Central Retinal Artery and Vein Occlusion

Central Retinal Artery Occlusion (CRAO)

• Embolic obstruction and thrombosis: The central retinal artery branches from the ophthalmic artery and supplies the inner retinal layers. In CRAO, occlusion occurs most commonly from arterial embolism (80% of cases), originating from carotid atherosclerotic plaques, cardiac sources (atrial fibrillation, mechanical valves, endocarditis), or paradoxical embolism through patent foramen ovale. These emboli lodge at the lamina cribrosa where the artery narrows as it penetrates the optic disc. In situ thrombosis contributes to approximately 20% of cases, occurring in the context of severe atherosclerotic disease, arteritis (giant cell arteritis), or hypercoagulable states. The occluded vessel prevents oxygen and glucose delivery to the inner retina (inner nuclear layer and ganglion cell layer), which depends almost exclusively on arterial supply, in contrast to the outer retina which receives nutrition from the underlying choroid.

• Acute ischemic cascade and neuronal death: Once arterial perfusion ceases, retinal tissue enters an ischemic cascade characterized by rapid depletion of ATP, loss of Na+/K+-ATPase function, and cytotoxic edema within minutes. Calcium influx through voltage-gated channels and NMDA receptors triggers protease activation and mitochondrial dysfunction. The retinal ganglion cells and inner nuclear layer are most vulnerable due to their high oxidative metabolism and limited collateral circulation. Within 90-100 minutes of complete ischemia, irreversible photoreceptor death begins, making this a true ophthalmologic emergency requiring intervention within this critical window. The duration and degree of arterial occlusion, presence of collateral circulation (including cilioretinal artery supply), and systemic blood pressure directly determine the extent of irreversible damage.

• Retinal whitening and cherry-red spot appearance: The acute ischemic retina swells and becomes opacified, appearing white or pale due to cellular edema obscuring the underlying choroidal blood supply. This whitening is most prominent in the area of maximum metabolic demand—the macula. However, at the fovea, the cherry-red spot appears because the foveal center lacks inner retinal layers (being composed entirely of photoreceptors supplied by the choroid), maintaining its normal red coloration from underlying choroidal circulation while surrounded by white, ischemic retina. This pathognomonic finding indicates foveal sparing of ischemia is not occurring and carries poor prognostic significance.

Central Retinal Vein Occlusion (CRVO)

• Thrombosis within the optic nerve sheath: The central retinal vein travels within the optic nerve sheath and converges with short and long posterior ciliary arteries at the lamina cribrosa, a region of anatomic compression. Thrombosis develops when blood stasis combines with endothelial injury and hypercoagulability (Virchow's triad). Unlike CRAO which is typically embolic, CRVO is predominantly thrombotic, occurring at sites of chronic vascular compression, atherosclerotic changes, or reduced blood flow velocity. The occlusion typically occurs at or posterior to the lamina cribrosa, explaining the distribution of retinal hemorrhages throughout all layers of the retina (superficial nerve fiber layer hemorrhages and deeper intraretinal hemorrhages).

• Venous congestion and hemorrhagic retinopathy: With venous obstruction, blood backs up within the retinal venous system, causing hydrostatic pressure elevation and increased capillary permeability. Red blood cells extravasate into the retina producing the characteristic "blood and thunder" funduscopic appearance with extensive retinal and flame-shaped hemorrhages, cotton-wool spots (nerve fiber layer infarcts), and venous dilation and tortuosity. Macular edema develops from vascular permeability alterations and contributes significantly to vision loss in CRVO, persisting beyond the acute phase.

• Secondary neovascularization and rubeosis iridis: The severe retinal ischemia in CRVO (particularly non-perfusion variants) triggers massive upregulation of vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF-1α), and other pro-angiogenic cytokines. These factors stimulate abnormal neovascularization of the iris (rubeosis iridis) and optic disc, which can lead to secondary neovascular glaucoma—a devastating blinding complication. This ischemic stimulus-driven neovascularization is a key pathophysiologic distinction between CRVO and CRAO, where neovascularization risk is lower due to less extensive retinal ischemia.

CRAO-Specific Risk Factors

• Arterial embolism sources (80% of CRAO cases): Atherosclerotic disease of the carotid artery produces ulcerated plaques that embolize cholesterol crystals, fibrin, and platelet aggregates to the central retinal artery; cardiac sources including atrial fibrillation with reduced left ventricular ejection fraction, mechanical prosthetic valves, recent myocardial infarction with mural thrombus, dilated cardiomyopathy, and infective endocarditis represent 20-30% of emboli; paradoxical embolism through patent foramen ovale (PFO) accounts for a subset of younger patients with CRAO; giant cell arteritis (temporal arteritis) classically causes CRAO in elderly patients through arteritic inflammation and thrombosis; arterial dissection of the carotid or ophthalmic artery following trauma or spontaneously in connective tissue disorders.

• Hypercoagulable states and thrombophilia: Antiphospholipid antibody syndrome, factor V Leiden mutation, prothrombin G20210A mutation, protein C/S deficiency, antithrombin III deficiency, and malignancy-associated hypercoagulability predispose to in situ thrombosis; elevated lipoprotein(a), elevated homocysteine, and myeloproliferative neoplasms increase thrombotic risk.

• Systemic vascular disease: Hypertension, diabetes mellitus, hyperlipidemia, smoking, and chronic kidney disease represent the major modifiable risk factors; age >50 years and male sex are non-modifiable risk factors.

CRVO-Specific Risk Factors

• Glaucoma: Elevated intraocular pressure (IOP) is the single strongest associated factor in CRVO, present in approximately 50% of cases. The anatomic compression at the lamina cribrosa, where the vein pierces the sclera under elevated IOP, explains this association. Some propose that elevated IOP directly compresses the vein lumen, reducing blood flow velocity and predisposing to thrombosis.

• Systemic hypertension and atherosclerosis: Similar to CRAO, hypertension, diabetes, and hyperlipidemia are significant risk factors; the pathophysiology involves endothelial injury and atherosclerotic changes at the site of vein compression.

• Hypercoagulability and blood dyscrasias: Antiphospholipid syndrome, myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia), and malignancy-associated hypercoagulability; lupus anticoagulant and elevated Factor VIII levels increase risk.

• Inflammatory and infectious conditions: Behçet's disease, sarcoidosis, and tuberculosis can trigger CRVO through vasculitis; HIV/AIDS increases thrombotic risk through multiple mechanisms.

Shared Risk Factors (CRAO and CRVO)

CRAO - Classic Acute Presentation

• Painless, sudden vision loss: Patients experience abrupt onset of monocular vision loss, often described as "a shade coming down" or "a curtain" over the visual field, typically occurring over seconds to minutes. The painless nature distinguishes it from acute angle-closure glaucoma or uveitis. The sudden onset reflects the abrupt cessation of arterial blood flow to the retina. Superior altitudinal defects (loss of upper half of visual field) occur when only a branch retinal artery is occluded (BRAO), whereas complete CRAO presents with profound vision loss (light perception to hand motion vision only, or complete blindness in that eye).

• Severely reduced visual acuity: Central vision deteriorates rapidly, often to counting fingers or worse; patients may note that they can see only the periphery if macular territory is spared (unusual in complete CRAO).

• Relative afferent pupillary defect (RAPD): The occluded eye demonstrates a positive RAPD because retinal ischemia damages ganglion cells and bipolar neurons necessary for normal pupillary light responses, whereas the opposite eye maintains normal pupillary function. The RAPD is a crucial finding indicating acute retinal pathology.

• Fundoscopic findings evolve temporally:
• Hyperacute phase (first hours): The retina appears normal or shows very subtle whitening.
• Acute phase (hours to days): Retinal whitening/edema predominates, with a pathognomonic cherry-red spot at the fovea (central red area surrounded by white, pale retina). Cotton-wool spots and superficial retinal hemorrhages may develop.
• Chronic phase (weeks) : The retina clears but shows optic atrophy and retinal thinning in the distribution of the occluded vessel; collateral vessels may develop if partial recanalization occurs.

• Branch retinal artery occlusion (BRAO) variant: A wedge-shaped area of retinal whitening in the distribution of a branch artery; visual field defect corresponds to the vascular territory; generally carries better prognosis than complete CRAO if only peripheral retina is affected.

CRVO - Variable Clinical Presentation

• Painless vision loss with gradual or acute onset: Vision loss in CRVO is often somewhat less abrupt than CRAO, developing over hours to days; patients may report floaters, photopsia, or visual field defects preceding central vision loss.

• Reduced visual acuity (variable degree): Ranges from 20/40 to light perception depending on degree of macular involvement and presence of macular edema; vision tends to be better than CRAO acutely (though may worsen over subsequent weeks with development of macular edema).

• Fundoscopic appearance - "blood and thunder" retinopathy:
• Extensive retinal hemorrhages in all layers: flame-shaped hemorrhages in the superficial nerve fiber layer, dark intraretinal (dot-blot) hemorrhages in inner retinal layers
• Venous dilation and tortuosity throughout the fundus ("sausaging")
• Cotton-wool spots reflecting retinal nerve fiber layer infarcts
• Optic disc swelling from acute venous congestion
• Macular edema contributing to vision loss
• The hemorrhagic appearance is much more florid than CRAO, earning the "blood and thunder" descriptor

• CRVO variants based on retinal perfusion status:
• Ischemic CRVO (non-perfusion): Extensive areas of retinal non-perfusion on fluorescein angiography, more profound vision loss, significantly higher risk of neovascularization and secondary glaucoma
• Non-ischemic CRVO (perfused): Better retinal perfusion, relatively preserved visual function, lower neovascularization risk, better overall prognosis
• Perfusion status determination requires fundus fluorescein angiography or optical coherence tomography angiography (OCTA)

• Secondary rubeosis iridis: In ischemic CRVO, abnormal iris neovascularization may develop 6-12 weeks after occlusion, best appreciated on slit-lamp examination; can progress to neovascular glaucoma with iris bombé and angle closure.

• Relative afferent pupillary defect: Present but less pronounced than CRAO due to less severe ganglion cell death.

Key Distinguishing Features Between CRAO and CRVO

Clinical Diagnosis - History and Physical Examination

Fundus Fluorescein Angiography (FFA)

• CRAO findings: Delayed filling of central retinal artery (prolonged arm-to-retina time >5-10 seconds compared to normal 10-12 seconds), areas of retinal non-perfusion corresponding to the vascular territory, possible visualization of embolic material at arterial bifurcations, late staining of the optic disc
• CRVO findings: Delayed filling of central retinal vein (stasis of dye in venous system), filling defects within the vein, diffuse retinal hemorrhages with corresponding non-perfusion areas, disc hyperfluorescence, late macular edema with cystoid changes
• Critical distinction: Perfusion status in CRVO (ischemic vs. non-ischemic) determined by calculating the area of retinal non-perfusion; ischemic CRVO has extensive areas (>10 disc diameters) of non-perfusion and carries much worse prognosis

Optical Coherence Tomography Angiography (OCTA)

• Provides high-resolution imaging of retinal vasculature without requiring intravenous dye injection
• Quantifies areas of capillary non-perfusion
• Detects macular edema with precise thickness measurements
• Particularly useful for CRVO monitoring and assessment of neovascularization

Spectral Domain Optical Coherence Tomography (SD-OCT)

• CRVO: Demonstrates characteristic cystoid macular edema with intraretinal fluid collections; central macular thickness often elevated
• CRAO: Typically shows retinal thickening acutely; chronic phases show retinal atrophy
• Serial OCT monitoring guides treatment decisions in CRVO

Carotid Duplex Ultrasonography and Cardiac Imaging (CRAO-specific)

Immediate steps in suspected CRAO (time-critical)

• Treat as an acute stroke: the 2021 AHA/ASA scientific statement on CRAO recommends emergent transfer to a facility with stroke expertise for urgent brain MRI with DWI, vessel imaging, and cardiac evaluation, because CRAO carries a high early risk of concurrent or subsequent cerebral infarction.
• Exclude giant cell arteritis first in patients over 50: send ESR and CRP immediately. If arteritic CRAO is suspected, the 2021 ACR/Vasculitis Foundation guideline calls for high-dose glucocorticoids (IV methylprednisolone for vision loss, transitioning to oral prednisone) started before temporal artery biopsy — the goal is protecting the fellow eye, not restoring vision in the affected one.
• Conservative ocular maneuvers: digital ocular massage, IOP-lowering agents (carbonic anhydrase inhibitor such as acetazolamide, topical beta blocker such as timolol), and anterior chamber paracentesis aim to dislodge the embolus distally by lowering IOP and widening the arterial pressure gradient. The AHA/ASA statement notes these have no proven benefit and should never delay stroke evaluation.
• Thrombolysis: IV tissue plasminogen activator within a narrow window (analogous to the acute stroke window) may be considered in selected patients or trial settings; benefit remains unproven and it is contraindicated in arteritic CRAO.

CRVO

• Intravitreal anti-VEGF (aflibercept, ranibizumab, or off-label bevacizumab) is first-line for macular edema per the AAO Preferred Practice Pattern on retinal vein occlusion; it blocks VEGF-driven permeability and also regresses neovascularization.
• Intravitreal corticosteroid (dexamethasone implant, triamcinolone) is second-line or adjunctive, weighed against cataract and steroid-induced IOP elevation.
• Panretinal photocoagulation is reserved for anterior- or posterior-segment neovascularization, ablating ischemic retina to cut VEGF production; it is not given prophylactically.
• Avoid: grid macular laser (ineffective for CRVO edema per the Central Vein Occlusion Study) and routine systemic anticoagulation, which increases hemorrhage without improving vision.

Complications of CRAO

• Permanent central vision loss: inner retinal infarction beyond the ~90–100 minute ischemic window produces ganglion cell death; signalled by persistent counting-fingers or worse acuity with later optic disc pallor and retinal thinning on OCT.
• Concurrent or subsequent cerebral infarction — emergency: the embolic source that reached the ophthalmic circulation also feeds the middle cerebral territory, and a substantial proportion of CRAO patients have acute DWI-positive brain lesions, often clinically silent. Any focal neurologic deficit mandates immediate stroke pathway activation.
• Fellow-eye blindness from unrecognized giant cell arteritis — emergency: arteritic occlusion of posterior ciliary vessels can bilateralize within days. Jaw claudication, scalp tenderness, and markedly elevated ESR/CRP are the signals.
• Ocular neovascularization and neovascular glaucoma: chronic retinal ischemia raises VEGF, producing rubeosis iridis and angle closure; look for a painful red eye with markedly elevated IOP weeks to months later.

Complications of CRVO

• Chronic cystoid macular edema: the dominant cause of vision loss; recognized by intraretinal cystic spaces and increased central subfield thickness on OCT.
• Conversion from non-ischemic to ischemic CRVO: worsening acuity, a deepening RAPD, and enlarging non-perfusion on angiography.
• **Neovascular (90-day) glaucoma** — emergency: iris neovascularization typically appears around 3 months in ischemic CRVO; presents with pain, corneal edema, and very high IOP.
• Vitreous hemorrhage and tractional retinal detachment: fragile new vessels bleed, giving sudden floaters and loss of the red reflex.

Treatment-related complications

• Endophthalmitis after intravitreal injection — emergency: pain, hypopyon, and vision decline days after injection; requires vitreous tap and intravitreal antibiotics.
• Steroid implant effects: posterior subcapsular cataract and steroid-induced IOP rise via trabecular outflow resistance.
• Thrombolysis: intracranial and vitreous hemorrhage.
• Systemic glucocorticoids for GCA: hyperglycemia, osteoporosis, adrenal suppression.

• **Painless, sudden, monocular vision loss + RAPD + pale retina with a *cherry-red spot*** = CRAO. The fovea looks red because it has no inner retina to become edematous and is nourished by the choroid.
• Single best next step in CRAO over age 50: immediate ESR and CRP to exclude giant cell arteritis, alongside emergent stroke-center evaluation per the AHA/ASA 2021 statement. If GCA is suspected, start high-dose glucocorticoids before temporal artery biopsy — the biopsy stays positive for days.
• The association examiners love: CRAO is an ocular stroke. Every case needs carotid imaging, ECG/telemetry for atrial fibrillation, and echocardiography; treat the vascular risk profile with antiplatelet plus high-intensity statin.
• **A *cilioretinal artery*** (present in a minority of eyes, arising from the ciliary circulation) can spare the fovea in CRAO and preserve central acuity despite a white retina — and conversely can infarct in isolation in CRVO.
• "Blood and thunder" fundus with dilated tortuous veins, diffuse hemorrhages in all layers, and disc swelling = CRVO. First-line treatment for the macular edema is intravitreal anti-VEGF (aflibercept/ranibizumab/bevacizumab) per AAO Preferred Practice Pattern.
• Neovascular glaucoma at ~3 months (90-day glaucoma) is the feared sequela of ischemic CRVO; panretinal photocoagulation is for neovascularization, never prophylactic grid laser for edema (CVOS showed no visual benefit).
• Cherry-red spot distractor: it is also seen in Tay-Sachs and Niemann-Pick disease — but those are bilateral, in infants, without RAPD or acute onset.
• Other distractors: amaurosis fugax is transient and resolves (still needs carotid workup); acute angle-closure glaucoma and optic neuritis are painful; retinal detachment gives flashes, floaters, and a curtain with a normal-colored retina. Systemic anticoagulation is not routine therapy for either CRAO or CRVO.