Isovolumic hemodilution is thought to work by decreasing blood viscosity, which has been associated with both CRVO and BRVO.286 Decreased viscosity of the blood is thought to improve retinal blood ßow and retinal oxygenation.

Plasmin is a serine protease involved in the Þbrinolysis biochemical pathway. It leads to proteolysis of Þbrin, laminin, and Þbronectin, and when injected into the vitreous produces a posterior vitreous detachment (PVD).245 This action may provide the beneÞts of vitrectomy for ME associated with RVO but without the risks of surgery.245

Tissue plasminogen activator (TPA) is a thrombolytic agent with a high afÞnity for Þbrin. It splits plasminogen to plasmin almost exclusively in Þbrinclots.ItsadvantagesovertheolderÞbrinolytic agents streptokinase and urokinase include lack of antigenicity and higher efÞcacy in lysing older thrombi.83 Intravitreal injection of TPA may work by a thrombolytic mechanism, by inducing a posterior vitreous detachment, thus improving intravitreal oxygen concentration, or by a combination of both mechanisms. If it does work by a thrombolytic mechanism, it must diffuse through the vitreous, the intervascular retina, and the retinal venous wall, a phenomenon that has not been demonstrated. In fact, experimental evidence in rabbits suggests that does not occur.83,131,245

A fraction of patients with macular edema do not respond to treatments designed to reduce the edema, hence the frequent reports of patients who have undergone a series of methods of treatments.209 Therefore, futility of treatment applies to a small but unfortunate fraction of patients with RVO. The deÞnition of futility varies across physicians, patients, and over time in any particular patient.

13.3.2Treatments for Intraocular Neovascularization

Panretinal photocoagulation (PRP) for proliferative retinopathy after RVO presumably works by raising the oxygen concentration of the inner retina and lowering the intraocular level of VEGF in analogy to what occurs after PRP for proliferative diabetic retinopathy.5 Aqueous levels of VEGF drop after

PRP for ASNV in RVO.23,166 Oxygen diffuses from the choroid through the photocoagulation scar to the hypoxic inner retina, thereby raising its oxygen concentration (Fig. 13.2).7,265,267,269 Sector PRP constricts retinal veins and collateral veins in the treated sector of the retina.81,172 Laser photocoagulation can downregulate VEGF and upregulate the expression of PEDF, which can antagonize the effects of VEGF and stabilize the bloodÐretina barrier.172,201 Sector PRP has also been described as an effective treatment for serous macular detachment from BRVO involving the midperipheral retina and not the macula. In this case, presumably the PRP improves outward pumping of subretinal ßuid by the retinal pigment epithelial pump.273

Intravitreal injections of anti-VEGF drugs cause regression of intraocular neovascularization by blocking the angiogenic actions of VEGF.6,17,173

Vitrectomy causes regression of posterior segment neovascularization after RVO by removing the vitreous scaffold.242,315 In the absence of some other interventions such as PRP or intravitreal injection of an anti-VEGF drug, the tendency of eyes with signiÞcant retinal ischemia to develop anterior segment neovascularization (ASNV) persists despite vitrectomy.

13.4Results of Clinical Studies of Treatments for Macular Edema Secondary to Retinal Vein Occlusions

13.4.1 Branch Retinal Vein Occlusion

13.4.1.1 Grid Laser

Grid laser for ME after BRVO has been done mostly with the argon green laser (514 nm), but similar techniques with similar results have been reported with the diode laser (810 nm) and the krypton laser (647 nm).70,219 Many early uncontrolled series suggested a beneÞcial treatment effect of GL.22,35,123,148 A small randomized clinical trial, however, showed no beneÞcial effect of argon-laser grid photocoagulation.255

To settle the issue of efÞcacy, a randomized controlled clinical trial known as the Branch Vein Occlusion Study (BVOS) was done. In the BVOS, GL photocoagulation was withheld for at least 3 months after onset of symptoms because spontaneous improvement of macular edema and VA can occur in 20Ð40% of cases.70,107,144,277 The delay was frequently longer because of the need for sufÞcient clearing of hemorrhage to allow ßuorescein angiography (FA) for assessment of capillary perfusion and application of GL. In one study, the average time between BRVO diagnosis and GL was 5.8 months.71 In the BVOS, eyes with macular capillary nonperfusion, progressive decrease in

BCVA, and eyes with marked CME were speciÞcally excluded.78,277 No eye was treated until the macular hemorrhage had cleared sufÞcient to grade an FA for ischemia.277

In the BVOS, GL burns were prescribed to be 100 m in diameter.277 Burns were speciÞed to involve the entire area of ME but to extend no closer to the center of the macula than the border of the foveal avascular zone (FAZ) and were not to extend further from the macula than the associated major temporal vascular arcade (Figs. 13.5 and 13.6). Burns were spaced one burn width apart over the area of the grid. The number of burns needed for a treatment depends on the size

Fig. 13.5 A 56-year-old man with macular BRVO and best corrected visual acuity of 20/30 had macular edema. (a) A few microaneurysms are seen superotemporal to the macula of the right eye. (b) A frame from the mid-phase ßuorescein angiogram shows hyperßuorescent microaneurysms and some dilated capillaries superotemporal to the foveal avascular zone. (c) A frame from the late-phase ßuorescein angiogram shows petalloid hyperßuorescence in the area of the microaneurysms. (d) A red-free, magniÞed view of the macula before the application of grid laser on 11/18/2010 is useful as a comparison with

posttreatment photographs in (e, f). (e) A posttreatment, red-free photograph of the macula taken on 3/24/2011 shows faint laser scars and some shrinkage of some microaneurysms and enlargement of others. (f) A posttreatment color photograph shows faint laser scars (the arrows). Bevacizumab on 3/24/2011 did reduce edema, and vision improved to 20/20. (g) A baseline line-scan OCT shows macular thickening. (h) A line-scan OCT 4 months after grid laser shows persistent macular thickening. (i) A line-scan OCT one month after bevacizumab shows incomplete resolution of the macular thickening

309

381

292 417 400 359 323

375

300

ILM-RPE thickness ( m)

f

g

h

i

Fig. 13.5 (continued)

Fig. 13.6 Appearance of argon green grid laser photocoagulation treatment immediately after the procedure. Burns are recommended to be made with the 100-m spot diameter setting, to be 0.1 s in duration, and of power sufÞcient to give a medium white burn. Grid laser covers the area of thickening from the edge of the foveal avascular zone to as far peripheral as the major vascular arcade186

315

384

292407 399 359 322

375

292

ILM-RPE thickness ( m)

of the edematous area, but one study in which 19 patients received grid laser reported that 65 ± SD8 burns were necessary to cover the area.219

In the BVOS at the end of 3 years of followup, 65% of treated eyes gained two or more Snellen lines of VA, and 60% attained 20/40 or

better VA. In the untreated control group, the comparable percentages were 37% and 34%, respectively. The mean change in VA in the treatment group was 1.3 lines of VA. The treatment effect was smaller for eyes with poorer baseline VA. Hypertension had a suggested negative inßuence on the effect of grid laser. Patients had a larger treatment effect if they were treated within 1 year of onset of the occlusion, but treatment was beneÞcial when given past 1 year.277

The consensus of the BVOS was that GL should be performed in eyes with ME of at least 3 months duration and a VA of 20/40 or worse with an FA showing capillary perfusion and absence of blood involving the fovea.277 The BVOS provided the basis for GLs serving as the standard treatment of ME associated with BRVO from 1984 to 2010, when the better results of intravitreal ranibizumab injections (IVRI) compared to placebo in the BRAVO study led to a shift away from GL, despite no head-to-head trial of IVRI versus GL.

The time course for thinning of the macula after GL is generally 3Ð6 months.219 If measurements are made in the Þrst 3 months, there may be early paradoxical increased thickening of the macula.58 Sometimes treatment must be repeated because of persistence of ME. In the BVOS, the mean number of treatments given over 3 years was 1.4, and the range of number of lasers given was 1Ð5.71,277 Some cases of macular edema resolve more slowly after grid laser and may take 12 months.195,277 It is controversial whether to persist with further grid laser treatment or switch to an alternative therapy. The argument against waiting longer is that long persistence of macular edema could lead to a poorer prognosis.195

It is probable that the execution of GL has changed over the past 25 years with smaller, lighter spots in analogy to the treatment of diabetic macular edema.62 GL for BRVO with ME is also probably given more frequently now than at the time of the BVOS. For example, in the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) BRVO study, the median number of GL treatments for the Þrst 12 months was 1.5, a higher number than in the BVOS. This was so, even though in the SCORE study 28% of eyes had dense macular hemorrhage and could not receive grid laser at baseline,

but had to wait for clearing of the hemorrhage to allow application of laser.281

Re-treatment criteria for GL have changed over time. There were no OCT criteria at the time of the BVOS, but in the SCORE study, eyes were reevaluated at 4-month intervals and retreated unless the OCT CPT was less than 225 m, the VA was 20/25 or better, maximal GL had been given, or there had been two consecutive GL treatments with a macular thinning response less than 50 m and less than 20% of the macular thickening present at the start of the interval considered.281 In eyes not retreated by these criteria, GL was deemed futile.281

The SCORE BRVO study provides outcome information for eyes with BRVO treated with contemporary-style GL. The mean changes in VA at 1, 2, and 3 years were 4.2, 11.3, and 12.9 ETDRS letters.281 The percentages of eyes with complete resolution of OCT-measured macular edema as assessed by center point (CPT) thickness (i.e., CPT < 250 m) at 1, 2, and 3 years were 53%, 67%, and 73%, respectively. Median CPT at 1, 2, and 3 years was 354, 233, and 171 m, respectively, from a baseline median of 501 m.281 In another study using a contemporary version of the BVOS regimen, 82% of the eyes had resolution of macular edema by clinical examination after an average follow-up of 17.5 months.71

The chance of improvement with more than one GL treatment when eyes have persistent ME is predicted by the response to the Þrst GL treatment.71 In one study, if the response to the Þrst laser treatment was improvement or stable VA, then a positive VA response to additional GL treatments was predicted.71 Conversely, if a patient demonstrated worsening of VA of two or more Snellen lines, only one-third improved by two or more Snellen lines from the baseline VA if further GL was given.71

Although the BVOS proved the efÞcacy of grid laser for BRVO with macular edema, this result was not replicated in a single-center randomized controlled trial conÞned to macular BRVO in which the treatment produced outcomes no better than controls.218 In another study of GL for macular BRVO with ME by the same group, the issue of treatment timing in patients with macular BRVO and macular edema was addressed. One hundred thirty-seven eyes were randomized to observation, early GL (3 months

after diagnosis), or delayed GL (6Ð18 months after diagnosis). After 2-year follow-up, the visual outcomes were not different among the three groups.18 It is therefore possible that the conclusions of the BVOS apply more to eyes with major BRVO with ME than to macular BRVO with ME.

One possible reason for the modest efÞcacy of GL for ME in BRVO is the unsuspected presence of subretinal ßuid present in 29Ð71% of cases (see Chap. 7).142,196 Subretinal ßuid may prevent laser treatment from achieving the desired visual end point of a light gray burn. The operator may treat more heavily to obtain an end point and may impair the outcome.142 Combining GL with pharmacologic pretreatment to dry up the subretinal ßuid may address this obstacle, but has not been tested in clinical trials.142

The BVOS speciÞcally excluded eyes with macular ischemia. However, in a different study, GL was applied to such eyes. In eyes with macular BRVO and ME that had disruption of 25Ð50% of the FAZ border in 88Ð90% of cases, VA or resolution of edema was no better in the treatment group than in the control group.218 An earlier study with a less precise deÞnition of macular ischemia and broader inclusion criteria that allowed major BRVO with ME also reported that GL for ME in the presence of macular ischemia was ineffective in improving VA, although ME reduction was achieved.255 Together with evidence that ischemic macular BRVO with ME often shows spontaneous resolution of edema and improvement in VA, there is little rationale to apply GL to such eyes.78

Grid laser treatment has been combined with laser treatment to the arteriole feeding the involved sector of retina, so-called arterial crimping, with a suggestion of greater efÞcacy than grid laser alone.70,123 The underlying idea is to reduce arterial inßow, thereby reducing the intraluminal pressure in the damaged capillaries of the involved sector. To accomplish this, laser spots are applied to the arteriole feeding the occluded area at one-half disc diameter intervals using a spot diameter greater than the arteriolar width and sufÞciently intense to constrict the arteriole. In a randomized trial of 72 eyes, there was a suggestion of improved resolution of ME

with grid laser together with arterial crimping. Statistical signiÞcance was not achieved.61

In addition to its use in ME, GL has been proposed as a treatment for serous retinal detachment of the macula and extramacular retina in cases of ischemic BRVO.220 In a prospective randomized clinical trial of 31 patients with this condition treated followed for 24 months, GL was associated with improved visual and anatomic outcomes. In the GL group, 40% of eyes gained three or more Snellen lines of VA compared to none in the control group. The mean difference in subretinal ßuid resorption time was 9.1 months for the GL group compared to 15.8 months in the control group.220

A disadvantage of GL is that it must be withheld until hemorrhage has cleared enough to assess ßuorescein angiography and apply the treatment. During this time, there may be damage to the retina from the edema. In contrast, intravitreal injection therapy, vitrectomy, or AVS can be administered during the acute phase when there may be a greater chance of salvaging viable retinal tissue.53 Another disadvantage is that the treatment is inherently destructive and can induce paracentral scotomata, enlarging scars, secondary choroidal neovascularization, diffuse subretinal Þbrosis, and worsening visual Þeld sensitivity.30,80,122,163,247,270 Finally, GL has a modest treatment effect to reduce ME, and many patients fail to respond and must be treated with other techniques.210

Although the BVOS demonstrated better results than observation for a regimen with at least 3 months of observation after the acute BRVO, others have advocated and reported case series with grid laser applied within a week of presentation.188 In the absence of a control group, the interpretation of the results is difÞcult, and early intervention with GL has not been adopted or tested in a clinical trial.

Some patients receiving intravitreal injections of anti-VEGF drugs for BRVO with ME desire less frequent injections, and for such patients, the application of grid laser has been offered for the purpose, although whether this alternative treatment truly reduces the need for further anti-VEGF drug injections has not been demonstrated.89

A cost-effectiveness study for treatment of macular edema associated with BRVO showed that treatment was worthwhile. The study found