Retinal vein occlusions are a common but heterogenous group of retinal disorders characterized by impaired venous return of the retinal circulation. Though RVOs share common clinical features, they’re distinct entities with their own risk factors, prognosis and—sometimes—treatments. There’s also a wide spectrum of clinical severity of RVO and, if left untreated, RVO can lead to permanent vision impairment. Early recognition and prompt treatment, if needed, are key to preserving vision. Here, I’ll outline the features of the different kinds of vein occlusions, the best way to diagnose them and the most effective course of treatment.
Classification of RVO can be divided into branch retinal vein occlusion, hemiretinal vein occlusion and central retinal vein occlusion, depending on the location of the obstruction. If the occlusion occurs within or posterior to the optic nerve head (often a thrombus in the central retinal vein near the lamina cribrosa), it’s termed a CRVO. If the occlusion is at the major bifurcation of the central retinal vein, it’s an HRVO, and any obstruction within a tributary vein (often a thrombus at the arteriovenous crossing point) is a BRVO. Often, HRVO is a considered a separate condition that can behave in a way that’s between a BRVO and CRVO.1,2
|Figure 1. Fundus photograph and fluorescein angiogram of a non-ischemic central retinal vein occlusion.|
Epidemiology and Risk Factors
Together, RVOs represent the second leading cause of retinal vascular blindness after diabetic retinopathy. BRVO is more common than CRVO.3-6 Worldwide prevalence of BRVO is estimated to be 0.4 percent, and CRVO around 0.08 percent, with a symmetrical distribution between men and women and increased risk with older age.7 In the Beaver Dam Eye Study, at 15 years the cumulative incidence of BRVO was 1.8 percent, vs. 0.5 percent for CRVO.8 The Blue Mountain Eye Study showed a 0.7-percent incidence in patients younger than 60 years, increasing to 4.6 percent in patients 80 years and older.5
The greatest predictor of developing RVO is an RVO in the contralateral eye. Individuals with BRVO in one eye have a 10-percent risk of any RVO in the contralateral eye within three years.9 The estimated risk of contralateral involvement in a patient with CRVO is approximately 1 percent per year, but increases to 7 percent at five years.9,10
RVOs have been associated with certain systemic vascular risk factors, including hypertension, hyperlipidemia, diabetes, active smoking and peripheral vascular disease.3-5,11,12 Of these systemic risk factors, one meta-analysis found that 47.9 percent of RVO cases were attributed to hypertension, 20.1 percent to hyperlipidemia and 4.9 percent to diabetes.13 The study concluded that hypertension and hyperlipidemia were common risk factors for all forms of RVO in adults, whereas diabetes was less significant due to its inconsistent association with BRVO. Some studies have shown an increased risk of cerebrovascular and cardiovascular disease in patients with RVO, including a greater risk of developing acute myocardial infarction after a diagnosis of RVO, although other studies have shown similar rates of stroke and myocardial infarction.14-17
There is some controversy surrounding hypercoagulable states and RVO. One meta-analysis of 26 studies found that thrombophilic risk factors, hyperhomocysteinemia and anticardiolipin antibodies were significantly independently associated with RVO.18 Other associations include proteins C and S deficiency, high alpha-2 globulin concentrations, higher activated factor VII concentrations, oral contraception use and increased blood viscosity.12,19
Additionally, open-angle glaucoma is a common ocular comorbidity in RVO patients.11,20 Glaucoma, along with sleep apnea, is more common in CRVO than BRVO.21,22
|Figure 2. Optical coherence topography of the patient from Figure 1 didn’t show any significant macular edema.|
RVO patients are at risk of vision loss from several complications of the interrupted blood flow, including macular edema, macular ischemia, optic neuropathy, vitreous hemorrhage and tractional retinal detachment. However, symptoms related to an RVO can be subtle, especially if the severity is mild or the impacted area is outside the macula. Acute RVO commonly presents with painless visual disturbances. Visual field abnormalities can be present but are rarely symptomatic.23 Increased intravenous pressure can result in vascular tortuosity, retinal hemorrhages (superficial flame-shaped and deep blot), cotton wool spots and optic nerve edema. RVO can be classified by anatomic location. BRVO occurs in one retinal quadrant and can be distinguished by hemorrhage in that area. HRVO patients show findings only in the impacted hemifield, while CRVO patients can show retinal hemorrhages in all four quadrants. Congestion of the capillary bed can lead to macular edema, metamorphopsia and decreased visual acuity. Severe congestion can also result in vitreous hemorrhage, which can be difficult to distinguish from vitreous hemorrhage related to ocular neovascularization.
BRVO typically occurs at arteriovenous crossings where the artery and vein share an adventitial sheath. The artery has been observed to cross the vein anteriorly in 98 to 99 percent of BRVO, compared with approximately 60 to 70 percent of unaffected arteriovenous crossings.4,24,25 This has been hypothesized to occur due to thickening of the overlying artery, which causes narrowing of the vein, with subsequent vascular turbulence and endothelial damage contributing to venous thrombosis. The superotemporal quadrant is most commonly involved (58.1 percent of eyes), followed by the inferotemporal quadrant (29 percent) and outside of the temporal quadrants (12.9 percent).3,25
Eyes with more nonperfusion carry a greater risk of ocular neovascularization and a guarded visual prognosis.26 CRVO generally causes greater degrees of vision loss and carries a more guarded prognosis. Abnormal new blood vessel growth can invade the iris, angle, optic nerve and retina. If the angle is involved, neovascular glaucoma can result. IOP elevation can occur within one month of onset or later, leading to the term “90-day glaucoma.”27
With time, collateralization (retina-retina and retina-choroid anastomoses) can bypass the obstruction and improve clinical signs, and the hemorrhages, cotton wool spots and optic nerve edema can improve.
While RVO is a clinical diagnosis, supplemental imaging can help confirm the diagnosis, monitor response to treatment and reveal complications such as macular edema and neovascularization.
Fluorescein angiography can illustrate the characteristic finding of delayed filling of the occluded retinal vein. In chronic cases, FA may only reveal microvascular changes, including microaneurysms and telangiectatic collateral vessels, after retinal hemorrhages have resolved. FA also permits visualization of peripheral capillary nonperfusion and macular ischemia, and detection of subtle neovascularization that may not be clinically apparent. Historically, FA was also used to classify RVO into groups of perfused, nonperfused or indeterminate by evaluating for five or more disc areas of capillary nonperfusion in the Branch Vein Occlusion Study (BVOS), and ten or more disc areas in the Central Vein Occlusion Studies (CVOS).26,28 According to the CVOS, CRVO were classified as ischemic if FA revealed more than 10 disc diameters of retinal capillary nonperfusion; they’re considered perfused if fewer than 10 disc diameters of ischemia are present, or as indeterminate if accurate determination of the degree of nonperfusion can’t be estimated due to significant retinal hemorrhage.29 While this framework was useful for study purposes, it’s been largely outdated with ultra-widefield imaging and its ability to help us easily detect nonperfusion and neovascularization.
Optical coherence tomography is critical in confirming the presence of macular edema, including cystoid changes and subretinal fluid, and monitoring response to treatment. Chronic cases can show ellipsoid zone loss from longstanding edema or ischemia. Images obtained with OCT can also provide additional information such as vitreoretinal interface abnormalities, neurosensory detachments and/or loss of outer retina integrity that may further limit vision or guide therapy. OCT angiography can also be helpful in diagnosing occult cases. OCTA allows imaging of the perfused retinal vasculature by acquiring high speed, sequential OCT A-scans at the same retinal locus and then processing complex digital subtraction algorithms to analyze differences created by the moving columns of blood. This technology can show a reduction of blood vessel density, mainly of the deep retinal plexus, in RVO.
|Figure 3. The patient from Figure 1, three months later. An ischemic CRVO has developed, as seen on the fundus photograph and fluorescein angiogram (top), with edema visible on OCT (bottom).|
Unfortunately, no treatment can reverse RVO, though attempts have been made to create anastomoses through surgery and laser, to relieve the obstruction through thrombolytic administration and bypass the congestion via optic nerve sheathotomy.30-33 As a result, the goal is to manage complications of macular edema and neovascularization.
Here, we’ll discuss several landmark trials that help provide guidance in improving visual outcomes for both BRVO and CRVO. We’ll also discuss the evolution of our treatment strategies, working our way from initial therapies that were used to our most current approaches.
• Laser for macular edema. The most common visually threatening complication of RVO is macular edema. In 1986, the National Eye Institute led the BVOS to examine laser treatment for ME from BRVO. In the study, researchers randomized patients with perfused BRVO and visual acuity of 20/40 or worse with ME to grid laser or observation. More patients gained two lines or more of visual acuity from baseline with laser than those without treatment (65 percent vs. 37 percent). Additionally, patients with laser were almost twice as likely to have a final visual acuity greater than 20/40. Given these findings, macular grid laser became the standard of care for ME associated with BRVO.28 Interestingly, the CVOS demonstrated a lack of benefit with respect to the use of macular grid laser for ME in CRVO. While grid laser photocoagulation was historically the gold-standard treatment for BRVO, intravitreal pharmacotherapy has largely replaced laser as the intervention of choice for both BRVO and CRVO.
|Figure 4. Fundus photograph and early (middle) and late (bottom) fluorescein angiograms showing twig branch retinal vein occlusion.|
More recently, researchers have explored the use of peripheral “targeted” laser photocoagulation on angiographically nonperfused retina to decrease the burden of treatment associated with intravitreal anti-vascular endothelial growth factor injections. However, no study has demonstrated a benefit.34-36
• Intravitreal steroids for macular edema. Intravitreal corticosteroids are an effective treatment for ME secondary to RVO.37-41 Use of intravitreal triamcinolone injection in the 2009 SCORE study resulted in superior visual outcomes in patients with CRVO compared to observation, but not compared to grid photocoagulation.37,38
The dexamethasone intravitreal implant 0.7 mg (Ozurdex; Allergan), in the GENEVA trial and in a head-to-head comparison versus ranibizumab in the COMRADE B and C trials, led to rapid visual acuity gain for two months (comparable to ranibizumab). However, visual acuity gain wasn’t sustained after month three in any of the trials, resulting in inferior overall performance compared to ranibizumab from month three to six.39-41 These outcomes may be related to undertreatment in the dexamethasone arm compared to anti-VEGF therapy, however.39-41 Also, it’s well-known that intravitreal corticosteroids can be associated with ocular hypertension and cataract progression. Even so, some studies have shown that intravitreal steroids may be useful for the treatment of ME unresponsive to anti-VEGF therapy.42,43
• Intravitreal anti-VEGF therapy. Intravitreal injection of anti-VEGF agents has become first-line therapy for ME secondary to RVO since numerous prospective studies have revealed its remarkable therapeutic effects.1,35,44–54 More than half of patients with nonischemic RVO will achieve rapid improvement in visual acuity and reduction in retinal thickness shortly after initiation of anti-VEGF therapy, and these improvements are largely maintained with adequate retreatment.1,6-19,35,44-54 Early initiation (less than three months from onset) of anti-VEGF therapy appears to lead to the greatest improvement in visual acuity.1,35,44-54
There don’t seem to be definitive differences in efficacy and safety among the different anti-VEGF agents.1,55 Different injection frequency practices have been evaluated, however. The SHORE study demonstrated that an as-needed regimen with monthly follow-up, after seven monthly injections, was as effective as a monthly treatment approach.49 Many of the pivotal trials have mandated a loading period, but other studies have shown that one or two injections may be enough before switching to PRN in cases where there has been complete ME resolution.56 During initial therapy, follow-up intervals beyond two months aren’t recommended. Visual acuity was maintained with bimonthly monitoring in the CRYSTAL study but not with quarterly monitoring in COPERNICUS.50,54
Figure 5. The macular edema of the patient in Figure 4 initially seen on optical coherence tomography (top) significantly improved on OCT one month after anti-VEGF treatment
Other studies suggest that switching anti-VEGF agents, or switching to a steroid agent, should be considered in eyes that don’t show a complete anatomic response.57 Switching anti-VEGF agents, particularly to aflibercept (Eylea, Regeneron), may be beneficial for extending treatment intervals as well. In NEWTON and other studies, refractory ME unresponsive to ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech) was anatomically improved with aflibercept, and treatment intervals were able to be extended.58-60
New therapeutics continue to be tested for macular edema. Two agents were recently tested in Phase III studies but, unfortunately, both studies were stopped.
Brolucizumab (Beovu, Novartis), an anti-VEGF injection approved for neovascular age-related macular degeneration, was being investigated in the Phase III RAPTOR and RAVEN studies for RVO; it included four-week dosing intervals. However, both studies were stopped, given safety concerns after higher rates of intraocular inflammation were seen in the brolucizumab group of another clinical trial with four-week dosing.61 Additionally, the Phase III SAPPHIRE study examined suprachoroidal triamcinolone acetonide (Clearside) in conjunction with aflibercept for RVO but the combination didn’t meet its primary endpoint compared to aflibercept alone so the study was stopped. Both of these agents showed promise, given their new mechanisms of action and modes of delivery but, unfortunately, they weren’t able to continue.62
Two agents are currently being investigated in Phase III studies for RVO. Faricimab (Genentech), a bispecific antibody targeting vascular endothelial growth factor-a and angiopoietin-2 is being investigated in the COMINO and BALATON RVO trials in comparison to aflibercept.63 Additionally, KSI-301 (Kodiak Sciences), an anti-VEGF injection, is being compared to aflibercept in the Phase III BEACON study.64
Besides macular edema, the other major visually threatening RVO complication is ocular neovascularization. Hypoxia and capillary nonperfusion can upregulate inflammatory cytokines, including VEGF, which promote increased vascular permeability and angiogenesis. The CVOS studied the risk of ocular neovascularization with and without pre-emptive panretinal photocoagulation, as determined by initial perfusion status. The study found that ocular neovascularization developed in 35 percent of ischemic or indeterminate eyes, compared with 10 percent of nonischemic eyes.26 Preemptive PRP reduced the likelihood of ocular neovascularization, but prompt resolution of ocular neovascularization occurred more frequently when laser treatment was deferred.26 Given these findings, the CVOS group recommended deferring PRP until ocular neovascularization develops.
Neovascular glaucoma has a guarded prognosis and treatment with PRP can be challenging if the patient is in pain, if there’s significant corneal edema or if there’s vitreous hemorrhage. Anti-VEGF medications can be used temporarily to treat neovascularization until PRP laser can be applied.
In conclusion, recognizing the clinical features of RVO and promptly treating the complications of macular edema and neovascularization is important to obtaining the best possible clinical outcomes. Unfortunately, there’s no direct treatment for improving perfusion. Instead, our current treatment focuses on minimizing and managing the complications of macular edema and neovascularization. Good treatments exist, including anti-VEGF therapy, intravitreal corticosteroids and panretinal photocoagulation. Future directions for therapy include novel, longer-acting anti-VEGF agents and new drug delivery systems.
Dr. Talcott is an assistant professor of ophthalmology and the residency associate program director at the Cleveland Clinic’s Cole Eye Institute. She is a consultant to Genentech and has received grants from Zeiss and Regenxbio. Address correspondence and requests for reprints to: Katherine E. Talcott, MD; phone: (440) 788-4040; e-mail: firstname.lastname@example.org.
Dr. Regillo is the director of the Retina Service of Wills Eye Hospital, a professor of ophthalmology at Thomas Jefferson University School of Medicine and the principle investigator for numerous major international clinical trials.
Dr. Yonekawa is an assistant professor of ophthalmology at Sidney Kimmel Medical College at Thomas Jefferson University. He serves on the Education Committee of the American Society of Retina Specialists and on the Executive Committee for the Vit Buckle Society, where he is also the vice president for academic programming.
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61. Novartis reports one year results of Phase III MERLIN study evaluating Beovu every four week dosing and provides update on Beovu clinical program. https://www.novartis.com/news/media-releases/novartis-reports-one-year-results-phase-iii-merlin-study-evaluating-beovu-every-four-week-dosing-and-provides-update-beovu-clinical-program. [Accessed November 1, 2021]
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64. Kodiak Sciences treats first patients in three Ph. 3 studies of KSI-301 – Two studies in DME and one study in macular edema due to RVO. https://kodiak.com/press-releases/kodiak-sciences-treats-first-patients-in-three-ph-3-studies-of-ksi-301-two-studies-in-dme-and-one-study-in-macular-edema-due-to-rvo/. [Accessed November 1, 2021]