Fig. 1.20 A frame from the mid-phase ßuorescein angiogram of the inferotemporal quadrant of the retina of a normal eye. The yellow arrows indicate arteriovenous crossings in which the artery lies in front of the vein. The turquoise arrow indicates an arteriovenous crossing in which the vein lies in front of the artery. Approximately 54Ð71% of arteriovenous crossings are normally of the Òartery in front of veinÓ type

front of the vein in 85Ð100% of cases implicating this anatomical relationship in the pathogenesis of the disease.50,97-102 In normal eyes, the percentage of arteriovenous crossings with the artery anterior to the vein is higher in the superotemporal quadrant (78%) than the inferotemporal quadrant (70%) and higher in the temporal quadrants (74%) than the nasal quadrants (60%), possibly because of the embryological relationship of the CRA nasal to the CRV.50,99 The parallelism with the regional variation in BRVO, in which 58Ð66% occur in the superotemporal quadrant, 20Ð38% in the inferotemporal quadrant, and 2Ð16% in the nasal quadrants, suggests the importance of arteriovenous crossings in the pathogenesis of the

disease.99,100,102-104

In an anatomical study of arteriovenous crossings in donor eyes from nonhypertensive subjects, artery-over-vein crossings were noted to have focal reductions in venous lumens in 27% (3/22) of cases, compared to no cases of vein- over-artery crossings, possibly providing an anatomic basis for the observation that artery-over-vein crossings are preferential sites for BRVO.95 Second-order AV crossings are most commonly involved (52Ð79%), with Þrst-order veins less commonly involved (21Ð35%).99,103 More peripheral BRVOs are least common but are probably underdiagnosed because they are asymptomatic.105 The proportion of arteriovenous

crossings with artery anterior to vein may be somewhat lower in BRVOs at Þrst order compared to second-order AV crossings.103 Because retinal veins lose muscularis more peripherally in the retina, it is possible that the retinal veins at second-order AV crossings are more compressible.103 In only 4.9% of cases does a BRVO occur at a location other than an arteriovenous crossing.78,106 In such cases, some other nonanatomic factor (such as inßammation, e.g., in sarcoidosis) is hypothesized to explain the location of the occlusion.107

The anatomic status of the vitreous has a relationship to sequelae of BRVO and CRVO. In ischemic CRVO, posterior vitreous detachment protects against development of retinal and disc neovascularization, but not anterior segment neovascularization.30 In nonischemic CRVO, but not in ischemic CRVO, posterior vitreous detachment protects against development of macular edema.30 The attached posterior vitreous is thought to retard diffusion of cytokines away from the site of action in the retinal microvasculature and to provide a scaffold for the growth of new vessels.30

1.4 Pathologic Anatomy

An understanding of all retinal vein occlusions can be organized by VirchowÕs triad of one anatomic emphasis and two physiologic emphases:

1.Abnormalities of the vessel walls

2.Abnormalities of the blood coagulability and viscosity

3.Abnormalities of blood ßow108

From an epidemiologic perspective, the most important of these three categories is a pathoanatomic one Ð degenerative changes in the vessel walls Ð and we will cover this category in the present chapter.109 Categories 2 and 3 relate more to physiology and will be covered in Chap. 2. The pathoanatomy of CRVO and HCRVO are considered to be identical and distinct from that of BRVO.1,110,111 Although many clinical studies have lumped HCRVO with BRVO, the evidence is strong that they are dissimilar.112

1.4.1Abnormalities of the Vessel Wall

For RVOs in general, the most common explanation of the etiology is that arteriosclerotic hypertrophy of a neighboring arterial wall causes compression of the involved vein where the artery and vein share a common indistensible sheath.113 Compression of the vein causes increased retinal venous blood ßow velocity by the Bernoulli effect, increased shear stress of blood on the venous endothelium, turbulence of blood ßow, endothelial injury, and secondary thrombosis.101,105,114 Hyperglycemia in diabetes increases retinal vascular ßow, produces a hypercoagulable state of the blood, and may predispose for such a

scenario.115 In the case of BRVO and possibly CRVO, sclerosis of the vessel wall and basement membrane thickening, as may occur with aging, hypertension, and diabetes, may limit the ability of the vessel wall to autoregulate in response to local metabolic changes which may increase risk for thrombosis.115 Abnormalities of aortic distensibility in patients with BRVO support the association of atherosclerotic arterial wall changes and BRVO.116

Among the most clearly deÞned mechanisms mediating venous wall injury is the metabolic pathway for homocysteine and its derangements. Homocysteine is a sulfur-containing amino acid formed during the metabolism of methionine (Fig. 1.21). Hyperhomocysteinemia occurs as a result of several different genetic mutations

Fig. 1.21 Metabolic pathway for homocysteine. Homocysteine is either metabolized to cystathionine and cysteine by transsulfuration or is remethylated to form methionine again. The remethylation pathway is catalyzed by the enzyme methionine synthase. The methyl group is donated by 5-methyltetrahydrofolate. Cobalamin (vitamin

B12) is required for this reaction. A deÞciency of vitamin B12 will tend to increase plasma homocysteine by decreasing the activity of this pathway. Likewise, a deÞciency of folate will decrease the concentration of tetrahydrofolate and slow remethylation, increasing plasma homocysteine

(see Chap. 3) and from effects of diet and other conditions (see Chap. 5). Hyperhomocysteinemia may be toxic to vascular walls by promoting deoxyribonucleic acid hypomethylation and expression of genes that mediate endothelial cell growth, by increasing oxidative stress of endothelial cells, and by promoting inßammation. All these effects lead to vasoconstriction, vascular intimal thickening, medial hyperplasia and hyalinization, and narrowing of the arteriolar lumen.117 Much of the vascular effect of homocysteine dysregulation involves the arteriolar wall. However, an indirect inßuence on RVO may be exerted by virtue of the intimate connections of central retinal artery and vein near the lamina cribrosa and of branch retinal arteries and veins at arteriovenous junctions within the retina.

1.4.2 Branch Retinal Vein Occlusion

Pathologic studies of acute human BRVO are rare, but animal models have been developed to simulate the early processes that may occur in human BRVO. In a pathologic study of acute BRVO induced in rhesus monkeys by laser photocoagulation, in the Þrst 6 h after occlusion, the capillary endothelium was undamaged, but the retinal nerve Þber layer showed intracellular edema with swollen mitochondria.118 Somewhat later, vacuolation developed in the nerve Þber layer with a regional gradient showing less severe changes adjacent to arterioles and worse changes adjacent to downstream venules. From 5 to 24 h postocclusion, erythrocytes were found outside the capillary lumen, lodged beneath the endothelial basement membrane, as well as in the extravascular tissues of the nerve Þber layer and outer plexiform layer.118 By 35 days postocclusion, capillary cellularity was lost and basement membrane ghosts remained, often invaded by processes of Muller cells. Photoreceptors and outer retinal cellularity were unaffected.118 Using a similar model of laserinduced BRVO in cynomolgus monkeys, collateral vessels developed and became fewer and larger in diameter over time.119

Although the disease is called branch retinal vein occlusion, the root cause of the condition is a diseased artery. The pathophysiology of BRVO

invokes the nearly universal Þnding that they occur at arteriovenous crossings. High shear stress gradients and turbulent ßow cause reactive proliferative changes in endothelial cells, endothelial damage, a nidus of clot with subsequent worsening, and eventual occlusion.97,120-122 Evidence supporting this scenario is found in ßuorescein angiography of BRVO cases in which the abrupt conversion of laminar venous blood ßow to more homogeneous mixing of the ßuoresceinated blood downstream to the involved arteriovenous crossing can be seen.105 In 7% of cases, thrombus can be identiÞed always downstream of the AV crossing, but the signs are subtle.101 Usually, the thrombus is white secondary to aggregated platelets with red ßecks, and the venule wall is dilated at the site (Fig. 1.22).101 In the FA, there is abnormal ßow either as sidestream ßow in which the central lumen is closed but the peripheral lumen has a small patent channel or else there is central narrowing of the lumen, reduced blood ßow

Fig. 1.22 A 69-year-old man with hypertension developed an inferotemporal BRVO of the left eye. This monochromatic fundus photograph of the involved arteriovenous crossing shows that the vein passes over the artery, an uncommon Þnding in BRVO. The thrombus can be seen as a white mass in the venous lumen just proximal to the crossing (red arrow). Small venous collaterals (green arrow) allow blood to ßow around the thrombus

downstream, and late staining focally.101 The abnormal ßow may correspond to recanalized thrombi.106

Fresh and recanalized thrombi have been histologically identiÞed at the site of BRVO. Recanalization can occur within 3 weeks in an experimental model of BRVO in cats.123 Once occlusion occurs, collateral vessels that carry venous ßow between retinal sectors enlarge and mature over a period of 6Ð24 months.105 More underlying normal but hidden venular anastomoses exist in the perimacular area, whence the Þnding that collateral vessels after BRVO are particularly commonly seen there.105

Human pathologic studies of more chronic BRVOs are more common. At arteriovenous crossings, but not venousÐarteriolar crossings within the retina, the direction of the vein changes as it crosses beneath the artery.95 The change of direction is more pronounced, the larger the vessel caliber. Thickening of the adventitia and stratiÞcation of the basement membrane of the vein wall opposite the point of contact with the overlying arteriole are also seen (Fig. 1.23).95 Whether this thickening arises from change in direction of the vein or as a response to turbulent blood ßow at the crossover is unknown.95 In 27% of cases of 11 cases of BRVO, the vein lumen

Fig. 1.24 Photomicrograph of an arteriovenous crossing from a nonhypertensive donor eye. The orange arrows denote a focal narrowing of the vein lumen by the artery. The green arrow denotes the shared adventitia between larger crossed arteries and veins. This tissue is severed in arteriovenous sheathotomy for BRVO (Reproduced with permission from Jefferies et al.95)

was reduced in diameter at the arteriovenous crossing (Fig. 1.24).95

A pathologic study showed that the vein downstream to a BRVO was narrowed relative to the dilated vein upstream of the occlusion.114 Recanalization of the occluded vein was evident (Fig. 1.25). In the area found to have capillary nonperfusion by ßuorescein angiography during life, loss of the nerve Þber layer, ganglion cell layer, and inner nuclear layer was found (Fig. 1.26).114,121 New vessels extending into the vitreous cavity were demonstrated at the border of nonperfused and perfused retina and at the disc.114 Other pathologic studies found loss of cellularity of the retinal capillary bed, cystic spaces especially prominent in the outer retina, recanalization of thrombi, sclerotic arterioles at involved arteriovenous crossings, associated epiretinal membranes, and hyperplastic retinal pigment epithelium (Fig. 1.27).121

Fig. 1.23 Photomicrograph of an arteriovenous crossing from a nonhypertensive donor eye. The orange arrow denotes focal basement membrane stratiÞcation opposite the site of the crossing. The green arrow denotes the shared adventitia between larger crossed arteries and veins. This tissue is severed in arteriovenous sheathotomy for BRVO. The blue arrow indicates the lumen of the overlying artery (Reproduced with permission from Jefferies et al.95)

1.4.3 Central Retinal Vein Occlusion

Our understanding of the pathoanatomy that leads to CRVO is not as clear as for BRVO because the site of the occlusion cannot be examined clinically during the process. Also, there have been

a

b

Fig. 1.25 Photomicrograph of an arteriovenous crossing in the postmortem eye that had a branch retinal vein occlusion 4 years before. The arrow points to the occluded branch vein with a single channel of recanalization. Just superior to and abutting the occluded, recanalized vein is a sclerotic arteriole (Reprinted with permission from Bowers et al.114)

Fig. 1.26 Photomicrograph of involved retina after BRVO. There is inner retinal atrophy with loss of all layers down to and involving the inner portion of the inner nuclear layer (atrophic area spanned by the double headed red arrows). The outer nuclear layer is denoted by the yellow oval (Reproduced with permission from Frangieh et al.121)

few pathologic studies in humans with recent CRVO and fewer experimental pathologic studies in animals. Nevertheless, the common feature in both cases of an indistensible sheath binding an adjacent vein and sclerotic artery suggests that a similar scenario may be occurring (Fig. 1.28).124 In the absence of a competing plausible hypothesis, the leading explanation for events is the same hypothesis based on turbulent venous blood ßow, endothelial injury, and subsequent thrombosis.124 Inßammatory cells are recruited within the thrombus, the wall of the vein, and in the perivenous tissue after several weeks, during which organization of the clot occurs and eventual recanalization. There is no pathological evidence to suggest that phlebitis is the primary event, as has been suggested in CRVO found in young patients.124

Any condition that contributes to further narrowing of the CRV as it passes through the choke point of the lamina cribrosa could theoretically increase turbulence of venous blood ßow and predispose to CRVO.129 Such conditions would include optic disc edema, optic disc drusen, hemorrhage within the optic disc, and a subdural cerebral hemorrhage.51,92,124 Although theoretically a small scleral outlet or small cup to disc ratio might be suspected of predisposing to CRVO and has been raised as a possible anatomic risk factor, there is no evidence to support either.3,51,92 In the case of a small scleral outlet, absence of evidence simply reßects absence of an effort to date to test the hypothesis.3

In a pathologic study of 29 eyes that had suffered CRVO, most cases had a thrombus at and posterior to the lamina cribrosa with some showing involvement slightly anterior to the lamina cribrosa (Figs. 1.29 and 1.30).47,124 Nonischemic CRVOs are hypothesized to have clots more posterior than the lamina cribrosa with more collateral veins available to provide egress for blood around the clot.125 The more posterior the occlusion occurs, the more collateral channels there are available for venous blood ßow. In this hypothesis, a relatively posterior location of thrombus correlates with a less ischemic form of CRVO.80 The phenomenon of conversion from a nonischemic to an ischemic CRVO is hypothesized to represent progression of thrombosis from a more posterior