Overview
Acute retinal vascular occlusive disorders collectively constitute a major cause of serious visual impairment. Despite the fact that retinal artery occlusion (RAO) and retinal vein occlusion (RVO) have been known for about almost 150 years, their pathogenesis, clinical features, and particularly their management have been plagued by controversy and misconceptions. RAO and RVO in fact comprise about a dozen separate clinical entities, and there is a voluminous literature on their pathogenesis and management. The following represents an abbreviated discussion of the salient aspects of the pathogenesis and management of these diseases.
Retinal Artery Occlusion
Central RAO (CRAO), branch RAO (BRAO), and cilioretinal artery occlusion have different clinical characteristics, etiologies, pathogenesis, and management. Therefore, they constitute distinct clinical entities. Of the three, CRAO is usually associated with the most extensive visual loss.
Pathogenesis
From the etiologic, pathogenetic, clinical characteristics, and management point of view, CRAO consists of nonarteritic CRAO, arteritic CRAO, transient CRAO, and nonarteritic CRAO with cilioretinal artery sparing.
Nonarteritic CRAO
This is the most common type, and studies have shown that embolism is a far more common cause than thrombosis. Rarely, vasculitis or trauma can cause CRAO. A detailed anatomical study of 100 human central retinal arteries showed that the narrowest lumen of the artery is where it pierces the dura mater of the optic nerve sheath before entering the optic nerve ( Figures 63.1 and 63.2 ). Therefore, the chances of an embolus becoming impacted at this site are much higher than at any other site in the artery. In contrast, histopathological studies show that the site of occlusion in thrombosis of the CRA is at the lamina cribrosa.
The site of occlusion is an important factor in determining the amount of residual retinal circulation. When the site of occlusion is in the dural sheath, multiple anastomoses established by all the pial and intraneural branches of the CRA distal to the occlusion site are left intact, and play a major role in determining the amount of residual retinal circulation. Also in this type of CRAO, fluorescein angiography shows the CRA trunk slowly filling from within the optic nerve. By contrast, when the site of occlusion is at the lamina cribrosa, no collaterals are available to establish retinal circulation; in these eyes, angiography shows only filling of capillaries on the surface layer of the optic disc from deeper posterior ciliary artery circulation, without any filling of the CRA trunk itself. Thus, angiography can provide useful information about the site of occlusion. The frequent presence of residual circulation in the retina in eyes with CRAO, and the belief that the site of occlusion is in the lamina cribrosa, has resulted in a prevalent misconception that there is usually incomplete occlusion of the artery in CRAO. (This misconception and its visual implications are discussed at length elsewhere. ) Briefly, in experimental CRAO studies in rhesus monkeys, where the CRA was completely occluded by clamping the artery, immediate postocclusion fluorescein fundus angiography showed a variable amount of slow filling of the retinal circulation in the vast majority of eyes. The basis for various treatments for CRAO and the visual improvement associated with those has often been erroneously attributed to this misconception of “incomplete CRAO.”
Arteritic CRAO
In this type, giant cell arteritis (see Chapter 40 ) is the cause of development of CRAO. Giant cell arteritis has a special predilection for involvement of the posterior ciliary arteries and only very rarely involves the CRA directly. CRA not infrequently arises from the ophthalmic artery by a common trunk with the posterior ciliary artery. When giant cell arteritis involves that common trunk, it results in occlusion of both the CRA and posterior ciliary artery, and consequently development of both arteritic CRAO and arteritic anterior ischemic optic neuropathy. Clinically, these eyes have the classical fundus findings of CRAO with or without optic disc edema, but, most importantly, on fluorescein angiography there is evidence of a posterior ciliary artery occlusion in addition to CRAO, which is a diagnostic feature of this type of CRAO. Since giant cell arteritis is a blinding disease and a prime medical emergency in ophthalmology, it is essential to rule out the presence of associated posterior ciliary artery occlusion by fluorescein angiography in all these eyes, as well as giant cell arteritis, in patients >50 years.
Transient nonarteritic CRAO
This can be produced by:
- 1.
Transient impaction of an embolus in the CRA. The most common type of embolus to cause this is a thrombotic or platelet-fibrin embolus and, less frequently, a cholesterol embolus; calcific emboli tend to remain impacted at one site because of their irregular texture.
- 2.
Vasospasm of the CRA. This is a rare cause of transient CRAO. There is evidence to suggest that platelets stick and aggregate on atherosclerotic plaques in the carotid arteries and release vasoactive substances, including serotonin and thromboxane. Serotonin can cause transient vasospasm of the CRA and result in transient CRAO.
- 3.
Fall of perfusion pressure below the critical level in the retinal vascular bed. Factors that produce fall of perfusion pressure below the critical level in the retinal vascular bed can result in transient CRAO. The perfusion pressure in the CRA is equal to the mean blood pressure in the artery minus the intraocular pressure (IOP). Therefore, a fall of perfusion pressure can be due to either a marked fall in mean arterial blood pressure or a rise of IOP, or a combination of the two. A marked fall in arterial blood pressure can occur for several reasons, including nocturnal arterial hypotension ( Figure 63.3A ), particularly in patients who take blood pressure-lowering medicines in the evening or at bedtime ( Figure 63.3B ), severe shock, during hemodialysis, spasm of the CRA, marked stenosis or occlusion of the internal carotid or ophthalmic artery, or ocular ischemia. A rise in IOP may be due to several causes, including ocular compression during certain surgical procedures or marked orbital swelling, acute angle closure glaucoma, or neovascular glaucoma (NVG) in association with ocular ischemia. The extent of retinal ischemia and consequent visual loss depends upon the duration of the transient CRAO (see below). In transient nonarteritic CRAO, fluorescein fundus angiography always shows normal or almost normal filling of the retinal vascular bed.
Figure 63.3
Ambulatory blood pressure and heart rate-monitoring records (based on individual readings) over a 24-hour period in two individuals.
(A) A 58-year-old woman on no medication.
(B) A 63-year-old woman who was taking verapamil (a calcium ion influx inhibitor) at bedtime. This shows a marked degree of nocturnal hypotension, which improved markedly on stopping the bedtime dose.
Nonarteritic CRAO with cilioretinal artery sparing
This type of nonarteritic CRAO only develops in eyes with a cilioretinal artery. The cilioretinal artery may vary in size from a minute one to one supplying a large part of the retina. The visual outcome and fundus findings in this type of CRAO are different from the classical nonarteritic CRAO.
Branch retinal artery occlusion
Most frequently, BRAO is caused by embolism, and only occasionally by vasculitis. When BRAO is due to embolism, the most common site is where the branch retinal arteries bifurcate because the embolus is not large enough to enter the smaller branches. That is not the case in BRAO due to vasculitis.
Cilioretinal artery occlusion
This is the least common type of RAO. Pathogenetically it can be divided into three types:
- 1.
Embolic: since the cilioretinal artery is supplied by the posterior ciliary artery, emboli going to the latter can result in cilioretinal artery occlusion.
- 2.
Giant cell arteritis: giant cell arteritis has a predilection for posterior ciliary artery involvement. If giant cell arteritis causes occlusion of the posterior ciliary artery supplying the cilioretinal artery, this results in cilioretinal artery occlusion. In such an eye there is almost invariably associated arteritic anterior ischemic optic neuropathy since the optic nerve head is mainly supplied by the posterior ciliary artery circulation. That combination is diagnostic of giant cell arteritis. Cilioretinal artery occlusion in these eyes has been misdiagnosed as BRAO caused by giant cell arteritis; the branch retinal artery is in fact an arteriole and giant cell arteritis is a disease of medium and large arteries and not of arterioles, therefore giant cell arteritis cannot cause BRAO. Since giant cell arteritis is a blinding disease and a prime medical emergency in ophthalmology, it is essential to rule out the presence of associated posterior ciliary artery occlusion by fluorescein angiography in all eyes with cilioretinal artery occlusion, as well as giant cell arteritis, in patients >50 years.
- 3.
Central or hemicentral RVO: this type of occlusion of cilioretinal artery is invariably due to hemodynamic blockage.
Retinal tolerance time to acute retinal ischemia
The chance of recovery of vision only exists as long as the retina has reversible ischemic damage. Experimental study of CRAO in elderly, atherosclerotic, and hypertensive rhesus monkeys (similar to most patients with CRAO) showed that the retina suffers no detectable damage with CRAO of up to 97 minutes, but after that, the longer the CRAO, the more extensive the irreversible ischemic retinal damage. CRAO lasting for about 240 minutes results in ischemic retinal damage that is massive and irreversible. Contrary to prevalent impression, the retinas of old, atherosclerotic, hypertensive rhesus monkeys could tolerate ischemia for much longer than younger, normal rhesus monkeys. In eyes where the retinal circulation was restored to normal after CRAO of more than 2 but less than 4 hours’ duration, retinal function did not show signs of major improvement until many hours or even a day or more after restoration of circulation – the longer the ischemia, the longer the lag before any improvement of function started.
Clinical background
CRAO is an ophthalmic emergency associated with a catastrophic visual loss. In one study, central scotoma was the most common visual field defect in CRAO. Following is the mechanism of selective development of central scotoma without any peripheral visual field defect in CRAO. Unlike the rest of the retina, the macular region has more than one layer of retinal ganglion cells, which are maximum close to the foveola, making that region the thickest part of the retina. Experimental and clinical CRAO studies showed that CRAO results in ischemic swelling of the inner retina, and this is maximal in the perifoveolar region ( Figure 63.4A ). If there is restoration of circulation in the CRA, as in transient CRAO, the retinal capillaries in the central, markedly swollen part of the macular region cannot fill ( Figure 63.4B ) because of compression by the surrounding swollen retinal tissue, resulting in the “no-reflow phenomenon.” Consequently, there is ganglion cell death in the nonperfused central retina. The area of central retinal capillary nonfilling may vary from eye to eye, depending upon the severity of retinal swelling in the macular region. This results in the variable size of the permanent central scotoma. The oxygen supply and nutrition from the choroidal vascular bed to the thinner peripheral retina help in its much longer survival, and the maintenance of peripheral visual fields.
Treatment
Since Von Graefe first described CRAO as a clinical entity in 1859, a voluminous literature has accumulated on its management, but no treatment has stood the test of time. Treatments include ocular massage in an effort to dislodge the embolus in the CRA, a reduction of IOP by various medical and surgical means to increase retinal perfusion pressure, vasodilatation of the CRA, antiplatelet therapy, heparin therapy, thrombolysis by administering a thrombolytic agent intravenously or local intra-arterial fibrinolysis by superselective administration of thrombolytic agent directly into the ophthalmic artery, isovolumic hemodilution, hyperbaric oxygen, and embolectomy. However, there are important considerations when evaluating claims of visual improvement associated with CRAO treatment:
- 1.
Experimental CRAO lasting for about 240 minutes results in massive, irreversible retinal damage. Thus, no treatment restoring CRA circulation instituted much longer than 4 hours after the onset of CRAO would be expected to restore vision.
- 2.
Most CRAO treatment studies do not demonstrate restoration or significant improvement of retinal circulation with fluorescein angiography, immediately after the treatment.
- 3.
It is usually claimed that visual improvement is due to treatment, when it may simply represent the natural history of the disease. For example, the claim of a 66% success rate for visual improvement with local fibrinolysis using tissue plasminogen activator in CRAO actually represented the natural history of the disease.
- 4.
In almost all CRAO studies, visual outcome is based on evaluation of visual acuity only. However, visual acuity is a function of the fovea only while CRAO involves the entire retina. Visual fields performed with a Goldmann perimeter provide information about the function of the entire retina, a far better measure than visual acuity alone. Furthermore, visual field information is essential to evaluate visual disability in any severely blinding disease, including CRAO. The constant tracking provided by the peripheral visual fields is essential for sensory input in our day-to-day activity, e.g., in routine “navigation.”
Thrombolysis is currently the most popular therapy and success has been enthusiastically claimed. However, a meta-analysis of studies of local intra-arterial fibrinolysis in CRAO concluded that, outside a randomized clinical trial, the use of superselective fibrinolytic therapy for CRAO cannot be recommended based on current evidence, because all studies were retrospective and nonrandomized and their methodology was often unsatisfactory.
In conclusion, none of the claimed treatments for CRAO produced a visual outcome better than that seen in the natural history of the disease. Treatments similar to those advocated in CRAO have also been advocated for BRAO, with similar problems.
In contrast, patients with arteritic CRAO (from giant cell arteritis) require immediate attention because there is a risk of developing irreversible bilateral visual loss if the patient is not immediately treated with high doses of corticosteroid therapy. (This is discussed further in Chapter 40 .) Similarly, patients with cilioretinal artery occlusion, for which giant cell arteritis is an important cause, should be worked up for the latter.
Diagnostic workup
Since embolism is the most common cause of nonarteritic CRAO and BRAO, an important part of the management of all patients is evaluation for the source of embolism by doing carotid and cardiac evaluation, to prevent further vascular accidents. However, one should be aware of the limitations of those tests in evaluation of embolism. In an eye with transient CRAO, evaluation of IOP and arterial hypertensive therapy are also essential.
Prognosis
Visual outcome in CRAO depends on the type. A natural history study showed that a significant improvement in visual acuity and visual field can occur without any treatment. Visual acuity improvement occurred primarily within the first 7 days. In eyes with vision of counting fingers or worse, visual acuity improved within 7 days in 82% of transient nonarteritic CRAO, 67% of nonarteritic CRAO with cilioretinal artery sparing, 22% of nonarteritic CRAO, and little in arteritic CRAO. The central visual field improved in 39% of transient nonarteritic CRAO, 25% of nonarteritic CRAO with cilioretinal artery sparing, and 21% of nonarteritic CRAO. The peripheral visual field was normal at initial visit in 63% of eyes with transient nonarteritic CRAO, 22% in those with nonarteritic CRAO, and in none of the other two types. Peripheral fields improved in nonarteritic CRAO (39%) and in transient nonarteritic CRAO (39%). When the junction between the infarcted and normal retinal artery passes through the foveal zone ( Figure 63.5 ), there is a marked spontaneous visual improvement within a few days to weeks, which has erroneously been attributed to various treatments.
Retinal Vein Occlusion
RVO is divided into the following six distinct clinical entities :
- •
Central RVO (CRVO): experimental and clinical studies have shown that CRVO consists of two distinct clinical entities: (1) nonischemic CRVO (or venous stasis retinopathy); and (2) ischemic CRVO (or hemorrhagic retinopathy).
- •
Hemicentral RVO (HCRVO): this is a variant of CRVO where, as a congenital anomaly, the central retinal vein (CRV) has two trunks in the optic nerve instead of one, and only one of those is occluded. Like CRVO, this can also be nonischemic or ischemic.
- •
Branch RVO (BRVO): this consists of: (1) major branch RVO when one of the major branch retinal veins is occluded, usually near, or rarely at, the optic disc; and (2) macular branch RVO, when only one of the macular venules is occluded.
Risk factors
Like all ocular vascular occlusive disorders, almost all types of RVO are multifactorial in origin; that is, there is rarely any one single factor that causes the occlusion ; there may be a whole host of local and systemic risk factors acting in different combinations and to different extents. The risk factors can be divided into two types, predisposing and precipitating, and they may play one role in one group and the other in another. CRVO and HCRVO are pathogenetically similar but very different from BRVO. In conclusion, all types of RVO cannot be explained by one common pathogenetic mechanism.
Local risk factors
CRVO and HCRVO
The CRA and CRV lie side by side in the center of the optic nerve, enclosed in a common fibrous tissue envelope ( Figure 63.6 ). Klien and Olwin postulated the following three occlusive mechanisms in CRVO: (1) occlusion of the vein by external compression by sclerotic adjacent structures (i.e., CRA and surrounding fibrous tissue envelope) ( Figure 63.6 right) and secondary endothelial proliferation; (2) occlusion by primary venous wall disease (degenerative or inflammatory in nature); and (3) hemodynamic disturbances produced by a variety of factors (e.g., subendothelial atheromatous lesions in the CRA, sudden reduction of blood pressure, blood dyscrasias, and further aggravated by arteriosclerosis or unfavorable anatomic relations). These produce stagnation of the blood flow in the vein. According to the Virchow’s triad for thrombus formation – (1) slowing of blood flow; (2) changes in vessel wall; and (3) changes in the blood – the stagnation finally results in primary thrombus formation in susceptible eyes.
CRVO is significantly more common in patients with ocular hypertension and glaucoma. Stasis in the CRV may be produced by several factors, including the following three factors in glaucoma/ocular hypertension:
- 1.
Blood pressure in the CRV at the optic disc depends upon the IOP, the former always being somewhat higher than the latter to maintain retinal blood flow. A rise of IOP could produce stasis and sluggish blood flow in the CRV, and may also collapse the vein on the optic disc. Hence, elevated IOP may be one of several predisposing factors in the etiology of CRVO and not the sole cause, except perhaps in eyes with a sudden increase of IOP to very high levels, e.g., acute angle closure.
- 2.
A histopathologic study of experimentally produced glaucomatous optic neuropathy in hypertensive and atherosclerotic rhesus monkeys showed a marked thickening of the fibrous tissue envelope around the central retinal vessels in the center of the optic nerve, as compared with age-matched controls ( Figure 63.6 ), that resulted in marked stenosis of the CRV during its intraneural course, which would consequently cause stasis of circulation.
- 3.
In some eyes, optic disc cupping may predispose to CRVO, either directly through a local mechanical effect or because of the secondary morphologic changes in the optic nerve in marked glaucomatous optic neuropathy associated with cupping. However, there is no strong evidence of a cause-and-effect relationship between cupping and development of CRVO/HCRVO.
Glaucoma or ocular hypertension does not influence the conversion rate between nonischemic CRVO and ischemic CRVO.
The site of occlusion of the CRV within the optic nerve (see below) has important implications, because that determines the number of venous collateral channels anterior to the site of occlusion which are available to restore circulation ( Figure 63.1 ); that in turn would determine the type and severity of the CRVO: the farther back the occlusion in the optic nerve, the more collaterals are available and the less severe the CRVO.
BRVO
Local risk factors in BRVO are discussed in the section on site of occlusion in BRVO, below.
Systemic risk factors
CRVO and HCRVO
A cross-sectional study of 197 patients with CRVO found a significantly higher prevalence of arterial hypertension and diabetes mellitus when compared to that in the National Health Interview Survey. The Eye Disease Case-Control Study Group found a significant association of diabetes mellitus, cardiovascular disease, and arterial hypertension in ischemic CRVO and arterial hypertension and fibrinogen levels in nonischemic CRVO. The odds ratio for ischemic CRVO was 4.8 for hypertension, 2.7 for diabetes mellitus, 2.1 for cardiovascular disease, and 2.1 for α 1 -globulin. The odds ratio for nonischemic CRVO was 1.8 for arterial hypertension and 1.8 for diabetes mellitus.
Hayreh et al prospectively investigated several risk factors in patients with CRVO (612 patients), HCRVO (130 patients), and BRVO (348 patients). The prevalence of systemic diseases was similar between CRVO and HCRVO – evidence that they are pathogenically identical. The combined group of CRVO and HCRVO patients had a higher prevalence of arterial hypertension, diabetes mellitus (in ischemic-type CRVO), peptic ulcer, and thyroid disorder relative to the control population. Arterial hypertension and diabetes mellitus were more common in ischemic CRVO than nonischemic CRVO. None of the systemic diseases had any significant effect on the rate of conversion of nonischemic to ischemic CRVO.
Compared to CRVO and HCRVO, patients with BRVO showed a higher prevalence of arterial hypertension, cerebrovascular disease, peripheral vascular disease, systemic venous disease, gastrointestinal disease, and peptic ulcer. Compared to the control population, patients with BRVO showed a greater prevalence of arterial hypertension, ischemic heart disease (in major BRVO only), cerebrovascular disease, chronic obstructive pulmonary disease, peptic ulcer, and thyroid disorder. Arterial hypertension and ischemic heart disease were more prevalent in major BRVO than in macular BRVO.
The presence of a particular disease may or may not be one of the risk factors in a multifactorial scenario predisposing an eye to develop a particular type of RVO, or may be just a coincidence. Apart from a routine medical evaluation, extensive and expensive workup for systemic diseases in patients with RVO is not cost-effective and not warranted in the vast majority of cases.
Hematological risk factors
There is no definite evidence of a cause-and-effect relationship between hematologic abnormalities associated with thrombosis and the development of various types of RVO in the vast majority of RVO patients; a chance occurrence of some of these hematologic abnormalities in RVO cases or the possibility of the findings due to unrelated associated systemic disease cannot be ruled out.
In young persons, although CRVO may be associated with any of the systemic diseases mentioned in the above studies, all the available evidence suggests that phlebitis of the CRV is probably the most common cause of thrombosis. CRVO due to phlebitis has been given different eponyms, including “papillophlebitis,” “retinal vasculitis,” “mild retinal and papillary vasculitis,” and “optic disc vasculitis type II.”
Nocturnal arterial hypotension in CRVO
Nocturnal arterial hypotension may play an important role in: (1) development of CRVO; and (2) conversion of nonischemic CRVO to ischemic CRVO. Retinal blood flow depends upon perfusion pressure. Nocturnal arterial hypotension is a physiological phenomenon ( Figure 63.3A ). Thus, a combination of very low mean blood pressure at night with a very high venous pressure from CRV narrowing (see above) would cause a precipitous fall of perfusion pressure → reduction of retinal blood flow to below the critical levels during sleep → retinal hypoxia/ischemia. This would explain why visual loss in CRVO is frequently discovered on waking up from sleep. With retinal ischemia, there is also ischemic capillaropathy. As the blood pressure returns to normal or even hypertensive levels during waking hours, there is an increase in retinal blood flow and associated rise in intraluminal pressure in ischemic retinal capillaries; this ruptures the weakened ischemic capillaries and produces extensive retinal hemorrhages. In some patients, this mechanism may also result in conversion of nonischemic CRVO to ischemic CRVO either overnight or gradually. The other mechanism for such a conversion (usually slow) may be a gradual extension of the thrombotic process in the CRV forward in the optic nerve, involving and eliminating many of the available venous collaterals in the optic nerve which previously protected these eyes from developing ischemic CRVO ( Figure 63.1 ).
BRVO
Systemic risk factors have already been discussed above. An increased risk of BRVO is associated with arterial hypertension, cardiovascular disease, and higher serum levels of α 2 -globulin.
Site of occlusion
CRVO and HCVO
This is an important issue because the rationale for various surgical procedures of “decompression of the CRV” for management of CRVO relies on this concept, which is based solely on histological examination of blind CRVO eyes, enucleated because of painful NVG. The histopathologic study by Green et al on CRVO is usually cited in support. In that study, 82.8% of the eyes had ocular neovascularization and most of the eyes were enucleated because of NVG – all definite signs of ischemic CRVO. Since nonischemic CRVO eyes never develop NVG, those are never enucleated. Thus, the study was essentially based on ischemic CRVO eyes, which must have skewed the sample. Clinical studies have shown that only about 20% of eyes with CRVO are of the ischemic type. In ischemic CRVO eyes, the maximum risk of developing NVG is only about 45% ( Figure 63.7 ); that means the overall risk of CRVO eyes developing NVG is only about 9%. Of the eyes that develop NVG, only a rare one is enucleated for pain or secondary phthisis bulbi – that means 1% or even less. Therefore, histopathological findings from less than 1% of CRVO eyes cannot be applied to more than 99% of CRVO eyes. Most importantly, the eyes enucleated for painful NVG have the most severe form of ischemic CRVO and are likely to have occlusion in the CRV at or close to the lamina cribrosa; therefore, they do not represent the vast majority of CRVO eyes; that provides a distorted impression about the site of occlusion in all CRVO eyes. This fact is critical when considering options for management of CRVO.
