Neuro-ophthalmic Manifestations of Vascular Eye Diseases

The ophthalmic artery originates from the distal end of the internal carotid artery (ICA). After several microscopic branches emerge from the ICA in the petrous region, the ophthalmic artery proceeds toward the globe. After the origin of the ophthalmic artery, the ICA gives off the anterior choroidal and posterior communicating arteries.

As the ophthalmic artery traverses the optic nerve, it gives off the central retinal artery and, more distally, the posterior ciliary arteries. The posterior one third of the optic nerve is supplied by penetrating arteries from the anterior communicating and anterior cerebral arteries. The anterior two thirds are supplied by the central retinal artery, which lies deep inside the optic nerve; the posterior ciliary arteries supply the peripheral nerve substance. A watershed area is delineated near the head of the optic nerve between the posterior ciliary artery and the central retinal artery.

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Background

Ischemic optic neuropathy (ION) includes a variety of disorders that produce ischemia to the optic nerve. By definition, ION is termed anterior if disc edema is present acutely. This clinical finding suggests infarction of the portion of the optic nerve closest to the globe. ION also may be posterior, lying several centimeters behind the globe. In this instance, swelling of the optic nerve head is not visible, and the practitioner will only witness a normal fundus. Specific arteriolar pathology, especially giant cell arteritis, also may be associated with ION. This section deals specifically with the entity of nonarteritic anterior ION.[1]

Clinical characteristics

Anterior ION (AION) typically develops as abrupt, painless monocular vision loss, though a few patients do experience some discomfort. Rizzo and Lessell found that 8% of patients with AION complained of pain.{ref1-INVALID REFERENCE} Visual acuity varies widely, ranging from 20/20 vision to complete blindness. As opposed to optic neuritis, in which color vision typically is reduced drastically, the color vision deficit in AION mirrors the degree of decrease in visual acuity. The visual field commonly shows an inferior altitudinal defect, although all visual field defects, including central and arcuate scotomas, can occur with this optic neuropathy. The optic nerve head acutely appears edematous, which confirms the anterior nature of this disorder. Hemorrhage on the disc is commonly present.

The appearance of sectoral swelling on only a portion of the optic nerve head virtually rules in the diagnosis of AION. Also, in the nonacute setting, the finding of a nerve with sectoral pallor in a patient who has a nerve in the other eye without a physiologic cup is highly suggestive of AION (see the image below).

A very common feature of patients with AION is the appearance of the accompanying optic nerve head of the unaffected fellow eye. The fellow nerve is commonly cupless, with arterioles emerging from the center of the disc. Crowding of the optic nerve head is believed to be associated with this disc appearance, termed "disc-at-risk." This appearance is due to nerve fibers traversing a small scleral canal. The optic nerve topography in healthy individuals at birth usually is near identical in both eyes. Thus, an assumption can be made that viewing the optic nerve head of the unaffected fellow eye can give the physician an indication of the anatomical shape of the affected eye prior to infarction.

Relief of constriction of nerve fibers as they traverse the scleral canal is believed to occur after infarction of the optic nerve head in AION cases. This probably explains the reduced recurrence of AION in this same eye. Likewise, the fellow eye maintains a crowded disc, yielding an increased risk of AION in the fellow eye. This risk, according to the Ischemic Optic Neuropathy Decompression Trial (IONDT), is 15% at 5 years.

Improvement of visual acuity is variable after onset of AION. A number of studies reported varying incidences of recovery. The IONDT found that 42.7% of patients improved at least 3 lines by the time of their follow-up visit. A small number of patients may progress to severe visual loss in the first 2 weeks after their initial attack.

Patients with AION have certain characteristics. Primarily, this is a disease of Caucasians. Essentially no sex predilection is reported, and average age of onset is in the mid-60s. These patients generally have an increased incidence of hypertension, hyperlipidemia, and diabetes. Smoking may predispose patients to an earlier onset of the disease. In a retrospective trial, stroke has been associated with both idiopathic AION and AION with hypertension, but no prospective data have been generated regarding this. The specific type of cerebrovascular disease associated with AION is therefore unknown. Most investigators believe that ION has no association with carotid stenosis, but this has not been evaluated systematically in a large number of patients.

The condition also has been associated with migraine, favism, nocturnal hypotension, increased intraocular pressure, cataract surgery, sleep apnea[2] , and, recently, with the use of sildenafil (Viagra) and tadalafil (Cialis). No cases have yet to be reported with the usage of vardenafil (Levitra). When this condition is associated with these medicines, the visual field defect and vision acuity reduction is not severe. Genetic risk factors associated with AION have been investigated. Currently, no association has been found with methylene tetrahydrofolate reductase, factor V Leiden, or prothrombin gene mutations. A number of environmental and systemic factors that modulate homocysteine levels have been investigated, and there is a strong suggestion that homocysteine levels are higher in patients with AION. However, homocysteine levels also increase with age.

Embolic AION is exceedingly rare since retinal emboli arise from a different circulation. For this reason, a diagnosis of embolic AION is a dubious consideration at best.

The exact mechanism of infarction of the optic nerve head is unknown, but it is believed to be secondary to hypotension and, possibly, watershed infarction between the central retinal artery and the posterior ciliary arteries. Likewise, AION with severe visual loss may occur following blood loss and hypotension, as in gastrointestinal hemorrhage, or during major cardiac or spine surgeries. AION rarely occurs in the setting of hypotension or blood loss alone, and the combination of the two is probably important in the pathogenesis. Simultaneous bilateral AION or posterior ION is not uncommon under these circumstances.[3, 4]

Neuroimaging is not necessary in an obvious case of AION. However, if neuroimaging is performed, a small number of patients will demonstrate enhancement of the optic nerve somewhat similar to that seen with optic neuritis. This can also be seen in cases of posterior ischemic optic neuropathy. The duration of the enhancement is currently unknown. Diffusion-weighted imaging is now being used in imaging for ischemic optic neuropathy. A recent case has been identified in which ischemic optic neuropathy occurred at the time of spine surgery.[5]

Frequency

In the United States: Depending on the study, the annual incidence of the illness ranges from 2-10 cases per 100,000 persons older than 50 years. This number decreases significantly for younger age groups.

Mortality/Morbidity

The morbidity of this condition specifically concerns vision loss. AION has little association with carotid artery disease; therefore, an attack of AION does not denote a risk for impending stroke as does amaurosis fugax. Guyer et al[6] and Hayreh et al[7] provided evidence that the risk of subsequent stroke, as well as the association with other risk factors (eg, hypertension, diabetes), is mildly elevated.

Race

AION is primarily a disease of whites. AION appears to be rare in African Americans.

Sex

No predilection for AION has been proven on the basis of sex. Patients in the IONDT were 55% male.

Age

ION is a disease of older individuals and most commonly occurs in patients older than 40 years. The average age of onset is the mid-60s. Smoking and other risk factors may decrease the age of onset in some patients.

Treatment

Giant cell arteritis must be ruled out in suspected cases. Symptoms such as scalp tenderness, jaw claudication, and unintentional weight loss may help solidify the clinical diagnosis. The vision loss in arteritic AION is typically severe, if not complete, and the nerve in the other eye does not have to appear with a disc-at-risk. In moderately to highly suspected cases, a temporal artery biopsy should be performed to rule out the disease. Bilateral temporal artery biopsies offer only a minimal benefit over single-sided biopsies.

Attention needs to be paid to controlling and treating vascular risk factors including hypertension, diabetes, hypercholesterolemia, and smoking. Anecdotal evidence suggests that aspirin may reduce recurrence in the fellow, and this author puts all patients on a baby (81 mg) aspirin daily. Essentially no solid evidence exists that levodopa improves visual outcome after an attack of AION, and this author does not start patients on this medication.

Because no treatment for this condition acutely is available[8] , it is recommended that patients who have AION in only one eye avoid usage of any phosphodiesterase type 5 (PDE5) inhibitor, such as sildenafil, vardenafil, or tadalafil.[9]

Pathophysiology

Retinal artery occlusion (RAO) is the ocular equivalent of cerebrovascular disease. Occlusion of a retinal vessel leads to ischemia of retinal tissue supplied by that arterial territory, resulting in acute retinal edema and death of retinal ganglion cells. By definition, a central RAO causes an infarction of the whole central retinal artery and loss of central vision in the affected eye. Branch RAO is an infarction of one of the branches that leaves the optic nerve. This problem will only affect a part of the retina served by that branch retinal vessel and often spares central acuity. Limited natural history studies of RAO suggest that less than 10% of patients with central RAO obtain visual acuity of 20/30 or better.

RAO may be preceded by amaurosis fugax, which typically is described as a shade coming down over the eye, receding minutes later. However, the deficit in central and branch RAO is permanent and stable vision loss. Central RAO most commonly occurs in the seventh decade of life, but this should not restrict consideration of this disease in the very young.

Clinical characteristics

Emboli may be visible in as many as 20% of cases and are due more frequently to platelet/fibrin and calcium than to cholesterol. Visual acuity is generally poor with central RAO, though it may be completely normal if an existing cilioretinal artery spares the macular region. Visual acuity is reduced infrequently in branch RAO. Reduction in visual field is commensurate with the degree of retinal infarction. This is generally much more severe with central RAO than with branch RAO.

A cherry-red spot in the macula is seen frequently in central RAO.[10] As the retinal circulation is compromised, retinal edema ensues (see the first image below). If the choroidal circulation is intact (which is common, unless the ophthalmic artery is occluded), a cherry-red spot becomes visible. Boxcarring of arteriolar flow occurs from stagnation of blood flow. Small branch occlusions may be asymptomatic if the ischemic event is in the far periphery of the retina (see the second image below).

Causes

Etiologies of RAO include carotid stenosis and, less commonly, cardiac embolism. Nearly 20% of patients with RAO have hemodynamically significant stenosis greater than 60%. Cardiac abnormalities requiring intervention have been documented in approximately 10% of patients in small series using transthoracic echocardiography. RAO also may occur in the settings of carotid dissection, hypercoagulable states, and vasospasm.[11]

An unusual disease can be associated with branch RAO called Susac syndrome. This disease is also associated with low-frequency hearing loss and encephalopathy. Two findings in the fundus are almost pathognomonic for the disorder and they include the appearance of pseudoemboli known as Gass plaques[12] and fluorescein leakage at sights remote from the actual branch RAO.[13] Patients with any amount of encephalopathy have at least one if not more lesions in the corpus callosum.[14]

Workup

Workup for RAO is identical to that of stroke in the brain. To assess the carotid vasculature, magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) is preferred because the intracranial ICA can be visualized. RAO has been reported in the presence of intracranial carotid stenosis. Vascular imaging also reveals any unusual abnormalities of the carotid arteries, including dissection or fibromuscular dysplasia. No studies have used transesophageal echocardiography, but the yield of abnormalities appears to increase when using this modality as compared to using transthoracic echocardiography. Cardiac sources of embolism in RAO are rare, and the very low yield of finding abnormalities on echocardiography may not warrant workup. Hypercoagulability workups should be considered in patients aged 50 years or much younger.

Frequency

In the United States: RAO is more common in the patients who are in the seventh decade of life or older.

Mortality/Morbidity

The main morbidity from RAO is vision loss. Other factors must be considered since this disease carries the same risk factors as stroke in the brain. These patients usually have an increased incidence of coexistent carotid disease, and a few patients have cardiac disease. Attention to these conditions assists in alleviating any future cardiac or neurological disability in affected patients.

Race

No racial predilection is known.

Age

RAO has its peak incidence in patients in their seventh decade of life. However, individuals as young as the third decade also may be affected by RAO.

Treatment

The natural history of this disorder suggests that it is highly unlikely for patients to regain any usable vision without intervention.

A variety of treatments have been considered for central RAO, but they have little proven efficacy.[15, 16] These treatments include lowering intraocular pressure via systemic or topical intraocular pressure-reducing agents or anterior chamber paracentesis, ocular massage to coax the embolus to the periphery, and hyperbaric oxygen.[17] Intraocular arterial cannulation also has been performed. In the last decade and a half, intra-arterial thrombolysis has been applied to the treatment of central RAO. In the ideal setting, intraarterial thrombolysis requires a neuro-ophthalmologist or ophthalmologist to confirm the disorder and direct management and an interventionist skilled in placing catheters in the ophthalmic artery.

Most patients do not arrive at the hospital for acute intervention within 100 minutes, which is the accepted time for treating irreversible retinal ischemia, identified by using an artificial occlusion experimental model that attempts to simulate the effects of thromboembolism. Natural history studies have documented cases of patients who regained vision many hours after central RAO, and prior reports of thrombolysis have indicated restored vision even when therapy was administered as long as 24 hours later.

Personal experience by this author suggests that patients do not improve unless treated by 8-10 hours after onset of vision loss. Most emboli studied pathologically in the middle cerebral artery are heterogeneous, suggesting that thrombolysis still may benefit a patient with an RAO associated with cholesterol emboli. Intraarterial thrombolysis is still considered investigational and has not been approved by the US Food and Drug Administration (FDA). However, a clinical trial is being conducted in Europe at this time.

Only 20-25% of patients have usable vision restored after thrombolysis. However, this is compared with probably less than 10% when only conservative treatment is administered. Complications occur, but they do not exceed the rates of natural complications of angiography. This author is only aware of one death associated with intra-arterial thrombolysis, which was performed at a Midwestern institution; this case is not in the published literature.

If a patient with branch RAO or recurrent branch RAO is determined to have Susac syndrome, then treatment should include high-dose oral prednisone initially in addition to intravenous immunoglobulin given monthly for at least 6 months. Repeat MRI and fluorescein angiography should be undertaken to assess adequacy of therapy and to determine if the patient requires additional therapy such as mofetil, rituximab, or cyclophosphamide.

Background

The most common emboli include (1) cholesterol, (2) fibrin/platelet, and (3) calcific. Their location, size, color, and shape can help distinguish them. Not all types of emboli are associated strongly with occlusive signs in the retina.

Pathophysiology

Cholesterol emboli were first described by Hollenhorst, who correctly surmised the association of these bright refractile particles to carotid disease. Cholesterol emboli are small, and as they travel, they most commonly lodge at bifurcations of arterioles (see the image below). The crystals tend to be flat and orange in appearance, and when light (eg, from a direct ophthalmoscope) is scanned to and fro across a plaque, it appears reflective. Since they are flat, they rarely obstruct the column of blood flow, and only rarely are they present in the setting of a branch RAO. Although found more commonly with ICA disease, these emboli also are found in the setting of atherosclerosis of the aortic arch and innominate arteries.

C. Miller Fisher described fibrin/platelet emboli prior to Hollenhorst's description of cholesterol emboli in patients with stroke or recurrent transient ischemic attacks in the retina or brain. The embolus appeared as a whitish plug that filled the whole vessel and, in some instances, migrated peripherally during observation. Some emboli exceeded several disc diameters in length. In contrast to cholesterol emboli, these plugs appeared to completely occlude the vessel or cause stagnation of blood flow within the arteriole; therefore, they more commonly cause branch RAOs (see the image below). These may appear close to the disc or in the far periphery. Several of the patients originally described with this condition had undergone carotid endarterectomy, and thrombi of platelet and fibrin were found organized in the ICA at the time of surgery.

Calcific emboli are chalk white in appearance and, because of their size, frequently lodge in the retinal arterial tree as it exits the disc (see the image below). Therefore, they are associated more commonly than the other types of emboli with central RAOs. The calcific plaques are round or ovoid, and they usually appear larger than the diameter of the vessel they reside in. Patients usually have a history of rheumatic heart disease or calcific aortic stenosis, and echocardiography or cardiac surgery may demonstrate abnormal heart valves with heavy calcification. Embolism occurs when calcific material breaks off from the diseased heart valve and travels to the eye.

Other types of retinal emboli include those composed of tumor, fat, microorganisms, air, amniotic fluid, and foreign material, including talc, which is seen most commonly in intravenous drug users (see the image below). Pseudoemboli or Gass plaques may also be seen in persons with Susac syndrome. These are bright yellow in appearance and are located distant from retinal arteriolar bifurcations. They are typically asymptomatic in that illness and are located distant from any branch retinal artery occlusions that may be present in the affected individual.

A common question from a referring physician is "What is the risk to my patient who has asymptomatic retinal emboli?" The presence of these emboli, even when asymptomatic, is not entirely benign. The US Physicians Health Study observed an association between emboli and hypertension, smoking, and heterogeneous carotid plaques. After an average follow-up of 3.4 years, these patients had a 10-fold increase in stroke, independent of other risk factors of stroke.

A screening study in Australia found emboli in 1.4% of 3654 patients. Eighty percent of the emboli discovered were of the cholesterol variety. Emboli were more frequent in men than women and were found to be associated with hypertension, smoking, and vascular disease. Carotid stenosis also appears to be more prevalent in patients with asymptomatic emboli. Life expectancy is reduced in patients with cholesterol emboli, and risk of stroke and cardiac-related deaths is increased.

Workup

Perform noninvasive testing of the carotid arteries, preferably with MRA or CTA, in a patient who harbors a cholesterol or fibrin/platelet embolus. Further clinical suspicion may suggest the use of noninvasive imaging of the heart and aortic arch. Echocardiography is the study of choice for evaluating patients with a calcific embolus.

Frequency

In the United States: The prevalence of retinal emboli is a little more than 1%, and the 5-year incidence is a little less than 1%.

Internationally: In Australia, a population-based study found a prevalence of 1.4%. The risk is slightly lower in younger patients and higher in older patients.

Mortality/Morbidity

Patients with asymptomatic retinal emboli are systemically sicker than patients without emboli. These patients are at a higher risk for stroke and cardiac-related deaths; emboli are associated with hypertension, smoking, and vascular disease.

Age

The presence of retinal emboli increases with age; prevalence increases to greater than 2% in those older than 80 years. The presence of retinal emboli is very low, probably less than 1%, in young patients.