The most common symptom of CRAO is a sudden, severe, unilateral visual impairment. The majority of patients presents a visual acuity of 20/400 or less [9]. Some patients may merely have problems to count fingers, while light perception in general may be severely reduced in others. CRAO is painless.

It is not uncommon for CRAO patients to report recent episodes of amaurosis fugax, a condition that does not necessarily prompt patients to seek medical attention since symptoms may remit spontaneously within seconds or minutes. However, amaurosis fugax may indicate serious problems with retinal blood flow. Differential diagnoses for amaurosis fugax are thromboembolism, hypercoagulability, arteritis, migraine and vasospasm [10]. The majority of these pathologies predisposes for CRAO.

Additionally, symptoms triggered by the underlying disease may be present.

• Hypertension is generally asymptomatic. Headaches may be observed.
• Diabetes mellitus may manifest in polyuria and polydipsia.
• Endocarditis is typically associated with malaise, fever, chills and night sweats.
• Clinical presentation of polyarteritis nodosa varies largely and may involve malaise, fever, weight loss, headaches, nausea and vomitus, myalgia, arthalgia and erythema.
• Temporal arteritis is related to fever, headaches, tenderness of the scalp and jaw claudication.

Prolonged pressure to the ocular globe may also induce CRAO and may occur during periods of reduced awareness, e.g., during alcohol- or drug-induced stupor or after sustaining a trauma.

• Fever

  Dengue fever is endemic in the tropics and subtropics and has become a worldwide health threat in recent years. Dengue-related ocular complications are increasingly being reported from countries in South-East Asia. [ncbi.nlm.nih.gov]

  Endocarditis is typically associated with malaise, fever, chills and night sweats. [symptoma.com]

• Asymptomatic

  Central retinal artery occlusion (CRAO) is an arterial ischemic stroke, rarely occurred in children accompanied with asymptomatic cerebral infarction and almost never involved in severe pneumonia related to Mycoplasma pneumonia infection. [ncbi.nlm.nih.gov]

  It is uncertain whether the temporal arteries are more commonly affected, or if nasal branch artery obstructions are generally asymptomatic. [williamsoneyeinstitute.com]

  Neuro-ophthalmological disturbances have been widely described in both asymptomatic HIV positive subjects and in those with full blown AIDS. [djo.org.in]

  Patients can present with a range of symptoms from being completely asymptomatic to having facial/neck pain, headaches, Horner's syndrome, amaurosis fugax, or transient ischemic attacks (TIAs) and stroke. [neurologyindia.com]

• Severe Pain

  There was preceding history of severe, throbbing pain on the right side of the neck radiating to the right hemicranial region associated with two episodes of vomiting. [neurologyindia.com]

  If abnormal blood vessels grow in the front part of the eye, they can cause the pressure in the eye to become very high, resulting in severe pain and even worse vision; if they grow in the back part of the eye, they can cause bleeding inside the eye. [iowaretina.com]

• Surgical Procedure

  Performing a minor surgical procedure known as anterior chamber paracentesis, in which numbing drops are used and a small amount of fluid is withdrawn from the front of the eye. [allaboutvision.com]

  procedure that involves the creation of an aqueous fistula (channel) between the anterior chamber and the subconjunctival space ( Harvey 2000 ). [cochranelibrary.com]

• Diarrhea

  Side effects of crizotinib mostly consist of grade 1-2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1-2 edema and fatigue; grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis. [ncbi.nlm.nih.gov]

  […] this decreases the effect of both drugs Cisapride: Acetazolamide increases the toxicity of cisapride by passive tubular resorption by increasing the pH Main side effects CNS: Confusion, Convulsions, Drowsiness, Flaccid paralysis, Malaise GI: Anorexia, Diarrhea [doi.org]

• Jaw Claudication

  An 82-year-old man presented with acute, painless vision loss in the left eye associated with headaches, jaw claudication, and scalp tenderness. [ncbi.nlm.nih.gov]

  Patients who have giant cell arteritis are 55 or older and may have a headache, a tender and palpable temporal artery, jaw claudication, fatigue, or a combination. [merckmanuals.com]

  MEDS : ASA, Plavix, nitroglycerine PRN and alfalfa pills ROS : denied headaches, jaw claudication, scalp tenderness, weight loss, and loss of appetite EXAM Best corrected visual acuities: 20/30 OD and HM OS. Pupils: greater than 2.5 LU RAPD OS. [webeye.ophth.uiowa.edu]

  Temporal arteritis is related to fever, headaches, tenderness of the scalp and jaw claudication. [symptoma.com]

• Flushing

  Ergopeptides (dihydroergotamine, ergotamine, methylergonovine, methysergide) Drugs which have an additive vasodilator effect Phosphodiesterase inhibitors Main side effects Common: Headache, hypotension, tachycardia, dizziness, lightheadedness, blurred vision, flushing [doi.org]

  Furthermore, local flushing supports the recanalization of occluded vessels. [ajnr.org]

• Erythema

  Clinical presentation of polyarteritis nodosa varies largely and may involve malaise, fever, weight loss, headaches, nausea and vomitus, myalgia, arthalgia and erythema. [symptoma.com]

• Scotoma

  VF was still affected with significant improvement and with residual scotoma left. On FA arterial phase was restored, OCT showed reduction of macular oedema and pale zone of the fovea has disappeared. [evrs.eu]

  He continued to note a scotoma in his right eye, which had improved since the initial visit. He was continued on timolol bid in both eyes and was advised not to perform endurance exercises. [cureus.com]

  […] seizures, confusion, depression anxiety), Cardiovascular (hypotension, edema, dyspnea) Respiratory (nasal congestion, nosebleed, breathing difficulty) Dermatological (rash, angioedema, urticaria, pruritus, brittle fingernails) Ear and eye related (earache, scotoma [doi.org]

  […] showed the no-reflow phenomenon in eyes with transient non-arteritic CRAO, where angiography shows normal retinal vascular bed filling with no filling in the macular region.[ 14 ] They suggested it as a cause of permanent ganglion cell death and central scotoma [journals.plos.org]

• Rubeosis Iridis

  iridis) 1st, marcus gunn pupil)) - ch macular edema, cystoid macular edema (CME) or macular scarring following hges in the acute st. £ NONISCHEMIC: occ post to lamina cribosa (have collateral) N vision/ slightly dec - vein (changes), retina (hge/exudate [quizlet.com]

  Neovascularization (abnormal new vessel formation) of the retina or iris (rubeosis iridis) with secondary (neovascular) glaucoma occurs in about 20% of patients within weeks to months after occlusion. [merckmanuals.com]

  Further management depends on the type of retinal vein occlusion : References: [6] [8] [9] [10] [1] Complications Release of vasoproliferative substances (e.g., VEGF ) from the ischemic retina causes: Neovascularization of the iris ; ( rubeosis iridis [amboss.com]

  Preliminary report on effect of retinal panphotocoagulation on rubeosis iridis and neovascular glaucoma. Br J Ophthalmol 1977 ; 61 : 278 –84. ↵ Duker JS, Brown GC. [emj.bmj.com]

• Prolapse

  An echocardiogram revealed single atrium and tricuspid valve prolapse ( arrow ) Discussion CRAO is an ocular emergency and the incidence is estimated to be 1 in 100,000 people [ 2 ]. [bmcophthalmol.biomedcentral.com]

  Bilateral involvement is even rarer, found in only 1-2% of total cases. [1] Bilateral CRAOs were reported in the setting of Wegener's granulomatosis, temporal arteritis, homocystinuria, sickle cell disease, Henoch-Schonlein purpura, mitral valve prolapse [mjdrdypu.org]

  […] elevation and Q waves. 29, 30 Cardiac abnormalities detected by echocardiography in a series of 11 young patients with CRAO and BRAO included mitral valve thickening, left ventricular hypertrophy, thrombus with bicuspic aortic valve and mitral valve prolapse [emj.bmj.com]

• Marcus-Gunn Pupil

  Marcus-Gunn pupils (RAPD) Red reflex — abnormal and asymmetrical Fundoscopy — a pale retina with areas of cilioretinal sparing and a classic ‘ cherry red spot ’ in the macula (may be subtle). [lifeinthefastlane.com]

  gunn pupil)) - ch macular edema, cystoid macular edema (CME) or macular scarring following hges in the acute st. £ NONISCHEMIC: occ post to lamina cribosa (have collateral) N vision/ slightly dec - vein (changes), retina (hge/exudate), macula & disc [quizlet.com]

• Headache

  An 82-year-old man presented with acute, painless vision loss in the left eye associated with headaches, jaw claudication, and scalp tenderness. [ncbi.nlm.nih.gov]

  Carotid dissections typically cause ipsilateral frontotemporal headaches with neck pain in 26% of ICA dissections. Ocular strokes due to carotid artery dissection are rare. [neurologyindia.com]

• Asthenia

  Patient has very good partial response to crizotinib and had some side effects of crizotinib like nausea, vomiting, diarrhea, fatigue, asthenia and anorexia, asymptomatic transaminitis in the first 2 to 3 weeks of therapy and managed symptomatically. [ncbi.nlm.nih.gov]

• Seizure

  Specific to ischaemic stroke: cerebral edema, cerebral herniation, seizure, new ischaemic stroke. Special considerations The role of adjuvant therapy with thrombolysis is not known. [doi.org]

Clinical presentation and severe reduction of visual acuity is highly suspicious for CRAO and should prompt a thorough ophthalmologic examination. CRAO patients often show a relative afferent pupillary defect, i.e., light perception is diminished in the affected eye but unaltered on the contralateral side and consequently, pupil constriction can only be induced by illumination of the healthy eye. With regards to the ocular fundus, a cherry-red spot can usually be observed in an otherwise pale, ground-glass retina. Of note, retinal alterations may only become visible hours after symptom onset and may resolve within a few days. In some cases, the causative embolus may be visible as a Hollenhorst plaque [11].

It is important to identify the underlying disease. In order to do so, laboratory analysis of blood samples should be carried out as well as coagulation tests, measurement of blood pressure and evaluation of cardiac function. With regards to the former, hyperglycemia, hypercholesterolemia, hemolytic anemia, polycythemia and other hematological disorders may be detected. Inflammatory parameters are generally elevated in patients suffering from arteritis. Blood cultures may be required to identify the causative agent in cases of endocarditis. Echocardiography and angiography are the methods of choice to detect cardiovascular pathologies.

There are no guidelines regarding treatment of CRAO and most recommendations given are based on empiric evidence collected in ophthalmology as well as stroke research.

In this context, administration of tissue plasminogen activator within the first four hours of symptom onset may prove beneficial [2] [3]. If thrombolysis can be achieved, retinal blood flow may be reestablished before permanent damage to retinal cells occurs. Both intravenous and intra-arterial thrombolysis should be considered.

Pentoxifylline, isosorbide dinitrate as well as carbogen and hyperbaric oxygen may contribute to restoration of retinal blood flow by means of improved rheological properties of the blood, vasodilation and increased oxygen provision.

Additionally, acetazolamide and other diuretics are frequently applied to reduce intraocular pressure and to facilitate blood supply to intraorbital tissues.

Although anterior chamber paracentesis has been recommended at some point, recent studies show it provides no additional benefit but does increase the risk of infection and injury [12].

Prognosis worsens significantly as time passes after symptom onset. The above mentioned results regarding retinal survival time as well as data collected in stroke research suggest an unfavorable prognosis for recovery of eye sight if more than four hours have passed. However, even shorter periods of retinal ischemia often cause extensive and severe visual impairment due to irreversible retinal damage.

Of note, etiological factors contributing to CRAO also dispose for ischemic heart disease and cerebral infarction [8].

As has been indicated above, virtually all cases of CRAO result from thromboembolism. Thus, any condition predisposing for thrombus formation and subsequent embolism may be considered a risk factor for CRAO. According to current knowledge, neither the time nor the localization of vessel occlusion due to displacement of thrombi can be predicted. Consequently, patients at risk of CRAO are also at risk of ischemic heart disease, cerebral infarction or ischemic stroke, and vice versa.

In this context, a large number of predisposing factors has been identified:

• Systemic hypertension is a major risk factor for thromboembolism and it has been estimated that more than 50% of all CRAO patients suffer from inadequately regulated blood pressure.
• Obese patients and those diagnosed with diabetes mellitus have higher risks of thrombosis.
• Atherosclerosis is another, highly prevalent disease predisposing for thrombus formation and embolism of peripheral arteries. Most older CRAO patients present some degree of atherosclerosis. Hypertension and diabetes mellitus accelerate progression of atherosclerotic plaque formation and thus increase the risk for CRAO directly and indirectly.
• In relatively young patients, septic thromboembolism due to endocarditis may be observed more often [4].
• Intravenous drug abuse may also cause occlusion of retinal arteries.
• Coagulopathies in general may predispose for thrombus formation and symptoms of thromboembolism may manifest at early ages. Hypercoagulability may, for instance, be seen in patients presenting with sickle cell disease, primary or secondary polycythemia.

Local or systemic vasculitis does increase the risk for thrombus formation within the central retinal artery. Pathologies that may be considered here are polyarteritis nodosa and temporal arteritis / giant cell arteritis.

Finally, iatrogen CRAO has been reported. Occlusion of retinal arteries has been related to drug administration in order to treat comorbidities and to cosmetic facial injections [5].

The overall incidence of CRAO has been estimated to be about 1 per 100,000 inhabitants.

CRAO is mostly diagnosed in the elderly and this age distribution is presumably due to high prevalence rates of obesity, diabetes mellitus and hypertension among people older than 50 years. Additionally, it is not uncommon to observe CRAO in patients with a medical history of ischemic heart disease or ischemic stroke. However, CRAO may also be diagnosed in pediatric patients presenting neither of the aforementioned risk factors [6].

The retina is a very complex organ that consists of many different cell types arranged in multiple distinct layers. Put in highly simplified terms, retinal ganglion cells, amacrine cells, bipolar cells, photoreceptors and pigment epithelium can be encountered in this order when passing through the retina from its inner layers to the outer strata. Single layers are partially separated by limiting membranes.

All retinal layers are supplied by branches of the ophthalmic artery that, in turn, originates from the internal carotid artery. After entering the orbita through the optic canal, it releases the central retinal artery and various, very small ciliary arteries. The former supplies the outer layers of the retina, mainly its photoreceptors, while retinal ganglion cells and underlying strata receive oxygen and nutrients from ciliary arteries. Thus, CRAO does not interfere with metabolism of inner retinal layers, but does interrupt blood supply to photoreceptors and adjacent tissues.

The central retinal artery eventually divides into four end branches, the superior and inferior nasal and temporal branches, respectively. Therefore, proximal CRAO will cause ischemia in all photoreceptors of the affected eye. In contrast, distal occlusion of end branches of the central retinal artery or obstruction of any one of the ciliary arteries disrupts blood supply to a restricted part of photoreceptors or retinal ganglion cells, respectively, and causes less detrimental effects than proximal CRAO. In no case, occlusion of end branches can be compensated by collateral blood flow before permanent damage to retinal cells occurs.

The fact that most CRAO patients claim complete or almost entire loss of vision argues for rather proximal occlusion of the central retinal artery. This vessel's lumen is constricted at certain anatomical sites, e.g., at the penetration point into the optic nerve. It seems plausible that thrombi are frequently captured here.

Although CRAO is usually associated with permanent visual impairment due to ischemic retinal cell death, a thrombus lodged in the central retinal artery may crumble, be partially or totally removed with blood flow. In these cases, patients may claim transient visual impairment, amaurosis fugax. Because it cannot be ruled out that the artery is still partially blocked - a condition that greatly facilitates renewed thromboembolism - this symptom should be taken very seriously.

There is no precise duration of CRAO that guarantees full recovery or that surely leads to permanent retinal damage. According to studies conducted in atherosclerotic and hypertensive rhesus monkeys, ischemia for less than two hours is generally well tolerated while arterial occlusion for more than four hours results detrimental [7]. These results imply a very short time window for diagnosis and initiation of treatment.

In general, any measure aiming at losing overweight, reducing hypertension, hypercholesterolemia and hyperglycemia may also contribute to lower the risk of CRAO. Unfortunately, certain risk factors are beyond the control of patient or physician and cannot be prevented by means of specific measures.

However, if a patient presents with CRAO, timely identification and adequate treatment of the underlying disease may largely contribute to reducing the risk of contralateral CRAO, ischemic heart disease and cerebral infarction.

Central retinal artery occlusion (CRAO) refers to the obstruction of the vessel supplying the inner layers of the retina, the central retinal artery. CRAO may be considered a type of ischemic stroke and indeed, etiology and pathogenesis of this disease largely resemble those of cerebrovascular accidents like middle cerebral artery occlusion. Both ocular and cerebral ischemic strokes are painless, reduce or interrupt blood flow to dependent tissues, and functional failure of these cells occurs within very short periods of time, usually within minutes or a few hours maximum. Therefore, CRAO is an ophthalmic emergency.

CRAO is caused by embolic artery occlusion and while distinct types of embolism may account for this disease, thromboembolism is the direct cause of CRAO in virtually all cases. Only few case reports exist regarding other sources of emboli, e.g., fat embolism [1]. CRAO is associated with sudden, severe, unilateral visual impairment.

Unfortunately, CRAO and cerebral infarction also share lack of treatment options. Recombinant tissue plasminogen activator has long since been the treatment of choice for cerebral infarction if patients receive medical attention within a few hours after symptom onset. This thrombolytic agent may also be administered to CRAO patients and similar to ischemic stroke, improvement of prognosis seems to depend on early administration of the drug [2]. Of note, controlled clinical trials regarding the use of tissue plasminogen activator to treat CRAO have not yet been conducted and are urgently required [3].

Additionally, pentoxifylline, vasodilators, diuretics, corticosteroids or hyperbaric oxygen are frequently used to improve blood supply to the retina, to reduce intraocular pressure and to avoid concurrent edema, but scientific evidence for their efficacy is scarce.

The retina coats the back of the eye and contains photoreceptors, neurons and supportive cells that allow perception of light and are therefore indispensable for vision. The retina is a very complex organ consisting of various layers that are differentially supplied with oxygen and nutrients: Only photoreceptors and cell in close proximity depend on central retinal artery blood flow.

If this vessel is obstructed, central retinal artery occlusion (CRAO) occurs. Etiology, pathophysiology and treatment largely resemble those of cerebral infarction - a very similar condition that does affect other vessels, though.

Causes

Virtually all cases of CRAO are caused by thromboembolism, i.e., a thrombus forms in any part of the cardiovascular system and is carried to the small vessels supplying the retina, lodge here and interrupt blood flow. If this condition persists for more than a few hours, irreversible damage to the retina occurs and symptoms become permanent.

Obese patients as well as those diagnosed with hypertension, diabetes mellitus, atherosclerosis, endocarditis, coagulopathies or vasculitis have increased risks of thromboembolism and thus of CRAO, ischemic heart disease and ischemic stroke.

Symptoms

The most common symptom of CRAO is a sudden, severe, unilateral visual impairment. CRAO is not painful.

Some patients report having experienced periods of transient loss of vision, a condition referred to as amaurosis fugax. Here, vision returns within a few minutes. While amaurosis fugax does not leave any sequelae, it indicates problems with retinal blood flow and should be taken seriously. Amaurosis fugax results from embolic occlusion of the retinal artery and subsequent displacement of the embolus. It is likely, though, that the source of thromboembolism persists and another thrombus may easily be carried to the retinal artery and may cause CRAO.

Diagnosis

Patients presenting with symptoms characteristic for CRAO are usually submitted to a thorough ophthalmologic examination. In some cases, the physician may be able to visualize the embolus. Typical alterations of the ocular fundus will support their tentative diagnosis.

Additional diagnostic measures will be undertaken to identify the underlying disease. Such measures may consist in laboratory analysis of blood samples, coagulation tests and diagnostic imaging to assess cardiac function.

Treatment

CRAO is an ophthalmologic emergency and immediate treatment with thrombolytic agents is required to improve the chance for recovery. Additional drug therapy is often recommended, but scientific evidence regarding its efficacy is scarce: Vasodilators may facilitate blood flow to the retina and reduction of intraocular pressure should reduce physical resistance against retinal blood supply.

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