Retinal artery occlusion is a disease that causes severe visual dysfunction due to retinal ischemia and necrosis from occlusion of the retinal artery. It is classified into the following three types based on the occlusion site:
In BRAO, the degree of macular involvement greatly affects visual acuity. If the macula is not affected, visual acuity does not decrease, but the visual field corresponding to the occluded area is lost. When occlusion occurs in the nasal artery or in the peripheral temporal area, there are often no subjective symptoms. On the other hand, even with occlusion of an arteriole that only shows cotton-wool spots, a scotoma may be noticed if it is near the macula.
BRAO is classified into two subtypes based on the persistence of occlusion.
Retinal artery occlusion is a highly urgent disease where very early intervention determines visual prognosis. The incidence of CRAO is estimated at about 1 per 100,000 per year, or 1 per 10,000 outpatients. The average age of onset for CRAO is early 60s, more common in men, and often occurs in one eye. 1–2% may occur in both eyes, and bilateral involvement should raise suspicion for giant cell arteritis (GCA) 5). The incidence in Japan is slightly lower than in Western countries.
Asymptomatic retinal emboli are found in about 1.4% of the general population aged 49 years and older (Blue Mountains Eye Study) 5).
In the 2013 AHA/ASA (American Heart Association/American Stroke Association) revised definition of stroke, retinal ischemia was explicitly classified as a type of CNS (central nervous system) infarction 5). About 30% of CRAO patients and about 25% of BRAO patients have concurrent cerebral infarction within one week of onset. The stroke risk in symptomatic RAO patients is highest from 2 weeks before to 1 month after onset 5).
BRAO may present as an ocular manifestation of stroke, and about 25% of BRAO patients have concurrent cerebral infarction within one week of onset. The AHA/ASA includes retinal ischemia as CNS infarction, and after onset, systemic evaluation in collaboration with neurology and cardiology is essential. Rapid search for embolic sources such as carotid ultrasound and echocardiography is necessary.
BRAO typically presents with painless acute visual field loss.
As examples, a 49-year-old woman developed acute painless visual field defect while taking phentermine, but corrected visual acuity remained 20/201). In a 22-year-old man, a curtain-like superior visual field defect occurred after laser pointer exposure3). A 61-year-old man developed a superior visual field defect during percutaneous transluminal coronary angioplasty (PTCA), and visual acuity decreased to 6/362).
The visual prognosis of BRAO is shown in the table below 5).
| Classification | Initial visit 20/40 or better | Follow-up 20/40 or better |
|---|---|---|
| Permanent BRAO | 74% | 89% |
| Transient BRAO | 94% | 100% |
80% of BRAO cases ultimately maintain a corrected visual acuity of 0.5 or better. In permanent BRAO, 89% maintain 20/40 or better at follow-up 5). In transient BRAO, 100% achieve 20/40 or better. However, if the branch to the macula is occluded, the visual prognosis may be poor. Patients should be informed that visual field defects often persist even after the opacity resolves.
The majority of BRAO cases are embolic. It tends to occur in elderly individuals with systemic diseases such as hypertension, arteriosclerosis, and diabetes. Atheromas of the internal carotid artery or intracardiac thrombi formed by heart disease become emboli. Vasculitis, infection, trauma, and vasospasm can also be causes. In young patients, abnormalities of the blood coagulation system, heart disease, congenital anomalies, and retinal vasculitis are often observed.
The main types and origins of emboli are shown below.
| Type of embolus | Main origin |
|---|---|
| Cholesterol/fibrin | Carotid artery, aortic arch |
| Calcific embolus | Calcified heart valve |
| Iatrogenic embolus | PTCA, endovascular treatment |
| Cosmetic filler | Hyaluronic acid injection (after facial injection) |
Cases have been reported as thromboembolism due to PTCA2) and as plaque dislodgement during neuroendovascular treatment4). Retinal artery occlusion due to cosmetic skin filler injections (e.g., hyaluronic acid) is increasing and attracting attention5).
Systemic risk factors include the following:
Phentermine (an appetite suppressant) has been reported to induce BRAO by causing vasoconstriction and vasospasm through its norepinephrine reuptake inhibition effect1). Cocaine, sildenafil, and filler injections can also be causes5). It is important to inform your ophthalmologist and internist of any pre-existing conditions and medications you are taking.
The diagnosis of BRAO is based on fundus findings and combines multiple imaging tests and systemic evaluation. It is highly urgent, and the time required for diagnosis should be minimized.
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 (outer layer preserved) |
| FA | Delayed filling of the occluded artery, arm-to-retina circulation time ≥30 seconds (normal 12 seconds) |
| ERG | Normal a-wave (photoreceptor survival) and reduced b-wave (inner layer damage) → negative-type ERG |
| OCTA | Non-perfusion areas of superficial retinal capillaries (non-invasive) |
Acute symptomatic RAO warrants immediate referral to a stroke center 5). CRAO, BRAO, and transient monocular vision loss share risk factors (atherosclerosis, carotid artery disease, atrial fibrillation, valvular heart disease, etc.) with cerebral infarction. When encountered, prompt evaluation for cerebral infarction and its risk should be performed.
On the other hand, for asymptomatic BRAO or incidentally discovered retinal emboli, there is currently no evidence supporting urgent stroke evaluation 5).
Irreversible retinal changes begin approximately 100 minutes after arterial occlusion. For CRAO, treatment immediately after onset is preferable, but active treatment should be considered even within one day of onset. For BRAO with visual impairment in the early stage, treatment similar to CRAO is performed.
Vasodilators
Amyl nitrite: Crush a 0.25 mL vial, absorb into a cover, and inhale through the nostrils (caution for hypotension; off-label use).
Isosorbide dinitrate sublingual: Promotes vasodilation.
Carbogen inhalation: Inhalation of a mixture of 95% oxygen and 5% CO₂.
Pharmacotherapy
Urokinase: Initial daily dose of 60,000 to 240,000 units, then gradually reduced over approximately 7 days. Caution for cerebral hemorrhage and systemic bleeding tendency.
Diamox injection: 500 mg intravenous injection once daily (off-label use). Lowers intraocular pressure to promote retinal artery dilation.
Ovalmon tablets: 5 μg × 6 tablets, divided into three doses after meals (for blood flow improvement).
Systemic Evaluation and Management
Search for embolic source: Carotid ultrasound, echocardiography, and coagulation tests are performed urgently.
Referral to stroke center: Acute symptomatic RAO is highly associated with stroke, and immediate referral is recommended5).
Antiplatelet therapy: Recommended according to AHA stroke guidelines if no contraindications.
In the acute phase, the following treatments are performed depending on symptoms.
If vasospasm is the cause, calcium channel blockers may be effective2).
t-PA preparations specifically adsorb to thrombi and act, making them superior in both efficacy and side effects. Currently, t-PA therapy is considered one of the best treatments for acute CRAO. Alteplase (Activacin®) is approved for cerebral infarction and myocardial infarction but is not approved for CRAO. Intravenous therapy is performed at multiple facilities after obtaining approval for off-label use.
The natural recovery rate of visual acuity in CRAO is 10–20%, but it is reported to increase to around 40% with early thrombolytic therapy. A meta-analysis has shown that intravenous (IV) tPA administration within 4.5 hours of onset may be associated with improved outcomes 5).
On the other hand, the EAGLE study (RCT) found no significant difference in visual improvement between intra-arterial (IA) tPA and conservative treatment, and safety concerns regarding intracranial hemorrhage (ICH) were raised 4). Currently, evidence for intra-arterial and intravenous fibrinolytic therapy for BRAO/CRAO is considered insufficient 5).
Hyperbaric oxygen therapy has been suggested to have mild effects in some small retrospective studies, but a Cochrane review concluded that the evidence is uncertain 5).
80% of BRAO patients ultimately maintain a corrected visual acuity of 0.5 or better. In permanent BRAO, 89% maintain 20/40 or better at follow-up 5). In transient BRAO, 100% achieve 20/40 or better.
Visual outcomes in CRAO are poor, with only about 18% of CRAO patients experiencing spontaneous visual recovery. Retinal opacification resolves after 4–6 weeks, but visual function does not recover unless early treatment is effective. In BRAO, even if the occluded vessel recanalizes, visual field defects usually persist, but visual acuity itself may be preserved if the macula is not affected.
Ischemic changes in the retina begin to become irreversible approximately 100 minutes after arterial occlusion. A general guideline is to actively attempt treatment within one day of onset, but earlier treatment leads to better prognosis. In CRAO, the rate of visual improvement is high if treatment is initiated within 100 minutes. Additionally, because the risk of stroke is high (about 25% in BRAO patients), it is important to immediately visit an ophthalmologist or emergency department and coordinate with a neurologist after symptom onset.
The retinal artery supplies 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 and survive. In BRAO, only the inner retina in the territory of the occluded branch becomes ischemic, while the outer layer is preserved by oxygen and nutrients from the choroid. The ERG finding of preserved a-wave (photoreceptor survival) and reduced b-wave (bipolar cell and Müller cell dysfunction) directly reflects this anatomical characteristic.
The cilioretinal artery, a branch of the short posterior ciliary artery, is present in about 32% of all eyes and supplies the retina near the papillomacular bundle. Even if CRAO occurs, if the cilioretinal artery is preserved, retinal function near the papillomacular bundle may be maintained, and central vision may be preserved.
The most common cause of RAO is thromboembolism, which often occurs at the narrowest part of the central retinal artery lumen, i.e., where it penetrates the dural sheath of the optic nerve. Emboli originate from plaques in the carotid artery or heart.
Hollenhorst plaques consist of cholesterol crystals that break off from atherosclerotic plaques in the carotid artery or aortic arch and become lodged at bifurcations of the retinal artery 5). The occluded artery may become markedly narrowed and white, with no blood visible inside the vessel.
Severe retinal damage occurs approximately 100 minutes after arterial occlusion. In the hyperacute phase (up to 2 hours), the fundus may appear nearly normal, but OCT shows the beginning of inner layer hyperreflectivity. In the acute phase (2 hours to several days), retinal whitening becomes clear, with arterial narrowing and OCT inner layer thickening and hyperreflectivity prominent. In the subacute phase (1 to 6 weeks), opacity subsides, and iris or retinal neovascularization may appear. In the chronic phase (after 6 weeks), inner layer thinning and retrograde atrophy extending to the outer layer occur, along with optic disc pallor. In chronic hypertension, the time to irreversible change may be extended up to 240 minutes according to some reports 4, 2).
Sano et al. (2025) retrospectively investigated the effect of early PGE₁ administration in CRAO patients within 24 hours of onset at Tokushima Red Cross Hospital6). In the PGE₁ group (n=4), alprostadil alfadex 40 μg was dissolved in 250 mL saline and infused 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 PGE₁ group had significantly better best-corrected visual acuity (BCVA) at 1 month. Baseline maximum retinal thickness (MRT) showed a negative correlation with 1-month BCVA, suggesting it may be a prognostic predictor. No adverse events were observed in either group6).
PGE₁ is thought to have neuroprotective effects through vasodilation and 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.
Since the 2013 AHA/ASA revised definition recognized retinal ischemia as CNS infarction5), momentum has increased for applying stroke protocols to acute RAO. Immediate referral to a stroke center and establishment of systemic management systems analogous to cerebral infarction are being promoted.
Meta-analyses have reported that IV tPA administration within 4.5 hours of onset may be associated with improved visual recovery rates, but the EAGLE study did not show efficacy of IA tPA and raised safety concerns4), and sufficient RCT evidence for IV tPA is lacking5).
Advances in OCTA technology have made it possible to track superficial retinal perfusion deficits for more than 9 years after onset 1). Research is investigating whether acute-phase perfusion deficit patterns may serve as predictors of long-term prognosis.
The “spot sign” for detecting calcific emboli on orbital ultrasound has been reported with a sensitivity of 83% and specificity of 100% 4), and is attracting attention as a non-invasive adjunct for acute-phase diagnosis.
Although some small retrospective studies suggest efficacy, a Cochrane review concluded that the evidence for interventions in non-arteritic CRAO overall is uncertain 5).
PGE₁ Therapy
Report from Japan: In CRAO, PGE₁ (alprostadil 80 μg/day × 5 days) significantly improved BCVA at 1 month 6).
Prognosis prediction: Baseline MRT (maximum retinal thickness) was negatively correlated with visual acuity at 1 month. No adverse events.
Current Status of tPA
EAGLE trial: IA tPA showed no visual improvement compared to conservative treatment and carried a risk of ICH 4).
IV tPA: Meta-analysis suggests potential for improved visual recovery rates within 4.5 hours of onset, but RCT evidence is insufficient 5).
