Much confusion exists in the literature because central retinal vein occlusions and branch retinal vein occlusions (BRVOs) are often grouped and studied together. The natural history and the complication rate for each entity differ. The treatments and their results vary from one condition to the other. This article deals exclusively with BRVOs. Hemiretinal vein occlusions are probably variants of central retinal vein occlusions, and, as such, they are not included in this discussion.
Hypertensive, atherosclerotic, inflammatory, or thrombophilic conditions may lead to retinal endothelial vascular damage. In eyes with an anatomical predisposition, intravascular thrombus formation may occur. Up to two thirds of BRVOs occur in the supertemporal quadrant. This rate may be related to the increased number of arteriovenous crossings in this quadrant with respect to the rest. In addition, nasal BRVOs often are asymptomatic; therefore, patients with this type of BRVO do not seek ophthalmic evaluation. Eyes with arteriovenous crossings appear to be at risk for BRVO. In these eyes, the artery is anterior to the vein in most cases. The artery and the vein share a common adventitial sheath. Increased arterial stiffness may be a mechanical factor in the pathogenesis of BRVO.
Arterial compression of the vein is believed to be the main cause of BRVO. Compression of the vein may lead to turbulent flow in the vein. The turbulent flow in combination with the preexisting endothelial vascular damage from the different conditions creates a local environment favorable to intravascular thrombus formation. Once the venous flow is compromised or interrupted, retinal ischemia ensues downstream from the site of occlusion. Retinal ischemia is one of the most important up-regulators of vascular endothelial growth factor (VEGF) production.[1]
In a rat model, BRVO resulted in a rapid transient increase in the expression of VEGF and a delayed increase in the expression of pigment epithelial derived factor (PEDF), the most potent endogenous inhibitor of VEGF.[2, 3] VEGF has been shown to be a key molecular player in the pathogenesis of the major complications of a BRVO, macular edema and retinal neovascularization.[4] VEGF secretion causes breakdown of the blood-retinal barrier, contributing to the formation of macular edema. The intraocular levels of VEGF are increased in eyes with macular edema secondary to BRVO. These elevated VEGF levels are correlated to the degree and severity of the areas of capillary nonperfusion and macular edema.[5] Undiluted vitreous samples from eyes with untreated acute BRVO demonstrate elevated levels of proinflammatory and proangiogenic cytokines.[6]
Rehak et al have also reported that there is down-regulation of potassium and water channels in Müller cells, which leads to intraretinal accumulation of fluid contributing to the formation of macular edema.[3]
United States
Retinal vein occlusions (branch and central) are the second most common retinal vascular diseases after diabetic retinopathy. The Beaver Dam Study reported a prevalence of 0.6% in patients older than 43 years. The 15-year cumulative incidence of BRVO was 1.8% in the Beaver Dam Eye Study.[7] A cross-sectional study from 6 communities across the United States reported that the prevalence of BRVO was 0.9%. Furthermore, this same study showed that the prevalence of BRVO was similar across different ethnic and racial groups.[8]
International
In a population-based study from Australia, the Blue Mountains Eye Study, the prevalence of BRVO in the population older than 48 years was 1.1%. The Singapore Malay Eye Study reported a 0.6% prevalence of BRVO in the Malay population of persons aged 40-80 years living in Singapore.[9] The Beijing Eye Study reported that the prevalence of BRVO in a Chinese population of people aged 40 years and older was 1.3%.[10]
A recent study pooled data from population studies from the United States, Europe, and Australia.[11] This study reported that the age- and sex-standardized prevalence of BRVO was 4.42 cases per 1000 people. The prevalence increased with increasing age but did not differ by sex. Ethnic and racial background influenced the prevalence of BRVO. For instance, white patients had an age-adjusted prevalence of 3.7 cases per 1000 people, compared with 3.9 cases per 1000 people in African Americans, 5.7 cases per 1000 people in Asians, and 6.9 cases per 1000 people in Latinos.
Given that BRVO is often associated with a concomitant systemic vascular condition, one has to wonder whether or not a BRVO is a marker for cardiovascular mortality or morbidity. There is conflicting evidence regarding the mortality in patients with BRVO.
A 9-year follow-up study in the United Kingdom suggested a relationship between cardiovascular mortality and all retinal vein occlusions (including branch, central, and hemiretinal).
In another study, the 10-year risk of developing cardiovascular complications was higher in patients with BRVO than in those with CRVO.
The Beaver Dam Eye Study reported that patients with BRVO at baseline did not have an increased 8-year risk of dying of ischemic heart disease.[12]
In a Danish study, the investigators did not find a significant difference in mortality between the patients with BRVO and the general population.[13]
No racial predilection for the disease is apparent.
No predilection for either sex is apparent.
The patients who are affected are usually in their fifth or sixth decade of life.
An analysis of several series indicates that 53% of eyes obtain 20/40 or better visual acuity, 25% have a visual acuity between 20/50 and 20/100, and 22% have a visual acuity of 20/200 or worse.[14]
The more distal the occlusion is from the optic disc, the better the visual prognosis.
According to Hayreh and Zimmerman, most eyes with macular edema secondary to BRVO improve to a certain degree without any intervention. The median time to macular edema resolution varied from 18-21 months.[15]
Instruct patients with BRVO to seek attention if further visual loss occurs during follow-up.
The Eye Disease Case-Control Study reported the following findings:[16]
Patients often complain of a sudden painless decrease of vision in the affected eye.
Some patients may complain of a scotoma.
In 1877, Leber first described the branch retinal vein occlusion ophthalmoscopically. During the acute phase, intraretinal hemorrhages (usually flame shaped), retinal edema, and cotton-wool spots are seen in the distribution of a retinal vessel. The horizontal raphe is respected. Intraretinal hemorrhages are shown in the image below.
View Image | This 42-year-old woman with hypertension noticed a sudden decrease in her vision. Visual acuity was 20/100. Note the intraretinal hemorrhages in just .... |
During the chronic stage, hemorrhages may be absent. Macular edema may be the only sign present. Telangiectatic vessels that extend across the horizontal raphe usually can be demonstrated angiographically.
Exudative retinal detachment is an infrequent complication of a BRVO. It is characterized by layered subretinal blood in the inferior portion of the detachment, very few collateral vessels, and capillary nonperfusion.[17]
In certain eyes with large areas of nonperfusion, retinal neovascularization may be seen. Vitreous hemorrhage with tractional retinal detachments may ensue. Further traction may create retinal breaks, creating combined rhegmatogenous and tractional retinal detachments. Neovascular glaucoma and neovascularization at the disc are rare events with BRVO.
Most cases of BRVO are due to idiopathic factors. Usually, patients have an anatomical predisposing factor, such as an arteriovenous crossing where the artery compresses the vein. This compression leads to clot formation and subsequent BRVO.
Inflammatory conditions that affect the retinal veins may cause local damage that predisposes the individual to intravascular clot formation with subsequent BRVO.
Some of the inflammatory conditions reported in the literature are the following:
Thrombophilic conditions, such as the following, may also be involved:
Potential complications of BRVO include the following:
The authors of the Branch Vein Occlusion Study (BVOS) have recommended against extensive testing in patients with typical BRVO.[19]
Certain laboratory studies may be useful in atypical cases (ie, bilateral cases, those in young patients, those in patients with a personal or family history for thromboembolism). Determinations of the following may be helpful:
A fluorescein angiogram is obtained as soon as the hemorrhages have cleared if the patient's vision is still depressed. The test is usually performed 3 months after the event.
The purpose is to determine the cause of the visual loss (eg, macular edema, macular ischemia). If the visual loss is secondary to macular edema, laser photocoagulation in a grid pattern may be of benefit. Conversely, if macular ischemia is responsible for the visual loss, laser photocoagulation should not be offered.
Fluorescein angiograms should be performed periodically to assess for retinal nonperfusion. Wide-angle angiograms are preferred.
Angiogram images are shown below.
View Image | Patient with an old branch retinal vein occlusion in which the hemorrhages have cleared. Note lipid exudation and evidence of cystoid macular edema. |
View Image | Arterial phase of an angiogram demonstrates the lack of filling in the first branch arteriole of the superior temporal artery. |
View Image | Late phase of an angiogram demonstrates late leakage in the macular area. |
Given its ability to measure retinal thickness in a quantitative fashion, OCT is a useful adjunct in the follow-up of patients with macular edema secondary to BRVO.
See the images below.
View Image | Optical coherence tomography (OCT) of a patient with macular edema secondary to branch retinal vein occlusion (BRVO) prior to the initiation of anti-V.... |
View Image | Optical coherence tomography (OCT) following 3 monthly intravitreal bevacizumab injections (1.25 mg). The visual acuity improved to 20/30. |
Optical coherence tomography angiography (OCTA) is a new imaging modality that can visualize the microcirculation of the retina. Unlike fluorescein angiography, OCTA does not require dye injection and clearly delineates the different retinal capillary plexuses. In a small series of 10 eyes with BRVO, foveal avascular zone enlargement was seen in both the superficial and deep capillary plexuses. Capillary nonperfusion was mostly documented in the superficial capillary plexus.[20]
Histopathologic studies confirm the importance of arteriovenous crossings in the pathogenesis of this condition. Inner retinal ischemic atrophic areas have been described distal to the occlusion site. Variable degrees of arteriolar sclerosis have been reported. An intravascular fresh or recanalized thrombus is often found at the site of venous occlusion.
Medical treatment of branch retinal vein occlusion (BRVO) is not effective. In the past, anticoagulants, fibrinolytic agents, clofibrate capsules (Atromid-S), and carbogen inhalation have been used but without success.
Hemodilution has been proposed as an alternative treatment of BRVO by lowering the hematocrit and plasma viscosity and by improving retinal perfusion. However, the true benefit of hemodilution has not been established because published reports have used combination therapy in the hemodilution group.
Intravitreal injection of triamcinolone has been used to treat macular edema of different etiologies because of its potent antipermeability and anti-inflammatory properties. A few cases of macular edema secondary to BRVO treated with an intravitreal triamcinolone injection have been reported. The exact dose remains unclear. Doses from 4 mg to 25 mg have been reported to be effective. Multiple doses appear to be needed.
In a retrospective uncontrolled case series of 92 eyes, intravitreal injection of 4 mg of triamcinolone improved the mean best corrected visual acuity by 2.5 lines at 12 months of follow-up. It is unclear how many eyes required re-injection since this series combined eyes with central and hemiretinal vein occlusion.[21] Trans-Tenon’s retrobulbar injection of 20 mg of triamcinolone acetonide has been reported to be effective. Interestingly, it appears to be more effective in eyes with a posterior vitreous detachment.[22]
Dexamethasone is a more potent corticosteroid than triamcinolone. Furthermore, intravitreal injections of dexamethasone achieves high intravitreal drug levels without any toxic effects. The main drawback of dexamethasone is its short intraocular half life of 3 hours. A biodegradable intravitreal 0.7 mg of dexamethasone implant (Ozurdex) has been designed and approved in patients with macular edema secondary to RVO.[23]
Clinical experience has shown that the effect of a single intravitreal injection of the dexamethasone intravitreal implant lasts close to 4 months. It may be re-injected and one can expect a similar effect with the exception that the effect does not last as long as the initial injection.[24, 25]
Complications resulting from corticosteroid therapy include cataract formation, elevation of intraocular pressure, infectious endophthalmitis, noninfectious endophthalmitis, and retinal detachment. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study compared the effects of macular laser photocoagulations with 1 mg and 4 mg of intravitreal triamcinolone in eyes with macular edema secondary to BRVO. At 12 months of follow-up, the visual acuity was similar in the 3 groups. However, the rates of elevated intraocular pressure and cataract formation were much higher in the 4-mg triamcinolone group.[26, 27]
Vascular endothelial growth factor (VEGF) is a potent inductor of vascular permeability and intraocular neovascularization. In humans, the aqueous levels of VEGF and interleukin 6 (IL-6) are correlated with the degree of retinal ischemia and the severity of macular edema in BRVO. Therefore, VEGF inhibition appears to be a promising treatment modality for macular edema.
Bevacizumab is a humanized recombinant monoclonal IgG antibody that binds and inhibits all VEGF isoforms. Several small retrospective and uncontrolled case series suggest that intravitreal bevacizumab at doses up to 2.5 mg are effective in improving visual acuity and reducing central macula thickness in eyes with macular edema secondary to BRVO. These results are often seen within 1 month of injection. However, most of the eyes will require additional injections to maintain the effects of bevacizumab.[28, 29, 30, 31] Other small, uncontrolled prospective studies have confirmed these initial observations.[32, 33, 34, 35, 36]
The optimum dosing and sequence for intravitreal bevacizumab in BRVO is still undetermined. The 2 most commonly used doses of bevacizumab evaluated were 1.25 mg and 2.5 mg. In a small comparative retrospective study, no differences with respect to central macular thickness, best corrected visual acuity, or total number of injections were observed between the 1.25 mg dose and the 2.5 mg dose.[37]
In a small prospective case series, 21 eyes received 3 initial intravitreal injections of 1 mg of intravitreal bevacizumab at monthly intervals and were followed for 12 months.[34] If macular edema persisted, the patient was retreated with up to 2.5 mg of bevacizumab.
In a small prospective pilot study, 1.25 mg of intravitreal bevacizumab was shown to reduce central macular thickness and improve visual acuity more efficiently than macular photocoagulation at 12 months of follow-up.[38]
A recent meta-analysis of the effect of intravitreal bevacizumab on macular edema secondary to BRVO concluded that intravitreal bevacizumab was beneficial in terms of improving visual acuity and reducing macular edema.[39] See the images below.
View Image | Optical coherence tomography (OCT) of a patient with macular edema secondary to branch retinal vein occlusion (BRVO) prior to the initiation of anti-V.... |
View Image | Optical coherence tomography (OCT) following 3 monthly intravitreal bevacizumab injections (1.25 mg). The visual acuity improved to 20/30. |
A multicenter, prospective, phase III trial (BRAVO Study) comparing intravitreal ranibizumab and sham injections demonstrated the value of VEGF inhibition in eyes with macular edema secondary to BRVO. In this study, eyes were randomized to monthly sham injections, 0.3 mg of ranibizumab and 0.5 mg of ranibizumab, for the first 6 months. Eyes were eligible for rescue laser at month 3 if the hemorrhages had sufficiently cleared to allow safe treatment and if the visual acuity remained at 20/40 or less and the central macular thickness was 250 µm or less.[40]
During months 6-12 of the study, eyes were injected as needed, and the sham group was offered 0.5 mg ranibizumab. Again at month 9, eyes that did not responding to intravitreal ranibizumab were allowed laser rescue. At 12 months, eyes gained an average of 12.1, 16.4, and 18.3 letters in the sham, 0.3 mg, and 0.5 mg groups, respectively. Similarly, central foveal thickness decreased with ranibizumab treatment. Sham eyes had gained 7.3 letters at 6 months and had an additional gain of 4.8 letters after intravitreal ranibizumab was instituted. This suggests that timing is important and eyes with macular edema secondary to BRVO should be offered VEGF inhibition upon diagnosis in order to achieve the best possible visual outcome.
During months 13 to 24 (HORIZON Trial), eyes were followed at least every 3 months and were re-injected with 0.5 mg of ranibizumab if macular edema was present. In addition, these eyes were eligible for rescue grid laser therapy if the visual acuity was less than 20/40 and macular edema was still present. A large percentage of eyes received grid macular laser rescue therapy during the first 12 months of the study in all the study arms. After 2 years of follow-up, the visual gains were maintained with continued VEGF suppression.[41]
Thirty-four eyes enrolled in the BRAVO and HORIZON Trials were followed for an average of 49 months (RETAIN Study). Half of these eyes experienced edema resolution, which was defined as an absence of intraretinal fluid for 6 months or longer since the last injection. The mean number of injections in eyes without edema resolution during year 4 of follow-up was 3.2. In eyes with resolution of edema, the mean gain of BCVA was 25.9 letters compared with 17.1 letters in eyes with unresolved edema. This difference was not statistically significant. Close to 80% of eyes obtained a BCVA of 20/40 or greater, regardless of edema resolution.[42]
A 2016 clinical trial, the BRIGHTER Study, has shown that an individualized visual acuity–based regimen of ranibizumab results in good visual acuity gains.[43]
In October 2014, the indication for aflibercept was expanded to include branch retinal vein occlusion (BRVO). The expanded indication is based on the previously approved indication for macular edema following CRVO and the positive results from the double-masked, randomized, controlled phase 3 VIBRANT study of 181 patients with macular edema following BRVO. The VIBRANT study compared intravitreal aflibercept 2 mg once every 4 weeks with macular laser photocoagulation (control).
At 24 weeks, significantly more patients treated with aflibercept gained at least 15 letters in vision (3 lines on an eye chart) from baseline as measured on the early treatment diabetic retinopathy study (ETDRS) chart, the primary endpoint of the study, compared with patients who received control (53% vs 27%; P< 0.01). Patients treated with aflibercept achieved a 17-letter mean improvement over baseline in best-corrected visual acuity (BCVA) compared to a 6.9-letter mean improvement in patients who received control (P< 0.01), a key secondary endpoint.[44]
Multiple clinical trials have shown that timing is an important prognostic factor in eyes with macular edema due to BRVO. In the past, time was given for spontaneous resolution and clearing of intraretinal hemorrhages to allow performance of a "good" fluorescein angiogram. The authors no longer recommend this waiting period. An OCT should be the first diagnostic test; and if macular edema is present, initiation of treatment should be strongly considered.[19, 23, 40]
Retinal nonperfusion is related to intravitreal VEGF levels. Progressive retinal nonperfusion may be responsible for loss of visual gains, particularly in eyes in which macular edema has not resolved and anti-VEGF injections are given sporadically. The authors from this study state that in eyes with macular edema secondary to RVO, the resolution of macular edema should not be the sole treatment objective. The prevention of worsening retinal nonperfusion should be a treatment objective as well. Periodic fluorescein angiograms, preferably wide-angle, should be performed to monitor perfusion status.[45, 46]
In a retrospective case control study, 22 eyes underwent subthreshold micropulse laser plus intravitreal ranibizumab, and 24 eyes underwent intravitreal ranibizumab monotherapy. Eyes in the ranibizumab monotherapy group received an initial injection and were then followed monthly with serial OCTs. Eyes were re-injected if macular edema recurred. Eyes in the combination arm received an initial ranibizumab injection followed by subthreshold micropulse laser treatment one month after the initial injection. Thereafter, the patients were monitored monthly and were re-injected if macular edema was observed in the OCTs. At 6 months, the visual results and the central macular thickness results were comparable in both treatment arms. The number of injections in the combination arm (1.9) were significantly fewer than the number of injections in the ranibizumab monotherapy group (2.3).[47]
Branch retinal vein occlusions (BRVOs) have a relatively benign course. Nevertheless, certain complications that lead to visual loss may occur. These complications include macular edema and the sequelae from retinal neovascularization (eg, vitreous hemorrhage, tractional retinal detachment, neovascular glaucoma). Several surgical and laser techniques are available to deal with these situations.
Macular grid laser photocoagulation was mildly effective in the treatment of macular edema in a small prospective trial, the BVOS.
The current recommendation is to wait 3 months to see if the patient's vision spontaneously improves.
If no improvement occurs and if the hemorrhages have mostly cleared from the macular area, a fluorescein angiogram is obtained. If the angiogram shows leakage in the macular area that is responsible for the decrease in vision, treatment with a macular grid laser is recommended. After 3 years of follow-up care, 63% of laser treated eyes improved by 2 or more lines of vision compared with 36% of control eyes.[19]
Despite macular photocoagulation, eyes gained on average 1.33 lines of vision with respect to baseline. At the 3-year follow-up, 40% of eyes had a visual acuity of less than 20/40 and 12% of eyes had a visual acuity of less than 20/200.[19]
If the fluorescein angiogram reveals macular nonperfusion, laser therapy is not warranted, and observation is recommended. Finkelstein reported that eyes with macular nonperfusion have a good visual prognosis.[48] In his series, the median visual acuity was 20/30.
Macular grid laser photocoagulation remains the criterion standard treatment of eyes with perfused macular edema secondary to BRVO.
The BVOS also demonstrated that scatter photocoagulation reduces the prevalence of neovascularization from 40% to 20%.
However, if all eyes with nonperfusion were treated, 60% of patients who would never develop neovascularization would be treated.
If only the eyes that develop neovascularization were treated, the events of vitreous hemorrhage would decrease from 60% to 30%.
Therefore, the recommendation is to wait until neovascularization actually develops before scatter photocoagulation is considered.
The introduction of ultra–wide-field FA imaging has allowed the identification of vascular abnormalities in the retinal periphery.
Bypass of the normal retinal venous drainage channels is attempted by creating a communication between the obstructed vessel and the choroid.
Problems with this technique are the lack of reliability in creating an anastomosis (most groups report a 30-50% success rate) and its complications. Complications from the procedure include tractional retinal detachment and vitreous hemorrhage.
Virtually all cases of BRVO occur at arteriovenous crossings.
Because arterial compression is believed to be the major cause of this condition, some have recommended lifting the artery from the underlying vein to relieve the compression.
Several small, uncontrolled series have shown good results in improving macular edema and macular perfusion. However, others have reported a lack of efficacy of this procedure. Planning of a multicenter controlled trial is currently underway.
Several surgeons have reported resolution of macular edema secondary to BRVO after vitrectomy with or without peeling of the internal limiting membrane.
Vitrectomy and posterior hyaloid separation improved the visual acuity in eyes with macular edema secondary to BRVO. The addition of intravitreal triamcinolone had no additional benefit.[49]
A number of eyes may develop a transient postoperative increase in macular edema following vitrectomy. The edema resolves spontaneously and does not appear to have an effect on visual acuity.[50]
Pars plana vitrectomy techniques with or without scleral buckling may be necessary in eyes with tractional and rhegmatogenous retinal detachments.
Consult a vitreoretinal specialist if complications arise.
In atypical cases where a thrombophilic condition is suspected, consultation with a hematologic specialist is recommended.
After branch retinal vein occlusion (BRVO) is diagnosed, a patient must receive follow-up care to monitor the development of possible complications.
If the patient's visual acuity remains depressed, a good quality fluorescein angiogram can be obtained when most of the hemorrhages have cleared, usually by 3 months. The angiogram guides further therapy.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Through its antipermeability properties secondary to its anti-VEGF effects, strengthens blood retinal barrier and prevents its disruption.
Clinical Context: Corticosteroids suppress inflammation by inhibiting multiple inflammatory cytokines, resulting in decreased edema, fibrin deposition, capillary leakage, and migration of inflammatory cells. Indicated for treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion.
Clinical Context: Murine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth.
Clinical Context: Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) age-related macular degeneration (ARMD). In clinical trials, about one third of patients had improved vision at 12 mo that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, (VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to ARMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.
Clinical Context: Binds and prevents activation of vascular endothelial growth factors (VEGF-A) and placental growth factor (PIGF). Activation of VEGF-A and PIGF can result in neovascularization and vascular permeability. It is indicated for treatment of macular edema following retinal vein occlusion (branched or central retinal vein occlusion).
Nonspecific monoclonal anti-VEGF angiogenesis that targets and inhibits vascular endothelial growth factor (VEGF) activity.