Central retinal vein occlusion (CRVO) is a disease in which the central retinal vein is occluded at the level of the lamina cribrosa within the optic nerve. The occlusion causes increased venous pressure, leading to blood stasis, ischemia, and exudation within the retina, resulting in flame-shaped hemorrhages, optic disc edema, and macular edema in all four quadrants.
Retinal vein occlusion overall is the second most common retinal vascular disease after diabetic retinopathy 9, 10). As of 2015, the global prevalence was approximately 0.77%, with an estimated 28 million affected individuals aged 30–89 years 10). The prevalence of CRVO in people aged 40 years and older is reported to be about 0.2%, which is one-sixth to one-seventh the frequency of branch retinal vein occlusion (BRVO) 10). It most commonly occurs in the 60s and 70s and is relatively rare under age 40 9, 10).
CRVO is broadly classified into perfused (non-ischemic) type and non-perfused (ischemic) type. Non-ischemic type accounts for approximately 75–80% of all CRVO. There is also hemi-central retinal vein occlusion (hemi-CRVO), which affects only the superior or inferior two quadrants, and its clinical course is similar to CRVO 9, 10). Hemi-CRVO occurs when one of two independent hemi-central veins is occluded at the lamina cribrosa level, and unlike BRVO, an arteriovenous crossing is often not visible. About 90% affect the superior or inferior hemifield 10). Note that, like CRVO, there is a high risk of neovascular glaucoma 10).
Important complications of CRVO are macular edema and neovascularization. Macular edema occurs in both non-ischemic and ischemic types and is the main cause of visual loss. Neovascularization (iris neovascularization, retinal neovascularization) occurs mainly in the ischemic type; about 25% of CRVO cases develop iris neovascularization, which can lead to blindness due to neovascular glaucoma 10). It has been reported that patients with CRVO have an increased risk of cardiovascular events and all-cause mortality compared to the general population 10), and collaboration with internal medicine is important from the perspective of systemic management.
CRVO is an occlusion of the main trunk vein within the optic nerve, causing hemorrhage throughout the entire retina (4 quadrants). BRVO is an occlusion of a branch vein at an arteriovenous crossing, and the damage is limited to 1-2 quadrants. BRVO is 6-7 times more common than CRVO 10). Compared to BRVO, CRVO has a higher risk of neovascular glaucoma and tends to require more frequent anti-VEGF treatments.
Symptoms of CRVO vary depending on the type of occlusion.
Typical fundus findings of CRVO are as follows:
The diagnosis itself is not difficult based on characteristic retinal hemorrhages, but detailed examinations beyond funduscopy are important for classification into non-ischemic and ischemic types, treatment indications, and prognosis prediction. Over time, acute hemorrhages are absorbed and soft exudates also resolve. In the long term, collateral circulation may develop around the optic disc and between retinal veins. Macular edema may resolve spontaneously, but if it persists, it leads to retinal pigment epithelium atrophy and worsens visual prognosis.
The key points for differentiating non-ischemic and ischemic types are shown in the table below. It has been reported that about one-third of non-ischemic cases convert to ischemic type during the course, with conversion occurring in 15% within 4 months and 34% within 3 years10).
| Feature | Non-ischemic type | Ischemic type |
|---|---|---|
| Visual acuity | 20/200 or better | Worse than 20/200 |
| RAPD | Mild/negative | Clear (positive in about 90%) |
| FA non-perfusion area | <10 disc areas | ≥10 disc areas (CVOS criteria) |
| ERG | Normal to mildly reduced | Reduced b/a ratio and b-wave amplitude |
| Prognosis | Relatively good | Poor (high risk of NVG) |
Non-ischemic type
Frequency: Accounts for approximately 75-80% of all CRVO.
Hemorrhage: Flame-shaped hemorrhages in all four quadrants (relatively superficial).
Edema: Accompanied by optic disc edema and macular edema.
Neovascularization: Usually does not occur. Some cases resolve spontaneously.
Visual acuity: Macular edema is the main cause of vision loss.
Ischemic type
Definition: Capillary non-perfusion area of 10 disc areas or more on FA (CVOS criteria) 9, 10).
RAPD: Relative afferent pupillary defect is positive in about 90%.
Rubeosis: Iris rubeosis occurs in 45–80%.
NVG: Neovascular glaucoma develops in more than half of untreated cases.
Conversion: About one-third of non-ischemic type convert to ischemic type (15% within 4 months, 34% within 3 years).
In CRVO, OCT B-scan may show a band-like hyperreflectivity in the inner nuclear layer of the parafovea, called PAMM (paracentral acute middle maculopathy). It is thought to be caused by circulatory disturbance of peripheral arterioles supplying the deep retinal capillary plexus due to venous perfusion impairment. Hyperreflectivity is not prominent on en face images of the superficial retina, but is clearly visualized on en face images of the deep retina, corresponding to whitened retina. PAMM reflects ischemia of the intermediate capillary plexus and is noted as an auxiliary indicator for assessing the degree of retinal ischemia in CRVO.
Matsuo T et al. (2025) reported a case of bilateral CRVO in a 71-year-old man 1). The right eye progressed to neovascular glaucoma with intraocular pressure of 35 mmHg 4 months after onset, eventually losing light perception. The left eye maintained vision with anti-VEGF therapy and conservative treatment. Right heart dysfunction after cardiac surgery was considered a trigger for bilateral onset.
Non-ischemic type should be re-evaluated 4–6 weeks after onset. Ischemic type has a high risk of neovascular glaucoma, requiring monthly visits and gonioscopy for 6 months 9). Since about one-third of non-ischemic type convert to ischemic type, gonioscopy should always be performed. During anti-VEGF therapy, monthly OCT is recommended to evaluate macular edema.
The pathophysiology of CRVO is explained by Virchow’s triad (vascular injury, blood stasis, hypercoagulability). Posterior to the lamina cribrosa, the central retinal artery and central retinal vein share a common adventitia. When the arterial wall thickens and hardens due to arteriosclerotic changes, the adjacent vein is compressed, leading to endothelial damage, thrombus formation, and occlusion.
Major risk factors are shown in the table below.
| Risk factor | Frequency/Association |
|---|---|
| Aging | Most important: over 90% are aged 55 or older |
| Hypertension | Up to 73% of those aged 50 or older have comorbidity 9, 10) |
| Hyperlipidemia | Major risk factor 7) |
| Diabetes mellitus | Independent risk factor 9, 10) |
| Glaucoma / high intraocular pressure | Independent risk factor 9, 10) |
Meta-analysis indicates that 48% of RVO is attributable to hypertension, 20% to hyperlipidemia, and 5% to diabetes mellitus 10).
Other important risk factors are listed below.
For onset under age 50, systemic evaluation is strongly recommended. It has been reported that 58% of cases have non-traditional risk factors (e.g., coagulation abnormalities, autoimmune diseases) identified 9, 10). Even in patients over 50, it is recommended to check the management status of hypertension, diabetes, and dyslipidemia, and to share information with the primary care physician.
Onset under age 40 is rare but possible. Coagulation abnormalities, MTHFR gene mutations, COVID-19 infection, post-vaccine VITT, and PDE5 inhibitors can be causes 2, 3, 4, 5, 6). In patients under 50, coagulation screening (protein C/S, antithrombin III, etc.) and autoantibody tests (antiphospholipid antibodies, antinuclear antibodies, etc.) are recommended 9, 10). In young CRVO, differentiation from papillophlebitis is also important, as the latter may require systemic steroid treatment.
Diagnosis is made by combining medical history, visual acuity, and fundus findings. The characteristic fundus findings of flame-shaped hemorrhages in all four quadrants and venous dilation and tortuosity make diagnosis straightforward, but the following tests are essential for classifying ischemic/non-ischemic type and determining treatment indications.
The roles of each examination are shown below.
| Examination | Purpose |
|---|---|
| FA (Fluorescein Angiography) | Assessment of ischemic area (CVOS criteria) 9, 10) |
| OCT (Optical Coherence Tomography) | Quantitative assessment of macular edema and detection of PAMM9, 10) |
| OCTA (Optical Coherence Tomography Angiography) | Noninvasive detection of capillary nonperfusion areas9) |
| ERG (Electroretinography) | Differentiation of ischemic type (reduced b/a ratio) |
| Visual field testing | Large central scotoma in ischemic type |
Since systemic vascular risk factors are involved in the onset of CRVO, the following systemic examinations are performed.
Treatment of CRVO consists of two main pillars: treatment for macular edema and treatment for neovascularization.
Intravitreal anti-VEGF injection is the first-line treatment for macular edema associated with CRVO 9, 10). Its efficacy has been confirmed in multiple large-scale RCTs. Compared to BRVO, more injections are required, and especially in the ischemic type, complete cure is rare, but it is currently the treatment with the most expected visual improvement.
Ranibizumab
CRUISE trial: The 0.5 mg group showed a mean improvement of +14.9 letters at 6 months. 47.7% improved by ≥15 letters (sham group: 0.8 letters improvement, 16.9% improved by ≥15 letters) 12).
Dosage: 0.5 mg/0.05 mL intravitreal injection monthly.
Insurance coverage: Indicated for “macular edema due to retinal vein occlusion”.
Aflibercept
COPERNICUS trial: In the 2 mg group, 56% improved by ≥15 letters (sham group: 12%) 13).
GALILEO trial: Similarly confirmed superiority over sham group 14).
Dosage: 2 mg/0.05 mL intravitreal injection monthly.
Insurance coverage: Indicated for “macular edema due to retinal vein occlusion”.
Faricimab
COMINO trial (CRVO/hemi-CRVO, n=729): Baseline BCVA 50.5 letters, CST 711.6 μm. The 6 mg group showed a mean improvement of +16.9 letters at 24 weeks. 56.6% improved by ≥15 letters. Non-inferiority to aflibercept was achieved 11).
CST change: CST reduction at 24 weeks was faricimab -461.6 μm vs. aflibercept -448.8 μm. Macular leakage resolution rate was faricimab 44.4% vs. aflibercept 30.0% 11).
Safety: The incidence of intraocular inflammation (IOI) was 2.2% for faricimab vs 1.1% for aflibercept. Serious IOI included 2 cases of uveitis in the faricimab group and 1 case of non-infectious endophthalmitis in the aflibercept group11).
Mechanism: It is a bispecific antibody that has anti-Ang-2 action in addition to anti-VEGF-A action.
Other anti-VEGF drugs and results of major clinical trials are shown below.
It is selected when anti-VEGF is ineffective or unsuitable.
PRP (panretinal photocoagulation) is used to manage neovascularization in ischemic CRVO 9). PRP does not improve visual acuity, but it prevents the development of neovascular glaucoma through regression and inhibition of neovascularization.
After the approval of VEGF inhibitors, vitrectomy is not performed as a first-line treatment. No large-scale clinical trials have been conducted for macular edema due to CRVO, and evidence is not established. Radial optic neurotomy, which was previously performed based on the theoretical rationale of reducing venous pressure by decompressing the lamina cribrosa, is no longer performed because it can cause serious complications such as visual field defects and hemorrhage.
In cases with vitreous hemorrhage, PRP can be performed simultaneously with hemorrhage removal. In cases complicated by tractional vitreomacular syndrome (epiretinal membrane, vitreomacular traction), vitrectomy may contribute to improvement of macular edema.
Follow-up is performed according to the following schedule to assess treatment efficacy and detect complications early.
In the CRUISE study, monthly injections for 6 months were administered, and significant visual improvement was confirmed 12). In actual treatment, monthly injections are started, and the interval is extended while confirming improvement of macular edema on OCT. It has been reported that approximately 56–75% of CRVO cases require treatment continuation beyond 5 years 10), making long-term regular follow-up essential. For faricimab, a treat-and-extend regimen with extension up to 16-week intervals is being considered 11).
Posterior to the lamina cribrosa, the central retinal artery and central retinal vein share a common adventitia (connective tissue sheath). Thickening and hardening of the arterial wall due to arteriosclerosis compress the adjacent vein, leading to endothelial damage → thrombus formation → occlusion 9, 10). In BRVO, occlusion mainly occurs at arteriovenous crossings, whereas in CRVO, occlusion near the lamina cribrosa is characteristic, but the mechanism of thrombus formation itself is considered similar to that of BRVO.
All three elements of Virchow’s triad (vascular injury, blood stasis, hypercoagulability) are involved. In BRVO, compression at the arteriovenous crossing is the main cause of occlusion, whereas in CRVO, the unique structure where the artery and vein share an adventitia in the narrow anatomical space of the lamina cribrosa forms the basis for occlusion.
Venous occlusion → increased venous pressure → leakage of plasma components → retinal edema and hemorrhage. Retinal ischemia → hypoxia → overproduction of VEGF (vascular endothelial growth factor) → worsening of macular edema and formation of neovascularization (iris neovascularization, retinal neovascularization) occur 9, 10).
Among all retinal vascular diseases, RVO has been reported to have the highest levels of Ang-2 (angiopoietin-2). Ang-2 competes with Ang-1 for binding to Tie2, inhibiting vascular stabilization by Ang-1/Tie2 signaling 11). This provides the rationale for the mechanism of action of faricimab, which targets both VEGF-A and Ang-2.
This mechanism is the theoretical basis for anti-VEGF therapy and anti-Ang-2 therapy. In ischemic CRVO, VEGF production is significantly higher than in non-ischemic CRVO, and neovascularization involving the iris, angle, and retina progresses rapidly. VEGF inhibitors not only improve macular edema but also induce regression of neovascularization; however, recurrence occurs when drug efficacy wanes, requiring continuous administration.
In CRVO, impaired venous perfusion leads to circulatory disturbance at the peripheral arteriolar level. On OCT B-scan, it appears as a band-like hyperreflectivity in the inner nuclear layer of the parafovea (PAMM finding). It is inconspicuous on superficial en face images, but the hyperreflective area corresponding to the whitened retina is clearly visible on deep en face images.
In ischemic CRVO, extensive retinal ischemia produces large amounts of VEGF, inducing iris neovascularization. Iris rubeosis occurs in 45–80% of ischemic cases, and these new vessels obstruct the angle, causing neovascular glaucoma. It often appears within 2–4 months (about 90 days) after onset, hence the name “90-day glaucoma” 9, 10). Regular angle examination is essential for early detection, and PRP and anti-VEGF therapy determine visual prognosis.
Reports on the risk of retinal vein occlusion after COVID-19 infection are accumulating.
RiaziEsfahani H et al. (2024) reported a case of hemi-CRVO in a young patient with a history of COVID-19 3). It suggested that RVO risk may persist for several months after infection.
In a review of 20 cases of RVO after vaccination, 7 cases were in individuals under 40 years of age 6). The incidence of thrombosis after ChAdOx1 (AstraZeneca) vaccination is reported as 1.13 per 100,000 doses, and a hypercoagulable state via VITT mechanism has been proposed 5, 6).
Torkashvand A et al. (2023) reported a case of combined CRVO and central retinal artery occlusion after sildenafil use 2). OCTA documented decreased vascular density, highlighting the impact of PDE5 inhibitors on retinal circulation.
Advances in wide-field imaging technology have refined the assessment of peripheral ischemic areas 9, 10). Wide-field FA can now detect non-perfused areas in the peripheral retina that were difficult to evaluate with conventional standard FA, improving the prediction of transition risk from non-ischemic to ischemic type. OCTA allows quantitative evaluation of FAZ enlargement and capillary density reduction without contrast agents, and its usefulness in follow-up of RVO patients has been reported. However, due to current limitations in imaging range, it has not yet fully replaced FA 9).
Automated detection of RVO from color fundus photographs using deep learning algorithms has been studied, with good discriminative ability reported 10). Future applications in screening and telemedicine are expected.
From 2021 to 2024, the FDA approved two ranibizumab biosimilars (ranibizumab-nuna [Byooviz], ranibizumab-eqrn [Cimerli]) and four aflibercept biosimilars (aflibercept-jbvf [Yesafili], aflibercept-yszy [Opuviz], aflibercept-mrbb [Ahzantive], aflibercept-ayyh [Pavblu]) for the indication of macular edema due to RVO 10). The widespread use of biosimilars is expected to improve treatment access and reduce healthcare costs.
In the COMINO trial of faricimab, after week 24 (Part 2: weeks 24-72), all patients were switched to faricimab 6 mg T&E dosing (up to 16-week intervals). Durability and long-term safety data at 72 weeks are expected to be published in the future, with important results anticipated regarding the potential for extended dosing intervals in RVO treatment 11).
Cases of right heart dysfunction discovered through bilateral CRVO have been reported, highlighting the importance of cross-disciplinary collaboration with cardiac surgery and cardiology 1).
