bubble_chart Overview

Central retinal vein occlusion is much more common than central retinal artery occlusion. Although the impairment of visual function is not as acute as in artery occlusion, it is still quite severe. Some cases may lead to complete blindness due to secondary neovascular glaucoma.

bubble_chart Etiology

The etiology of this disease varies significantly between the elderly and young adults. The majority of cases in the elderly are secondary to retinal artery sclerosis, while in young adults, it is often due to inflammation of the vein itself. Retinal artery sclerosis is commonly associated with chronic progressive hypertension or artery sclerosis. Venous inflammation can be caused by periphlebitis (Eales' disease), uveitis, Behcet's syndrome, sarcoidosis, Coats' disease, septic emboli, etc. However, cases where no clear cause can be identified clinically are not uncommon.

The pathogenesis of this disease is complex and not yet fully understood. Most researchers believe it results from the interplay of multiple factors, including insufficient arterial blood supply, damage to the vessel wall, changes in hemorheology, and hemodynamic alterations. Among these, damage to the vessel wall may be the primary factor.

1. Insufficient arterial blood supply Hhayreh (1965, 1971) pointed out through arterial experiments that the occurrence of central retinal vein occlusion is predicated on insufficient arterial blood supply. In laboratory settings, merely blocking a vein is insufficient to induce the typical clinical changes; these only manifest when arterial blood supply is also impaired. Although Hayreh's theory has garnered support from some clinicians, direct evidence linking insufficient arterial blood supply to venous occlusion remains insufficient. For instance, this disease does not show any arterial occlusion on fundus fluorescein angiography. Retinal blood circulation operates within a relatively closed vascular circuit (Gass, 1968). Reduced arterial blood flow during venous occlusion may merely reflect obstructed venous return rather than being the cause of venous occlusion.

2. Damage to the vessel wall This can arise from two causes: one is the impact of adjacent arterial sclerosis, and the other is inflammation of the vein itself. Both can lead to thickening of the vessel wall and narrowing of the lumen. Sclerosis can also cause hyperplasia of the intima and subintimal cells, while inflammation can lead to intimal swelling. Hyperplasia and intimal swelling further exacerbate lumen narrowing. In severe cases, direct occlusion may occur due to contact between the intima, or the roughened intimal surface and altered charge may induce platelet adhesion and aggregation, forming a thrombus and leading to partial or complete occlusion of the vessel lumen.

It is well known that central retinal vein trunk occlusion often occurs where the vein traverses the lamina cribrosa, while branch occlusion is more common at arteriovenous crossings. This may be related to the fact that arteries and veins in these locations are enveloped by a common connective tissue sheath (Scherer, 1923), making it difficult for the vessel lumen to expand once narrowed due to the aforementioned reasons.

3. Changes in hemorheology and hemodynamics Most patients with this disease exhibit alterations in blood composition, increased blood viscosity, and heightened platelet aggregation, making blood flow through narrowed vessel passages more difficult and thrombosis more likely.

In addition to the above causes, venous occlusion, particularly trunk occlusion, is somewhat linked to elevated intraocular pressure. Statistics show that 10–20% of patients with this disease also have primary open-angle glaucoma. The reasons include: (1) patients with open-angle glaucoma often have elevated blood viscosity, and (2) pathological cupping of the scleral lamina cribrosa may affect arterial perfusion and venous return in the lamina cribrosa region. Other factors, such as cardiac decompensation, bradycardia, or sudden drops in blood pressure leading to slowed blood flow, can also accelerate the formation of occlusion.

A series of ocular signs caused by central retinal vein occlusion are all secondary to the disruption of retinal blood circulation following the obstruction. For example: retinal hemorrhage results from impaired venous return, vascular wall fragility, and blood stasis, leading to localized hyperfunction of fibrinolysis; venous engorgement and tortuosity with dark purple blood columns are caused by obstructed blood flow; cotton-wool spots arise from ischemia in the inner capillary bed; and yellowish-white hard exudates are due to the deposition of lipid substances in the blood. Additionally, retinal edema and opacification, neovascularization, vascular shunts, collateral circulation, fusiform capillary dilation, macular cystoid edema, and the appearance of dense neovascularization on the iris (rubeosis iridis) are all related to this condition.

bubble_chart Clinical Manifestations

There are several classification methods in the literature: ① According to the cause of obstruction, it can be divided into sclerotic and inflammatory types; ② Based on the site of obstruction, it can be classified into main trunk, branch, and hemi-central obstruction; ③ According to the degree of obstruction, it can be categorized as complete or incomplete; ④ Depending on the presence or absence of stirred pulse ischemia, it can be divided into non-ischemic (stagnant) and ischemic (hemorrhagic) types (Hayreh). However, some scholars disagree with this classification, arguing that the so-called non-ischemic and ischemic obstructions are essentially incomplete and complete obstructions, respectively.

1. Visual function impairment The extent of visual function impairment varies depending on whether the obstruction affects the macula. Once the macula is involved, central vision may suddenly or significantly decline within days, accompanied by micropsia and metamorphopsia. In severe cases, only finger counting or hand motion vision may remain. When venous obstruction occurs but some vision is preserved, the peripheral visual field often shows shadows or irregular concentric narrowing corresponding to the obstructed area. The central visual field may exhibit central or paracentral scotomas due to damage to the macula and its vicinity.

2. Fundus findings In cases of total trunk obstruction, fundus changes vary depending on the stage of the disease and the degree of obstruction. The optic disc appears edematous and cloudy, with blurred margins. The entire retina is edematous and cloudy, covered with linear, flame-shaped, or comet-tail hemorrhages of varying sizes in the nerve fiber layer. Occasionally, dot-like or irregularly shaped deep hemorrhages may also be seen. The retinal veins are dilated and tortuous, partially obscured by tissue edema and hemorrhage, appearing segmented. The retinal stirred pulse appears relatively narrow due to reflex contraction. Additionally, cotton-wool spots are often observed, particularly in the posterior pole. The macula may show radial folds, star-shaped exudates, or cystoid edema. Superficial and deep retinal hemorrhages result from capillary, venule, or larger vein rupture due to high pressure and localized hyperfunction of fibrinolytic activity. In severe cases, preretinal hemorrhage may occur, and blood may even break through the inner limiting membrane into the vitreous, causing vitreous hemorrhage and obscuring the fundus view.

Branch obstructions most commonly affect the superior temporal branch, followed by the inferior temporal branch, and then the nasal branch. In branch obstructions, the aforementioned fundus changes (hemorrhage, edema, exudates, vessel dilation, tortuosity, etc.) are confined to the drainage area of the affected branch. However, obstruction of the superior or inferior temporal branch may also involve the macula.

Most primary branches of the central retinal vein form a common trunk before entering the lamina cribrosa of the sclera. However, in some congenital anomalies, the branches merge into a common trunk only after passing some distance behind the lamina cribrosa, resulting in two or more venous branches within the retrobulbar optic nerve, hence termed "divided trunks." When one of these branches becomes obstructed, it is referred to as hemi-central vein obstruction.

The extent of pathology caused by hemi-central obstruction is greater than that of branch obstruction, affecting one-half to two-thirds of the entire fundus. The optic disc shows localized edema and cloudiness corresponding to the obstructed area.

Main trunk, branch, and hemi-retinal vein occlusion can all result in varying degrees of fundus changes depending on the severity of the blockage. In cases of incomplete occlusion, the amount of retinal hemorrhage, the area of bleeding, and the degree of retinal edema and turbidity are less severe compared to complete occlusion. Cotton-wool spots are absent or occasionally seen, and the incidence of macular cystic edema is much lower. After collateral circulation gradually develops in the occluded vein, there is a tendency for blood circulation to slowly recover on its own. Over approximately a year, retinal edema and hemorrhage gradually disappear, and the venous caliber returns to its original width or becomes irregular. Parallel or tubular white sheathing may be visible. The accompanying retinal artery may develop secondary sclerosis, and microaneurysms are often observed. In severe cases of venous occlusion with hemorrhage and turbid edema, after the hemorrhage and edema subside, aside from residual pigmentary disturbances, granular or mottled appearances may occur due to atrophy of the inner retinal layers. Sometimes, fibroblast proliferation leads to the formation of preretinal membranes in front of the optic disc or elsewhere in the retina. Behind the retinal vessels, grayish-white or slightly yellowish-white clustered spots may be seen. These spots are formed by lipid deposits and vary in shape—those in the macula may appear star-shaped, while those at the macular margin may form a semicircular pattern. These changes typically appear around two months after the onset of occlusion. Initially, they coexist with retinal hemorrhage and edema, but they may persist long after the hemorrhage and edema have resolved, sometimes remaining visible even years later.

The absorption of retinal hemorrhage and edema relies on the establishment of collateral circulation, which originates from the dilation of retinal capillaries. It forms the shortest pathway connecting the blocked vessel with nearby open vessels or creates a channel between the blocked segments of the vessel itself, akin to a spillway when a dam's gate is closed. This collateral circulation begins at the onset of the condition but is often obscured by hemorrhage and edema, becoming visible only after the hemorrhage and edema resolve, appearing as looped or spiral tortuosity. In cases of total occlusion, hemi-occlusion, or branch occlusion near the myopic disc, collateral circulation is commonly observed on or at the edge of the optic disc.

The timing and effectiveness of collateral circulation formation directly impact visual function. Particularly when the macula is involved, the presence of an early-opened collateral between the fovea and the occluded vein indicates a more favorable prognosis. Even if temporary hemorrhage or edema occurs due to overloaded collaterals, useful vision can still recover after absorption. Conversely, if irreversible retinal damage occurs before collateral formation, vision cannot be salvaged.

In complete occlusion, the inner retinal capillary bed (including the entire microcirculatory unit of precapillary arterioles, capillaries, and postcapillary venules) is obstructed, creating large ischemic areas. This forms the basis of cotton-wool spots seen on ophthalmoscopy. In the late stage (third stage), cotton-wool spots fade, and reticular or filamentous neovascularization appears around the ischemic area. Neovascularization and collateral circulation are difficult to distinguish under ophthalmoscopy.

In cases of total or hemi-occlusion, some patients may develop iris neovascularization (rubeosis iridis). When these new vessels extend to the anterior chamber angle and obstruct the trabecular meshwork, neovascular glaucoma ensues.

3. Fluorescein Angiography Fluorescein angiography findings vary depending on the occlusion site (total, hemi-, branch), severity (complete, incomplete), and disease stage.

In the early stage of total complete occlusion, early-phase angiography shows masking of choroidal and retinal fluorescence due to extensive hemorrhage. In unobscured areas, delayed filling of arteries and veins is visible. In the late phase, the venous wall and surrounding tissues stain diffusely with strong fluorescence. When fluorescence reaches the perimacular capillaries, if unobstructed by hemorrhage, significant fluorescein leakage occurs, gradually accumulating in cystoid spaces. In advanced stages, non-perfusion zones appear due to ischemia in the inner retinal capillary bed. Residual capillaries around these zones dilate into microaneurysms. Abnormal collateral pathways and neovascularization can occur anywhere in the fundus but are most common on the optic disc. Disc neovascularization may extend into the vitreous. Neovascularization can be distinguished from collateral circulation by its prominent fluorescein leakage.

In the initial stage (first stage) of total incomplete occlusion, early-phase angiography shows less hemorrhage and correspondingly less fluorescence masking. Delayed arterial and venous filling (especially arteriolar) is less pronounced. Venous wall leakage and subsequent staining are milder than in complete occlusion. If the macula is affected without effective collaterals, perifoveal capillary leakage creates a petaloid hyperfluorescent zone (cystoid edema). Disruption of the perifoveal capillary arcade leads to leakage. In advanced stages, non-perfusion zones and neovascularization are typically absent.

Hemi-occlusion and branch occlusion exhibit similar fluorescein angiography findings to total occlusion in early and advanced stages, but the changes are confined to the drainage area of the affected vessel. Additionally, some branch occlusion cases show focal narrowing at the occlusion site and localized hyperfluorescence near the upstream end in the earliest phase.

bubble_chart Treatment Measures

1. Anticoagulants Although some studies in the past two decades have disputed the thrombus theory proposed by von Michel (1878), anticoagulant drugs remain the first-line treatment for this disease.

(1) Fibrinolytic agents: These include urokinase, streptokinase, plasmin, and snake venom antithrombotic enzymes. Among them, urokinase is non-antigenic, does not require allergy testing before use, and has fewer side effects, making it the most commonly used.

Urokinase: It directly activates the conversion of plasminogen in plasma and blood clots into plasmin, enhancing fibrinolytic activity and thereby dissolving thrombi. The usual dose is 10,000 IU, administered intravenously by adding it to 250–500 ml of low-molecular-weight dextran or 20 ml of saline, once daily for 10–15 sessions per course. Alternatively, 100–150 IU can be dissolved in 0.5–1 ml of saline for retrobulbar injection, once daily or every other day, with 5 sessions per course.

(2) Antiplatelet agents: Common preparations include enteric-coated acetylsalicylic acid tablets and dipyridamole. The former inhibits collagen-induced platelet aggregation and adenosine diphosphate (ADP) release, providing relatively long-lasting antiplatelet effects. The dose is 50–75 mg once daily after meals. The latter inhibits platelet release reactions, thereby reducing aggregation. The oral dose is 25–50 mg, three times daily.

(3) Heparin and dicoumarol also have anticoagulant effects but are now rarely used.

2. Hemodilution Therapy The principle of isovolemic hemodilution is to reduce hematocrit, decrease blood viscosity, and improve microcirculation. Blood (400–500 ml) is drawn from the cubital vein and mixed with 75 ml of sterile sodium citrate as an anticoagulant. The blood is then centrifuged at high speed to separate blood cells from plasma. During this process, low-molecular-weight dextran is infused intravenously, and the separated plasma is later transfused back to the patient. This is repeated every 2–3 days for 3–6 sessions until the hematocrit drops to 30–50%. This therapy is contraindicated in patients with blood disorders (e.g., leukemia, severe anemia, thrombocytopenic purpura), major organ diseases (e.g., severe coronary heart disease), acute infectious diseases, or pestilence.

Low-molecular-weight dextran (molecular weight 10,000–45,000) is administered intravenously once daily, 500 ml per session, for 10–15 sessions per course. This is also a form of hemodilution therapy. In addition to reducing blood viscosity, it alters the charge at damaged vessel walls, preventing platelet adhesion.

3. Chinese Medicinal Therapy Invigorating blood and resolving stasis Chinese medicinals (compound formulas or single herbs) have certain anticoagulant effects, improve microcirculation, and enhance tissue hypoxia tolerance. A commonly used formula is Modified Taohong Siwu Decoction (Unprocessed Rehmannia Root, Sichuan Lovage Rhizome, Peach Kernel, Carthamus, Earthworm, Red Peony Root, Chinese Angelica, Submature Bitter Orange, Turmeric, Diverse Wormwood Herb, Bupleurum, Cyathula Root). One dose is taken daily, divided into two servings, decocted with water and consumed warm. For cases caused by arterial sclerosis, additional ingredients like Hawthorn, Kelp (salt-washed), and Salvia may be added. For cases caused by venous inflammation, additional ingredients like Scrophularia Root, Moutan Bark, Prepared Rhubarb Rhizome, Forsythia, and Lonicera may be included. The decoction can be used alone or combined with urokinase or enteric-coated acetylsalicylic acid tablets. A course consists of 30–50 doses.

4. Laser Photocoagulation Laser photocoagulation can reduce capillary leakage in fistula disease, particularly by preventing the leakage from entering the macular area and causing cystoid edema. Photocoagulating non-perfused areas can prevent the formation of new blood vessels or seal off already formed neovascularization, thereby reducing the chances of hemorrhage and blood entering the vitreous. The mechanism of laser photocoagulation in treating this disease lies in its ability to disrupt the barrier function of the retinal pigment epithelial layer, creating a communication pathway between the retinal neurosensory layer and the choroid. This allows pathological products to drain into the choroidal circulation. Additionally, photocoagulation destroys the remaining viable retinal tissue in the affected area, thereby reducing tissue hypoxia and alleviating pathological reactions in retinal blood vessels. It also directly normalizes the permeability of vascular walls (Shimizu, 1973).

bubble_chart Prognosis

The prognosis of this disease varies greatly depending on the cause, location, and severity of the obstruction. In terms of etiology, obstructions caused by inflammation are reversible due to swelling of the vascular wall and inner membrane, unlike those caused by arteriosclerosis, where the thickening of the venous wall and narrowing of the lumen result from hyperplasia of the subendothelial and endothelial cells, making them irreversible. Therefore, the prognosis for inflammatory obstructions is better than for sclerotic ones. Regarding the location of the obstruction, branch obstructions have a better prognosis than hemi-obstructions, which in turn are better than total trunk obstructions. In terms of severity, incomplete obstructions (non-ischemic, as termed by Hayreh) have a better prognosis than complete (ischemic) obstructions. Of course, these prognostic assessments are not absolute. Factors such as whether effective collateral circulation can be established early or whether timely and appropriate treatment is received can directly influence the outcome. The presence of macular edema that does not resolve in the short term is likely to severely impair central vision. Particularly in cases of complete total trunk obstruction with large non-perfusion areas observed on fluorescein angiography, not only is the rate of blindness high, but the incidence of neovascular glaucoma is also elevated, resulting in a poor long-term prognosis.