9.1 Terminology

Many terms are used in a synonymous fashion in the literature on retinal vein occlusion (RVO). The following are synonyms for a type of RVO manifesting little imbalance between oxygen demand and supply – nonischemic, perfused, venous stasis retinopathy, partial, incipient, imminent, threatened, impending, mild, incomplete, papillophlebitis, and hyperpermeability type.22 The more serious type of RVO, in which inner retinal oxygen demand outstrips oxygen supply by a larger margin, has synonyms too – ischemic, hemorrhagic, complete, stagnation thrombosis, combined occlusion of the retinal vessels, and nonperfused.22 Although there are many published discussions about which terms are preferable, in this book, the arbitrary choice is made to use the terms nonischemic and ischemic to describe RVOs.22 The classification of RVO based on ischemia is covered in Chap. 4, as well as the controversies and confusion surrounding the various definitions of ischemia. In this chapter, the perspective is, instead, practical and clinical.

In practice, the classification of patients with RVO by ischemic status is uncertain. Therefore, a broad rather than restrictive definition is preferred, because sensitivity is more important than specificity when attempting to detect the sightthreatening complications that can follow ischemia – varieties of ocular neovascularization.7,37 Ocular neovascularization includes anterior segment neovascularization (ASNV) and posterior segment neovascularization. ASNV is, in turn, divided into

neovascularization of the iris (NVI) and neovascularization of the angle (NVA) (see Chap. 11). Posterior segment neovascularization includes neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) (see Chap. 10). Our confidence in any test’s ability to predict ischemic status or the probability of later ocular neovascularization is low, because RVO is dynamic and because of poor reproducibility of each study in its claimed predictive power. There is no substitute for more frequent follow-up when there is clinical doubt as to which ischemic subtype of RVO the patient has.7

Vascular endothelial growth factor (VEGF) exhibits the characteristics required of the angiogenic factor originally hypothesized to exist by Michelson in 1948. VEGF is produced in the retina, its levels increase in ischemia, and it must be present for NVI to occur (see Chap. 2).1 VEGF mRNA levels are increased in the ischemic retina, and intraocular VEGF levels are spatially and temporally associated with neovascularization.39 Injection of anti-VEGF antibodies prevents NVI following RVO.1 The observation that anti-VEGF drugs improve visual acuity and decrease macular edema (ME) in the majority of RVOs whether they are classified as ischemic or not has led to the conclusion that all RVOs exhibit some degree of ischemia, even those conventionally classified as nonischemic.29

Table 9.1 lists abbreviations commonly used in the discussion of retinal ischemia in RVO. Each abbreviation will be spelled out at its first occurrence.

Table 9.1 Abbreviations used in ischemia and retinal vein occlusions

9.2 Branch Retinal Vein Occlusion

The relative proportions of BRVOs characterized as nonischemic and ischemic are inconsistent in the literature. The inconsistency arises from the variability in definitions of ischemia for BRVOs, from lack of reproducibility of measurement techniques across different clinicians, and from differences in patient samples studied. Hayreh reported that most major BRVOs were ischemic.18,20 However, in a population-based study of pooled RVOs from China, of which 58 of 63 RVOs were BRVO, nonischemic occlusions were nine times more common than ischemic ones.34 In the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) BRVO study, 12–18% of BRVOs were ischemic at baseline.52

Although judging ischemia in a case of BRVO by fluorescein angiography (FA) can be difficult when hemorrhage, cataract, and poor pupillary dilation confound interpretation, in many cases, the situation is uncomplicated and can be clearly

categorized as nonischemic (Fig. 9.1) or ischemic (Fig. 9.2). Therefore, FA is selectively useful for assessing ischemia in BRVO.

Vitreous levels of VEGF and soluble intercellular adhesion molecule-1 (sICAM-1) are correlated with the area of nonperfused retina in BRVO.41 Fluorescein leakage in ischemic zones tends to resolve spontaneously over a period of months (Fig. 9.3).11 Ischemia causes atrophy of the inner retina that can be seen in pathologic specimens (see Chap. 1) and in OCT scans (Fig. 9.2). The influence of macular ischemia associated with BRVO on final visual outcome has been judged inconsistently. Nonischemic BRVO has been associated with either a poorer prognosis10,38,47 or a better visual acuity prognosis.12 Generally, the greater the area of ischemia in BRVO, the higher the risk of secondary NVD and NVE, and the more closely the patient should be followed to detect and treat neovascularization (see Chaps. 10 and 12). In accord with this idea, macular BRVOs are not associated with intraocular neovascularization even when they are ischemic, because the area involved is small (Fig. 9.4).

Conversion from nonischemic to ischemic BRVO can occur.5 The rate of conversion from nonischemic to ischemic BRVO varies with the definitions used for these terms. In the SCORE BRVO study, using a definition of ischemia as more than five disc areas (DAs) of capillary nonperfusion, the percentage of eyes judged ischemic at 12 and 24 months’ follow-up was approximately double the percentage judged ischemic at baseline.52 The rate of conversion was uninfluenced by treatment group.52 At baseline, the percentages of ischemic BRVO were 13%, 18%, and 12% for the grid laser, 1 mg intravitreal triamcinolone acetonide (IVTA), and 4 mg IVTA groups, respectively. At 1-year follow-up, the percentages were 29%, 31%, and 23%, respectively.52 In another study using a different definition of ischemia, 29% of nonischemic BRVOs became ischemic over the course of 1 year of follow-up.2 Increased intraretinal hemorrhage at presentation was associated with an increased risk of conversion from nonischemia to ischemia.2 In another study of 31 nonischemic BRVOs, 16% had progressive ischemia from 1 to