Emerging Treatments for Central Retinal Vein Occlusion
JONATHAN ETTER, SHARON FEKRAT, MD

Figure1. Color photograph of a central retinal vein occlusion.

Based on outcomes from the Central Vein Occlusion Study (CVOS), observation is the treatment recommendation for eyes with a central retinal vein occlusion (CRVO), (Figure 1) but no neovascularization and remains the standard of care.^1-4 If neovascularization develops, panretinal laser photocoagulation is recommended. Currently, no proven treatment option to improve visual acuity in eyes with neovascularization exists.

Since the CVOS ended many years ago, numerous investigational treatment options have been explored in an attempt to improve visual acuity in these eyes.

NATURAL HISTORY

Visual Acuity

The natural history of visual acuity in eyes with CRVO has not been well documented. The CVOS data on this topic must be interpreted cautiously because the study only considered visual acuity across all subgroups, as opposed to considering perfused (Figure 2) and nonperfused groups separately.¹ Moreover, CRVO of varying durations are lumped together in this analysis. Nevertheless, the CVOS data indicate that visual acuity outcome correlates well with initial acuity. Of eyes with initial visual acuity of 20/40 or better at presentation, 65% maintained their vision in that range. Similarly, of eyes seeing <20/200 at presentation, 80% had a final visual acuity of <20/200.¹

A retrospective study by Quinlan and associates chronicled visual acuity in nonischemic and ischemic eyes separately. In general, the study's data demonstrated Chi-square correlation between initial acuity and visual prognosis. However, within the nonischemic group, 15% of eyes gained 3 or more lines of acuity, while 31% lost 3 or more lines of visual acuity.⁵ Within the ischemic group, 28% gained 3 or more lines of visual acuity, while 24% lost the same amount of visual acuity.⁵ Therefore, the study demonstrates a lack of visual stability in untreated eyes with CRVO.⁵ Moreover, a 1994 report by Hayreh analyzed 144 eyes with nonischemic CRVO and found significant visual improvement following resolution. Sixty-five percent of all eyes in the study had a visual acuity between 20/15 and 20/40 following resolution.⁶

Iris and Angle Neovascularization

In the CVOS, 714 (in 711 patients) eyes with diagnosed CRVO were followed for 3 years. Overall, 117 eyes (16%) developed iris neovascularization (INV) (of at least 2 clock hours) and/or angle neovascularization (ANV) by the study's completion. Thirty-five percent (61/176) of eyes initially diagnosed as nonperfused or indeterminate ultimately developed INV and/or ANV compared with 10% (56/538) of the initially perfused group.¹ The fact that a significant percentage of perfused eyes ultimately possessed INV/ANV is underscored by one of the early findings of the CVOS: 1/6 of all eyes initially characterized as perfused converted to nonperfused status and/or developed INV/ANV by the 4-month follow-up. In fact, the conversion to nonperfusion was most rapid within the first 4 months of the study.³ Multivariate regression demonstrated that the 2 factors with the strongest association to the development of INV/ANV were visual acuity and degree of nonperfusion.¹

MEDICAL INTERVENTION

Currently no proven medical intervention to improve visual acuity for eyes with CRVO exists. Various interventions, including pentoxifylline and common systemic anticoagulants have been attempted.

The synthetic xanthine derivative, pentoxifylline, may enhance pulsatile flow in nonoccluded retinal veins. Proposed mechanisms for this include the ability of pentoxifylline to decrease blood viscosity and promote vasodilation. However, the drug's ability to prevent or alter the course of CRVO is unknown.⁷ De Sanctis and colleagues evaluated pentoxifylline vs. placebo in 18 patients with retinal vein thrombosis. The 9 patients receiving pentoxifylline were each given 1800 mg daily for 3 weeks. Evaluation of retinal vein flow velocity was performed before the intervention and at 4 weeks after. Average retinal vein flow velocity increased by 300% in the pentoxifylline group (from 4­14 cm/sec) compared with only a 200% increase in the placebo group (from

4­8 cm/sec).⁸ These results suggest that there may be a role for pentoxifylline in the management of CRVO, though more evaluation is needed.

Figure 2. Fluorescein angiography demonstrates a perfused central retinal vein occlusion.

Various systemic medications, such as aspirin, heparin, and warfarin among others, have not been shown to prevent or alter the course of eyes with a CRVO. Lai and associates performed a retrospective study in which they observed out of 84 consecutive patients presenting with CRVO, 6 were on warfarin anticoagulation. Five out of the 6 patients (83%) were in the therapeutic range for anticoagulation.⁹ The observation that patients on chronic-systemic coagulation could acquire CRVO suggests that warfarin may not have utility in the management of CRVO.⁹

It is unknown whether the lowering of a normal intraocular pressure (IOP) in eyes without glaucoma prevents or alters the course of the CRVO. Altering the IOP may have some secondary effect on the position of the lamina cribrosa and, in turn, on any associated compression of the central retinal vein.

Grid-pattern Laser Photocoagulation

The CVOS demonstrated that grid-pattern laser photocoagulation did decrease macular edema angiographically; however, there is no associated visual acuity improvement. Based on the data, the CVOS did not recommend grid-pattern laser photocoagulation in eyes with macular edema from CRVO. A clinical trend suggested that photocoagulation may have a more beneficial effect on visual acuity in those under the age of 65. This trend must be further evaluated to consider an age-based treatment approach.⁴

Panretinal Photocoagulation

The CVOS data do not support the recommendation for prophylactic panretinal photocoagulation (PRP).² The CVOS found that early PRP decreased the rate of INV; however, the reduction was not statistically significant.² Moreover, the study showed that early PRP reduced, but did not eliminate, the possibility of anterior-segment neovascularization. The CVOS recommended close follow-up of eyes with CRVO during the first 6 months, including gonioscopy and undilated examination of the iris, to monitor for INV/ANV.

The CVOS found that many eyes with CRVO never developed INV/ANV, and thus recommends that PRP should only be implemented after a diagnosis of anterior-segment neovascularization, to prevent unnecessary photocoagulation.^1-2 Per CVOS results, the only acceptable scenario in which prophylactic PRP may be implemented is when close follow-up is impossible.¹ If PRP is appropriately initiated following the first identification of neovascularization, postprocedural follow-up is recommended at 2­4 weeks to ensure that there is no progression. If progression is noted, additional PRP is indicated. Panretinal photocoagulation does not improve visual acuity in these eyes.

Intravitreal Triamcinolone Acetonide

Intravitreal triamcinolone (Kenalog-40) injections can lead to resolution of macular edema and corresponding visual improvement in eyes with CRVO. A small, retrospective study, entitled Intravitreal Triamcinolone Acetonide in Eyes with Cystoid Macular Edema Associated with CRVO, showed that the administration of intravitreal triamcinolone in patients with CRVO resulted in a mean visual acuity increase of 20 letters, and a mean improvement in volumetric optical coherence tomography measurements by 1.6 mm³.¹⁰ However, the effect of intravitreal triamcinolone is transient, and its use may lead to steroid-induced cataract formation, as well as steroid-induced IOP elevation.

Currently a multicenter, randomized clinical trial, sponsored by the National Eye Institute, called The Standard of Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) Study is ongoing.¹¹ The SCORE study will randomize eyes with macular edema secondary to CRVO into 3 treatment groups. One group will receive the standard of care (observation); a second group will receive 4 mg of intravitreal triamcinolone; and a third group will receive 1 mg of intravitreal triamcinolone. In total, these groups will be followed for 36 months. The primary efficacy will be measured by an improvement of 15 or more letters in visual acuity at the 12-month visit. The SCORE study will evaluate the safety profile of intravitreal triamcinolone by monitoring cataract formation, IOP changes, and injection-related events such as endophthalmitis, vitreous hemorrhage, and retinal detachment.

Pegaptanib Sodium Injections

Pegaptanib sodium (Macugen) is a pegylated aptamer that selectively inhibits vascular endothelial growth factor 165. Its ability to reduce macular edema in eyes with CRVO is currently under study and is in phase 2 of a pharmaceutical clinical trial. Between 50 and 100 patients will be enrolled in this trial and will be treated for 12­30 weeks.¹⁴

Although intravitreal injection may rarely result in endophthalmitis or retinal detachment, pegaptanib sodium itself is associated with few deleterious effects.

SURGICAL INTERVENTIONS

Sustained Drug Release Devices

A fluocinolone acetonide implant (Retisert) is a sustained drug release device that is currently being evaluated in eyes with macular edema in the setting of CRVO. Proposed advantages of this device include constant drug levels and duration of treatment tailored to the appropriate disease.¹² The implant is nonbiodegradable and is secured intraocularly with scleral suture. The device contains a total of 0.5 mg fluocinolone and is designed to release 0.5 mcg per day for 3 years. Increased IOP and cataract progression may occur with increased frequency in these eyes. Most cases of elevated IOP can be satisfactorily treated with drops, but surgical intervention may be required. A multicenter trial by Pearson et al is ongoing to determine the role of the fluocinolone implant in diabetic macular edema (DME). The study involves 80 patients with DME, randomized into an implant or standard-of-care group.¹³

Plasmapheresis

Increased blood viscosity and fibrinogen levels have had a positive correlation with CRVO.¹⁵ Plasmapheresis can reduce blood viscosity; however, its role in eyes with CRVO remains unclear. Hansen and associates found that plasmapheresis increased the visual acuity at the 3-month follow-up visit in 8 patients over 50 years of age with nonischemic CRVO.¹⁶ They suggested that increased blood velocity increased circulation in retinal microvasculature. More evidence is needed regarding the clinical efficacy of plasmapheresis before it can be widely adopted.

Laser Chorioretinal Venous Anastomosis

A chorioretinal anastomosis (CRA) bypasses the occluded retinal venous system by creating an anastomotic outflow channel from the retinal venous system to the choroidal circulation. The creation of an outflow channel may reduce macular edema and result in improved visual acuity. Enhanced outflow may also halt the progression of perfused CRVO to nonperfused CRVO.^17,18 In eyes already classified as nonperfused, CRA is contraindicated because it may increase the risk of choroidovitreal neovascularization and may be less likely to improve visual outcome.

The most common method for creating a CRA is using the argon laser, usually at powers as high as 6 watts. Chorioretinal anastomosis is performed by directing a 50 micron spot of argon green laser at a 0.1 second duration at an area adjacent to a branch retinal vein nasal to the optic nerve head. The goal is to rupture the Bruch's membrane in this location; a "bubble" is usually visualized upon successful rupture. It is preferable to find a branch vein without any intervening branching from the optic nerve head. Another laser spot using the same parameters is then placed on the branch retinal vein to rupture it. Some investigators have attempted to create an anastomosis by only rupturing the Bruch's membrane and not an adjacent branch retinal vein. A retrospective study by McAllister and Constable demonstrated a 33% success rate (measured by a functioning anastomosis).¹⁷ In their study, 24 patients underwent an attempt to create a laser CRA and follow-up ranged from 1­3 years. McAllister and Constable showed an association between anastomotic success and the following 2 fundoscopic signs: retinal venous hemorrhage and choroidal vacuole. These findings probably indicate venous and Bruch's rupture respectively, but were not always associated with successful anastomosis in follow-up studies. All 8 eyes with a successful anastomosis had a preoperative visual acuity of 6/36 or less. Six of these eyes experienced an improvement in final visual acuity. In the other 2 eyes, acuity remained stable. All 16 eyes without successful anastomosis possessed a preoperative visual acuity of 6/18 or less. Out of the 16 eyes without a successful anastomosis, only 6 experienced a postoperative improvement in vision, while the vision in 7 eyes decreased.

Browning and Antoszyk performed laser CRA on 8 eyes with CRVO ranging in visual acuity from 20/60 to count fingers (CF) vision. Patients were observed from 1­19 months. Visual acuity improved in 2 patients by final follow-up, despite failed anastomoses.¹⁸ Visual acuity did not improve or worsened in 6 eyes by final follow-up; 2 eyes in this group did have successful anastomosis.¹⁸ Therefore, the 2 anastomoses that were created were not of the same therapeutic nature that the anastomoses created by McAllister and Constable were. Moreover, their series was fraught with complications, such as vitreous hemorrhage, rubeosis, retinal neovascularization, retinal detachment, and neovascular glaucoma. Fekrat and colleagues performed CRA on 24 eyes with preoperative visual acuity of 20/100 or less. They achieved successful anastomoses in 9 eyes within 8 weeks after the procedure. By 8 weeks following treatment, the visual acuity outcomes of the 9 eyes with successful anastomosis were as follows: 2 eyes experienced visual improvement of 6 or more lines, 5 eyes experienced visual improvement of 1­3 lines, and 2 eyes did not have visual improvement.¹⁹ Of those eyes that did not experience successful anastomosis, 3 progressed to nonperfusion. Adverse events of the study included neovascular complications, as well as retinal fibrosis and detachment.¹⁹ Overall, a low success rate and high incidence of complications render CRA still investigational for eyes with nonischemic CRVO.

Pars Plana Vitrectomy with Posterior Hyaloid or ILM Removal

Pars plana vitrectomy with removal of the posterior hyaloid alone may contribute to resolution of cystoid macular edema in eyes with CRVO. Data from a retrospective study entitled Role of Vitreous in CRVO by Hikichi and associates demonstrated an association between the presence of vitreomacular attachment and the development of macular edema in eyes with CRVO. In their study sample, the majority of eyes (76%) with macular edema either possessed no posterior vitreous detachment (PVD) or only partial PVD; whereas in the group of eyes without macular edema, most eyes (75%) did have PVD or partial PVD. The authors further speculated that there is a pharmacologic agent present in the vitreous that causes macular edema. No further details were provided. They also suggested the possibility that macular edema may be caused in part by vitreous traction in eyes with CRVO.²⁰

Mandelcorn and Nrusimhadevara demonstrated improvement in macular edema in all eyes (including those with macular edema from CRVO and branch retinal vein occlusion [BRVO]) by 6 weeks after pars plana vitrectomy, as well as improved visual acuity in 79%.²¹ They theorized that simultaneous removal of the internal limiting membrane would promote the movement of fluid out of the inner retinal layers, resulting in decreased macular edema.²¹ A limited case series performed by Sekiryu and associates showed optical coherence tomography improvement in all of its subjects with macular edema from CRVO that received surgical separation of cortical vitreous from the posterior retina and optic nerve.²²

Pars Plana Vitrectomy with Radial Optic Neurotomy

Radial optic neurotomy (RON) is a surgical procedure designed to improve venous outflow in eyes with CRVO by relieving pressure on the occluded vein as it crosses the cribiform plate and scleral outlet. Radial optic neurotomy may relieve the "compartment syndrome" in these eyes.²⁵ The procedure consists of pars plana vitrectomy followed by the use of a 20 g microvitreoretinal blade to radially cut the scleral ring and its adjacent sclera transvitreally. The posterior hyaloid should also be separated from the retina and removed in all eyes.

Opremcak and associates performed RON on 11 eyes. All eyes had an initial visual acuity of 20/400 or worse. Postoperative follow-up ranged from 5­12 months, and the mean follow-up interval was 9 months. At final follow-up, 8 out of 11 eyes (73%) demonstrated visual improvement.²⁵ Their average improvement was 5 lines. By 2 months, 8 of 11 eyes had a mean improvement in acuity of 2.5 lines. This rapid improvement in acuity was concomitant with resolution of intraretinal blood and improvement of venous dilation in those 8 eyes. At final follow-up, 7 of the eyes had a final visual acuity of 20/200 or better, while 5 possessed vision of at least 20/70. Interestingly, 1 eye that was initially no light perception improved to CF at final observation. Two eyes acquired INV following RON and experienced a worse final visual acuity.²⁵ A potential issue with this study is 5 eyes were classified as perfused preoperatively and 6 were indeterminate. The varied perfusion status of eyes in this study may have affected the outcome and thus the evaluation of this technique in eyes with CRVO.

Weizer and associates performed RON on 4 patients with CRVO (and 1 with hemiretinal vein occlusion), with a mean preoperative visual acuity of 4/200.²⁶ Mean follow-up time was 4.5 months. Two eyes improved to 20/80 (each was 5/200 preoperatively). Interestingly, 1 of these eyes was classified as perfused postoperatively, while the other was classified as nonperfused. The overall mean postoperative visual acuity was 20/400. One eye developed INV and another developed choroidovitreal neovascularization. Overall, visual acuity in this study did not improve as much or as quickly as in Opremcak's series.

In a study by Garcia-Arumi and colleagues, 14 patients with CRVO (with initial visual acuity less than 20/125) underwent RON.²⁷ Mean postoperative visual acuity was 20/80 and the mean visual acuity gain was 3 lines. Investigators in this study agreed with the notion that RON may improve retinal blood flow by relieving compression. Chorioretinal shunts formed in 6 eyes, which may further improve venous outflow. Eyes with shunts experienced a better median visual acuity (20/60) than those without (20/110).²⁷ No overall significant difference in visual acuity in those eyes with and without chorioretinal shunts (P=0.28) was observed. Moreover, of those eyes with chorioretinal shunts that did not experience improvement in acuity, all had submacular hemorrhage.²⁷ This suggests the possibility that chorioretinal shunts may contribute to any positive effects yielded by RON.

A recent interventional case series by Nomoto and associates used indocyanine green videoangiography, as well as computer-assisted image analysis to evaluate the efficacy of RON in improving the retinal circulation in eyes with CRVO. The study showed improvement of circulation in 53% of eyes receiving RON. The study also showed correlation between the development of CRA (shunts) at the RON site and improved circulation, as well as improved visual acuity.²⁸

Czajka and associates studied the histopathology in 14 healthy porcine eyes following RON.²⁹ The eyes were organized into 4 groups; in each group, histopathologic findings were assessed following enucleation at a different follow-up interval. Prior to histopathologic evaluation, each eye was routinely examined by weekly ophthalmoscopy. Six of the eyes developed engorged blood vessels immediately after RON, which persisted for 3 weeks. Histopathologic findings of the optic nerve included reactive gliosis, interstitial edema, foci of hemorrhage, and rare inflammatory cells. No chorioretinal shunt formation was observed in any of the eyes; however, the porcine eyes were nonischemic, follow-up was short, and fluorescein angiography was not performed. Finally, complete axonal-nerve fiber loss distal to the neurotomy site at 3 weeks was observed.²⁹

Despite the previous findings, there is debate regarding the efficacy and safety of RON. Some contend that the development of retinociliary collateral vessels is common in the natural history of CRVO, and it may be incorrect to attribute their presence to RON.³⁰ Conversely, in eyes that receive RON the collateral vessels usually develop in the exact location of the neurotomy. Perhaps this is evidence that that the anatomoses are directly resulting from RON itself. There are also postoperative complications associated with RON, including neovascularization of the anterior segment or at the neurotomy site, as well as retinal detachment originating at the RON site.^26,31 It is also important to re-evaluate the surgical parameters themselves. Standardization of incision lengths in the optic disc may or may not be necessary; disc sizes are not standardized, nor do they have the same sized central cups or vessel placement. Approaching such variation with the same approach may affect outcomes.³² Finally, more data is needed on the visual fields of those receiving RON. Some theorize cutting optic-nerve fibers and nearby vessels results in a significant visual-field defect.³⁰ Radial optic neurotomy is still being investigated as a treatment choice for eyes with CRVO.

A pilot study of Pars Plana Vitrectomy, Intraocular Gas, and Radial Neurotomy in Ischemic CRVO, by Williamson and colleagues, attempted to assess the effect of vitrectomy on venous dilation, hemorrhage, and visual acuity in eyes with CRVO. Their intention was to compare the safety of vitrectomy alone with vitrectomy plus RON. Data demonstrated visual recovery in some eyes in both groups, along with reduction in venous dilation and hemorrhage.²³ The visual acuity data from the vitrectomy group was slightly skewed because some patients needed concurrent cataract extraction intraoperatively.

Williamson and colleagues suggested that removal of the vitreous results in increased oxygenation to the inner retinal layers. They based this postulation on Fick's diffusion equation and the ability of a high-molecular weight gas, such as perfluoropropane to draw oxygen from the ciliary circulation into the vitreous cavity. All eyes in the study received PRP intraoperatively to prevent anterior-segment neovascularization postoperatively. This pilot study did not have a control group; therefore, no direct comparison of vitrectomy to the natural history of the disease was provided.²³

Stefansson and colleagues studied the role of vitreous on the preretinal oxygen tension in feline eyes with induced BRVO. They evaluated 5 vitrectomized eyes and 10 nonvitrectomized eyes and measured the preretinal oxygen tension before and after induction of BRVO. In the nonvitrectomized group the oxygen tension fell from 20+7 to 6+5 mm Hg (P=0.001) while the vitrectomized group experienced a much smaller decrease in oxygen tension from 19+11 to 16+11. Stefansson and associates hypothesized that the absence of vitreous allows fluid in the vitreous cavity to circulate oxygen to ischemic portions of the retina. This may lead to resolution of cystoid macular edema. They further suggested that improved retinal oxygenation from vitrectomy prevents retinal neovascularization.²⁴

These studies suggest that there may be a role for pars plana vitrectomy in the reduction of macular edema secondary to CRVO, as well as in the improvement of visual acuity. Larger scale, randomized trials are needed to further evaluate the role of pars plana vitrectomy in CRVO.

Optic Nerve Sheath Decompression via an Orbital Approach

Optic nerve sheath decompression (ONSD) has been performed in eyes with CRVO and secondary optic-nerve swelling. Decompression of the central retinal artery and vein is performed via an orbital approach by cutting the posterior scleral ring and optic-nerve dura.³³

Sonographic reduction in intrathecal fluid has been observed in eyes that have underwent ONSD for CRVO.³⁴ Early retrospective studies of ONSD for CRVO noted improved visual acuity in up to 39% of eyes.^33,35 Dev and Buckley performed ONSD on 8 eyes with CRVO and found visual acuity to improve postoperatively in 6 eyes. The mean preoperative visual acuity of 20/160 improved to 20/70 at an average postoperative follow-up of 1 year, and a documented decrease or resolution in optic-disc edema in all cases was observed. No complications were noted.³⁶ Small study numbers and the risk of significant complications have limited the use of an orbital approach to nerve sheath decompression in treating CRVO.

CONCLUSIONS

Central retinal vein occlusion has been a disease without adequate therapy. In recent years, new interventions have been suggested in an attempt to broaden the treatment paradigm. As current investigational modalities are re-evaluated there will perhaps be new treatments in the near future that will prove to be more effective.

Address correspondence to: Sharon Fekrat, MD, Associate Professor, Vitreoretinal Surgery Department, Duke University Eye Center, Box 3802, DUMC, Durham, NC 27710, Telephone: (919) 681-0341, Fax: (919) 681-6474, E-mail: fekra001@mc.duke.edu.

From Vitrectomy Surgery Department; Duke University Eye Center, Durham, NC. Jonathan Etter and Dr. Fekrat have no financial interest in this information.

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