and Þnal VA were signiÞcantly correlated.2,113 In one study, younger patient age was predictive of a favorable response to serial intravitreal injections with bevacizumab.2 Factors found not to be correlated with outcome include subretinal ßuid status, intraretinal cyst diameter, and change in retinal thickness induced by repetitive bevacizumab injections.112,113

A combination regimen of IVBI 1.25 mg and IVTI 2 mg given repetitively if needed was effective in treating ME from pooled RVO (eight BRVO and eight CRVO), but no more effective than previously reported results with bevacizumab alone.68

The use of intravitreal injections for CRVO has been increasing. In a study of a random sample from Medicare claims, intravitreal injections were used in less than 1% of CRVOs in 2001 compared to more than 16% in 2006.73 This trend has increased in the subsequent years.

13.4.2.2Combination Regimen: Bevacizumab, Panretinal Laser, and Grid Laser

One pilot study of nine patients without a control group has used a combination regimen of IVBI, PRP, and GL with the rationale that the frequency of intravitreal injections of bevacizumab might be reduced and the lesser effects of PRP and grid laser might be synergistic in beneÞcially affecting intraocular VEGF levels and ME.252 The mean baseline VA was 20/320 compared to a mean Þnal VA of 20/63. No patient had recurrence of ME over follow-up of at least 18 months.252 No eye converted from nonischemic to ischemic CRVO during follow-up and no patient developed optic disc collaterals, suggesting to the authors that in an unspeciÞed manner, venous drainage was likely improved as the natural history rate of collateral formation is higher.252 Further study in larger samples with a control group is needed to test these suggestions.

13.4.2.3 Systemic Corticosteroids

Corticosteroids have been used to treat both inßammatory and noninßammatory components involved in CRVO with ME, to stabilize the

bloodÐretina barrier, and to inhibit VEGF expression.108,192,298 Systemic corticosteroids have anecdotally been associated with clinical improvement in cases of nonischemic CRVO.100,108,254 The typical regimen described has been to use oral prednisone 1Ð1.5 mg/kg/day with gradual tapering of the dose once the VA has improved. The objective is to reach the lowest dose maintaining visual improvement.100 Some patients are nonresponders.108 The disadvantage of systemic corticosteroid therapy is the wide range of adverse side effects including weight gain, fat redistribution, osteopenia, mood change, and altered facies.100 With the advent of anti-VEGF therapy, systemic corticosteroids are rarely used.

13.4.2.4Posterior Subtenon’s Triamcinolone Injection

PSTI has been used to treat ME associated with CRVO soon after symptom onset.9,165 A single injection reduced ME for 1 month in CRVO compared to untreated controls.9 In an uncontrolled prospective study of 18 patients, three biweekly injections of 4 mg triamcinolone were associated with VA improvement from a baseline mean of 37 ± SD18 ETDRS letters (~20/200) to a 9-month follow-up mean of 59 ± SD23 ETDRS letters (~20/70) (P < 0.001). Mean CSMT improved from 566 ± SD42 to 210 ± 30 m (P < 0.001).165 Sixteen percent of patients had recurrence of ME, 11% required topical glaucoma drops for elevated intraocular pressure, and no patient was noted to have progression of cataract. For certain patients, this modality may have a favorable side effect proÞle compared to IVTI, but the absence of prospective randomized comparative trials is a drawback. It has not been adopted widely.100

13.4.2.5 Intravitreal Corticosteroids

Many case reports and case series suggested that the intravitreal injection of triamcinolone in doses ranging from 1 to 25 mg might be effective in the treatment of ME associated with CRVO.61,126,133,297 In a small series, short-term improvement in VA and decrease in retinal ßuorescein leakage by ßuorescein angiography were observed.126,139 A small prospective randomized clinical trial of

27 eyes likewise found intravitreal triamcinolone to be associated with suggestive beneÞcial effects on macular thickness and VA, but was underpowered to be conclusive.229 This led to the SCORE study, a randomized controlled clinical trial comparing serial 1 and 4 mg triamcinolone injections based on re-treatment criteria to sham injections.281 The primary outcome measure was the proportion of eyes gaining 15 or more letters at 1 year. Twenty-seven percent and 26% of eyes in the 1- and 4-mg groups, respectively, gained 15 or more letters compared to 7% in the sham group. A smaller percentage of eyes in the 1-mg group required initiation of glaucoma drops by 12 months (20% vs. 35% for the 1- and 4-mg groups, respectively). Re-treatment was given every 4 months unless the macular edema had resolved or treatment was futile. Futility was deÞned as two consecutive intravitreal injections without at least improvement in VA by Þve ETDRS letters or a reduction in retinal thickening of 50 m and at least 20% of the retinal thickening at the start of the period assessed for futility.281 Because of similar efÞcacy of the 4 and 1 mg doses, but a superior proÞle of side effects with the 1 mg dose, serial 1 mg intravitreal triamcinolone injections were recommended for the treatment of ME associated with CRVO.

In the SCORE CRVO study, prognostic factors for VA outcome were younger age, lower macular thickness, smaller area of retinal hemorrhage, smaller area of macular thickening, and less ßuorescein leakage.250 Prognostic factors for OCT outcomes were younger age and higher baseline VA letter score.250

Various other doses of triamcinolone have been used up to a maximal dose of 25 mg.126,297 The duration of action depends on the dose injected with higher doses lasting longer.262 It also depends on the status of the vitreous with shorter duration of action in vitrectomized eyes and more elderly patients with greater vitreous liquefaction.49,139 Triamcinolone crystals are visible in the vitreous cavity for a mean interval of 142 ± SD 140 days after intravitreal injection, and a pharmacokinetic model predicts an active concentration in the human vitreous cavity of 140 ± SD 17 days.11,139 Some pharmacodynamic

effect is commonly evident for 6 months or longer, although reinjection after 3 months as effects wane and edema recurs is common clinical practice.139 In one study allowing prn reinjections, the mean duration between injections was 4.1 months (range 2Ð9 months).297

Cataract development or progression is predictable after IVTI, and intraocular pressure elevation occurs in 30Ð61% at anywhere from 1 day to 8 months after the injection.51,126,133,297 Most cases of intraocular pressure rise can be successfully managed with topical hypotensive agents, but in up to 2.9% of cases it may be necessary to perform vitrectomy to remove the steroid from the vitreous or trabeculectomy or a tube-shunt procedure to lower the pressure surgically.51,133,297 Higher doses of intravitreal triamcinolone are associated with intraocular pressure rises that are more difÞcult to control.51 The risk of pressure rise with intravitreal injection of triamcinolone may be higher in patients with CRVO and ME because a greater proportion of such patients may have glaucoma as a risk factor than, for example, patients with diabetic macular edema.297 Young adults with CRVO may have unusually large swings in diurnal intraocular pressure, representing a status as latent glaucoma suspects unusually predisposed to a steroid pressure response.48

Fluocinolone implants releasing 0.5 mg/day for up to 3 years have been evaluated in nonischemic CRVO with ME. At 12 months, the median VA improved 2.5 lines, and the median baseline macular thickness decreased by 382 m, both of which were statistically signiÞcant changes. However, IOP increased in 92% with 29% requiring surgical therapy. All phakic eyes had cataract progression.228

A dexamethasone drug-delivery system that produces a fairly constant intraocular concentration of dexamethasone for up to 180 days has been studied in a prospective randomized clinical trial of patients with macular edema from various etiologies including BRVO and CRVO. The eyes with BRVO and CRVO were pooled for analysis in this study. The primary outcome was the percentage of patients with ten or more ETDRS letters improvement at 90 days. For the pooled group of 35 patients with RVO receiving the