inconvenience, or cost of treatment outweighed the perceived beneÞt.89,144

Adjuncts to IVBI have been tested to see if they increase efÞcacy. In a comparative case series of 17 patients treated with IVTI 4 mg, 14 patients treated with IVBI 1.25 mg, and 21 patients treated with IVTI 2 mg plus IVBI 1.25 mg, similar reductions in ME and improvements in VA were achieved in all groups at 1 month, but the IVBI monotherapy group had superior VA outcomes at 6 months.39

The local risks of intravitreal injections are endophthalmitis, sterile uveitis, retinal detachment, cataract, and vitreous hemorrhage. The rates of these complications are not higher with anti-VEGF drugs than with other intravitreal injections.144,243 Some case reports have suggested that intravitreal anti-VEGF injections may be associated with central and branch retinal artery occlusions.178,293 The concerns that bevacizumab, a drug not speciÞcally designed for use intraocularly, might be associated with an increased incidence of iritis seem unfounded after extensive use.314 Based on mfERG, full-Þeld ERG, and pattern VEP measurements before and after a single dose of bevacizumab for BRVO with ME, there was no electrophysiologic evidence of retinal or optic nerve toxicity.212 The systemic absorption of intravitreal anti-VEGF injections is low, but not zero, and systemic risk of increased thromboembolism is low.

A case report describes a patient with BRVO and macular edema in one eye and neovascular macular degeneration in the fellow eye. Treatment of the fellow eye with either bevacizumab or ranibizumab caused transient reductions in macular edema in the eye with the BRVO, suggesting some systemic absorption to account for the contralateral eye effect.307

While there are theoretical concerns of differential systemic risks with ranibizumab and bevacizumab based on molecular weight and dosage injected, in actual clinical experience, no clear signal for a difference in risk has been detected. A suggestion has been made in a case report that intravitreal bevacizumab may be associated with erectile dysfunction, but the quality of the evidence is weak.316

Although both GL and anti-VEGF injections are effective in treating BRVO with ME, few studies have compared GL and anti-VEGF injection therapy. One small trial comparing IVBI and GL found that IVBI was superior.243 Despite the paucity of head-to-head trials, based on the effect sizes of the two treatments, the consensus is that anti-VEGF therapy with either bevacizumab or ranibizumab is superior to GL for ME associated with BRVO.36,243 In age-related macular degeneration, a disease in which intraocular VEGF concentrations are generally lower than in RVO, treatment of subretinal neovascularization with the IVBI and IVRI using identical injection schedules had equivalent efÞcacy.38 Given the high cost differential between the two drugs, a head-to-head trial in BRVO will be important in the future, given scarce economic resources.

The high recurrence rate, short-term effectiveness, and high cost are the main drawbacks of intravitreal injections of anti-VEGF drugs.205 Intravitreal anti-VEGF therapy may have some ancillary beneÞts such as prevention of secondary retinal and disc neovascularization, but a study to test this hypothesis has not been done.243 The use of intravitreal injections for BRVO and ME has been increasing. In a study of a random sample from Medicare claims, intravitreal injections were used in less than 1% of BRVOs in 2001 compared to more than 13% in 2006.73 This trend has increased in subsequent years.

13.4.1.5Posterior Subtenon’s Triamcinolone

Posterior subtenonÕs triamcinolone injection (PSTI) of 20Ð40 mg has been used to treat BRVO with macular edema.99,134,135 PSTI, 20 mg, was used in a case series of 50 patients with BRVO and ME but no foveal ischemia.135 With mean follow-up of 17 months, improvement in logMAR visual acuity of 0.2 log units or greater was found in 44%. Mean baseline OCT-measured macular thickness of 607 ± SD 193 m improved at 3 months follow-up to 301 ± 140 m. Of the 50 eyes, 74% required more than one injection due to recurrence of macular edema, and 24% were eventually treated with pars plana vitrectomy

because of recurrent macular edema.135 Another study used a regimen of three PSTIs separated by 2 weeks and starting 1 week after grid laser photocoagulation. For the 25 eyes so treated and followed for 3 months, VA did not change

change signiÞcantly (388 ± 178 vs. 316 ± 158 m, P = 0.2139).99 The results of this treatment regimen were also less effective than a single IVTI 4 mg at 3 months follow-up both with respect to VA improvement and reduction in macular thickening as determined in a randomized controlled clinical trial of 52 patients.99 After 3 months, 76% of the patients receiving PSTI required repeat posterior subtenons or intravitreal triamcinolone injection because of recurrence of macular edema.99

A particularly useful application of this technique is the patient with a BRVO and ME who has previously undergone vitrectomy surgery. Kawaji and colleagues described 20 such cases treated with 20 mg of posterior subtenonÕs triamcinolone. Seventy percent of the cases gained 0.2 logMAR units or more of VA at 6 months followup. Mean foveal thickness improved from 499 ± 209 m at baseline to 197 ± 92 m at 6 months follow-up (P < 0.0001). The technique circumvents the problems of invitreal injections in a vitrectomized eye in which drug elution is accelerated.134

PSTI is associated with intraocular pressure elevation, ptosis, and herpetic epithelial keratitis.57,63,97,187 Elevated intraocular pressure has been reported in 7Ð23% of the patients receiving PSTIs with 4% requiring trabeculectomy to control pressure.99 The frequency of IOP of 30 mmHg or more is lower after PSTI than IVTI, and fewer glaucoma medications are required typically to control elevated IOP after PSTI.110

13.4.1.6 Intravitreal Corticosteroids

Several uncontrolled studies have shown that intravitreal triamcinolone injection in doses from 1 to 25 mg temporarily reduces macular thickening and improves VA in BRVO with ME at the price of an increased risk of elevated IOP (20Ð40%), a

1Ð2% risk of requiring incisional glaucoma surgery, a 15Ð20% risk in phakic patients of requiring cataract surgery within 1 year, and the need for repetitive injections when the initial effect

wears off.20,34,42,46,61,99,124,125,127,132,145,210,211,292 Similar

results have been obtained whether there is foveal capillary border irregularity or not.42

The Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) BRVO study compared grid laser and serial 1 and 4 mg IVTIs based on re-treatment criteria for ME associated with BRVO.281 The primary outcome measure was the proportion of eyes gaining 15 or more letters at 1 year. Twenty-nine percent, 26%, and 27% of eyes achieved this outcome in the grid laser, 1- and 4-mg groups, respectively. A secondary outcome was mean ETDRS letter change at 12 months. The change was 4.2, 8.0, and 5.0 letters for the grid laser, 1- and 4-mg groups, respectively (P = 0.70). Without any improvement in visual outcome, and with the adverse side effect of inducing intraocular pressure rises (7% and 41% of eyes in the 1 and 4 mg triamcinolone groups, respectively, compared to 2% in the grid laser group), the study showed that GL remains the standard of care and the benchmark therapy against which new contending improved therapies must be compared.281 An additional negative effect of triamcinolone therapy was progression of cataract found in 25% and 35% of the 1- and 4-mg groups, respectively, compared to 13% in the GL group over the course of 1 year followup.281 The mean numbers of intravitreal triamcinolone injections given in 12 months in the SCORE study were 2.2 and 2.1 for the 1- and 4-mg groups, respectively.281 In some cases, especially in postvitrectomy eyes, a syndrome of pseudoendophthalmitis may be seen characterized by a layer of triamcinolone crystals that pool in the anterior chamber angle that may simulate a hypopyon.43 Patients generally have no pain, and if treated as though they have endophthalmitis with vitreous culture and intravitreal antibiotic injections, the cultures are negative. Estimates for the frequency of this complication are lacking.240

Although the average patient fares better with GL than with IVTI, there may be a role for IVTI in cases unhelped by GL or with clearly ischemic

macular edema, for which GL has not been proven effective in a randomized clinical trial.42,210 No randomized clinical trials have demonstrated efÞcacy of these injections compared to a control group, but uncontrolled studies suggest that a treatment effect, if short lived, does exist. In an uncontrolled case series, suggestive evidence was given that visual outcomes were superior if treatment was given before 3 months after onset of symptoms than after 3 months.203

Various dosages of intravitreal triamcinolone have been used for BRVO with ME ranging from 1 to 25 mg. Generally, the duration of action of drug increases with increasing dosage. A single dose of 4 mg frequently lasts 2.75 months and can last 6 months. A dose of 25 mg can last 9 months.124,127 The half-life decreases in a vitrectomized eye and is lengthened in eyes of younger patients with more formed vitreous gels and in eyes with silicone oil Þlling the vitreous cavity.124,139

Risk factors for elevated pressure after IVTI include diagnosis of glaucoma and higher baseline IOP. A history of previous vitrectomy is associated with a lower IOP after IVTI.292

A retrospective nonrandomized comparative trial of serial IVTI (n = 16) versus IVBI (n = 13) with follow-up of at least 6 months suggested roughly equal efÞcacy in reducing macular thickening and improving VA, but more adverse effects were found with IVTI and higher cost with IVBI.47 With triamcinolone therapy, mean VA improved from 0.77 ± .45 to 0.39 ± .32 and CSMT from 534 ± 164 to 254 ± 80 m. With bevacizumab therapy, mean VA improved from logMAR 0.99 ± 0.48 to 0.35 ± .32 and CSMT from 539 ± 190 to 222 ± 37 m. On neither VA nor CSMT did the results differ to a statistically signiÞcant degree.47

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. BRVOs and CRVOs were pooled in the report. The primary outcome for the study was the percent of patients with ten letters or more improvement at 90 days. For the pooled group of 35 patients with RVO receiving the 700 mg implant, 31% had ten

or more letter improvement at 90 days compared to 15% of 34 patients in the control group, a result similar to the overall study result for all eyes that reached signiÞcance with P < 0.001.155

A phase one study of intravitreal triamcinolone delivered using a biodegradable, liquid sus- tained-delivery system was used in a sample of patients pooling BRVOs and CRVOs with macular edema.164 Use of the drug was associated with decreased macular thickening 360 days after injection. Intraocular pressure elevation occurred in three of ten eyes.164

Most cases of intraocular hypertension occurring after intravitreal injection of steroids can be managed by topical hypotensive therapy, but argon-laser trabeculoplasty is also effective, and rarely incisional surgical therapy is necessary.233

Prognostic factors for the VA outcome in the SCORE study were younger age and absence of coronary artery disease.250 Prognostic factors for OCT outcomes were younger age, lower baseline VA letter score, presence of dense macular hemorrhage, and no prior grid laser photocoagulation.250 These prognostic factors came from analyses pooling both the standard care (GL) and the IVTI arms of the trial.250 In a separate study, nonresponders to IVTI had higher aqueous levels of VEGF and IL-6 and had greater ischemia.214

In view of the results from the SCORE study, IVTI for BRVO with ME has largely been abandoned as a Þrst-choice therapy. However, because IVTI is efÞcacious in some eyes, not all eyes respond to GL, and some eyes respond to bevacizumab but respond with a greater decrease in edema to triamcinolone, it is still a useful treatment to have available when clinical circumstances dictate.89

13.4.1.7Combination Treatments Involving Intravitreal Triamcinolone Injections

The SCORE BRVO study showed that serial intravitreal triamcinolone injections are inferior to GL for ME associated with BRVO. However, what about a treatment regimen that combines intravitreal triamcinolone injection with GL? In a small case series in which GL was followed by IVTI if

VA did not improve by at least two lines, the authors reported no improvement in VA and only a 1-month reduction in macular thickening.34

A combination injection regimen employing both IVTI 2.0 mg and IVBI 1.25 mg in pooled BRVOs and CRVOs with ME reported no better visual results than with serial IVBI over 6 months.68 Elevated intraocular pressures were found in 31% of eyes treated with this regimen, a percentage similar to that reported with IVTIs alone.68

13.4.1.8 Arteriovenous Sheathotomy

Arteriovenous sheathotomy (AVS) was Þrst described as a treatment for BRVO with ME by Osterloh and Charles.208 Since that time there have been many variations described Ð with vitrectomy, with internal limiting membrane peeling (ILMP), with IH, with incomplete separation of the artery from the vein, with intraoperative IVTI, and

with GL after surgery.77,158,159,179,184,190,202,206,237,257,302

Although it is likely that these variations change outcomes, this section pools all studies in which AVS is the main intervention.

AVS was associated with a decrease in the circulation time to the involved retina in 61% of cases in one study, but the natural history of the ßuorescein circulation time in BRVO is unknown, and so it is not possible to say whether this represents an effect of the sheathotomy.

However, in another series, the improvement in retinal blood ßow to the affected area after AVS was not sustained at 1 month.114 Successful AVS can be followed by disappearance of collateral vessels.190 Improvement in perfusion after AVS has been correlated to having the conventional anatomy of the artery above the vein. Cases with the vein above the artery were less successful in this regard, although the numbers studied were small.309

The area of the FAZ did not increase 1 year after AVS for BRVO with ME in one series.151 Because the natural history of the FAZ area in such cases is unknown, the effect of AVS cannot be deduced.151 In another series, improved foveal capillary circulation compared with baseline was observed.179

Case series are consistent in showing that ME can be reduced with AVS, but inconsistent in showing that VA improves. Moreover, complications can be severe, including epiretinal membrane in up to 75% and retinal detachment in up

to 14%.12,33,114,179,184,190,202,206,257,310 Mean time for

edema resolution and stabilization of VA improvement after AVS has been reported to be 9 months.77 The technique seems to be effective for reducing ME in the less-common case where the vein crosses over rather than under the arteriole.237 Some studies have reported improvement in VA with AVS that occurs more slowly than does VA improvement after IVTI.53 Recurrences of ME after an initial decrease following surgery has been reported.257

Various factors have been associated with better results after AVS including shorter duration of BRVO, younger patient age, ILMP, better capillary perfusion preoperatively, and a higher preoperative vitreous IL-6 concentration.184,202,257 Many authors have suggested the need for a prospective randomized clinical trial of this approach to determine whether it is warranted, but none has been done, and its place in the management of BRVO remains conjectural.56,309,310

There is limited information regarding longterm follow-up of eyes with BRVO and ME receiving AVS. In one case series of Þve eyes with baseline VA of less than 20/200 followed for a mean of 6.5 years, the BCVA improved to 20/70 or better in four cases and remained poor in one case.251 One case of a macular BRVO followed for 5 years had improvement of vision from 20/63 to 20/20 and return of fundus appearance to normal.302 In a series of 20 eyes followed for a mean of 14 months, the average VA improvement was 4.55 Snellen lines.179 In a series of eight patients followed for a mean of 34.5 months, Þnal VA did not improve signiÞcantly compared to baseline VA.190

AVS has been combined with simultaneous IVTI in several series, sometimes with favorable results, but the small number and uncontrolled nature of the studies prevents extrapolation regarding efÞcacy. AVS has also been combined with intravenous administration of edaravone, a free radical scavenger developed as a neuroprotective drug. In an uncontrolled series of