12.1Branch Retinal Vein Occlusion with Macular Edema

In human BRVO, intraocular levels of VEGF, interleukin 6, soluble VEGF receptor 2 (sVEGFR-2), and soluble intercellular adhesion molecule-1 (sICAM-1) were correlated with the severity of ME in BRVO.32,35-37 The levels of VEGF in BRVO with ME were signiÞcantly higher than the serum levels.32 Vitreous levels of VEGF vary widely in BRVO with ME from 15.6 pg/ml to greater than 1,000 pg/ml, depending on the level of ischemia.32 VEGF activates VEGFR-2, which causes decreased expression of occludin in tight junctions, and a breakdown in the bloodÐretina barrier.32,48

In a rat model of BRVO, numerous molecular changes were observed that could cause ME, including upregulation of VEGF, downregulation of inward rectifying K+ (Kir) 4.1 channels and aquaporin-1 and aquaporin-4, mislocation of the Kir 4.1 protein, and osmotic swelling of Muller cells.44 In human BRVO, macrophage inßammatory protein-1b (MIP-1b) and monocyte chemotactic protein-1 are upregulated in eyes with BRVO and ME.34 Successful treatment of ME with intravitreal triamcinolone was associated with reductions.34

Not all ME in BRVO is likely to be mediated by VEGF because there are some cases in which antibodies that block VEGF, such as bevacizumab and ranibizumab, fail to cause resolution of edema.1,11 This suggests that other pathways may be involved in causing ME in BRVO in some cases.32 Intercellular adhesion molecule-1 (ICAM-1) and VEGF receptor 2 (VEGFR-2) have been proposed as candidates.32

In the population-based study Beaver Dam Eye Study (BDES), ME involving the fovea was found in 9.7% of cases of prevalent BRVO.29 In that study, 61 eyes suffered incident BRVO during 15 years of follow-up. Of these, 17 (28%) had ME.30 The percentage of ME in BRVO is higher in case series reported from clinics because the decrease in visual acuity (VA) brings the patient

to the doctor. In case series of major BRVO, ME occurred in 60% of cases of which two-thirds went on to chronic involvement.20,21,23 In macular BRVO, ME occurred in 84% of cases.28 Macular edema in BRVO spontaneously improved in 30Ð40% of cases.16,25 In cases with ME but without ischemia, spontaneous resolution of the edema occurred in approximately 30% of cases.12 In ischemic BRVO, the rate of spontaneous resolution was higher Ð approximately 100%.17

The proportion of patients with BRVO that develop ME depends on the status of the vitreous.2 In a case series of 53 BRVOs in which 25 had total PVD and 28 did not, the proportion of cases developing ME was 59% in the non-PVD group versus 20% in the PVD group (P < 0.01).2

Macular blood ßow velocity is negatively correlated with ME in BRVO.33 The macular blood ßow velocity on average is lower in eyes with BRVO that also have disruption of the perifoveal capillary border or areas of ischemia, suggesting that these may be negative factors for ME in BRVO.33

There is a modest correlation between ME and best corrected logarithm of the minimum angle of resolution (logMAR) VA in BRVO. Using OCT, the correlation coefÞcient between logMAR VA and macular thickness ranged between −0.232 and −0.591.4,27,38 Similarly, using the retinal thickness analyzer, the linear relationship had a correlation coefÞcient of −0.58.49 This relationship is comparable to that reported in diabetic macular edema (correlation coefÞcient of −0.52).9,15

The relationships of the FA and clinically observed and OCT-measured macular thickening can be complex (Fig. 12.1). In some cases, there is consonance between FA and OCT (Fig. 12.1d, e). In other cases, they can be discrepant with hyperßuorescence on the FA but no thickening on the OCT, implying a robust RPE pump, or with no hyperßuorescence but a thickened OCT (see Chap. 8, Fig. 8.3), implying intracellular edema or a hypofunctioning RPE pump. Acutely, an ischemic zone in BRVO may be edematous, but over time such zones often deturgesce (Fig. 12.1i, h).17

Fig. 12.1 A 72-year-old man had suffered a BRVO of the left eye 8 years previously and had received sector panretinal laser photocoagulation for retinal neovascularization. The patient had 20/20 visual acuity in both eyes. On routine follow-up, and without new symptoms, he was found to have a new BRVO in the right eye. Fundus images, ßuorescein angiography, and optical coherence tomography were obtained from both eyes. (a) Monochromatic fundus photograph of the right eye shows a superotemporal sector of intraretinal hemorrhages sparing the fovea. (b) Monochromatic fundus photograph of the left eye shows collateral vessels that bridge the horizontal raphe dividing the involved inferotemporal quadrant from the uninvolved superotemporal quadrant (the turquoise oval). The red arrow denotes a sclerotic white vein draining part of the involved sector of the retina. (c) Frame from the mid-phase ßuorescein angiogram of the right eye. There are relatively few hemorrhages and it is possible to discern the perfusion characteristics of the BRVO. The capillary detail is present (the yellow oval), placing this BRVO in the category of a nonischemic BRVO. (d) Frame from the late phase of the ßuorescein angiogram showing late hyperßuorescence (the yellow oval). (e) False-color map from the spectral domain OCT

(SD-OCT) study of the right eye shows that the area of thickening colocalizes with the area of heaviest hyperßuorescence in the ßuorescein angiogram (compare d). (f) Line scans from the SD-OCT study of the right eye showing that the edematous area spares the fovea (note the normal foveal depression) consistent with the 20/20 visual acuity. (g) Frame from the mid-phase ßuorescein angiogram of the left eye. The involved retina has a zone of nonischemia (the yellow oval) and a zone of ischemia (the orange oval). (h) Frame from the late-phase ßuorescein angiogram of the left eye. The nonischemic zone shows ßuorescein leakage (the yellow oval). The ischemic zone shows no ßuorescein leakage (orange oval). The red arrow denotes the nonischemic, edematous zone corresponding to the red arrow in the line scan OCT of panel i. (i) False color map from the SD-OCT study of the left eye. The nonischemic zone of the BRVO is edematous (the yellow oval) but the ischemic zone is nonedematous (the orange oval). The red arrow denotes cysts in the inner nuclear and outer nuclear layers of the temporal parafovea. In this case, because the patient was asymptomatic, observation was recommended with follow-up in 6 weeks to look for conversion of the nonischemic BRVO to an ischemic form

Macular edema not only adversely affects VA but also perimetric threshold on visual Þeld testing. In BRVO with associated ME, the correlation is linear, negative, and modest, with the correlation coefÞcient equal to −0.68 in the fovea and −0.62 in extrafoveal retina, respectively.27,52 Improvement in ME associated with intravitreal triamcinolone injection was paralleled by improvements in perimetric sensitivity.52

The literature is somewhat inconsistent in its conclusions regarding VA outcomes in ischemic BRVO with ME, with some reporting favorable and others unfavorable outcomes.14,17,46 More reports suggest that the visual prognosis in cases of BRVO and ME is worse in cases with macular ischemia than in cases without macular ischemia.13,20

There are two treatments proven to be effective in ME associated with BRVO. Argon laser grid photocoagulation produces visual outcomes modestly better than the natural history.6 Monthly intravitreal ranibizumab injections produces visual outcomes much better than the natural history, and by inference, but not by a head-to-head clinical trial, better than grid laser.11 More detail regarding treatment of ME in BRVO is found in Chap. 13.

12.2Central Retinal Vein Occlusion with Macular Edema

Macular edema is commonly associated with CRVO although reliable estimates of the proportion affected are sparse.31 In the population-based BDES, 18 eyes suffered incident CRVO during 15 years of follow-up. Of these, seven (39%) had ME.30 In clinic-based series, the proportion of cases with ME is higher. In a series of 136 cases, 96% had ME.26 ME is common in both ischemic and nonischemic CRVOs.26

Morphologically, ME in CRVO often appears as cystic spaces in the inner and outer nuclear layers (Fig. 12.2). However, the nerve Þber layer also swells, although often without cysts (Fig. 12.3). A careful comparison of OCT asym-

metry between eyes is required to detect this subtle form of edema (Fig. 12.3). Although it has been stated that ME in RVO begins as diffuse thickening and later forms cystoid spaces, there are documented cases of acute CRVO and HCRVO witnessed within 1 week of onset that have cystoid spaces (Fig. 12.4). Ischemia interacts with morphology in ME associated with CRVO, although a large series of cases has not been systematically analyzed for correlations (Fig. 12.5).

In nonischemic CRVO, ME depends on the vitreous status. Detachment of the posterior vitreous protects against ME in nonischemic CRVO. In a case series of 84 nonischemic CRVOs in which 44 had total PVD and 40 did not, the proportion of cases developing ME was 63% in the non-PVD group versus 18% in the PVD group (P < 0.01).26 For ischemic CRVO, however, there is no interaction of vitreous status and ME. Macular edema can be present in ischemic CRVO even when the posterior vitreous is detached.26

The correlation of visual acuity and OCTmeasured macular thickness in CRVO is modest.45 In the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) CRVO study, the correlation coefÞcient was −0.27.45 Using the retinal thickness analyzer, the correlation coefÞcient was −0.63.49 The relationship is comparable to that reported in diabetic macular edema (correlation coefÞcient of −0.52).9,15 Macular ischemia and macular cell death may prevent closer correlation in many cases (Fig. 12.2).

Macular edema in CRVO frequently persists in the absence of treatment, with a wide range of estimates of the proportion persisting (see Chap. 7).31 In the Central Vein Occlusion Study (CVOS), no untreated case of CRVO with ME had resolution over 12 months of follow-up.50 One meta-analysis offered 30% as a good approximation of the rate of spontaneous resolution of ME in CRVO.31

When resolution of ME does occur, it can be long delayed. In one study, the time to resolution of ME in untreated nonischemic CRVO with ME averaged 23 months compared to 29 months for ischemic CRVO.24

Fig. 12.2 Images from a patient with a nonischemic CRVO of the left eye and ME. An 83-year-old man with longstanding hypertension complained of sudden loss of vision of the left eye. On examination, the visual acuity was 20/200 on the left. There was no relative afferent defect. The left fundus examination showed optic disc edema, intraretinal hemorrhages in all quadrants, and marked ME (panels a and d). Fluorescein angiography showed good capillary perfusion and marked late macular cystoid hyperßuorescence (panels b and c). OCT showed a central subÞeld mean thickness (CSMT) of 865 m (panel d). Intraretinal edema and submacular ßuid were present (panel d). The patient was advised to have intravitreal bevacizumab injections, and after two injections at monthly intervals, the ME had resolved with some inspissated exudate in the subretinal space (panel e). The CSMT decreased to 275 m. The visual acuity remained 20/200 on the left. Because the patient was unable to appreciate any improvement in vision, the injections were discontinued, but fol- low-up at 1Ð2-month intervals continued to allow detection

of anterior segment neovascularization. This case exempliÞes the principle that macular thickening and best corrected visual acuity are only modestly correlated. (a) Color fundus photograph showing the initial fundus appearance of disc edema nasally, four quadrant intraretinal hemorrhage, venous dilation, and ME. (b) Venousphase ßuorescein angiogram frame showing good capillary perfusion consistent with classiÞcation as a nonischemic CRVO. (c) Recirculation-phase ßuorescein angiogram frame showing petalloid macular hyperßuorescence and disc hyperßuorescence. (d) Spectral domain OCT (SD-OCT) image at presentation showing cystoid edema and subretinal ßuid under the macula (the turquoise arrow). Cysts are present in the inner nuclear (the purple arrow) and outer nuclear (the orange arrow) layers. (e) SD-OCT image after one intravitreal injection of bevacizumab. Complete resolution of edema has occurred. Mild vitreomacular traction is evident (the yellow arrow). Inspissated exudate is present in the subfoveal space (the green arrow)

Macular edema is, generally, a negative prognostic factor for ultimate VA. In one study, the odds ratio for a three or more Snellen line loss of VA at 2Ð5 years follow-up was 3.22 (95%CI 1.86Ð5.57) for eyes with nonischemic CRVO

with ME and VA of 20/60 or worse.24 In eyes having nonischemic CRVO with baseline visual acuity of 20/70 or worse, spontaneous resolution of ME was associated with an odds ratio of 4.00 (95% CI 2.29Ð6.98) of achieving three or more

lines of VA improvement at the 2Ð5-year followup visit.24 Eyes with ischemic CRVO did not show an association with VA improvement with resolution of ME.24

In a prospective study of 67 nonischemic CRVOs that remained nonischemic over a

duration of follow-up averaging 2 years, multiple regression analysis showed the following factors to be independently associated with persistent ME: history of cardiovascular disease, hyperlipidemia, and initial severity of ME.19 Chronic ME and macular cysts in CRVO can

Fig. 12.3 A 44-year-old woman with hypertension noted sudden onset of painless blurring of the left eye 2 weeks before being examined. Examination showed a nonischemic central retinal vein occlusion (CRVO) of the left eye. (a) Color fundus photograph of the unaffected, normal right eye. (b) Color fundus photograph of the left eye with a nonischemic CRVO. Optic disc edema, peripapillary hemorrhage, and venous dilation are present. (c) Frame from the early-phase ßuorescein angiogram shows good capillary perfusion. (d) Frame from the late-phase

ßuorescein angiogram shows inferior optic disc hyperßuorescence but no macular leakage. (e) Optic nerve OCT shows a thickened nerve Þber layer of the left eye (compare the green arrows to the orange arrows). (f) False-color maps of the macular OCTs of both eyes show asymmetry with the peripapillary macula thicker on the left than the right. The gray scale for interpreting the difference between eyes is denoted by the orange arrow. Black indicates a 30 m or greater difference with the left thicker than the right

m] [ Thickness