Central Retinal Vein Occlusion Treatment & Management
- Author: Lakshmana M Kooragayala, MD; Chief Editor: Douglas R Lazzaro, MD, FAAO, FACS more...
No known effective medical treatment is available for either the prevention of or the treatment of central retinal vein occlusion (CRVO). Identifying and treating any systemic medical problems to reduce further complications is important. Because the exact pathogenesis of the CRVO is not known, various medical modalities of treatment have been advocated by multiple authors with varying success in preventing complications and in preserving vision.
Macular edema is one of the prominent treatable causes of decreased visual acuity in patients with CRVO. The exact mechanism of macular edema is unclear, but multiple factors involved include increased venous pressure, elevated levels of VEGF, and deregulation of multiple inflammatory mediators leading to increased capillary permeability and leakage.
Various treatment modalities have been used to counter different components of macular edema pathogenesis, with significant progress in stabilizing or improving visual acuity.
Advocated treatments are as follows:
Systemic anticoagulation with warfarin, heparin, and alteplase
Local anticoagulation with intravitreal injection of alteplase
Intravitreal injection of ranibizumab
Intravitreal injection of aflibercept
Intravitreal injection of triamcinolone
Intravitreal injection of bevacizumab
Dexamethasone intravitreal implant
The Ophthalmic Technology Assessment Committee Retina/Vitreous panel of the American Academy of Ophthalmology evaluated available literature regarding efficacy of available pharmacotherapies in the treatment of macular edema due to CRVO. The panel reported that intravitreal anti-VEGF therapy is safe and effective over 2 years for macular edema and that delayed treatment is associated with worse visual outcomes. Intravitreal corticosteroid therapy yielded short-term efficacy but was associated with a higher frequency of adverse events.
Intraocular steroid injection has been shown to be effective in decreasing macular edema. Although the exact mechanism of action is unknown, steroids work by targeting various inflammatory pathways and decreasing expression of VEGF, reducing vascular permeability, stabilizing endothelial tight junctions, and decreasing macular edema.
Currently, triamcinolone acetonide and dexamethasone are the two steroid preparations used to treat macular edema associated with central retinal vein occlusion (CRVO).
Intravitreal injection of triamcinolone
The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study is a National Eye Institute–sponsored randomized controlled trial comparing 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone acetonide versus observation for visual acuity loss due to macular edema associated with perfused CRVO.
The SCORE study reported that intravitreal triamcinolone (both 1-mg and 4-mg dose groups) yielded better visual acuity outcomes over 12 months than observation alone. Beyond 12 months, the greater likelihood of visual acuity gain with triamcinolone persists, although there is a mild attenuation of the effect of triamcinolone with respect to mean change in visual acuity.
Both triamcinolone groups had a similar change in mean visual acuity letter score compared with the observation group, but the 4-mg group had the highest rate of cataract formation, cataract surgery, and intraocular pressure (IOP) elevation. The risk factors for IOP-related events included higher treatment dose, younger age, and higher baseline IOP. IOP-related events may take several months from the time of first triamcinolone injection to occur, so it is recommended to assess the risks and benefits of triamcinolone therapy and to maintain long-term follow-up of patients at risk for this complication.
Based on safety and efficacy findings from the SCORE-CRVO trial, administering intravitreal triamcinolone in a 1-mg dose and following the retreatment criteria used in this study should be considered for up to 1 year, and possibly 2 years, in patients with vision loss associated with macular edema secondary to CRVO.[20, 21]
Dexamethasone intravitreal implant
Dexamethasone is a potent, water-soluble corticosteroid that can be delivered to the vitreous cavity by the dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan; Irvine, Calif). A dexamethasone implant is composed of a biodegradable copolymer of lactic acid and glycolic acid containing micronized dexamethasone. The drug-copolymer complex gradually releases the total dose of dexamethasone over a series of months after insertion into the eye through a small pars plana puncture using a customized applicator system.
A 6-month study evaluated the safety and efficacy of dexamethasone implant 0.35 mg and 0.7 mg compared with a sham procedure in eyes with vision loss due to macular edema associated with BRVO and CRVO. In conclusion, the results of the study demonstrated that the dexamethasone implant reduced the risk of further vision loss and increased the chance of improvement in visual acuity in eyes with CRVO.
The percentage of eyes with a greater than or equal to 15-letter improvement in BCVA was significantly higher in both dexamethasone implant groups compared with sham at days 30 to 90 (P < .001). The results of this study further demonstrate that when these eyes were left untreated, a significant percentage will either fail to improve or will experience further loss of visual acuity. The dexamethasone implant was well tolerated, producing generally transient, moderate, and readily managed increases in IOP in less than 16% of eyes. Overall, this study suggests that the DEX implant could be a valuable treatment option for eyes with visual loss due to CRVO.
Antivascular endothelial growth factors
The postulated mechanism for macular edema is up-regulation of VEGF in response to retinal ischemia secondary to increased resistance to venous blood flow. The reported intravitreal levels of VEGF-A are higher in CRVO than in any other ischemic retinal vascular disease. VEGF increases vascular permeability, leading to macular edema and development of neovascularization. Multiple anti-VEGF medications have been shown to be effective in reducing edema.
Intravitreal injection of ranibizumab
Ranibizumab (Lucentis, Genentech, Inc.) is a humanized, affinity-matured VEGF antibody fragment that binds to and neutralizes all isoforms of VEGF.
The role of ranibizumab in the management of CRVO was reported in multiple studies. In the CRUISE and HORIZON studies, intravitreal injection of ranibizumab improved visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events. Results suggest that, during the second year of ranibizumab treatment, follow-up and injections should be individualized. On average, patients with CRVO may require follow-up more frequent than every 3 months.
The CRYSTAL study was a 24-month phase-3b, open-label, single-arm, multicenter study conducted in a broad patient population with visual impairment resulting from macular edema secondary to CRVO, including those with macular ischemia or greater disease duration. An individualized dosing regimen of ranibizumab 0.5 mg driven by stabilization criteria for up to 12 months resulted in significant best-corrected visual acuity gain in a broad population of patients with macular edema secondary to CRVO, including those with macular ischemia at baseline. The safety findings were consistent with those reported in previous ranibizumab studies in patients with CRVO.[23, 24, 25, 26, 27, 28]
Intravitreal injection of aflibercept
Intravitreal aflibercept (VEGF Trap-Eylea; Regeneron Pharmaceuticals, Inc.) is a fusion protein comprising key domains of human VEGF receptors 1 and 2 with immunoglobulin-G Fc. Intravitreal aflibercept binds multiple isoforms of human VEGF-A and placental growth factor with high affinity.
Two parallel trials, the COPERNICUS and GALILEO studies, evaluated the efficacy and safety of intravitreal aflibercept injection for the treatment of macular edema secondary to CRVO. Aflibercept injection demonstrated a statistically significant difference in the proportion of patients who gained 15 or more letters from baseline at week 24 compared with placebo in each study. The visual and anatomic improvements were diminished after continued PRN dosing, with a reduced monitoring frequency from weeks 52 to 100.
In conclusion, the studies demonstrate that long-term anti-VEGF therapy and more frequent monitoring is necessary to control macular edema in many patients with CRVO, likely because the continued ischemia leads to continued excessive VEGF production.[29, 19, 30, 31, 32]
Intravitreal Injection of bevacizumab
Bevacizumab (Avastin, Genentech, Inc.) is a recombinant, humanized monoclonal antibody that binds all isoforms of VEGF-A. Intravitreal injection of bevacizumab (0.05 mL/1.25 mg) has been shown to be effective not only in resolving the edema but also in corresponding improvement in vision. In a prospective, randomized, double-masked clinical study by Epstein et al, intravitreal injections of bevacizumab given every 6 weeks for 12 months improve visual acuity and significantly reduce edema compared with sham. Early treatment is important in these patients to optimize visual outcome, as patients in whom treatment is delayed have limited visual improvement. In addition, none of the patients developed neovascular glaucoma when treated with bevacizumab.
Bevacizumab is approved for treatment of various metastatic cancers, including metastatic colorectal cancer, non-small cell lung cancer, and glioblastoma multiforme. Intravitreal injection of bevacizumab is considered off-label use. Bevacizumab is not commercially available as an intravitreal injection. Reports of small series of eye infections due to contamination from repackaging into preservative-free single use vials have been reported.
Significant complications were reported with high doses of bevacizumab given intravenously for the treatment of cancer. There have been no significant reports of these complications when used in low dosage in eye.[13, 33, 34, 19, 35]
Laser photocoagulation is the known treatment of choice in the treatment of various complications associated with retinal vascular diseases (eg, diabetic retinopathy, branch retinal vein occlusion). Panretinal photocoagulation (PRP) has been used in the treatment of neovascular complications of central retinal vein occlusion (CRVO) for a long time. However, no definite guidelines exist regarding exact indication and timing of PRP. A National Eye Institute (NEI) sponsored multicenter prospective study, the Central Vein Occlusion Study (CVOS), provided guidelines for the treatment and follow-up care of patients with CRVO.[1, 10, 36, 37, 38]
CVOS evaluated the efficacy of prophylactic PRP in eyes with 10 or more disc areas of retinal capillary nonperfusion, confirmed by fluorescein angiography, in preventing development of 2 clock hours of iris neovascularization or any angle neovascularization or whether it is more appropriate to apply PRP only when iris neovascularization or any angle neovascularization occurs. CVOS concluded that prophylactic PRP did not prevent the development of iris neovascularization and recommended to wait for the development of early iris neovascularization and then apply PRP.
Argon green laser usually is used. Laser parameters should be about 500-µm size, 0.1-0.2 second duration, and power should be sufficient to give medium white burns. Laser spots are applied around the posterior pole, extending anterior to equator. They should be about 1 burn apart and total 1200-2500 spots.
If ocular media is hazy for laser to be applied, cryoablation of the peripheral fundus is performed. About 16-32 transscleral cryo spots are applied from ora serrata posteriorly.
CVOS evaluated the efficacy of macular grid photocoagulation in preserving or improving central visual acuity in eyes with macular edema due to central vein occlusion (CVO) and best-corrected visual acuity of 20/50 or poorer. Macular grid photocoagulation was effective in reducing angiographic evidence of macular edema, but it did not improve visual acuity in eyes with reduced vision due to macular edema from CVO. At present, the results of this study do not support a recommendation for macular grid photocoagulation for macular edema.
Chorioretinal venous anastomosis
Chorioretinal venous anastomosis[39, 40, 41, 42, 43] is performed by creating an anastomosis to bypass the site of venous occlusion in the optic disc. In this procedure, retinal veins are punctured, either using laser or by surgery, through the retinal pigment epithelium and the Bruch membrane into the choroid, thereby developing anastomotic channels into the choroid.
Chorioretinal venous anastomosis reduces macular edema and may improve vision in nonischemic CRVO. The success rate is low, and the complication rate can be quite high, including vitreous hemorrhages and choroidal neovascularization at the anastomosis site.
The exact indication and timing of the procedure has not been clearly studied.
Radial optic neurotomy
Radial optic neurotomy (RON)[44, 45, 46, 47, 48, 49] is a new surgical technique in which a microvitreoretinal blade is used during pars plana vitrectomy to relax the scleral ring around the optic nerve. The central retinal artery and vein passes through the narrow openings of the cribriform plate in the optic disc.
Promoters of this technique suggest that CRVO may be due to the compression of the central retinal vein at this location creating a compartment syndrome. If this procedure is successful, it decompresses the closed compartment and leads to an improvement in venous outflow and a reduction of macular edema.
In one recent study, RON resulted in clinically relevant improvements on a long-term basis. Patients with nonischemic CRVO may respond more favorably than patients with ischemic CRVO.
In another study, significant improvements were observed in the b-to-a ratio of the standard combined ERG after surgery in eyes with CRVO.
The benefits from surgery have not been clearly documented. One study, looking into the biomechanical effect of RON, found negligible change in the space around the central retinal vein; RON is unlikely to be a procedure that could mechanically ameliorate the clinical sequelae of a central vein occlusion. The improvement of retinal function is most likely due to improved oxygenation of the retina caused by vitrectomy and not by RON.
In addition to the regular complications of vitrectomy, RON can result in significant hemorrhage and neovascularization at the incision site.
No consensus currently exists among various researchers regarding the exact criteria for the use of RON.
A vitrectomy is a technique in which the vitreous is surgically removed along with removal of the posterior hyaloid.
Some studies have shown that a vitrectomy may be beneficial for macular edema due to CRVO. One theory is that a vitrectomy may relieve traction on the macula and, thus, reduce macular edema. According to another hypothesis, removing the vitreous will also remove cytokines and VEGF associated with a venous occlusive event; thus, the stimulus for macular edema will be reduced.
At the present time, no convincing evidence indicates that a vitrectomy is the best approach.
A general ophthalmologist should consult a retinal specialist for management of CRVO complications. Other consults include an internist for proper evaluation and management of any systemic medical problems. If patients develop neovascular glaucoma, a glaucoma specialist should be consulted.
Diet should be tailored to systemic medical problems.
No restrictions usually exist. If patients develop vitreous hemorrhage, they are advised to avoid strenuous activities, sleep with few pillows, and avoid bending and lifting heavy weights.
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