Studies are under way to evaluate much-needed alternatives to treating macular edema associated with central and branch retinal vein occlusion.
Where are they leading, and what hope can they offer patients facing visual impairment?
Retinal vein occlusion remains second only to diabetic retinopathy as the most common retinal vascular disorder, and treatment—especially for the associated macular edema that can severely reduce visual acuity—has always been challenging. In fact, no proven, effective therapy currently exists for central retinal vein occlusion (CRVO); patient prognosis is dictated to a large extent by the severity of the occlusion and the natural history of the disease, rather than by compelling evidence that any intervention actually alters the outcome, according to Paul Sternberg Jr., MD.
For branch retinal vein occlusion (BRVO), which occurs about three times as often as CRVO, the only proven treatment for the condition’s associated macular edema is grid laser photocoagulation, and even that yields only modest visual acuity improvement (see “Grid Laser for BRVO: Still the Only Game in Town?”).
Which is why researchers are looking in multiple directions for new and effective therapies for retinal vein occlusion. “Whenever you start seeing a large number of newer treatments being developed and tested, it means that we don’t have a good therapy for the disease,” said Nelson R. Sabates, MD. Current experimental treatments range from intravitreal corticosteroid injections to surgical procedures. Although some of these newer approaches appear promising, the evidence demonstrating efficacy is not yet definitive for any of them.
Many retinal specialists believe that new pharmacologic interventions—from corticosteroids, like triamcinolone acetonide, to anti-VEGF agents—offer the greatest promise for the management of CRVO and BRVO. In fact, as interest in some of the experimental surgical treatments (see below) wanes, newer drug treatments may be the wave of the future.
“Since about 1999, intravitreal corticosteroid injections have been gaining in popularity,” said Michael S. Ip, MD. Although these injections have been used in patients with either central or branch retinal vein occlusion, the literature has many more reports of its use to manage macular edema associated with CRVO.
“To date, there have been small case series that have shown some apparent short-term benefits associated with triamcinolone injections,” said William F. Mieler, MD. He pointed out, however, that longer-term studies with greater numbers of patients are needed.
In a study at Duke University involving a small series of nine eyes with perfused CRVO (and visual acuity of 20/50 or worse), intravitreal injections of 4 milligrams of triamcinolone produced biomicroscopic improvement in cystoid macular edema in all treated eyes. “The injections were very effective in resolving the edema, but there also was a corresponding improvement in vision,” recalled Sharon Fekrat, MD, the study’s senior author. The mean BCVA improved from 58 letters at baseline to 78 letters at an average follow-up of 4.8 months.1
The increasing popularity of corticosteroid injections is due in part to the “immediate gratification” that many patients experience. “Some of these individuals have a very rapid improvement in visual acuity, with a reduction in macular edema,” noted Dr. Ip.
Nevertheless, because of the short-term follow-up in most case series, unanswered questions remain not only about long-term benefits, but also about possible long-term side effects of triamcinolone injections, including whether the incidence of cataract and glaucoma might increase with treatment. Also, added Dr. Ip, because the drug is given via an intravitreal injection, there are potential side effects such as retinal detachment, vitreous hemorrhage and endophthalmitis.
Researchers at the University of Wisconsin in Madison and the Bascom Palmer Eye Institute in Miami reported minimal serious adverse effects (as well as significant improvements in visual acuity) in a small sample size of 13 consecutive patients with macular edema associated with CRVO, treated with intravitreal triamcinolone and followed for up to six months. One patient showed an increase in IOP, which was managed with aqueous suppressants.2
Some patient series have reported post-treatment recurrences of macular edema (accompanied by declines in visual acuity), requiring repeat triamcinolone injections, typically every three to six months. “It’s not known whether the side effects will increase with additional injections, and whether the treatment effect will wane with these repeated injections,” said Dr. Ip.
The SCORE Study. A large controlled, randomized clinical trial called the SCORE (Standard Care vs. COrticosteroid for REtinal Vein Occlusion) study is now under way in about 90 centers in the United States, funded by the NEI to evaluate the use of intravitreal triamcinolone for macular edema in about 1,200 patients with CRVO or BRVO. All patients are being randomized to either 1 mg or 4 mg of triamcinolone, vs. standard care therapy (e.g., observation in CRVO, laser photocoagulation in BRVO). Patients will be followed for up to three years to measure long-term treatment efficacy and safety; reinjections (if needed) will be performed beginning at four months after the initial therapy.
Although previous case series have used the triamcinolone formulation found in Kenalog, the SCORE study is using a preservative-free triamcinolone product from Allergan formulated specifically for use in this study.
“Enough of us have been doing intravitreal triamcinolone injections for enough years, and seeing the edema dry up, that it has called for a study on a much wider scale like the SCORE study,” said Dr. Sabates. “The questions to be answered include whether it should be used in place of the laser in BRVO patients, or as an adjunct to the laser, as well as whether you should use it at initial presentation or, rather, wait several months and try the laser first.”
To date, there is no consensus on the precise mechanism of action of intravitreal injections of corticosteroids. One theory is that corticosteroids may inhibit vascular endothelial growth factor, thereby reducing VEGF concentrations in the vitreous cavity, and in turn curtailing the capillary leakage that contributes to macular edema.
One anti-VEGF drug, pegaptanib sodium injection (Macugen), is already FDA-approved for neovascular AMD. A Phase 2, randomized, double-blind, placebo-controlled trial was initiated in 2004 to evaluate the safety and efficacy of Macugen in the treatment of macular edema secondary to CRVO. In the trial, the drug is administered in a 0.3-mg dose every six weeks, with a total of five doses. The patients enrolled in the trial must have developed CRVO within six months of entry into the trial.
Anti-VEGF compounds have two possible modes of action—antiangiogenic and antipermeability mechanisms, according to Dr. Sabates. The hope is that Macugen can suppress leakage and dry up the retina, improving functionality.
Serious adverse events associated with the Macugen injection procedure itself in the AMD trials occurred in less than 1 percent of cases, and included endophthalmitis, retinal detachment and iatrogenic traumatic cataract. Although rises in IOP were noted within about 30 minutes of injection, pressure rapidly normalized and remained normal with more than two years of follow-up.
Caption: Macugen (yellow shapes) blocks VEGF-165
from binding to receptors, giving the drug antiangiogenic
and antipermeability properties in AMD. Ongoing trials are
testing the drug’s effectiveness against macular edema
secondary to CRVO.
A biodegradable implant, Posurdex delivers sustained-release dexamethasone, another corticosteroid. Thus far, although short-term benefits may occur with Posurdex in BRVO and CRVO patients who have macular edema, “there’s no convincing evidence of long-term benefits at this time, or of whether these patients will do any better than natural history alone,” said Dr. Mieler.
Infusions of tPA
The use of tPA (recombinant tissue plasminogen activator) is another approach being evaluated in CRVO patients. In initial case series, tPA was administered systemically, with no observable proven benefit. But more recently, researchers are studying other means of administration, including the use of cannulization techniques to thread a catheter into the central vein; tPA is then injected directly into the central retinal vein in an attempt to lyse the thrombus, improve perfusion and reduce macular edema. However, studies to date have provided only limited evidence of beneficial outcomes, and no randomized clinical trial has studied this treatment approach yet.
|COMPARING TREATMENT OPTIONS: Drug Therapies|
|Many of the treatments listed below are being studied or are planned for study.|
|Triamcinolone acetonide injection||√||√||Shown to resolve macular edema and improve BCVA in CRVO.|
Acts quickly, raising patient satisfaction.
Recurring macular edema may require repeat injections every three to six months.
Long-term benefits and possible side effects not yet fully studied.
Carries risk of intravitreal side effects (retinal detachment, vitreous hemorrhage, endophthalmitis).
|Three-year NEI-unded multicenter SCORE study of 1,200 patients using a triamcinolone formulation now under way.|
FDA-approved for neovascular AMD.
<1% AMD trial participants reported adverse events (injection-related endophthalmitis, retinal detachment, traumatic cataract).
|Long-term benefits unknown.||Phase 2, randomized, double-blind, placebo-controlled trial in progress.|
|Posurdex|| ||√||Biodegradable sustained-release implant.||No convincing evidence of long-term benefits yet.|| |
|tPA infusion|| ||√||May lyse the thrombus, improve pefusion, reduce macular edema.||Systemic injection found to be ineffective, injection directly into central retinal vein now being studied.||No randomized clinical trial studies being conducted.|
Despite the recent promise of new drug therapies, researchers have not abandoned surgical procedures for the mitigation of complications associated with retinal vein occlusion.
A number of case series have been published evaluating arteriovenous (AV) sheathotomy for the management of macular edema associated with BRVO.
AV sheathotomy is intended to reduce compression of the artery over the branch retinal vein, therefore relieving blockage in the vein. However, some ophthalmologists remain unconvinced about the efficacy of the procedure. “There have been conflicting reports about the use of arteriovenous sheathotomy in helping patients with branch retinal vein occlusion,” said Dr. Ip. “As a result, it appears to be a treatment that is decreasing in popularity.”
In a recent prospective, nonrandomized comparative study of 40 BRVO patients, John O. Mason III, MD, assistant clinical professor of ophthalmology, and his colleagues at the University of Alabama reported that sheathotomy produced significant improvements in vision, with mean visual acuity improving from 20/250 preoperatively to a mean 12-month BCVA of 20/63 postoperatively (14 months after surgery).3 In another study, this one at Duke University, AV sheathotomy produced a complete resolution of macular edema and significant visual improvement in only one-third of 27 consecutive BRVO cases; in the majority of patients, no improvement in vision occurred postprocedure.4
Dr. Mieler would like to see data comparing sheathotomy to the natural history of BRVO and/or the use of corticosteroids to determine its efficacy with more precision. At this point, he said, it appears that certain patient criteria may improve the chances of success, including occlusions that have been present for shorter periods of time (e.g., six to 12 months) rather than years.
“I rarely perform arteriovenous sheathotomy in eyes with BRVO anymore,” said Dr. Fekrat. “Visual improvement following this procedure is uncommon. There are still proponents of sheathotomy, but I think it’s more likely to show no improvement in vision and macular function than it is to show improvement.”
Although AV sheathotomy is often performed in conjunction with vitrectomy, some data indicate that vitrectomy alone might be just as beneficial. A recent retrospective study of BRVO patients with macular edema reviewed 36 eyes treated with vitrectomy alone or with vitrectomy plus AV sheathotomy; researchers found no significant differences in improvements in macular function between the treatments.5
“Because some studies have shown that vitrectomy alone may be beneficial for macular edema in BRVO—whether or not you also do a sheathotomy—it may be the vitrectomy that’s making the difference,” said Dr. Fekrat.
In fact, some clinicians believe that vitrectomy alone might be a viable treatment choice for macular edema in both branch and central retinal vein occlusion. One theory is that a vitrectomy may relieve traction on the macula, and thus reduce macular edema. According to another hypothesis, removing the vitreous also will remove the cytokines and vascular endothelial growth factor associated with a venous occlusive event and, thus, the stimulus for macular edema will be reduced. “But at the present time,” said Dr. Sabates, “there have been no large multicenter, randomized prospective trials indicating that vitrectomy alone is the best approach.”
Radial Optic Neurotomy
In CRVO patients, radial optic neurotomy has emerged as a relatively recent experimental surgical treatment. In this technique, a microvitreoretinal blade is used to relax the scleral ring around the optic nerve; some investigators believe the procedure can relieve the “compartment syndrome” associated with compression of the central retinal vein, leading to an improvement in venous outflow. However, there is not yet a consensus on how radial optic neurotomy may work—or even if it works at all.
“You can find journal articles that say that radial optic neurotomy improves central retinal vein occlusion,” noted Dr. Sabates, “but other articles say it doesn’t. So without a prospective randomized study involving a fairly significant number of patients, there’s no way we can know for sure.”
Although Dr. Sabates said he has done “a fair number of radial optic neurotomies myself, to be honest I’ve been underwhelmed by the outcomes. Some patients have done very well, and have come back from 20/400 to 20/40. But others haven’t improved at all.”
The optimal patient criteria for the use of radial optic neurotomy are still unclear. Some ophthalmologists believe that those with ischemic CRVO may be the best candidates. “The natural history of ischemic CRVO tends to be worse than the nonischemic form of the disease, and this may justify undertaking the added surgical risk of radial optic neurotomy, which involves an incision in the optic nerve,” said Dr. Ip.
Adverse effects such as significant hemorrhage and neovascularization at the incision site have been reported in patients undergoing radial optic neurotomy.
For more than a decade, laser-induced chorioretinal venous anastomosis has been investigated as an experimental therapy for central retinal vein occlusion. It is a technique that attempts to bypass the central retinal vein outflow. There were a few initial favorable reports describing use of the technique, but some negative findings as well. A study in the 1990s, involving 24 patients with nonischemic CRVO, found that a successful chorioretinal venous anastomosis could be performed in only one-third of cases, with improvements in visual acuity; in the remaining patients, an anastomosis could not be successfully created.6
Reports of frequent adverse events have further reduced interest in laser-induced anastomosis. The adverse effects have included vitreous hemorrhages and choroidal neovascularization at the anastomosis site.
“There has been a decline in interest in the technique,” said Dr. Fekrat. “The success rate is low, and the complication rate can be quite high. However, when a functioning anastomosis does form, it is usually a permanent fix.”
|COMPARING TREATMENT OPTIONS: Surgeries|
|Many of the treatments listed below are being studied or are planned for study.|
|Arteriovenous sheathotomy||√|| ||Mean VA improved from 20/250 preop to 20/63 postop in one study.1||Another study showed no improvement of macular edema or visual acuity in most cases.2||Is believed to relieve blockage by reducing compression of artery overlying branch retinal vein.|
Success may depend on patient criteria (e.g., how long occlusion has been present).
|Vitrectomy||√||√||FDA-approved for neovascular AMD.|
May reduce edema by relieving vitreal traction on macula.
May forestall venous occlusion by removing predisposing substances in vitreous.
|No large trials yet conducted to evaluate vitrectomy alone.||May be performed +/- AV sheathotomy, although research shows no significant differences in improvement.|
|Radial optic neurotomy|| ||√||Anecdotal evidence of VA improvement (from 20/400 to 20/40) in some patients.||Optimal patient criteria not yet clear.|
Incision-site hemorrhage and neovascularization reported.
|Risks may be justified in patients with ischemic CRVO, which tends to be worse than nonischemic CRVO.|
|Laser-induced chorioretinal anastomosis|| ||√||VA improvement reported in appropriate surgical candidates.|
Tends to be a permanent fix if anastomosis forms.
|Low success rate.|
Vitreous hemorrhage and choroidal neovascularization may occur.
|Grid laser photocoagulation||√|| ||Only proven treatment for BRVO.|
May modestly improve VA.
|Not appropriate in eyes with significant, uncleared intraretinal hemorrhage or nonperfused edema.|| |
|1 Mason, J. et al. Ophthalmology 2004;111:540–545.|
2 Cahill, M. T. et al. Br J Ophthalmology 2003;87:1329–1332.
WHAT DO WE TELL OUR PATIENTS?
“From my point of view,” said Dr. Sternberg, “the real problem with interventions where a goal is to reestablish blood flow—whether it’s with a radial optic neurotomy, an AV sheathotomy or tPA—is that they’re based on the presumption that you can reverse the course of the disease after the occlusion has occurred. But I don’t think the evidence is compelling that reestablishment of blood flow with these interventions after a delay of weeks to months is going to have a significant impact on the natural course of the disease.”
When a patient with BRVO or CRVO shows up in his office, Dr. Sternberg explains that while a variety of treatments are being evaluated for the disease, “we think the best option today is to participate in the SCORE study.”
Meanwhile, several other drugs are in the pipeline, said Dr. Sabates. “So in the next five to 10 years, there may be a significant number of new pharmacologic agents to choose from.”
1 Park, C. H. et al. Am J Ophthalmol 2003;136:419–425.
2 Ip, M. S. et al. Arch Ophthalmol 2004;122:1131–1136.
3 Mason, J. et al. Ophthalmology 2004;111:540–545.
4 Cahill, M. T. et al. Br J Ophthalmol 2003;87:1329–1332.
5 Yamamoto, S. et al. Am J Ophthalmol 2004;138:907–914.
6 McAllister, I. L. et al. Arch Ophthalmol 1995;113:456–462.
|GRID LASER FOR BRVO: Still the Only Game in Town?|
|In the mid-1980s, grid pattern laser photocoagulation was shown to modestly improve visual acuity during three years of follow-up in the Branch Vein Occlusion Study (BVOS). 1 “Even though the benefit wasn’t overwhelming, it was still statistically significant and probably had some clinical merit,” said Dr. Sternberg.|
After treatment with grid pattern laser, the average visual improvement in eyes with BRVO is only 1.3 lines of Snellen acuity, noted Dr. Fekrat. “In addition,” she cautioned, “the ophthalmologist should not perform the laser treatment until the majority of the intraretinal hemorrhage clears, which may take many months. Most eyes have a significant amount of hemorrhage early in the course of the BRVO and are not candidates for laser treatment. After waiting months for the hemorrhage to clear, there are still those eyes with nonperfused edema that are not even candidates for this laser because the laser is only recommended in those eyes with perfused macular edema observed on a fluorescein angiogram.”
|1 Branch Vein Occlusion Study Group. Am J Ophthalmol 1984;98: 271–282.|
|MEET THE EXPERTS|
|SHARON FEKRAT, MD Associate professor of ophthalmology at Duke University. Financial interests: None.|
MICHAEL S. IP, MD Associate professor of ophthalmology at the University of Wisconsin. Financial interests: None.
WILLIAM F. MIELER, MD Professor and chairman of ophthalmology at the University of Chicago. Financial interests: None.
NELSON R. SABATES, MD Vice-chairman of ophthalmology at the University of Missouri, Kansas City. Financial interests: None.
PAUL STERNBERG JR., MD Professor and chairman of ophthalmology and visual sciences at Vanderbilt University. Financial interests: None.