15.2 Failed and Unadopted Treatments for Central Retinal Vein Occlusion

damage, but IVIs were associated with ophthalmoscopic and electroretinographic toxicity at dosages greater than 50 mg.4,27 Evidence from a rabbit model suggests the arginine in the vehicle may be toxic to the retina.30 There have been reports of retinal toxicity with the use of subretinal TPA in humans.8

In humans, IVI of less than 25 mg has been recommended to avoid toxicity, but studies have not adhered to this limit.8,28 A study of IVI of TPA in dosages of 75–100 mg together with daily subcutaneous injections of low molecular weight heparin for 7 days showed no adverse side effects but no dramatic improvement in outcome compared to the expected natural history. Some studies do not report doses in micrograms but rather in international units (IU); for example, Murakami and colleagues used 40,000 IU in eyes with BRVO and ME.41,42 In this study of 17 eyes with BRVO and ME, mean logarithm of the minimum angle of resolution (logMAR) VA improved from 0.603 ± 0.327 at baseline to 0.359 ± 0.319 at 6 months follow-up. Mean foveal thickness decreased from 738 ± 156 to 253 ± 164 m.41 Improvement of 0.2 logMAR units or more was reported in 59% and deterioration of 0.2 logMAR units or more in 12% at 6 months.41 Electroretinograms performed in 8 of 17 patients showed no evidence of toxicity.41 One study combined vitrectomy and intravitreal TPA but without evidence that this modification represented an improvement.9 A randomized clinical trial would be necessary to prove efficacy, and the fact that none has been initiated indicates lack of enthusiasm among investigators for this treatment modality.20

15.1.5Macular Puncture for Branch Retinal Vein Occlusion with Macular Edema

In refractory ME with cysts associated with BRVO and CRVO, a technique called cystoid puncture has been described. In this method, a

vitrectomy is performed followed by drainage of macular cysts with a 39-gauge cannula. In a case series of seven patients with median follow-up of 234 days, the edema resolved in all cases but the VA did not improve.51 This treatment has failed from lack of efficacy regarding VA and its relative invasiveness.

15.2Failed and Unadopted Treatments for Central Retinal Vein Occlusion

15.2.1Grid Laser for Macular Edema in Central Retinal Vein Occlusion

In the Central Vein Occlusion Study (CVOS), a subgroup of 155 patients with ME on FA and clinical examination was studied. Patients had duration of occlusion of 3 months or more, and VA (VA) of 20/50 or worse. Eyes were randomly assigned to either argon laser grid photocoagulation or observation. Ninety-five percent of the eyes had 1 year or more of follow-up. Grid laser treatment reduced ME as assessed by FA. Whereas 100% of control group patients had ME at 12 months, only 31% of patients in the grid laser group did. However, there was no significant difference in the VA between the two groups at 12 months. There was a trend toward VA improvement in the subgroup of patients who were 65 years old or younger, but the trend did not reach statistical significance. It is possible that the CVOS was underpowered to show a true beneficial effect of grid laser in younger patients.52,55

One reason for the lack of efficacy of grid laser for ME in CRVO may be that CRVO is associated with a higher incidence of concomitant subretinal fluid that may impede attainment of the desired grid laser burn endpoint. Measurement of macular thickening may show a paradoxical increase in thickening during the first 3 months

following grid laser.11 A combination approach to treatment with pharmacologic therapy to reduce subretinal fluid followed by grid laser is a theoretical work-around that has not been put to the test in a clinical trial.

At the time the study results were published, some clinicians participating in the CVOS would treat younger patients with ME with grid pattern photocoagulation.55 This is unlikely to be the case in 2012 with the advent of IVI of anti-VEGF drugs.

15.2.2Chorioretinal Venous Anastomosis for Nonischemic Central Retinal Vein Occlusion with Macular Edema

LCRVA is a technique devised by McAllister and Constable to allow hemodynamic bypass of the central vein thrombus in CRVO. It was developed in an animal model and eventually shown to be

effective in human nonischemic CRVO with ME. An anastomosis can be formed in 38–54% of eyes within 1–8 months of treatment.13,38 High-powered (4–9.6 W) argon green laser burns are applied at the edge of a branch vein from 2 to 5 disc diameters (DD) of the optic disc. Treatment in the inferotemporal and inferonasal quadrants is preferred.13,38 Variations in technique have been described in the power used and in the addition of a neodymium YAG laser application to burst the vein itself after bursting Bruch’s membrane with the argon green laser. Some investigators have used a combined laser technique.13,32,34 Sometimes multiple sessions are necessary to create an anastomosis (average of 2.1, range 2–8), and sometimes multiple anastomoses are needed to cause ME to resolve.38 The average time until shunt formation is 6.7±5.7 weeks.38 Signs of success of an anastomosis include abrupt caliber change in the retinal vein at the anastomosis site, patterns of fluorescein flow during the FA (FA), and reversal in the usual declining diameter as one traverses the retinal venous tree distally (Fig. 15.1).7

Fig. 15.1 Fundus images of a 60-year-old man with diabetes and hypertension who developed a nonischemic central retinal vein occlusion of the right eye with ME. An argon laser procedure to induce formation of a chorioretinal venous anastomosis was done with success and without complication. (a) Baseline appearance of the fundus

on 2-16-2000. The VA was 20/80. (b) Fundus appearance on 9-13-2001. The black arrow indicates the matured chorioretinal shunt. Note the abrupt change in diameter of the inferotemporal vein at the side branching that leads to the shunt. The VA was 20/20 and has remained so with a functioning shunt through 11-23-2011

Fig. 15.2 Fundus images of the right eye of a 58-year- old man with hypertension who developed a nonischemic central retinal vein occlusion. The VA was 20/100 due to ME. He underwent laser chorioretinal venous anastomosis. Four months later, the superonasal anastomosis site developed an elevated fibrovascular frond of choroidovitreal neovascularization. (a) Color fundus photograph of the right eye. The black arrow denotes the choroidovitreal neovascularization. The anastomosis was functional. Note that the more proximal vein draining the sector is thread-

like (the green arrow). Where this thin vein bifurcates, the venous drainage makes a nonphysiologic U-turn so that the blood drains at the anastomosis to the choroid (the blue arrows). (b) Frame from the mid-phase FA showing leakage of fluorescein from the elevated new vessels (orange arrow). The two distal venules have a larger diameter than the proximal parent vein (the yellow oval), implying that blood flow has a reversed direction due to a functioning anastomosis

When the technique works, as it does in onethird to one-half of patients, VA improvement is seen in 84% (4.3 ± SD3.8 lines), but in 16% of eyes with successful shunts, VA fails to improve or can decrease.38

The technique is not recommended for ischemic CRVO because of the risk of developing choroidovitreal neovascularization (5% of eyes) (Fig. 15.2).38 It is probably best to use the technique within 3 months of CRVO because of progressive capillary nonperfusion witnessed in 21% of eyes during the interval between treatment and development of a shunt.38 Localized choroidal neovascularization (2–21% of eyes), preretinal fibrosis (9–12% of eyes) (Fig. 15.3), traction retinal detachment (rare), distal closure of the treated retinal vein (15%), and vitreous hemorrhage are complications reported after this technique, more frequently seen in eyes with greater degrees of ischemia (Fig. 15.2).13 Sixteen percent of successful anastomoses that initially drain blood away from the central vein lose this characteristic with narrowing of the proximal

venous segment; these successful shunts thus end up draining but a small peripheral sector of the retina.38 A randomized clinical trial has demonstrated the efficacy of this technique.39 Nevertheless, given the relative infrequency of creating a successful anastomosis, the risk of a variety of complications, uncertainty regarding the best lasers and settings to use to achieve success, and the impression of a more uniformly successful outcome with anti-VEGF therapy, the use of this technique has waned.49

Surgically induced chorioretinal venous anastomosis has also been described in which vitrectomy with scalpel puncture of Bruch’s membrane and stent-like use of suture in the incisions was associated with functional shunt formation in some cases.32,40,45 In one series of ten cases, functional shunts developed in 90% of eyes and mean VA improvement was 0.95 logMAR units, but retinal detachment, vitreous hemorrhage, and cataract requiring surgery developed in 30%.40 This aggressive idea has not stimulated follow-up research to date.

Fig. 15.3 Fundus photographs of a 72-year-old female who developed a nonischemic CRVO of the left eye with ME, reducing VA to 20/160. She underwent laser chorioretinal venous anastomosis with three sites chosen. (a) Immediately after the procedure, the three sites are shown with arrows. At one site, minimal retinal venous hemorrhage occurred after the treatment (black arrow). A moderate overlying hemorrhage developed at the superonasal site (green arrow). A more extensive plume of vitreous hemorrhage occurred at the superotemporal site (yellow

arrow). The hemorrhage was stopped by direct pressure on the fundus contact lens for less than 1 min. (b) Three months later, preretinal fibrosis has developed (yellow arrow). The inferonasal site did not develop a shunt (green arrow), but the superonasal and superotemporal sites did develop chorioretinal anastomoses (black arrows) sufficient to decompress the retinal venous system and lead to improvement in venous dilation, intraretinal hemorrhage, and disc edema

15.2.3Radial Optic Neurotomy for Central Retinal Vein Occlusion

Radial optic neurotomy (RON) was first described by Opremcak et al.43 The rationale for this technique is based on the idea that the scleral outlet constricts the central retinal vein (CRV) and that incising the cribriform plate, the scleral ring, and the adjacent sclera will improve central retinal venous drainage.21,43 The rationale has been contested on numerous bases. Some have suggested that the greater diameter of the retrobulbar optic nerve compared to the prelaminar optic nerve should not be construed as a bottleneck for the central vein but only a reflection of loss of myelination at this juncture.49 Another criticism of the proposed mechanism of action of the treatment is that the CRV lies temporal to the central retinal artery, thus a nasal cut should have no effect on the fibrous sheath encasing the temporally situated CRV.25 The lamina cribrosa is not an elastic structure, thus incising it should not release constricting pressure on the CRV.23 Releasing pressure on the CRV when the CRV already has a

thrombus would not in any case be expected to improve blood flow through the CRV.23 In a case of CRVO that underwent RON and subsequently was enucleated after uncontrolled neovascular glaucoma, no incision of the peripapillary sclera was found, calling into question whether the hypothesized mechanism of the treatment in fact is realized.59

Many uncontrolled case series have been published on the technique, and therefore all results must be interpreted with caution.18,21,25,37,43,49 Many variations have been described – some incorporate adjunctive internal limiting membrane peeling, some simultaneous laser panretinal photocoagulation, and some perform two neurotomies instead of one.5,21,43,50,67 Inferior neurotomies are advocated rather than superior ones because of the high rate of induced sector visual field defects that should impact quality of life less if located in the superior visual field.21 All the complications of vitrectomy surgery, including entry site breaks, retinal detachment, cataract progression, and endophthalmitis, are possible with RON, and some specific to the surgery such as visual field defects that could be

related to the section of a part of the nerve fiber layer (25%), perforation of the central retinal artery, hemorrhagic choroidal detachment, and secondary choroidal neovascularization (12% at

6 months).3,21,31,37,67

Tables 15.2 and 15.3 summarize results from a sample of published reports on RON. A consistent theme is the disproportionate response between reduction in ME and the VA improvement achieved, which is thought to arise from the inferior performance of RON in eyes with ischemic CRVO.5,21,37,67 Although ME can be reduced with this surgery, in 80% of cases it fails to return to normal values.5,67 Reduction in hemorrhages and venous congestion after surgery is the rule, but in the absence of controls, it is not possible to say if the effect surpasses the natural history (Fig. 15.4).5 Chorioretinal anastomoses develop after RON in 21–84% of cases between 4 and 12 months after surgery and have been inconsistently credited with the chief beneficial effects of the surgery, tending to suggest that the hypothesis of a constricted compartment released by surgery may not account for the observed relationship of

benefit to collaterals.5,17,21,31,53,67 No association between development of chorioretinal anastomosis and improvement in VA has been found by

others.17,31,67

Multifocal electroretinogram (mfERG) b-wave amplitudes improve inconsistently following RON, with no improvements seen in ischemic cases.5,37 Color flow mapping with spectral Doppler ultrasound in three patients with CRVO did not show improvement in central venous blood flow.10 Many authors who have been favorably disposed to RON based on pilot studies have noted the need for a randomized controlled trial to truly determine if the surgery is effective.5,21,67 The rationale for RON is to decompress suspected constriction of the CRV at the lamina cribrosa, but color Doppler imaging in patients who have had RON for CRVO showed no change in mean lamina cribrosa/optic nerve peak velocity ratios after surgery, tending to falsify its hypothesized mechanism of action.63 Others have declared that it has no rationale to expect success and that its promise is so small relative to its potential complications that it should be abandoned.25 With the advent of