8 Arterial Occlusive Disease
Arterial occlusive (obstructive) diseases affecting the retinal circulation are reviewed in this chapter. Diseases affecting the larger vessels, such as the carotid arteries, are addressed first, followed by those of the ophthalmic artery and then those of the retinal arterial circulation. Among the subcategories are the following:
Ocular ischemic syndrome (symptoms and signs occurring secondary to carotid artery occlusion)
Ophthalmic artery occlusion
Central retinal artery occlusion
Combined central retinal artery/vein occlusion
Branch retinal artery occlusion
Cilioretinal artery occlusion
Cotton-wool spot (retinal arteriolar occlusion)
8.2 Ocular Ischemic Syndrome
In 1963, Kearns and Hollenhorst 1 introduced the term “venous stasis retinopathy” to describe the posterior segment manifestations seen with severe carotid artery occlusive disease. They noted this abnormality in approximately 5% of patients with carotid artery occlusive disease. Other authors have since used the same term to signify mild (nonischemic, or perfused) central retinal vein occlusion. 2 Because of this discrepancy in the ophthalmic literature, the preferred term (introduced by Brown and Magargal on the Rtina Vascular Unit at Will’s Eye Hospital) for the ocular symptoms and signs that occur secondary to severe carotid artery occlusive disease is “ocular ischemic syndrome” (OIS). 2 , 3
The OIS is typically caused by carotid artery occlusion, although chronic ophthalmic artery, and rarely central retinal artery, occlusions can also cause the clinical picture. Atherosclerosis is the most common etiology, but giant cell arteritis, radiation therapy, and other inflammatory diseases causing arteritis can also be responsible. Eisenmenger’s syndrome has been implicated as well, indicating that diffuse systemic ischemia can also play an etiologic role. 2
Flow within an artery is not usually affected substantially unless there is at least a 70% occlusion. 3 With a 90% occlusion in the ipsilateral internal carotid system, the retinal arterial perfusion pressure is decreased by approximately 50%. 1 With most cases of the OIS, there is at least a 90% ipsilateral carotid artery occlusion. 3 In up to 50% of cases, there is a 100% ipsilateral carotid artery occlusion, while there can be a bilateral 100% carotid occlusion in approximately 10% of cases. 3 The occlusion is most commonly located at the bifurcation of the common carotid into the internal and external carotids, but it can be located anywhere from the aortic arch distally (Fig. 8-1).
Involvement is bilateral in 90% of instances, and men comprise about two-thirds of cases. 3 The mean age is 65 years, and most patients are older than 50 years. No racial predilection has been identified. The exact incidence is unknown, but Sturrock and Mueller 4 noted six cases in an area serving a population of 400,000 over a 2-year period. Extrapolating these data to the United States, there are probably at least 7 to 8 cases per million patients, or 2,000 cases per year in the United States. Nevertheless, the syndrome can be subtle and difficult to recognize, thereby causing underestimation of the true incidence.
Approximately 90% of patients relate a history of visual loss. 3 It is typically gradual, occurring over a period of weeks or longer, but in about 12% of cases it is abrupt. In this latter instance, a cherry-red spot may be seen, indicating acute retinal ischemia. Amaurosis fugax is present in about 10% of cases. 3 Prolonged visual recovery following exposure to bright light is also a symptom frequently experienced by patients with OIS. 5
An intermittent, dull aching pain is found in about 40% of cases. 3 Patients generally localize it to the orbital area of the affected eye. The pain, which we have elected to call ocular angina, may occur secondary to (1) ischemia of the globe, (2) increased intraocular pressure from neovascular glaucoma, (3) ipsilateral dural ischemia, or (4) a combination of these mechanisms.
Symptoms of Ocular Ischemic Syndrome (OIS) 3
Symptoms of the OIS include vision loss over days to weeks in 90% (12% are acute), ocular pain (“ocular angina”) in 40%, and prolonged recovery upon exposure to bright light.
8.2.3 External Signs
Collateral vessels on the forehead (Fig. 8-2) can occasionally be seen in patients with the OIS. These typically shift blood from the external carotid system on one side to that on the contralateral side with the severe carotid artery occlusion. Although giant cell arteritis is a rare cause of the OIS, the clinician should be wary of performing a superficial temporal artery biopsy unless it is certain the vessel is not a collateral vessel.
The visual acuity in eyes with OIS is highly variable. 3 About 35% of affected eyes have 20/20 to 20/40 vision at the time of discovery, whereas approximately 30% initially have 20/50 to 20/400 vision, and 35% have counting fingers or worse. By the end of a year, however, more than 70% of OIS eyes have vision of counting fingers or less. 3
8.2.5 Anterior Segment
Iris neovascularization is seen in about two-thirds of eyes at the time of presentation of OIS (Fig. 8-3). Accompanying ciliary injection is often present when the intraocular pressure is elevated. Despite the prevalence of iris neovascularization, only one-half of these eyes (one-third of all patients) have an increase in intraocular pressure. In some cases, the anterior chamber angle can be closed by fibrovascular tissue and the intraocular pressure is normal or low because of impaired ciliary body perfusion and decreased aqueous production. It should be kept in mind that immediately after carotid endarterectomy the ciliary body perfusion can improve, although the anterior chamber angle still remains closed. In these instances, the intraocular pressure can rise acutely, with accompanying severe pain. Since the visual prognosis is typically poor by the time iris neovascularization is present, it is desirable to discover the OIS prior to this stage.
Overall, OIS is the third leading cause of iris neovascularization in an adult population and is responsible for approximately 13% of cases. 6 The leading causes of iris neovascularization in adults are diabetic retinopathy and central retinal venous occlusion (CRVO), each accounting for about one-third of cases.
Anterior chamber flare is present in the majority of eyes with iris neovascularization, whether it be secondary to the OIS or another underlying cause. In 20% of OIS eyes, there is also an anterior chamber cellular response. 3 It is usually mild, and rarely accompanied by large keratic precipitates. Cataracts can occur in eyes with the advanced OIS, but these are not usually a prominent feature of the earlier stages.
Anterior segment signs associated with the OIS include iris neovascularization and anterior chamber flare in two-thirds of eyes, while a mild anterior chamber cellular response is observed in 20% of eyes.
8.2.6 Posterior Segment
Retinal arterial narrowing is commonly present in OIS eyes, although this is subjective and can be difficult to quantitate. The retinal veins are usually dilated (Fig. 8-4) and may be beaded, both generalized responses to ischemia that can also be seen with diabetic retinopathy. Retinal tortuosity is typically not a feature of OIS and is seen more commonly with CRVO, with which there is an outflow obstruction.
Retinal hemorrhages are seen in about 80% of affected eyes. 3 They are typically dot and blot, and are most commonly located in the midperiphery (Fig. 8-5), but can be the streak variant and be located in the posterior pole. The dot and blot hemorrhages are typically located in the outer plexiform layer but can also traverse the full thickness of the retina in some instances.
Hard exudate is generally not encountered in eyes with the OIS. When hard exudate is seen, a component of diabetic retinopathy is usually present in conjunction with OIS.
Neovascularization of the optic disc (NVD) (Fig. 8-6) is encountered in about 35% of eyes, and neovascularization of the retina (NVE) is seen in about 8% of eyes (Fig. 8-7a). Rarely, the neovascularization can become sufficiently severe to cause traction retinal detachment. Retinal capillary nonperfusion can be seen with fluorescein angiography (Fig. 8-7a). This correlates histopathologically with acellular retinal capillary tubules (Fig. 8-7b). As is the case with retinal capillary nonperfusion associated with other entities, it is not reversible.
Microaneurysms are often present, most commonly in the retinal periphery. In the posterior pole, they can leak and contribute to macular edema. 7 The macular edema is often more pronounced with fluorescein angiography (Fig. 8-8) than clinically, and marked cystic changes are usually absent. Despite the fact that eyes with OIS and macular edema routinely demonstrate hyperfluorescence of the optic disc with fluorescein angiography, the disc generally appears normal ophthalmoscopically. Telangiectatic vascular changes may be present.
Cotton-wool spots are found in approximately 4% of affected eyes, as are spontaneous retinal arterial pulsations. 3 The arterial pulsations are most pronounced over the optic disc and extend to one to two disc diameters from the edge of the disc. Although spontaneous retinal arterial pulsations are also seen with cardiac valvular disease and increased intraocular pressure, their presence in a person older than 50 years should strongly arouse suspicion of OIS. Ischemic optic neuropathy, characterized by acute visual loss and optic disc swelling, has been observed in 1 to 2% of cases. 8
If spontaneous retinal arterial pulsations are not present, light digital pressure on the lid will often induce them, which is not usually the case with CRVO. This can be a helpful method to differentiate between the two diseases.
A list of the key clinical features seen with OIS is shown in Table 8-1
90% of eyes with the OIS have dilated, but not tortuous, retinal veins, while 80% have peripheral, midperipheral, or posterior pole dot and blot retinal hemorrhages.
8.2.7 Ancillary Tests
Fluorescein angiography reveals delayed filling of the choroid in approximately 60% of OIS eyes (Fig. 8-9). 3 Normally, the choroid is completely filled within 5 seconds after the first appearance of dye within it. A marked delay in choroidal filling is perhaps the most specific fluorescein angiographic sign of the OIS. Delayed retinal arteriovenous transit time (time from the first appearance of dye within the temporal retinal arteries until the corresponding retinal veins are completely filled; normally less than 11 seconds) is found in 95% of affected eyes, but this is not as specific for OIS as is delayed choroidal filling. It can also be seen with central retinal artery occlusion (CRAO), diabetic retinopathy, and central retinal vein occlusion. Staining of the retinal vessels (Fig. 8-10), often more so the arteries than the veins, is seen in about 85% of OIS eyes, probably as a consequence of endothelial cell ischemia.
The fluorescein angiographic signs associated with the OIS include (1) delayed choroidal filling, (2) increased arteriovenous transit time, and (3) late staining of the retinal arteries and arterioles.
Electroretinography often reveals diminution of the amplitudes of the a- and b-waves (Fig. 8-11), corresponding to outer and inner retinal ischemia, respectively. 3 Histopathology reveals damage to both the inner and outer retinal layers (Fig. 8-12). While retinal pigment epithelial (RPE) disturbance is often a long-term feature of the acute choroidal ischemia encountered with acute ophthalmic artery occlusion, it is not typically a manifestation of the OIS.
Carotid noninvasive testing, particularly duplex scanning (real-time B-mode arterial imaging with a pulsed Doppler to record blood flow velocity, or color duplex ultrasound), has been shown in a meta-analysis to have a 98% sensitivity and 88% specificity in detecting angiographic carotid stenoses of =50% and a 90% sensitivity and 94% specificity for identifying stenosis =70%. 10 Computed tomography (CT) angiography and magnetic resonance angiography (MRA) can be employed as confirmatory tests. In instances in which the carotid arteries appear normal with noninvasive testing, color Doppler ultrasonography of the eye and orbital vessels, in addition to CT angiography and MRA, can be helpful in identifying an underlying ophthalmic artery occlusion.
8.2.8 Differential Diagnosis
Diabetic retinopathy, in particular, can be confused with the OIS. This occurs because more than 50% of patients with the OIS also have diabetes mellitus, a known risk factor for increased atherosclerosis. In some instances, both diabetic retinopathy and the OIS are present concomitantly.
Features more suggestive of diabetic retinopathy than the OIS include bilaterality, the presence of hard exudate, thick macular edema, and numerous microaneurysms in the posterior pole. While it may occur without diabetes, We are unaware of a clinical case of the OIS in which hard exudate is present in the fundus unless the patient also has diabetes mellitus and a component of diabetic retinopathy. In cases of severely asymmetric diabetic retinopathy (nonproliferative disease in one eye and high-risk proliferative disease in the other eye), carotid artery occlusion has not been demonstrated convincingly to have a protective or exacerbating effect on the diabetic retinopathy. 11 Notwithstanding, there are anecdotal cases in which severe unilateral carotid artery occlusion has markedly worsened ipsilateral proliferative diabetic retinopathy.
Eyes with mild CRVO usually demonstrate venous tortuosity and prominent retinal edema, both features rarely seen with OIS. Additionally, ophthalmoscopic optic disc swelling is rarely seen with the OIS, but is common with CRVO.
While spontaneous retinal arterial pulsations are seen in only 4% of OIS eyes, light digital pressure on the upper lid of these eyes usually produces arterial pulsations. Because OIS is unilateral in 80% of cases, 3 the amount of pressure needed to cause pulsations in the affected eye can be compared with that in the contralateral eye. Ophthalmodynamometry better helps to quantitate the differences. The pulsations are best seen on the optic disc, but can extend outward for several disc diameters from the disc. With CRVO and diabetic retinopathy, substantial digital pressure must be exerted to cause retinal arterial pulsations.
8.2.9 Associated Systemic Diseases
Since marked atherosclerosis is generally not an isolated phenomenon, there is a high prevalence of diseases associated with systemic atherosclerosis in patients with OIS. 12 More than one-half of patients with OIS have diabetes mellitus and nearly one-half have ischemic cardiac disease. Approximately one-fourth of patients have had a previous cerebrovascular accident, and almost one-fifth have required peripheral bypass surgery before the discovery of OIS.
The 5-year mortality rate in patients with OIS is 40%. 12 Despite a stroke rate of 0.4% per year in patients with OIS (more than four times that of an age-matched population), the leading cause of death is cardiac disease. Thus, cardiac evaluation should be considered, depending on the clinical circumstances.
8.2.10 Management and Course
Local therapy for OIS is usually temporizing. 13 Eyes with iris neovascularization and an open anterior chamber angle can be considered for panretinal laser photocoagulation, which is successful in eradicating the new vessels in about 35% of cases. 13 The use of intraocular vascular endothelial growth factor (VEGF) inhibitors in OIS eyes with iris neovascularization should be undertaken with caution. In one series, the authors noted that two of four eyes (50%) receiving intravitreal bevacizumab developed CRAO. 9
Although no clinical trials have evaluated surgical therapy for vision in OIS, carotid endarterectomy appears to be beneficial for maintaining or improving vision in select cases. 13 Unfortunately, once iris neovascularization is present, more than 90% of eyes are legally blind at the end of 1 year, with or without surgery. 13
Overall, carotid endarterectomy has been proved to be of benefit in preventing disabling stroke in symptomatic patients (those with amaurosis fugax, hemispheric transient ischemic attack, or nondisabling stroke) with 70 to 99% carotid artery stenosis. The North American Carotid Endarterectomy Trial Collaborators 14 found the stroke rate in endarterectomy patients by 2 years was 0.9% at institutions that frequently performed the surgery. This compares with 26% in a control group using aspirin. Surgical benefit appears to be best in men aged 75 years or older and those who undergo surgery within 2 weeks of an ischemic event. 15 A Cochrane review 15 of carotid endarterectomy for symptomatic patients found that those with an associated 0 to 29% stenosis had an increased 5-year risk of ischemic stroke with endarterectomy (absolute risk reduction [ARR] = –2.2%, p = 0.05), those with a 30 to 49% stenosis had no significant effect (ARR = 3.2%, p = 0.60), those with a 50 to 69% stenosis had marginal benefit (ARR = 4.6%, p = 0.04), and those with a 70 to 99% stenosis had a considerable benefit (ARR = 16.0%, p < 0.001). 15 Thus, many patients with symptoms from ulcerated carotid plaques fare just as well with aspirin therapy as with endarterectomy.
In asymptomatic patients with a carotid artery stenosis randomized to endarterectomy versus medical management, the 5-year stroke rate is 6.4 versus 11.8% (ARR = 5.4%, p < 0.0001). 16 The benefit was more pronounced in those with greater stenosis (70–90%) on ultrasonography.
In a large analysis from the Society for Vascular Surgery, the 30-day incidence of death, stroke, and/or myocardial infarction was 7.1% in symptomatic stented patients and 3.8% in endarterectomy patients. For asymptomatic patients, the comparative rates were 4.6 and 2.0%, respectively. 17 Additional follow-up data were similar. 18 Thus, stenting had a higher postoperative complication rate in patients aged 65 years or older. Refinement of comparative data outcomes will surely follow.
Treatment of symptomatic carotid stenosis is less clear. A consortium of professional medical societies 19 , 20 suggests carotid endarterectomy is reasonable “in asymptomatic patients who have more than 70% stenosis of the internal carotid artery if the risk of perioperative stroke, MI (myocardial infarction), and death is low.” Nonetheless, it has been shown that high-dose statins decrease stroke among patients with high-risk cardiovascular disease by one-third. 21 A meta-analysis of 30 studies showed the stroke rate in patients with symptomatic internal carotid disease before the year 2000 was 2.83%, versus 1.13% after the year 2000. 22 Since this has likely occurred, in large part, due to statin therapy, the aggressive use of the most effective statins, rosuvastatin and atorvastatin, can be considered. These drugs have been shown to decrease atherosclerosis that has already formed. 23
When a 100% carotid artery stenosis is present, a thrombus usually propagates distally, typically precluding successful endarterectomy. In such instances, extracranial to intracranial (e.g., superficial temporal artery to middle cerebral artery) bypass has been attempted. Although it may help vision transiently, at 1 year there appears to be no long-term visual advantage over observation for OIS patients. 13 Additionally, this procedure has been shown in a clinical trial not to be more beneficial than aspirin in preventing stroke 24 , 25 or improving cognition. 26
Signs arousing suspicion of the OIS include (1) iris or posterior segment neovascularization with no obvious cause, (2) spontaneous retinal arterial pulsations, and (3) delayed choroidal filling and/or later retinal arterial (arteriolar) staining on fluorescein angiography.
8.3 Acute Ophthalmic Artery Occlusion
Approximately 5 to 10% of cases of acute CRAO are probably acute ophthalmic artery occlusion. 27
Acute ophthalmic artery occlusion is characterized by sudden, severe visual loss. The vision is no light perception (NLP) in 90% of cases, and there is marked opacification of the retina in the macular region and sometimes more peripherally (Fig. 8-13). 27 The NLP vision is an important feature for differentiating acute ophthalmic artery occlusion from acute CRAO; the latter is typically associated with counting fingers to hand-motion vision in the far temporal field. 28
The ischemic retinal opacification seen with acute ophthalmic artery occlusion is usually more marked than that seen with acute CRAO. In some eyes, the whitening is so severe that there is ischemic opacification of the retinal pigment epithelium and choroid. Approximately 30% of cases lack a cherry-red spot, in 40% it is questionable, and in the remaining 30% it is present as the choroid reperfuses. 27
Fluorescein angiography often reveals choroidal perfusion defects in addition to delayed arteriovenous transit time. In the later phases, there may be focal or generalized staining of the retinal pigment epithelium (Fig. 8-14). 27 Electroretinography discloses reduction of both the a-wave and the b-wave. 27
Because of the choroidal ischemia, there are often long-term RPE changes after acute ophthalmic artery occlusion. They can occur in both the posterior pole and the peripheral fundus. RPE changes are not typically present from CRAO alone. 27
The causes of acute ophthalmic artery occlusion are generally similar to those for acute CRAO. 27 In particular, giant cell arteritis should be considered in patients older than 55 years with acute ophthalmic artery occlusion. Orbital mucormycosis, in the clinical setting of periorbital infection, has been repeatedly observed to cause acute ophthalmic artery occlusion due to vasculitis. 27
Treatment of acute ophthalmic artery occlusion is generally unsatisfactory.
8.4 Central Retinal Artery Occlusion
In 1859, von Graefe 29 reported the case of a patient who experienced an acute Central Retinal Artery Occlusion (CRAO). By the beginning of the 20th century, more than two dozen cases of retinal arterial occlusion had appeared in the literature. The mechanisms responsible for CRAO include embolization, intraluminal thrombus, atherosclerotic plaque, hemorrhage under an atherosclerotic plaque, dissecting aneurysm, hypertensive arterial necrosis, vasospasm, circulatory collapse, and vascular inflammation with thickening of arterial walls. 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50
8.4.1 Clinical Features
Data from the Retina Vascular Unit at Wills Eye Hospital suggest that CRAO occurs in approximately 1/10,000 outpatient ophthalmologic visits. 28 The mean age at the time of presentation is about 65 years, and men are affected more frequently than women. 28 There appears to be no predilection for one eye over the other. Approximately 1 to 2% of cases are bilateral. 28 When both eyes are affected simultaneously by retinal arterial occlusion, the index of suspicion for cardiac embolic disease, giant cell arteritis, and other vascular inflammations should be heightened. A history of headache, jaw claudication, or recent joint aching should alert the clinician of possible giant cell arteritis as a cause. Since occlusions due to giant cell arteritis have a tendency to be more severe, and because we have seen the fellow eye involved by CRAO within hours after the first, prompt treatment with high-dose corticosteroids should be considered, more so to protect the second eye than to help the first. Nevertheless, anecdotal cases suggest that high-dose corticosteroids can be of benefit in reversing some cases of incomplete occlusion as well.
Patients with acute CRAO typically relate a history of abrupt, painless, unilateral visual loss occurring over a period of seconds. Some may have a previous history of amaurosis before the episode of severe visual loss, no matter the cause.
The visual acuity in eyes with CRAO is usually in the counting fingers to hand-motion range. 28 In most instances, at least a temporal island of vision remains. An afferent pupillary defect appears within seconds after the development of the occlusion.
Fundus examination discloses superficial whitening of the retina, which is most pronounced in the macular region (Fig. 8-15). The whitening typically develops within hours, although in the primate model we have seen it develop within minutes after complete occlusion. In the foveola, where the retina is only 0.1 mm in thickness, a cherry-red spot can be seen. In comparison with the ischemic and opacified perifoveolar retina (approximately 0.5 mm in thickness), the thin foveolar retina still allows visualization of the underlying retinal pigment epithelium and choroid, thus accounting for the cherry-red spot. In mild cases, the whitening can resolve over a period of days. In severe cases, it may take 4 to 10 weeks to disappear. Segmentation of the blood column, or “boxcarring,” is present in both the retinal arteries and veins in eyes with severe CRAO.
In approximately 10% of eyes, a patent cilioretinal artery derived from the posterior ciliary arteries, the choroid, or the circle of Zinn–Haller supplies the foveola (Fig. 8-16). 24 These cilioretinal arteries typically originate separately from the central retinal arteries on the optic nerve head or in the temporal peripapillary retina. In these instances, the visual acuity improves to 20/50 or better in 80% of eyes over a period of weeks. The remaining visual field in such cases is variable, but with severe occlusion only a central island of vision may remain. If a patent cilioretinal artery does not reach the foveola, the contribution to visual improvement is minimal.