusion status of the CRVO was important for determining the natural history of the disease.⁹ Poor visual acuity and large areas of retinal capillary nonperfusion were significant factors associated with an increased risk of developing NVI/NVA. In eyes initially categorized as perfused, 10% (56/538) developed NVI/NVA compared to 35% (61/176) of eyes initially characterized as nonperfused or indeterminate. At 3 years, there was a 45% chance of developing neovascular glaucoma after onset of ischemic CRVO.¹ Overall, 34% of initially perfused eyes converted to nonperfused status after 3 years.⁹ In the CVOS, 38 eyes (83%) with an indeterminate CRVO at baseline were ultimately determined to be nonperfused. Initial visual acuity was highly correlated with degree of nonperfusion – eyes with nonperfused CRVO were much more likely than those with perfused CRVO to have poor visual acuity at initial presentation and final visit.^9,18

Ultrawide-field angiography has enabled mapping of peripheral retinal nonperfusion not easily visualized with a conventional fundus camera. Adjusted protocols for grading extent of nonperfusion are being developed from photographs taken with ultrawide-field angiography, which may prove important in redefining characteristics of perfused versus nonperfused CRVO.^19,20

Pathogenesis

The pathophysiology of CRVO is not clearly understood. Histopathologic studies of eyes enucleated for CRVO demonstrated a thrombus occluding the lumen of the central retinal vein at or just proximal to the lamina cribrosa,²¹ suggesting that the anatomic variations at the level of the lamina cribrosa may be important in the development of a CRVO. Within the retrolaminar portion of the optic nerve, the central retinal artery and vein are aligned parallel to each other in a common tissue sheath. The central retinal artery and vein are naturally compressed as they cross through the rigid sieve-like openings in the lamina cribrosa but typically give off branching collateral vessels just before piercing the lamina. These vessels may be subject to compression from mechanical stretching of the lamina, as with increases in intraocular pressure, which may cause a posterior bowing of the lamina and subsequent impingement on the central retinal vein. Furthermore, local factors may predispose to occlusion of the central retinal vein, including compression by an atherosclerotic central retinal artery or primary occlusion of the central retinal vein from inflammation.

Hemodynamic alterations may produce stagnant flow and subsequent thrombus formation in the central retinal vein, including diminished blood flow, increased blood viscosity, and an altered lumen wall (also known as Virchow’s triad). Experimentally, occlusion of both the retrolaminar central retinal artery and central retinal vein, posterior to the lamina cribrosa and prior to the branching of collateral channels from the main trunk, was required to produce the clinical appearance of a hemorrhagic (ischemic) CRVO.¹⁸ This implies that concurrent retinal artery insufficiency or occlusion may play a role in an ischemic CRVO. It is hypothesized that a less hemorrhagic, more likely nonischemic, CRVO may be due to occlusion of the central retinal vein at a site further posterior, allowing normal collateral channels to provide alternative routes of venous drainage.

In the largest histopathologic study of eyes with CRVO, 29 eyes enucleated for acute (within 6 hours) and chronic (up to 10 years) occlusions were reviewed,²¹ some of which had concurrent neovascular glaucoma. In acute occlusions, a thrombus at the level of the lamina cribrosa was adherent to a portion of the vein wall devoid of an endothelial lining. Subsequently, there was endothelial cell proliferation within the vein and secondary inflammatory cell infiltrates. Recanalization of the thrombus was demonstrated in eyes 1–5 years after the documented occlusion.

Neovascularization of the anterior and posterior segment and severity of macular edema are modulated by growth factors released from the ischemic retina. Green and colleagues demonstrated inner retinal ischemic changes in 25% of eyes enucleated for CRVO.²¹ In a study of enucleated eyes with CRVO and neovascular glaucoma, intraretinal vascular endothelial growth factor (VEGF) production from areas of ischemic retina was demonstrated.²² Analysis of vitreous fluid from patients with CRVO demonstrated increased levels of VEGF along with other cytokines and growth factors, including interleukin-6 (IL-6), IL-8, interferon-induced protein-10, monocyte chemotactic protein-1, and platelet-derived growth factor-AA.^23–25 Intraocular VEGF levels correlate with severity of ocular findings, including neovascularization and vascular permeability,²⁶ prompting the development of anti-VEGF agents for the treatment of CRVO (see below).

Risk factors and associations

Concurrent systemic vascular disease is a risk factor for CRVO (Box 54.1). The Eye Disease Case-Control Study found an increased risk of any type of CRVO in persons with systemic hypertension and diabetes mellitus.⁴ Similar associations with systemic hypertension were found in other studies.^27–31 Diabetes mellitus was more prevalent in individuals with nonperfused CRVO than in matched controls from large population databases.^27,28 Hyperlipidemia, arteriosclerosis, and smoking have also been linked to the development of vein occlusions.^2,30,32

Hematologic abnormalities, particularly conditions that predispose to a hypercoagulable state, have been identified in persons with CRVO. Individuals less than 60 years of age may have a greater association with hypercoagulable states and inflammatory conditions compared to older persons with a higher incidence of systemic vascular disease risk factors.^5,6 Lahey and colleagues found one abnormal laboratory value suggesting systemic hypercoagulability in 27% of 55 patients younger than 56 years of age.³³ Studies have demonstrated an increased incidence of coagulation cascade abnormalities, including protein C and S deficiency, activated protein C resistance, presence of factor V Leiden, presence of antiphospholipid antibodies, hyperhomocysteinemia, antithrombin III deficiency, prothrombin gene mutations, and abnormal fibrinogen levels.^34–41 Hyperviscosity from blood dyscrasias, dysproteinemias, and dehydration have also been reported with CRVO.^42–45

An increased risk of CRVO is present in eyes with open angle glaucoma.^4,46 Other ocular conditions causing deformation or mechanical pressure on the optic nerve head and lamina cribrosa, including ischemic optic neuropathy, tilted optic nerve head, optic nerve head drusen, optic disc traction syndrome, and pseudotumor cerebri,^42,47 have also been associated with CRVO. External compression of the globe and optic nerve from thyroid-related ophthalmopathy, mass lesions, or head trauma with orbital fracture may also result in CRVO.⁵

Clinical evaluation

At the time of initial presentation, a careful assessment of the CRVO duration and the degree of macular edema and retinal ischemia will determine treatment options and the follow-up schedule. An ocular history may determine the onset of the occlusion, although individuals may not have noted vision loss if the fellow eye has maintained good acuity. A history of systemic diseases, such as hypertension, diabetes, and heart disease, and a personal or family history of thrombosis or hypercoagulable state should be determined.

The ophthalmic examination should be performed on both eyes and include visual acuity, pupillary reaction, and intraocular pressure. Undilated slit-lamp examination is performed to detect NVI or NVA. Undilated gonioscopy is essential to determine the presence of NVA or evidence of angle closure from peripheral anterior synechiae, as NVA may be present without any NVI in up to 12% of eyes.¹⁶ Ophthalmoscopic examination will help differentiate a CRVO from intraretinal hemorrhage associated with carotid occlusive disease.⁴⁸ Adjunctive imaging studies, including optical coherence tomography (OCT) and fluorescein angiography, are helpful in evaluating and following the presence of macular edema and perfusion status.

In general, a systemic workup is not indicated in persons older than 60 years of age with known systemic vascular risk factors for CRVO. Younger patients are more likely to have predisposing conditions resulting in thrombotic disease.^6,33 A limited systemic workup may be considered in those with a prior occlusion in the fellow eye, prior systemic thrombotic disease, family history of thrombosis, or other symptoms suggestive of a hematologic or rheumatologic condition. An initial laboratory investigation may include an erythrocyte sedimentation rate, antinuclear antibody, antiphospholipid antibody, and fasting plasma homocysteine levels. An elevated plasma homocysteine level may uncover a correctable etiology of CRVO, which may also influence cardiovascular health.³⁸ Individuals with bilateral, simultaneous CRVO or mixed-type retinal vascular occlusions should have a detailed evaluation for a hypercoagulable condition, as these persons may be at risk for future, nonocular thrombotic events.⁹

Therapeutic options

Treatment for CRVO is directed at treating the sequelae of CRVO, particularly macular edema and neovascularization. The recent development of intravitreal pharmacotherapy has revolutionized the treatment of CRVO-associated macular edema (Fig. 54.6). While these intravitreal agents can also improve secondary neovascularization, panretinal photocoagulation (PRP) remains the definitive treatment. Alternative experimental therapies have sought to modify the anatomic alterations believed to be responsible for CRVO. Of course, appropriate management of blood pressure and other systemic factors is always of paramount importance.

Fig. 54.6 A 67-year-old male with 5-month history of vision loss from a central retinal vein occlusion who received a single intravitreal injection of triamcinolone acetonide (4 mg) to treat persistent cystoid macular edema. (A) Preinjection optical coherence tomography (OCT) demonstrating prominent retinal thickening in the macular region with inner and outer retinal cysts and subretinal fluid accumulation. (B) 4-month postinjection OCT demonstrating dramatic resolution of retinal thickening and return of normal foveal contour. (C) Retinal thickness map and corresponding color map from A with marked macular thickening. (D) Retinal thickness map and corresponding color map from B with normal retinal thickness measurements. Similar resolution of macular edema can be observed with intravitreal injections of antivascular endothelial growth factor agents, including ranibizumab and bevacizumab.