Central Retinal Artery Occlusion

Key Points at a Glance

Central retinal artery occlusion (CRAO) is an ophthalmic emergency characterized by sudden, painless, severe vision loss due to abrupt occlusion of the central retinal artery.
Irreversible retinal damage begins approximately 100 minutes after arterial occlusion, so early intervention is essential.
CRAO is broadly classified into non-arteritic (over 90%) and arteritic types. There are three subtypes: permanent, transient, and cilioretinal artery-sparing.
CRAO shares the same risk factors as stroke, and 15–20% of CRAO patients develop a stroke within 30 days.
In all patients aged 50 years or older, it is crucial to rule out giant cell arteritis; if suspected, steroids should be started before a definitive diagnosis.
Without treatment, the chance of visual recovery is only about 18%, and visual outcomes are poor, often resulting in counting fingers or worse.
In the acute phase, treatments include amyl nitrite inhalation, intravenous Diamox, urokinase administration, ocular massage, and anterior chamber paracentesis. Active treatment is recommended within 24 hours of onset.
Early administration of PGE₁ (prostaglandin E₁) has been reported to improve visual acuity (still under investigation).

1. What is Central Retinal Artery Occlusion?

Retinal artery occlusion is a disease that causes severe visual impairment due to retinal ischemia and necrosis from occlusion of the retinal artery. Irreversible retinal changes begin approximately 100 minutes after arterial occlusion, so visual outcomes are often poor even with treatment. It is classified into the following three types based on the occlusion site.

CRAO

Central Retinal Artery Occlusion (CRAO): Occlusion of the central retinal artery. This is the most severe type, and vision often decreases to hand motion or light perception.

Incidence: 1 per 100,000 per year, 1 per 10,000 outpatients⁸⁾.

BRAO

Branch Retinal Artery Occlusion: occlusion of a branch. Visual prognosis varies greatly depending on the occlusion site.

Features: 80% eventually maintain corrected visual acuity of 0.5 or better. Visual acuity does not decrease if the macula is not affected.

Cilioretinal Artery Occlusion

Cilioretinal Artery Occlusion: occlusion of the cilioretinal artery. It is a branch of the short posterior ciliary artery and is present in about 32% of all eyes. It supplies the retina near the papillomacular bundle.

Features: It may occur in combination with CRAO or alone.

CRAO is further classified into non-arteritic and arteritic types. Non-arteritic CRAO accounts for over 90% of all cases and has the following three subtypes:

Persistent non-arteritic CRAO: Caused by thrombosis or embolism due to atherosclerosis. Accounts for about two-thirds of all CRAO cases. Visual acuity is usually less than 0.1, and a cherry-red spot is a typical finding.
Transient non-arteritic CRAO: Similar to TIA (transient ischemic attack), lasting from minutes to hours. The most common cause is a migrating embolus, and the visual prognosis is the best.
Non-arteritic CRAO with patent cilioretinal artery: Because the cilioretinal artery maintains foveal circulation, central vision may be preserved.

Arteritic CRAO is secondary to giant cell arteritis (GCA) and accounts for about 4% of CRAO patients. It has the worst prognosis among the four types, and vision loss is almost irreversible. It is more likely to occur in patients aged 70 years or older and is often accompanied by GCA-related symptoms such as headache, scalp tenderness, jaw claudication, malaise, and weight loss. The most important step in all CRAO patients aged 50 years or older is to rule out arteritic CRAO, by rapid measurement of ESR and CRP and, if necessary, temporal artery biopsy. If GCA is strongly suspected, systemic steroid therapy should be started immediately without waiting for a definitive diagnosis ⁸⁾. Delay in treatment increases the risk of contralateral eye blindness.

Epidemiology

The incidence of CRAO is estimated at about 1 per 100,000 population per year, or 1 per 10,000 outpatients. The average age of onset is in the early 60s, and the incidence increases with age ⁸⁾. It is more common in men and usually occurs in one eye, but 1-2% occur in both eyes. Bilateral involvement should raise suspicion of giant cell arteritis ⁸⁾. The incidence in Japan is lower than in Western countries, making it a relatively rare disease, but it is a highly urgent condition where very early response determines visual prognosis.

The retina is a tissue that differentiates from the brain during embryonic development and is considered part of the central nervous system. Its relationship with stroke is close; in 2013, the AHA/ASA (American Heart Association/American Stroke Association) revised the definition of stroke to explicitly include retinal ischemia as a type of CNS (central nervous system) infarction ⁸⁾. 15–20% of CRAO patients develop a stroke within 30 days, and as an “eye stroke,” emergency systemic evaluation at a stroke center is recommended ⁸⁾.

Q Is CRAO related to stroke?

CRAO shares the same risk factors as stroke (arteriosclerosis, atrial fibrillation, embolism, etc.) and has a high risk of stroke within 30 days after onset, at 15–20% ⁸⁾. The AHA/ASA defines retinal ischemia as CNS infarction, and after CRAO onset, emergency systemic evaluation in collaboration with neurology and cardiology is essential.

2. Main Symptoms and Clinical Findings

OCT image of central retinal artery occlusion. Diffuse hyperreflectivity and thickening of the inner retina in the macular area.

Louie E, et al. Paracentral acute middle maculopathy presenting as a sign of impending central retinal artery occlusion: a case report. BMC Ophthalmol. 2023. Figure 3. PMCID: PMC10262410. License: CC BY.

Infrared fundus image and macular OCT tomogram. The OCT shows diffuse hyperreflectivity and thickening of the inner retina, which is a finding indicating acute retinal ischemia and is suitable for an article on central retinal artery occlusion.

Subjective Symptoms

Sudden onset of painless severe vision loss is the most characteristic feature.

Rapid vision loss: Completes within seconds to minutes, often reducing vision to hand motion or light perception. Since it is painless, patients may not recognize the urgency.
Prodromal transient vision loss: Some patients experience repeated transient vision loss (amaurosis fugax) before CRAO occurs. This is important as a precursor symptom of stroke (TIA).
Preserved vision when cilioretinal artery is spared: In individuals where the cilioretinal artery supplies the fovea (about 32% of all eyes, about 1/3 of CRAO cases), central vision may be preserved because this artery is not affected by the occlusion.

In CRAO, some patients experience repeated transient vision loss before onset. This is called amaurosis fugax and is an important warning sign as a precursor symptom of stroke (TIA). Vision loss lasts a few minutes and then recovers spontaneously, but it often precedes the main attack.

A case of COVID-19-related CRAO in a 6-year-old girl has been reported, presenting with sudden bilateral vision loss, indicating that (though rare) onset can occur in children ¹⁾.

Clinical Findings (Findings Confirmed by Physician Examination)

Characteristic findings appear in the acute phase but change over time. In the hyperacute phase within 2 hours of onset, fundus findings may be normal or show only slight macular opacity.

Fundus Findings

Cherry-red spot: The most typical finding of CRAO. The retina becomes milky white, mainly in the posterior pole. The fovea, which consists only of the outer retinal layers and is nourished by the choroid, does not become cloudy and appears red in contrast to the surrounding whitening. In ophthalmic artery occlusion (OAO), the cherry-red spot is absent because choroidal circulation is also impaired⁸⁾.
Arterial narrowing and white-line appearance: The occluded retinal artery becomes markedly narrowed and may appear as a white line with no blood visible inside.
Beading and fragmentation: In the occluded artery, characteristic findings of slow-moving micro-columns of blood are observed.
Boxcar segmentation: Blood in the artery or vein is segmented and appears as columns. This finding indicates severe ischemia in the acute phase⁸⁾.

Imaging Findings

OCT: In the acute phase, hyperreflectivity and thickening of the inner retinal layers (from the nerve fiber layer to the inner nuclear layer) are observed. Unlike typical retinal edema, this reflects intracellular edema (cell swelling) due to ischemia. Paracentral acute middle maculopathy (PAMM) is a hyperreflective band in the middle retinal layer detected by OCT and is characteristic of the acute phase⁸⁾. In transient non-arteritic CRAO, inner retinal thickening is mild and inner layer hyperreflectivity is present. After several weeks, the retina and choroid become thin, and the retinal opacity disappears 4–6 weeks after onset, but retrograde atrophy occurs not only in the inner layers but also in the outer layers, making the layered structure difficult to identify.
Fluorescein angiography (FA): The arm-to-retina circulation time is prolonged to 30 seconds or more (normally about 12 seconds), and marked delay in retinal vessel filling is observed. Irregularities of the vessel wall, significant fluorescein leakage, and delayed intraretinal circulation time are present. It is useful for identifying the occlusion site and evaluating the presence and perfusion area of the cilioretinal artery.
Electroretinography (ERG): The a-wave is normal because photoreceptors survive due to choroidal nourishment, but the b-wave is reduced or absent due to damage to bipolar cells and Müller cells, showing a negative-type ERG. This is characteristic of CRAO and electrophysiologically confirms inner-layer-dominant ischemia.
OCTA (Optical Coherence Tomography Angiography): Non-invasively visualizes perfusion deficits in the superficial retinal capillaries. The pattern of perfusion deficit in the acute phase may be a predictor of long-term prognosis, as studied.

In a 6-year-old girl with COVID-19-associated CRAO, thinning of the RNFL (retinal nerve fiber layer) persisted even 5 months after onset¹⁾. In the chronic phase, OCT shows retinal thinning, and retrograde atrophy occurs not only in the inner layers but also in the outer layers, making the layered structure difficult to identify.

Q Why does a cherry-red spot occur?

In CRAO, the entire inner retinal layer becomes milky white due to ischemic intracellular edema. However, the fovea, which consists only of the outer retinal layer and receives nutrition from the choriocapillaris, does not become opaque. The mechanism of cherry-red spot is that the red color of the choroid becomes visible against the surrounding white opacity. For detailed vascular anatomy, refer to the “Pathophysiology” section.

3. Causes and Risk Factors

The main cause of CRAO is embolism, accounting for approximately 95% of all cases⁸⁾. The distribution of causes varies by age and underlying disease.

Main Causes by Age

Age Group	Main Cause	Conditions to Investigate
50 years and older	Arteriosclerotic embolism/thrombus	Carotid artery stenosis, atrial fibrillation, hypertension
Under 50 years	Coagulation abnormality, PFO, vasculitis	Paradoxical embolism, autoimmune disease

Main Causes

Arteriosclerotic embolism: It tends to occur in elderly patients with systemic diseases such as hypertension, arteriosclerosis, and diabetes. Atheromas of the internal carotid artery or intracardiac thrombi formed by heart disease become emboli. Cholesterol emboli (Hollenhorst plaque) or calcified emboli detach from the carotid artery or aortic arch and cause occlusion at the narrowest part of the central retinal artery lumen (the site where it penetrates the dural sheath of the optic nerve).
Patent Foramen Ovale (PFO): An important cause of CRAO in patients under 50 years old. It occurs via paradoxical embolism where venous thrombi enter the arterial system through the PFO. The diagnostic yield of transesophageal echocardiography (TEE) reaches 85.7%, while transthoracic echocardiography (TTE) detects only 14.3% ³⁾.
Giant Cell Arteritis (GCA): More common in patients aged 50 years and older, especially those over 70. It accounts for approximately 4% of CRAO cases and carries a risk of contralateral eye blindness if untreated. Screening with ESR, CRP, and CBC is essential ⁸⁾.
Hyaluronic Acid (HA) Injection: Cases of retinal artery occlusion (RAO) following facial HA subcutaneous injection for cosmetic purposes are increasing ⁸⁾. The mechanism is thought to be retrograde embolism, and occlusion can occur even with a small amount of HA (0.08 mL) ²⁾.
Vasculitis, Infection, Trauma, Vasospasm: Although less frequent, these can be causes. Vasospasm has been reported in association with migraine and cocaine use.
Special Causes in Young Patients: In patients under 50 years old, abnormalities of the blood coagulation system (such as antiphospholipid antibody syndrome, thrombophilia), heart disease, congenital anomalies, and retinal vasculitis are more common than atherosclerosis. In young patients with CRAO, active investigation for embolic sources using transesophageal echocardiography and coagulation studies is necessary.
COVID-19: Can cause CRAO through a hypercoagulable state and endothelial injury leading to thrombus formation, with cases reported even in children ¹⁾.

Risk Factors

Modifiable risk factors include smoking, hypertension, high BMI, dyslipidemia, diabetes, coagulation disorders, and heart disease (including atrial fibrillation) ⁸⁾. Approximately 60% of CRAO patients have at least one undiagnosed vascular risk factor, with dyslipidemia being the most common. Low HDL cholesterol has also been reported as an independent risk factor ⁸⁾.

Systemic risk factors are listed below.

Hypertension: The most important modifiable risk factor
Dyslipidemia: The most frequent undiagnosed risk factor in CRAO patients
Diabetes: Combined risk with retinal microvascular disease. Cases have been reported where a diabetic patient developed BRAO in one eye and later CRAO in the contralateral eye ⁴⁾
Smoking: Promotes atherosclerosis
Atrial Fibrillation: Major risk for cardioembolism
High BMI and Obstructive Sleep Apnea: Factors related to atherosclerosis
Cosmetic filler injections: An iatrogenic risk factor that is increasing in frequency⁸⁾

4. Diagnosis and Examination Methods

CRAO can often be diagnosed by fundus findings, but systemic evaluation to search for the cause is essential. Management of CRAO is divided into three stages: first, restoration of blood flow in the acute phase; second, prevention of secondary complications in the subacute phase; and third, systemic control and prevention of future vascular ischemic events.

Ophthalmic Examinations

Slit-lamp microscopy and fundus examination: Confirm cherry-red spot, retinal whitening, arteriolar narrowing, and boxcarring. Visualize emboli, assess the presence of cilioretinal artery, and evaluate the extent of occlusion.
Optical coherence tomography (OCT): In the acute phase, confirm hyperreflectivity and thickening of the inner retinal layers. Useful for detecting paracentral acute middle maculopathy (PAMM)⁸⁾. In chronic stages, thinning and atrophy of the inner retinal layers remain.
Fluorescein angiography (FA): Confirm delayed filling or filling defects of the retinal arteries and identify the occlusion site. Prolonged arm-to-retina circulation time (≥30 seconds) is a characteristic finding.
Electroretinography (ERG): A negative-type ERG (normal a-wave, reduced b-wave) is characteristic of CRAO, reflecting inner-layer predominant ischemia.

The main findings obtained from each examination are shown below.

Examination Method	Main Findings
OCT	Acute phase: inner layer hyperreflectivity and thickening → Chronic phase: inner layer thinning
FA	Delayed filling, arm-to-retina circulation time ≥30 seconds
ERG	Normal a-wave, reduced b-wave (negative-type ERG)

Systemic evaluation (search for cause)

Acute CRAO requires immediate referral to a stroke center for urgent systemic evaluation ⁸⁾. The stroke risk in symptomatic RAO patients is highest from 2 weeks before to 1 month after onset ⁸⁾.

Carotid ultrasound/MRA: Search for atherosclerotic lesions and embolic sources. Symptomatic carotid stenosis (50–99%) shows better outcomes with carotid endarterectomy than medical therapy ⁸⁾.
ECG/Holter ECG: Detection of atrial fibrillation.
Echocardiography (transthoracic: TTE): Evaluation of valvular heart disease and intracardiac thrombus. In young CRAO patients under 50 years, the diagnostic yield of TTE is only 14.3%, and TEE is required in 85.7% ³⁾.
Transesophageal echocardiography (TEE): Performed in cases where PFO is suspected. It is easily overlooked on TTE ³⁾.
Blood tests: CBC, coagulation (PT, APTT, D-dimer), ESR, CRP (to rule out GCA). In new-onset CRAO in patients aged 50 years or older, ESR and CRP must be measured to differentiate giant cell arteritis ⁸⁾.
TOAST classification: Causes are classified using the same framework as for cerebral infarction (large artery atherosclerosis, cardioembolism, small vessel occlusion, other determined etiology, undetermined etiology) ⁵⁾.

Key points for differential diagnosis

Exclusion of arteritic CRAO: Mandatory in all patients aged 50 years or older. Check for headache, scalp tenderness, and jaw claudication, and promptly measure ESR and CRP. Elevated platelet count is also a supportive indicator of GCA. If strongly suspected, start steroids before definitive diagnosis by temporal artery biopsy ⁸⁾.
Differentiation from cilioretinal artery-sparing CRAO: Determined by whether central vision is preserved. On fundoscopy, there is typical CRAO whitening around the cherry-red spot, but the papillomacular bundle area is spared.
Differentiation between transient CRAO and BRAO: Distinguished by symptom duration (transient resolves spontaneously within minutes to hours) and occlusion extent (BRAO is limited to a sector-shaped visual field defect).
Ophthalmic artery occlusion (OAO): Both retinal and choroidal circulations are impaired, and the absence of a cherry-red spot distinguishes it from CRAO ⁸⁾. Delayed choroidal filling is also confirmed on FA.
Asymptomatic retinal emboli: Found in approximately 1.4% of the general population aged 49 years or older ⁸⁾. Currently, there is no evidence supporting urgent stroke evaluation for asymptomatic retinal emboli ⁸⁾.

Q What is the most important differential diagnosis in CRAO patients aged 50 years or older?

Exclusion of arteritic CRAO due to giant cell arteritis (GCA) is most important. GCA-related CRAO accounts for about 4% of all CRAO cases and has the worst prognosis. If GCA is suspected, start systemic steroids immediately without waiting for definitive diagnosis (temporal artery biopsy) ⁸⁾. Untreated, there is a risk of contralateral eye blindness.

5. Standard Treatment

CRAO is an ophthalmic emergency, and prompt management in the hyperacute phase is essential to improve visual prognosis. Treatment immediately after onset is preferable, and active treatment should be considered for cases within one day of onset.

Urgency and Time Window for Treatment

Severe retinal damage begins approximately 100 minutes after arterial occlusion. Treatment is most favorable immediately after onset, and within about 4 hours is considered the target for acute-phase treatment ⁶⁾. The longer the time from onset to consultation, the worse the prognosis, but active treatment should be considered for cases within one day of onset. For BRAO with early visual impairment, the same treatment strategy as for CRAO is followed.

Zokri MF et al. (2024) emphasized in a case series of acute RAO that time to treatment initiation is the most important factor determining visual outcome ⁶⁾. Many cases lose the opportunity for therapeutic intervention due to delayed consultation.

Acute Phase Treatment

The following treatments are used depending on symptoms.

Vasodilators

Amyl nitrite: Crush a 0.25 mL vial, absorb into a covering, and inhale through the nostrils (caution for blood pressure drop; off-label use).

Isosorbide dinitrate sublingual: Promotes vasodilation.

Carbogen inhalation: Inhalation of a 95% oxygen + 5% CO₂ gas mixture. Promotes blood flow but carries a risk of systemic hypotension.

Pentoxifylline: A peripheral circulation-improving drug. Enhances retinal blood flow by improving red blood cell deformability.

Pharmacotherapy

Diamox injection: 500 mg intravenously once daily (off-label use). As a carbonic anhydrase inhibitor, it lowers intraocular pressure and promotes retinal artery dilation.

Urokinase: Initial daily dose of 60,000 to 240,000 units, then gradually reduced over about 7 days. Caution for cerebral hemorrhage and systemic bleeding.

Obalmon tablets: 5 μg × 6 tablets, divided into three doses after meals. As a prostaglandin E₁ derivative, it aims to improve peripheral blood flow.

Procedures and Systemic Management

Ocular massage: Lowers intraocular pressure and moves the embolus peripherally. It is a procedure that can be performed immediately.

Anterior chamber paracentesis: Aspirates aqueous humor to rapidly lower intraocular pressure, relatively increasing arterial perfusion pressure.

Stellate ganglion block: May be performed to improve ocular blood flow.

However, conservative treatments (ocular massage, anterior chamber paracentesis, carbogen inhalation) have not been proven to have significant efficacy⁸⁾. These procedures are theoretically meaningful only in the very early stage after onset, but there is no solid evidence that they improve prognosis compared to the natural course.

Acute CRAO should be urgently referred to a stroke center, and evaluation and treatment should be performed according to the “Eye stroke protocol”⁸⁾. At stroke centers, CRAO is treated as an emergency equivalent to cerebral infarction, and systems are being established to centrally manage tPA administration eligibility assessment, systemic vascular evaluation, and secondary prevention.

Example of Pharmacotherapy Prescription

Use the following as appropriate depending on symptoms.

Amyl nitrite: Crush 0.25 mL/vial, absorb into a covering, and inhale through the nostrils (caution for hypotension; off-label use)
Diamox injection: 500 mg intravenous injection once daily. As a carbonic anhydrase inhibitor, it lowers intraocular pressure and promotes retinal artery dilation (off-label use)
Urokinase intravenous injection: Initial daily dose 60,000–240,000 units, then gradually tapered over approximately 7 days. Caution is required for cerebral hemorrhage and systemic bleeding tendency.
Opalmon tablets (limaprost alfadex): 5 μg × 6 tablets, divided into three doses after meals. As a prostaglandin E₁ derivative, it aims to improve peripheral blood flow.

Thrombolytic therapy

Intravenous tPA administration: Administered to eligible patients within 4.5 hours of onset. Meta-analysis suggests that intravenous tPA within 4.5 hours may be associated with improved outcomes⁸⁾. Decision made in coordination with a stroke center.
Intra-arterial thrombolytic therapy: Selective intra-ophthalmic artery infusion of urokinase is performed at some institutions.

A case has been reported in which visual acuity dramatically improved from 20/2000 to 20/33.3 after intra-arterial administration of 300,000 units of urokinase⁴⁾.

The spontaneous visual recovery rate in CRAO is approximately 18%, but early thrombolytic therapy is reported to increase it to around 40%. However, the EAGLE trial (RCT) found no significant difference in visual improvement between intra-arterial (IA) tPA and conservative treatment, and safety concerns regarding intracranial hemorrhage (ICH) were noted⁷⁾. Currently, evidence for intra-arterial and intravenous fibrinolytic therapy for CRAO is considered insufficient⁸⁾.

Giant cell arteritis (GCA)-associated CRAO

If arteritic CRAO is suspected, systemic steroid administration should be initiated immediately without waiting for a definitive diagnosis. Delay in treatment carries a risk of contralateral eye blindness⁸⁾.

Hyperbaric oxygen therapy

Some small retrospective studies suggest a mild effect, but a Cochrane review concluded that the evidence is uncertain⁸⁾.

Subacute phase management

In the subacute phase after CRAO, chronic retinal ischemia due to reperfusion failure may cause ocular neovascularization. The prevalence of neovascularization is reported to be 2.5–31.6%, and the mean time to observation of neovascularization is 8.5 weeks. Iris neovascularization has been reported in 18% of CRAO cases, and regular ophthalmologic examinations are important for about 4 months after onset. When iris or retinal neovascularization occurs, panretinal photocoagulation (PRP) is indicated ⁸⁾.

Chronic Phase and Complication Prevention

Patients with CRAO have an increased risk of systemic ischemic events, and collaboration with internists, stroke specialists, and cardiologists is important for long-term complication prevention. Approximately 60% of CRAO patients have at least one undiagnosed vascular risk factor, and systemic evaluation triggered by CRAO onset is the first step in secondary prevention.

Antiplatelet therapy: If an atherosclerotic embolic source is suspected, aspirin is the basic treatment. Antiplatelet therapy for CRAO follows the same guidelines as for minor stroke and is recommended unless contraindicated ⁵⁾.
Anticoagulation therapy: If a cardioembolic source such as atrial fibrillation is present, anticoagulants are selected. Since the recurrence prevention strategy differs between cardioembolic and atherosclerotic embolism, treatment selection based on etiological investigation is required.
Carotid endarterectomy: When symptomatic carotid stenosis (50–99%) is identified, carotid endarterectomy shows better outcomes than medical therapy ⁸⁾.
PFO closure: In young CRAO patients where PFO is considered the cause, percutaneous PFO closure may be considered ³⁾.
Risk factor management: Manage hypertension, diabetes, and dyslipidemia, and provide thorough smoking cessation guidance. Diet therapy and regular exercise are also recommended. The cardiovascular risk reduction effect of statin therapy has also been reported ⁸⁾.

Prognosis

The visual outcome of CRAO is poor, often resulting in counting fingers or worse. Without treatment, the chance of visual recovery is only about 18%. At initial presentation, 61% have visual acuity of 20/400 or worse ⁸⁾. Retinal opacity resolves 4–6 weeks after onset, and the retina returns to a normal color, but visual function does not recover unless early treatment is effective. Neovascular glaucoma may develop 4–10 weeks after onset.

On the other hand, in CRAO with preserved cilioretinal artery, the perfusion area of the cilioretinal artery is preserved, so central vision may be maintained. In transient CRAO, the occlusion resolves spontaneously, so the visual prognosis is best. In BRAO, 80% maintain a corrected visual acuity of 0.5 or better, but if the branch to the macula is occluded, the visual prognosis is poor.

After CRAO, attention must also be paid to complications associated with reperfusion failure. Iris neovascularization occurs in about 18% of CRAO cases and may progress to neovascular glaucoma 4–10 weeks after onset. If neovascularization occurs, panretinal photocoagulation (PRP) should be performed promptly ⁸⁾.

Irreversible changes begin approximately 100 minutes after arterial occlusion. Early intervention is essential.
Amyl nitrite inhalation carries a risk of hypotension and should be used under blood pressure monitoring. It is not covered by insurance.
Intravenous Diamox is also used off-label.
Urokinase carries risks of cerebral hemorrhage and systemic bleeding, requiring careful administration management.
tPA therapy is not established as a standard treatment for CRAO and carries risks of serious complications such as ICH.
In GCA-related CRAO, steroids should be started without hesitation. Treatment should be prioritized even before biopsy confirmation.
Neovascular complications commonly occur 4 to 10 weeks after onset, so regular fundus and intraocular pressure examinations should be continued for about 4 months.

Q Within how many hours after onset should a patient be seen for possible treatment?

Irreversible retinal damage begins approximately 100 minutes after occlusion. Active treatment is recommended within 1 day of onset, and earlier treatment leads to better prognosis. Intravenous tPA is indicated within 4.5 hours of onset ⁸⁾. In any case, as an “ocular stroke,” emergency consultation at a stroke center is essential.

6. Pathophysiology and detailed mechanism of onset

Vascular anatomy and characteristics of ischemia

The central retinal artery, a branch of the ophthalmic artery (first branch of the internal carotid artery), enters the retina at the optic disc and supplies oxygen and nutrients to the inner two-thirds of the retina (from the nerve fiber layer to the inner nuclear layer). Photoreceptors in the outer retina receive nutrition from the choroidal vessels, so the outer layer is relatively preserved in CRAO.

The cilioretinal artery, a branch of the short posterior ciliary arteries, is present in about 32% of all eyes and supplies the area near the papillomacular bundle. Since the cilioretinal artery branches off before the ophthalmic artery becomes the central retinal artery, it is not affected by CRAO. Therefore, if this artery is preserved, central foveal vision may be maintained.

Mechanism of cherry-red spot formation

The mechanism of cherry-red spot formation is as follows. In CRAO, the inner retinal layers supplied by the retinal artery undergo acute ischemia, leading to cellular swelling (intracellular edema) and ischemic necrosis, resulting in a milky-white opacity centered on the posterior pole. This opacity differs in mechanism from ordinary retinal edema (extracellular edema). In ordinary retinal edema, extracellular fluid accumulation causes low reflectivity on OCT, whereas in CRAO, ischemic intracellular edema (cellular swelling) causes high reflectivity in the inner retinal layers. OCT shows the inner retinal layers as hyperreflective and thickened.

The fovea is composed only of the outer retinal layers and is nourished by the choroid, so it does not become opaque. In the fovea, the inner layers (ganglion cell layer, inner plexiform layer, inner nuclear layer) are almost absent, and only the outer layer (photoreceptor layer) exists. Therefore, the normal red color (color of the choroidal capillaries) appears to stand out within the surrounding milky-white opacity. This is the cause of the cherry-red spot.

In ophthalmic artery occlusion (OAO), the main trunk of the ophthalmic artery is occluded, impairing both retinal and choroidal circulation. Due to choroidal ischemia, a cherry-red spot does not appear ⁸⁾.

Mechanism of Embolism

The most common cause of CRAO is thromboembolism, with occlusion occurring at the narrowest part of the central retinal artery lumen (where it penetrates the dural sheath of the optic nerve). Emboli originate from plaques in the carotid artery or heart.

Cardio-aortic emboli: Cholesterol emboli (Hollenhorst plaque), calcific emboli, and platelet-fibrin thrombi detach from carotid artery plaques or the aortic arch and occlude the central retinal artery.
Paradoxical emboli (via PFO): Venous thrombi enter the arterial system through a patent foramen ovale (PFO) and occlude the retinal artery. There are case reports where the arm-retinal circulation time was prolonged to about 25 seconds, approximately twice the normal time ⁵⁾. The risk of overlooking PFO without TEE has been demonstrated ³⁾.
Retrograde emboli (after HA injection): Hyaluronic acid (HA) injected into the facial artery reaches the ophthalmic artery and retinal artery in a retrograde manner. Occlusion can occur with as little as 0.08 mL of HA ²⁾.

Time Course from Ischemia to Irreversible Change

Retinal ganglion cells are extremely vulnerable to ischemia, with functional impairment beginning within minutes of blood flow cessation. Irreversible damage is thought to occur from approximately 100 to 105 minutes ⁸⁾. This is the basis for the urgency of this disease.

Tissue changes according to the time course of ischemia are as follows.

Hyperacute phase (up to 2 hours): Fundus findings are almost normal or show only slight opacity in the macular area. On OCT, hyperreflectivity of the inner retinal layers has already begun to appear.
Acute phase (2 hours to several days): The retina becomes milky-white opaque centered on the posterior pole, and the cherry-red spot becomes clear. Arteries are markedly narrowed, and bead-like blood flow is observed. OCT shows marked thickening and hyperreflectivity of the inner retinal layers.
Subacute phase (1–6 weeks): Retinal opacity gradually resolves, and after 4–6 weeks, the color tone of the retina returns to normal. However, unless early treatment is effective, visual function does not recover. Iris and retinal neovascularization may appear during this period.
Chronic phase (after 6 weeks): OCT shows retinal thinning, with retrograde atrophy affecting not only the inner layers but also the outer layers. Pallor of the optic disc progresses. Even if the occluded vessel eventually recanalizes, vision usually does not recover.

In chronic hypertension, it has been reported that the time until irreversible changes occur may be extended up to 240 minutes⁶⁾.

In a 6-year-old girl with COVID-19-associated CRAO, low molecular weight heparin (LMWH) 100 mg/kg and methylprednisolone 30 mg/kg were used, and RNFL thinning persisted at the 5-month follow-up¹⁾.

7. Latest Research and Future Perspectives (Investigational Reports)

PGE₁ (Prostaglandin E₁) Therapy

Sano et al. (2025) retrospectively examined the effect of early PGE₁ administration in CRAO patients within 24 hours of onset at Tokushima Red Cross Hospital⁹⁾. In the PGE₁ group (n=4), alprostadil alfadex 40 μg was dissolved in 250 mL saline and infused intravenously at 125 mL/h twice daily (80 μg/day) for 5 days, followed by oral limaprost alfadex 10 μg three times daily (30 μg/day) for at least 1 month. Compared to the conventional treatment group (n=6), the best-corrected visual acuity (BCVA) at 1 month was significantly better in the PGE₁ group. In the PGE₁ group, baseline maximum retinal thickness (MRT) showed a negative correlation with BCVA at 1 month. No adverse events were observed in either group⁹⁾.

PGE₁ is thought to have neuroprotective effects through vasodilation as well as reduction of oxidative stress and inflammation. Although the sample size is small and a prospective RCT is needed, these findings are noteworthy given the lack of proven efficacy of existing treatments.

Development of Eye Stroke Protocols

The “Eye stroke protocol,” which treats CRAO as an equivalent of cerebral stroke and involves stroke centers collaborating with ophthalmology for acute evaluation and treatment, is becoming more widespread⁸⁾. This protocol is expected to improve tPA administration rates and enable early detection and secondary prevention of stroke.

Evidence for Intra-arterial Thrombolysis

Selective intra-ophthalmic artery infusion of urokinase/tPA is performed at some institutions, but evidence from randomized controlled trials is limited. The EAGLE trial showed no significant difference in visual improvement between IA tPA and conservative treatment, and safety concerns regarding ICH (intracranial hemorrhage) were raised⁷⁾.

In a case of CRAO, intra-arterial administration of 300,000 units of urokinase resulted in dramatic visual improvement from 20/2000 to 20/33.3⁴⁾. However, IA tPA carries risks of vascular dissection and intracranial hemorrhage⁷⁾, and accumulation of cases and establishment of indication criteria remain future challenges.

External Counterpulsation (ECP)

This is a non-invasive treatment that mimics intra-aortic balloon pumping by compressing the lower limbs during diastole to increase ocular perfusion pressure.

A case has been reported of a 40-year-old woman with RAO after HA injection and concomitant PFO who underwent ECP, with visual acuity improving from CF 30 cm to 20/133²⁾. However, evidence for ECP in RAO is limited to case reports and small studies.

PFO Closure for Recurrence Prevention

When PFO is identified as the cause in young patients with CRAO, percutaneous PFO closure to prevent paradoxical embolism may be considered.

Wieder MS et al. (2021) concluded in a literature review of 7 cases of CRAO with PFO that appropriate anticoagulation/antiplatelet therapy or PFO closure is recommended³⁾. However, no randomized trial of PFO closure specifically for CRAO has been conducted.

PGE₁ Therapy

Report from Japan: In CRAO, PGE₁ (alprostadil 80 μg/day IV for 5 days followed by limaprost 30 μg/day orally) significantly improved BCVA at 1 month⁹⁾.

Mechanism: Vasodilation + neuroprotection (reduction of oxidative stress and inflammation). No adverse events.

Current Status of tPA

EAGLE trial: IA tPA showed no visual improvement benefit compared to conservative treatment and carried a risk of ICH⁷⁾.

IV tPA: May improve outcomes within 4.5 hours of onset (meta-analysis), but RCT evidence is insufficient⁸⁾.

8. References

Abbati G, Battini R, Bartalena L, et al. Central retinal artery occlusion in a 6-year-old girl with COVID-19. BMC Pediatrics. 2023;23:462.
Si M, Ma S, Lin H, et al. Retinal artery occlusion after hyaluronic acid rhinoplasty with patent foramen ovale: a case report. J Int Med Res. 2023;51:1-9.
Wieder MS, Barreto GNS, Barreto MNS, et al. Central retinal artery occlusion and patent foramen ovale. Arq Bras Oftalmol. 2021;84:494-498.
Li Z, Li M, Zhao Y, et al. Intra-arterial thrombolysis for bilateral sequential retinal artery occlusion in a diabetic patient: a case report and literature review. BMC Ophthalmology. 2025;25:331.
Zhu L, Gu X, Cai D, et al. Central retinal artery occlusion combined with internal carotid artery dysplasia and patent foramen ovale: a case report and literature review. Eur J Med Res. 2021;26:55.
Zokri MF, Othman O. A case series of retinal artery occlusion: when time is of the essence. Cureus. 2024;16(5):e60520.
Dalzotto K, Richards P, Boulter TD, Kay M, Mititelu M. Complications of intra-arterial tPA for iatrogenic branch retinal artery occlusion: a case report through multimodal imaging and literature review. Medicina. 2021;57(9):963.
American Academy of Ophthalmology Retina/Vitreous Panel. Retinal and Ophthalmic Artery Occlusions Preferred Practice Pattern. AAO; 2024.
Sano H, Yanai R, Kondo H, Mitamura Y. Early prostaglandin E₁ treatment improves visual outcomes in central retinal artery occlusion: a retrospective study. Front Med (Lausanne). 2025.

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