Fig. 13.11 Fundus photographs before and 1 month after a single injection of bevacizumab 1.25 mg for an inferior hemicentral retinal vein occlusion of the right eye in a 27-year-old man with hypertension. (a) At baseline, the

inferior retinal veins are dilated, and prominent intraretinal and preretinal hemorrhages are shown. (b) One month after bevacizumab, the inferior retinal veins are less dilated, and the clearing of hemorrhage is dramatic

13.4.1.10Intravitreal Injection of Autologous Plasmin

In an uncontrolled study of 26 eyes with BRVO, injection of one international unit of autologous plasmin produced PVD in 23 of 26 eyes. At 12 months postinjection, the mean macular thickness decreased from a baseline of 602 ± SD149 to 254 ± SD117 m associated with an improvement in mean BCVA from 0.55 ± SD0.30 (Snellen equivalent 20/71) to 0.18 ± SD0.21(Snellen equivalent 20/30).245 Similar results were reported in eight patients previously refractory to GL, IVBI, IVTI, or combination methods treated with intravitreal injection of 0.2 ml of autologous plasmin enzyme and followed for 6 months.288 A PVD was created in all patients, and all patients experienced ten or more ETDRS letters of improvement in VA at the 6-month follow-up. The mean BCVA improved from logMAR 0.552 ± SD0.17 (Snellen 20/70) to 0.217 ± SD0.087 (Snellen 20/32) at 6 months. The mean CSMT decreased from baseline 495 ± SD69 to 226 ± SD29 m at 6 months. The effects were rapid with full effects seen by 1 month.288 Others have reported positive results in 36 patients with BRVO and macular edema over 12 months of follow-up with 80.5% of patients showing improved VA and 88.8% showing decreased macular thickness after a single injection of autologous plasmin.289 The promising results of these

pilot trials need to be conÞrmed in randomized controlled clinical trials with larger numbers of patients. The customized methods for preparing autologous plasmin are not easily transferable to everyday practice, and a commercial, standardized source of plasmin or a derivative with similar activity and absence of side effects will be necessary before adoption is feasible.

13.4.2 Central Retinal Vein Occlusion

13.4.2.1Intravitreal Injection of Antivascular Endothelial Growth Factor Drugs

Anti-VEGF drugs are effective in reducing ME in CRVO and HCRVO. However, the effects of VEGF blockade go beyond ME reduction. There is rapid reduction of intraretinal hemorrhage, decrease in venous dilation, and there may be reduction in the propensity of nonischemic CRVO to convert to ischemic CRVO over time (Fig. 13.11).87

The least studied of the anti-VEGF drugs, pegaptanib, has shown evidence of efÞcacy at both the 0.3- and 1-mg doses given every 6 weeks for Þve injections to reduce macular edema and improve mean VA at 30 weeks in CRVO.303

Fig. 13.12 Mean change in best corrected visual acuity from baseline to 6 months in the CRUISE trial for the three groups of patients. The vertical bars are ± one standard error of the mean. BCVA best corrected visual acuity, ETDRS Early Treatment Diabetic Retinopathy Study.

*P < 0.0001 versus sham (Reproduced with permission from Brown et al.29)

Fig. 13.13 Mean change in excess foveal thickness over time to month 6 in the CRUISE study. The vertical bars are ± one standard error of the mean. *P < 0.0001 versus sham (Reproduced with permission from Brown et al.29)

The Central Retinal Vein Occlusion (CRUISE) study was a randomized prospective controlled clinical trial of serial IVRI in 392 patients with CRVO and ME.29 Three groups were compared: 0.3 mg ranibizumab, 0.5 mg ranibizumab, and sham injection. All groups received a baseline and Þve subsequent monthly injections. At 6 months follow-up, the mean change from baseline BCVA letter score was +12.7 and +14.9 for the 0.3- and 0.5-mg ranibizumab groups, respec-

patients who gained 15 or more ETDRS letters were 46.2% and 47.7%, respectively, compared

to 16.9% in the sham group (P < 0.001). The CPT had decreased by a mean of 434 and 452 m, respectively, compared to 168 m in the control group (Fig. 13.13). Beginning at month 6, patients in all groups were followed with monthly examinations and prn treatment with 0.5 mg ranibizumab (Table 13.4 for re-treatment criteria). At month 12, the mean BCVA changes were +13.9 letters for each of the 0.3- and 0.5-mg ranibizumab groups compared to +7.3 letters for the sham group. There were no signiÞcant safety issues with the ranibizumab injections in this trial. With continued, but fewer injections through 2 years, reductions in macular edema and

improvement in BCVA are possible.29 A smaller study of 14 patients showed that monthly IVRI for 3 months followed by variable treatment the Þrst year and a mean of 3.4 IVRIs in the second year produced a mean improvement from baseline in BCVA of +8.5 letters and a mean CPT of 337.7 m at year 2.36

Dosages of ranibizumab used in CRVO include 0.3, 0.5, and 2.0 mg with no evidence favoring one dose over another.236

Fewer patients with CRVO-associated ME can be weaned off intermittent IVRI to reduce or eliminate ME than in BRVO-associated ME. The mean number of IVRIs to treat recurrent ME is

Fig. 13.14 Images of a superior hemicentral retinal vein occlusion that developed in a 71-year-old woman with type 2 diabetes mellitus, hypertension, and primary openangle glaucoma. The VA of the left eye was 20/125. (a) The superior 200¡ of retina is involved with hemorrhages. The hemorrhages extend into the inferonasal quadrant below the horizontal raphe because of a branch retinal vein denoted by the green arrow that drains this region of the retina, yet empties into the superior hemicentral retinal vein. (b) A retina vein to retina vein collateral vessel is seen in this frame from the early phase ßuorescein angiogram (the yellow arrow). (c) In a magniÞed image of the optic disc from the mid-phase ßuorescein angiogram, the relative stagnation of venous ßow superiorly is

indicated by hyperßuorescent foci in the tributaries of the superior hemicentral retinal vein. Optic disc collateral vessels connecting the inferonasal retinal venous return to the choroidal circulation are indicated by the gray arrow. Unlike new vessels, these collaterals do not leak ßuorescein. (d) Frame from the late phase of the ßuorescein angiogram showing superior macular ßuorescein leakage. (e) Three vertical SD-OCT line scans through the macula at different times following the H-CRVO. Five monthly injections of bevacizumab have led to less macular hemorrhage and edema, but incomplete resolution of the edema. The VA on 11/4/2009 was 20/80 and on 6/25/2010 was 20/50. CSMT central subÞeld mean thickness

higher in eyes with CRVO than eyes with BRVO.36 The mean number of IVRIs in the second year of serial ranibizumab therapy was 3.4 for CRVOassociated ME compared to 2.0 for eyes with BRVO-associated ME.36

Lower-level evidence indicates that IVBI is also effective for CRVO with ME. A single IVBI is effective in the short term for reducing ME, subretinal ßuid, optic disc edema, intraretinal hemorrhage, and venous distention, and improving VA in patients with CRVO and associated macular edema.55,117,236,239,263 Serial injections of bevacizumab often reduce macular thickening in CRVO more than one injection, therefore a therapeutic trial of this modality should generally include more than one injection (Fig. 13.14).117 Usually, multiple IVBIs are required to maintain macular deturgescence.117,225,264 One study reported 85% of patients requiring more than one injection over the Þrst year of follow-up.87 The duration of effect of bevacizumab is variable, but a consensus seems to be that the beneÞcial effect lasts no more than 2 months.117 Re-treatment rules for IVBI have been variable and are similar to those suggested for BRVO with ME (Table 13.4). Eyes that develop disc collaterals may need fewer re-treatments than eyes without formation of collaterals.87

The results with intravitreal bevacizumab injections are also favorable (Table 13.7). Pooling Þve studies with a total of 129 eyes that received intravitreal bevacizumab injection regimens for CRVO with ME, the weighted-mean baseline visual acuity was logMAR 1.08 (Snellen 20/238) compared to the weighted-mean Þnal logMAR visual acuity of 0.79 (Snellen 20/123). At a weighted-mean follow-up of 9 months, the difference was +14.5 ETDRS letters Ð similar to the results of the CRUISE study (Table 13.7).55,121,212,225 As with ranibizumab, most patients will need to be reinjected because of recurrent ME after a single injection.55,212,225 The weighted-mean number of injections required to manage eyes with CRVO with ME in the Þve studies of Table 13.7 was 3.3 over 9 months.55,121,212,225

Aßibercept is a fusion protein comprised of the extracellular domains of human VEGF receptors 1 and 2 fused to the constant region of human IgG1. It works as a decoy receptor, binding soluble VEGF and preventing VEGF binding to retinal cell receptors. Aßibercept has a higher afÞnity for VEGF than ranibizumab or bevacizumab. Two parallel randomized controlled clinical trials, COPERNICUS and GALILEO, have been performed but not published as of December 2011 except in Abstract form.19 COPERNICUS

studied 187 patients with CRVO and ME randomized to monthly injections of aßibercept or sham for 6 months with subsequent monthly examinations and aßibercept prn for all patients for an additional 6 months. At month 12, 56% of eyes in the aßibercept group compared to 12% in the sham group gained 15 or more ETDRS letters (P < 0.0001). Mean changes in BCVA were +17.3 letters for aßibercept-treated eyes compared to −4.0 ETDRS letters for sham eyes (P < 0.0001). Serious ocular adverse events occurred in 3.5% of the aßibercept group compared to 13.5% in the sham group. The results of the GALILEO trial were similar.19

Regimens involving serial injections of antiVEGF drugs not only reduce the macular edema, they also reduce the proportion of eyes that go on to intraocular neovascularization and its consequences, presumably because of the antiproliferative effect of the drugs.55,137,236 There is evidence that intravitreal injections of bevacizumab also reduce retinal venous diameter.55

As in BRVO with ME, concerns have been raised that global anti-VEGF blockade could be harmful to eyes with CRVO, perhaps increasing the area of capillary nonperfusion or decreasing shunt formation, as VEGF has functions in maintaining retinal cellular viability.117,137 To date, evidence to support these concerns has not been found.55,225 In one study of 20 patients with nonischemic CRVO treated with serial injections of ranibizumab, disc collateral vessels formed in 50% of eyes over 1Ð24 months, rates and time courses compatible with the natural history of disc collateral formation.236

If frequency of dosing is decreased in an effort to determine if continued need for injections exists, the possibility of recurrence of edema always exists. In such cases, preliminary evidence suggests that increasing the frequency of injections is successful in eliminating recurrent edema.236

The safety proÞle of intravitreal bevacizumab injections has been good. Rates of endophthalmitis, retinal detachment, uveitis, retinal tears, traumatic cataract, vitreous hemorrhage, and systemic side effects such as myocardial infarction and stroke have been low.87,225 There are case reports of central and branch retinal artery occlusions following intravitreal ranibizumab and bevacizumab injections for CRVO. Although associated, no causal connection has been established, but a mechanism was advanced citing reduced nitric oxide production and consequential vasoconstriction following anti-VEGF therapy.178,293 There was no evidence of electrophysiologic toxicity of a single injection of bevacizumab to the retina or optic nerve by full-Þeld ERG, mfERG, or VEP in patients with CRVO.212

Rebound ME after injection of intravitreal anti-VEGF drugs has been described and is estimated to occur in 10.8% of cases.313 The suggestion has been made that treatment too early is associated with this effect and that it may be preferable to allow at least 8 weeks from onset of symptoms before consideration of anti-VEGF therapy to avoid rebound.313

Some studies have examined factors that might predict VA outcomes after intravitreal bevacizumab injections. In two studies, baseline CSMT