Branch retinal vein occlusion

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Branch retinal vein occlusion
Classification and external resources
ICD-10 H34.8
ICD-9 362.36


Branch retinal vein occlusion is the most common retinal vein occlusion.

Branch retinal vein occlusion of superotemporal branch vein in the right eye.  Fundus photograph showing widespread haemorrhages and axonal congestion (cotton wool spots; white circles) upstream of the venous occlusion.

Disease Entity

Branch retinal vein occlusion is recognized by the following codes by the International Classification of Diseases (ICD) nomenclature:

ICD-9 Codes

  • 362.30 Retinal vein occlusion
  • 362.35 Central retinal vein occlusion
  • 362.36 Branch retinal vein occlusion
  • 362.36 Tributary retinal vein occlusion
  • 362.37 Incipient retinal vein occlusion
  • 362.37 Partial retinal vein occlusion


ICD-10 Codes

  • H34.83 Branch retinal vein occlusion
  • H34.831 Branch retinal vein occlusion, right eye
  • H34.832 Branch retinal vein occlusion, left eye
  • H34.833 Branch retinal vein occlusion, bilateral
  • H34.839 Branch retinal vein occlusion, unspecified eye
The first case of BRVO was described by Richard Liebreich in 1855. Liebreich was Helmoholtz’s assistant in 1851 when he invented the ophthalmoscope in Konigsberg.  He completed his medical studies in Halle in 1853 and then joined von Graefe’s Clinic to become his assistant in 1854. Liebreich and von Graefe were the first adopters of the ophthalmoscope in clinical practice. Liebreich published the first volumes of Archiv fur Ophthalmologie in 1854/1855 on the appearance of normal and pathological fundi and correlated ophthalmoscopic findings with histology. The description of the first branch retinal vein occlusion was in one of these papers. As von Graefe’s clinic grew, and became a center for post-graduate teaching, Liebreich became the primary teacher in von Graefe’s center. During his time in Berlin, he wrote the first paper in the field of ophthalmic genetics about the influence of consanguinity on retinitis pigmentosa.[1]

Disease

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder after diabetic retinopathy.[2] Retinal vein occlusions are divided into central (CRVO), hemi (HRVO), and branch retinal vein occlusions (BRVO). BRVO is a venous occlusion at any branch of the central retinal vein. Occlusions occurring at the anterior part of the central retinal artery trunk results in a HRVO, which is consider as a subtype of either CRVO or BRVO. The retina has a dual blood supply, with retinal vessels supplying the inner retina, and choroidal vessels supplying the outer retina extending from the outer part of inner nuclear layer.

Classification

BRVO is classified according to the anatomical location as major or macular. Major BRVO refers to occlusion of a retinal vein that drains one of the quadrants. Macular BRVO refers to occlusion of a venule within the macula. The incidence of BRVO is most common in the superotemporal quadrant (58.1-66%), followed by the inferotemporal quadrant (29%), and least common in the nasal quadrants (12.9%).[3] [4] Macular BRVO involves the superior macular region in 81% of cases and the inferior macular region in 19% of cases.[5] The increased incidence in the superotemporal quadrant is thought to be due to increased arteriovenous crossings in that quadrant. BRVO is further classified into perfused (non-ischemic) or nonperfused (ischemic). Ischemic BRVO is defined as > 5 disc diameters of nonperfusion on fluorescein angiography (FA).[6] [7]

Epidemiology

BRVO is the most common RVO with an incidence of 0.44%-1.6%. [4][8] A meta-analysis completed in 2010 by Rogers et al pooled data from 11 studies from the United States, Europe, Asia and Australia with 49,869 subjects and the estimated prevalence of any RVO 0.52%, BRVO 0.442%, and CRVO 0.08%. There was an association of higher prevalence with race, but not with gender. Overall the prevalence of any RVO and BRVO in increasing order by ethnicity was: whites, blacks, Asians, and then Hispanics. (The prevalence of BRVO was 0.282% in whites, 0.353% in blacks, 0.498% in Asians, and 0.598% in Hispanics.)[8] Five to ten percent BRVOs are bilateral.

Risk Factors

BRVO has many known ophthalmic and systemic risk factors including age, hypertension, hyperlipidemia, ocular hypertension, and glaucoma.[9][10] There is a significant association of advancing age with BRVO, and the incidence of BRVO increases with age. The prevalence of BRVO is 0.157 per 100 in 40-49 year olds, 0.458 per 100 in 50-59 year olds, 1.11 per 100 in 60-69 year olds, and 1.276 per 100 in 70-79 year olds.[8]

After adjusting for age The Beaver Dam Eye Study showed that BRVO was associated with hypertension, elevated systolic and diastolic pressure, pulse pressure, ocular perfusion, focal arteriolar narrowing, and arteriovenous nicking. After controlling for hypertension status, arteriovenous nicking and focal arteriolar narrowing remained as independent factors associated with BRVO.[4]

A large meta-analysis by O’Mahoney et al, showed a significant association of hypertension and hyperlipidemia with BRVO. However, there was no association of diabetes mellitus with BRVO (unlike the association found with CRVO in the same study).[9][11] Other factors that are significantly associated with BRVO are glaucoma and body mass index (BMI).[9] [12] BRVO is uncommon in patients younger than 50 years and there is a significant association of BMI with BRVO in patients younger than 50 years.[13]

Various meta-analysis studies have examined prevalence and association of thrombophilic risk factors and BRVO. The only significant associations are hyperhomocysteinemia and anti-cardiolipin antibodies with BRVO. However, controversy remains about association with MTHFR gene mutation, factor V Leiden mutation, protein C and S deficiency, prothrombin gene mutation, or antithrombin deficiency. Anti-cardiolipin antibodies can be found in anti-phospholipid syndrome, systemic lupus erythematosus, and Behcet disease.[12][14][15]

Summary of risk factors:

  • Age
  • Ocular hypertension/glaucoma
  • Hypertension
  • Hyperlipidemia
  • Body mass index
  • Hyperhomocysteinemia
  • Anti-cardiolipin antibodies

Pathogenesis

The pathogenesis of BRVO is multifactorial in origin and not completely defined. Possible mechanisms include a combination of mechanical compression, degenerative changes in vessel walls, and/or hypercoagulable factors. The arteriosclerotic changes (specifically arteriovenous crossing) are believed to result in venule occlusion through endothelial cell damage and thrombosis. Another hypothesis is that arteriosclerosis results in arteriolar insufficiency leading to BRVO.

The association between BRVO and arteriovenous crossing has been established in multiple studies. In almost all cases of BRVO (97.6-100%)[16][17][18] the thick-walled artery is found anterior to the thin-walled vein. The artery and vein also share a common adventitial sheath at these crossings, which contributes to the predisposition of vein occlusion at these crossings. Arteriolar sclerosis increases the rigidity of the artery and further provides support for the mechanical basis of BRVO at arteriovenous crossings.[16][19] Mechanical obstruction of the vein by the rigid artery results in turbulent blood flow at arteriovenous crossings, resulting in venous intima media and endothelial damage which leads to vein occlusion.[3][20] Virchow's triad[21] consists of 3 important factors for vascular thrombosis- hypercoagulability, abnormal blood flow, and endothelial injury.

In histological studies of BRVO, the endothelium and intima media are found to be thickened and altered at the arteriovenous crossings, with no blood thrombus obliterating the venous lumen at the arteriovenous crossing, which suggests a compression as a major factor in the pathogenesis of BRVO. Post- mortem and post enucleation histological studies of chronic BRVO have shown the thickening of the common adventitial tissue of the artery and vein at the arteriovenous crossings.[22]

Recent use of OCT has shown that retinal veins exhibit luminal narrowing at arteriovenous crossing, rather than compression or flattening of venous lumen, which might seem contradictory to the compressive mechanism of BRVO. However, there is a degree of venous narrowing correlated with the diameter of the crossing artery (Figure D). Arteries which are larger due to arteriosclerosis result in veins with narrower lumens at arteriovenous crossing. The narrowed veins retain their circular shape in cross-section. The narrowed veins have to change their course at the arteriovenous crossing, resulting in venous tortuosity that extends beyond the external limiting membrane line on OCT. The change in course of the vein results in turbulent blood flow, which causes chronic damage to the venous endothelial cells, and leads to endothelial cell proliferation and venous wall modeling. The endothelial cell dysfunction with narrowing of the venous lumen contributes to BRVOs.[23]

The higher incidence of superotemporal BRVO compared to other quadrants is speculated due to larger number arteriovenous crossings in that quadrant, which supports the hypothesis of arteriovenous nicking as a cause. The Eye Disease Case-control Study Group showed patients’ with BRVO had significantly more arteriovenous crossings than in age-sex-race matched subjects. Also, in the 106 eyes with BRVO, 105 out of 106 had the artery located anterior to the vein at the site of blockage.[3]

Macular edema is the main cause of vision loss in BRVO. The pathogenesis of macular edema is believed to be a result of multiple inflammatory cascades. Analysis of vitreous samples from patients with BRVO has established the increased levels of VEGF, IL-6, IL-8, and monocyte chemoattractant protein-1 compared to controls.[24][25][26] Excess VEGF is produced from retinal epithelial cells, endothelial cells and Muller cells in setting of BRVO, resulting in vascular permeability and contributing to macular edema.[27]
Figure 1: color fundus photograph of acute branch retinal vein occlusion. There is arteriovenous crossing in the superotemporal quadrant with diffuse dot and blot hemorrhages in the superotemporal quadrant. [28]

Diagnosis

BRVO is a clinical diagnosis that is further classified with OCT and FA.

History/Symptoms

Patients presenting with BRVO have a range of symptoms depending on the site and severity of occlusion. Typically, patients present with sudden painless vision loss or visual field defect. Rarely, patients present with floaters from vitreous hemorrhage if the initial vein occlusion was asymptomatic and retinal neovascularization had developed.
Figure 2: Color fundus photography of chronic branch retinal vein occlusion depicting sclerosed inferotemporal retinal vein (arrow).

Physical examination/Signs

Typical funduscopic examination consists of flame hemorrhages, dot and blot hemorrhages, cotton wool spots, hard exudates, retinal edema, and dilated tortuous veins (Figure 1). Classically there is a wedge-shaped distribution of intraretinal hemorrhage that is more extensive if the occlusion is ischemic compared to a non-ischemic BRVO. A hemorrhage can be present at the arteriovenous crossing, which is called the Bonet sign.[29] Bonnet's sign in hypertensive retinopathy denotes banking (dilatation) of vein distal to the arteriovenous crossing.

Patients can present with visual field defects. Patients with macular BRVO presents with a central field defect, while major BRVO present with a peripheral field defect corresponding to the retinal quadrant that is affected. The field defects are relative in cases of capillary nonperfusion and can become absolute scotomas in long-standing occlusions.

In patients with chronic BRVO, the intraretinal hemorrhages are absorbed and subsequent retinal vascular abnormalities develop in the distribution of the BRVO. The resulting changes include capillary nonperfusion, collateral formation, microaneuryms, sclerosed veins, and telangectatic vessels (Figure 2).

Rarely, patients that present with chronic macular edema due to undiagnosed BRVO or nasal BRVO, can present with neovascularization of iris, angle, and posterior segment. They can present with floaters from vitreous hemorrhage, rubeosis, and pain from neovascular glaucoma.

Clinical diagnosis

Patients with BRVO should have a complete history and ophthalmic examination, with particular attention to the history of glaucoma, intraocular inflammation, and systemic risk factors for BRVO. Careful examination of the undilated iris and angle should be performed on initial and subsequent examinations to monitor for early signs of rubeosis and neovascular glaucoma.

Cause of visual decline in BRVO

  • Macular edema
  • Macular ischemia
  • Hemorrhage over the fovea
  • Vitreous hemorrhage from neovascularizations of the retina or the optic disc
  • Epiretinal membrane/vitreomacular traction
  • Tractional retinal detachment/combined tractional and rhegmatogenous retinal detachment./Rhegmatogenous retinal detachment

Diagnostic procedures

Fluorescein angiography (FA)

Figure 3: Color fundus photograph and series of fluorescein angiograms showing chronic branch retinal vein occlusion with sclerotic superotemporal arcade vessel (arrow). The small collateral vessels (black arrowhead) can be confused with neovascularization but do not leak on FA. There is also significant surrounding capillary nonperfusion and areas of neovascularization with leakage (open arrows).

In patients with BRVO, FA helps to characterize retinal vasculature including the extent of nonperfusion, macular ischemia, macular edema and leakage. However, on initial presentation, intraretinal hemorrhages may make obtaining a quality FA difficult. The various retinal abnormalities on OCT and FA have prognostic significance and help identify complications due to BRVO.

The characteristic FA for BRVO is delayed filling of the occluded retinal vein with varying degrees of capillary nonperfusion. Intraretinal hemorrhages will result in blockage, and macular edema or retinal neovascularization will results in dye extravasation (Figure 3).
Figure 4: Spectral-domain optical coherence tomography of an eye with a branch retinal vein occlusion (BRVO).  A scan of the BRVO reveals cystoid macular edema with intraretinal fluid, and subretinal fluid (open arrow). Intraretinal heme (arrow) appears hyperreflective with a shadow.

Optical coherence tomography (OCT)

OCT allows for rapid, non-invasive, and quantitative analysis of the macula and has become an important imaging modality in the assessment and treatment of BRVO. OCT has been used in many studies as the primary study modality in preference to FA, since assessment and treatment most often focus on macular edema.

Characteristic findings of BRVO on OCT are cystoid macular edema, intraretinal hyperreflectivity from hemorrhages, shadowing from edema and hemorrhages, and occasionally subretinal fluid (Figure 4). Unlike FA, OCT images are minimally affected by intraretinal hemorrhages. The third high reflectance band in the parafoveal area corresponds to the junction between inner segments (IS) and outer segments of photoreceptors. This band (also called the ellipsoid zone) has prognostic significance on visual acuity. Disruption or absence of the third reflectance band after macular edema resolution is an indication of photoreceptor cell death or disarrangement, which results in poor visual outcome(Figure 5).[30]

Figure 5: Optical coherence tomography image of horizontal sections of the fovea with mostly resolved macular edema. The third high reflectance band (red arrow) is continuous in the parafoveal region and discontinuous in the fovea (blue arrow).

Laboratory test

The diagnosis of BRVO is based on clinical examination. Typical patients will present with history of known risk factors (hypertension, hyperlipidemia, or glaucoma). Initial work-up includes a detailed history to define risk-factors. Initial laboratory work-up consists of comprehensive metabolic panel, complete blood count, and lipid panel to help optimize known risk factors in consultation with the primary care physician.

In patients younger than 50 years old, bilateral BRVO at presentation, or history of numerous BRVOs a search for infectious, inflammatory or hypercoagulable cause is warranted. Initial work-up includes a detailed history with attention to other risk factors that might predispose to a hypercoagulable state, including medications (such as oral contraceptives). The work-up should be performed in consultation with the primary care doctor. Laboratory work up should include complete metabolic panel, complete blood count, prothrombin time/partial thromboplastin time, vitamin B6/B12 and folate levels, homocysteine level, antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody), and activated protein C resistance (factor V Leiden).

Inflammatory BRVO is clinically identified with evidence of vasculitis and intraocular inflammation (paravascular infiltrates, vitritis, snow balls). The blockage of the vein in such cases do not necessarily correspond to the arteriovenous crossing. These BRVOs are usually peripheral and multiple and the vasculitis may be in different stages (active/healing/or healed) in the same eye.

Differential diagnosis

  • Hypertensive retinopathy
  • Diabetic retinopathy
  • Radiation retinopathy
  • Macular telangiectasia
  • Retinal angiomatous proliferation
  • Age-related macular degeneration or variants such as retinal angiomatous proliferation
  • Ocular contusion or retinal trauma

Management

The treatment for BRVO is aimed at treatment/prevention of the complications that cause vision loss including macular edema, macular ischemia and neovascularization. The systemic risk factors should be optimized in consultation the primary care doctor. Anticoagulation have no proven benefit in the management of BRVO associated with a hypercoagulopathy.[31]

Laser Photocoagulation

Prior to the advent of anti-vascular endothelial growth factor (VEGF) agents, laser photocoagulation was considered the gold standard for the treatment of BRVO as established by the BVOS Group.[6][7] Photocoagulation can be considered in patients with perfused macular edema with VA ≤ 20/40 without improvement in visual acuity for at least 3 months. Before application of laser photocoagulation, an FA of the macula is obtained to demonstrate the absence of a large area of capillary nonperfusion adjacent to the capillary free zone that could explain the vision loss.

The recommended parameters for grid laser include duration of 0.1 seconds, 100 µm diameter spot size, and power to produce a medium white burn. FA is repeated in 2-4 months to assess the need for additional laser and resolution of macular edema. Laser photocoagulation is applied in a grid pattern throughout a leaking area, but not involving the edge of the capillary-free zone or beyond the major vascular arcades peripherally.

The mechanism of action of laser photocoagulation in macular edema is thought to be destruction of nearby capillary beds, reducing input of arterial blood supply and allows remaining capillaries to drain into less congested intact capillary bed.

Laser photocoagulation is also used to prevent vitreous hemorrhage. According to results of the BVOS Group, patients with BRVO and > 5 disc diameters of retinal capillary nonperfusion should undergo scattered laser photocoagulation only once neovascularization has developed. BVOS data showed that scatter photocoagulation after neovascularization develops is as effective as before neovascularization in preventing vitreous hemorrhage.

The recommended parameters for scatter laser include duration of 0.2 seconds, 200-500 µm diameter spot size, and power to produce a medium white burn. Scatter laser is applied in the area of capillary nonperfusion as defined by FA, with laser applied peripherally at least to the equator and no closer than tow disc diameters from the center of the fovea.

Steroid Treatment

Corticosteroids have been shown to be effective for treatment of macular edema in BRVO.[32] However, intraocular corticosteroids have significant side effects including progression of cataracts formation and elevation of intraocular pressure. The SCORE-BRVO study is the largest trial that evaluated the safety and efficacy of intravitreal triamcinolone compared to grid laser in the treatment of macular edema.[33]  At 12 months, the study concluded that there is no difference in visual acuity gained between the two triamcinolone groups and grid laser group. There was significant cataract formation and elevation of intraocular pressure in the intravitreal triamcinolone groups. However, the three year results showed a significant increase in vision in the laser group compared to the intravitreal triamcinolone groups. From the results of this study, intravitreal triamcinolone is not recommended as a first-line therapy for macular edema due to BRVO. It is utilized as an adjunct to laser or anti-VEGF agents or as second line agent.

Ozurdex, a dexamethasone implant has been evaluated in the GENEVA study for macular edema in CRVO and BRVO. The implant is injected using a 22-guage custom injector and gradually releases dexamethasone over several months (1-3 months), with peak response at 60 days. The study found that the Ozurdex implant group had higher percentage of patients with gain ≥ 15 letters at the 90 day period compared to sham group and also a lower percentage of patients with losses of ≥ 15 letters. However, the study is limited by the absence of comparison of standard treatment that is rescue treatment for the sham group.[34]

Anti-Vascular Endothelial Growth Factor (VEGF) Agents

In patients with BRVO, retinal ischemia results in elevated secretion of VEGF leading to increased vascular permeability and vasodilation.[25][26][27] There are several anti-VEGF agents available to treat macular edema due to BRVO including ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea).

Both ranibizumab and aflibercept are FDA approved for the treatment of macular edema following RVO. Ranibizumab is a recombinant humanized monoclonal antibody fragment (Fab) that binds all VEGF-A isoforms at higher affinity than bevacizumab. Bevacizumab is a full length, humanized monoclonal antibody that binds all VEGF-A isoforms and is used off label in the eye. Aflibercept (VEGF-trap) is a recombinant fusion protein that consists of human VEGF receptor 1 and 2 extracellular domains fused to Fc portion of human IgG1. Aflibercept binds to all forms of VEGF-A with higher affinity than bevacizumab and ranibizumab. It also targets VEGF-B and PlGF.[35]

Ranibizumab (Lucentis)

In the BRAVO study patients with macular edema due to BRVO were randomized to 0.5mg ranibizumab, 0.3mg ranibizumab and sham injections for monthly injections for the first six months (treatment period). Patients were allowed one rescue grid laser treatment during the treatment period and were screened for rescue grid laser at 3 months. If they had gain of < 5 ETDRS letters or < 50 µm improvement in central subfield thickness they qualified for rescue grid laser. If rescue laser was not used at the 3 month time point, they were further screened monthly for possible rescue laser.

At the 6 month time point there was 16.6 and 18.3 letter gain in the 0.3mg and 0.5mg ranibizumab groups, respectively. There was a 7.3 letter gain in the sham group with 54.5% of the sham group requiring rescue laser. Only 18.7% and 19.8% of the 0.3mg and 0.5mg ranibizumab groups, respectively, required rescue laser. 

After the first six months all groups were allowed as needed (PRN) of ranibizumab (observation period). The qualification for PRN ranibizumab was vision ≤ 20/40 or mean central subfield thickness ≥ 250 µm. Patients were again allowed one rescue grid laser treatment starting at 9 months. At 12 months, the mean letter gain was 16.4 and 18.3 in the 0.3mg and 0.5mg groups, and 12.1 in the sham/0.5mg group. 

The BRAVO study showed that ranibizumab is superior to traditional grid laser for macular edema from BRVO. The study also showed that PRN treatment was able to maintain gains in vision after 5 monthly injections. However, the study did not evaluate when to switch to PRN schedule. 

The HORIZON trial was a 12 month extension of the BRAVO and CRUISE trials and followed patients every 3 months for 12 months. Patients were given PRN ranibizumab 0.5mg based on the criteria in the BRAVO study. Overall, HORIZON concluded that PRN use of ranibizumab after an intensive year of treatment was able to maintain visual acuity gains.[36][37][38]

Aflibercept (Eylea)

The VIBRANT study compared intravitreal aflibercept 2.0mg to grid laser. Patients with macular edema due to BRVO that occurred within 12 months with BCVA 20/40 to 20/320 were included in the trial.

Patients were randomized to aflibercept drug injections every 4 weeks for the first 20 weeks or grid laser at baseline followed by a single rescue grid laser from weeks 12 through 20. After 24 weeks, the drug injection group received IAI every 8 weeks, while the grid laser group received sham injections. Patient in the grid laser group that qualified for rescue laser were given 3 monthly drug injections followed by drug injections every 8 weeks. Rescue treatment criteria included > 50µm increase in central subfield thickness compared with lowest previous measurements, loss of ≥ 5 letters compared with best previous measurement in conjunction with any increase in central subfield thickness, or presence of new or persistent cystic retinal changes, subretinal fluid or persistent diffuse edema. 

At 24 weeks the mean change of BCVA was 17.0 in drug injections group compared to 6.9 in grid laser group. At 52 weeks the mean change of BCVA was 17.1 in drug injection group compared to 12.2 in grid laser group. Rescue treatment was required in 10% of drug group and in 80% eyes in the laser/drug group. 

Overall, the VIBRANT study showed that aflibercept is more effective than gird laser in treatment of macular edema from BRVO, and the vision gains established after monthly injections can be maintained by extending out treatment. 

The VIBRANT study included patient with perfused and nonperfused BRVO, unlike the BRAVO study which only included perfused BRVO. The VIBRANT study evaluated retinal perfusion at baseline, 24 weeks and 52 weeks. They showed an improvement in retinal perfusion and reversal of nonperfusion after treatment with intravitreal aflibercept. This effect was also noted in the laser/drug group at 52 weeks after they received drug from weeks 24 to 52, but not during the laser only duration of the study.[36][39][40]

Bevacizumab (Avastin)

There are numerous small prospective studies in evaluating 1.25mg bevacizumab in the treatment of macular edema due to BRVO. One of the larger studies by Russo et al assigned 30 eyes were to either grid laser or intravitreal bevacizumab. Bevacizumab was given at 1, 3, 6 and 12 months. Grid laser was applied at baseline and reassessed at 3 months for possible retreatment. At 12 months the mean gain in BCVA was 0.31 logMAR (15 letters) in the bevacizumab group compared with 0.20 logMAR (10 letters) in the grid laser group.[41] The mean gain in this study is similar to mean gains in the BRAVO/HORIZON and VIBRANT studies.

The dose of bevacizumab was evaluated by Wu et al, were 2.5mg and 1.25mg doses of bevacizumab were compared retrospectively on BCVA gain and central subfield thickness. The mean BCVA gain at 6 months was 5.1 lines and 4.5 lines in the 1.25mg group and 2.5mg group, respectively. There was no statistically significant difference between the two doses on BCVA and central subfield thickness.[42]

The BERVOLT study, a retrospective study, looked at the efficacy and safety of bevacizumab in macular edema due to BRVO and CRVO. They concluded that the overall mean change in BCVA in the BRVO group treated with bevacizumab 1.25mg was 0.25 logMAR (13 letters) with no significant adverse events.[43]

Surgical Management

Sheathotomy

Most venous obstructions in BRVO occur at an arteriovenous crossing. In histopathologic studies in BRVO, arteries and veins share a common adventitial sheath. The first case report for pars-plana vitrectomy combined with sheathotomy for BRVO was done by Osterloh et al. The patient improved from 20/200 to 20/25+ over an eight month period.[44] Since then there have been various case series assessing surgical treatment options for BRVO.

Mester et al published a case series of 43 patients with macular edema due to BRVO treated with arteriovenous decompression and isovolemic hemodilution and compared to 25 patients that underwent isovolemic hemodilution only after 6 weeks. 16 of the 43 patients also underwent internal limiting membrane removal in the macular area, besides the arteriovenous dissection. At 6 weeks, the mean BCVA improved by 0.19 logMAR (10 letters) in the arteriovenous decompression group compared with no change in mean BCVA in the isovolemic hemodilution.[45]

Muqit et al published on long-term prospective visual outcomes of arteriovenous sheathotomy with or without intravitreal triamcinolone. The study included eight patients and three received intravitreal triamcinolone. The mean follow up was 34.5 months with no overall improvement in BCVA; however, there was improvement in vascular perfusion.[46]

The literature is not conclusive on the benefits of surgical management of macular edema due to BRVO. Possible mechanism for improvements in visual acuity in vitrectomized eyes is hypothesized to be due to increased oxygenation of the macula. Overall, this modality remains controversial and has fallen out of favor as a treatment method by most retinal surgeons.

Vitrectomy

In those cases where neovascular complications such as non-clearing vitreous hemorrhage, pars-plana vitrectomy may be considered usually in combination with intraoperative endolaser to the portion of the retina affected by the BRVO. Some retinal surgeons also consider pars-plana vitrectomy with internal limiting membrane peeling for treatment of recalcitrant RVO-associated macular edema, but this remains controversial.

Isovolemic Hemodilution

Chen et al published the first results of isovolemic hemodilution in patients with BRVO and decreased visual acuity with hematocrit ≥ 35%. Patients were randomized to treatment with volume replacement using hydroxyethylstarch compared to untreated patients. At one year follow up the final VA was 20/40 in the treated group compared with 20/80 in the untreated group.[47]

Since then, there have been further studies have evaluating various agents for hemodilution and there has been a consistent VA improvement of 2 lines. However, there many reported systemic complications due to hemodilution including headaches, exertional dyspnea, fatigue, deep vein thrombosis and hypotension. Due to the systemic invasiveness of the treatment and the many systemic complications from isovolemic hemodilution it is not generally accepted to treat BRVO.[19]

Medical follow up

The major complications that result in vision loss in BRVO include macular edema, macular ischemia, and neovascularization. The typical follow up should be tailored on an individual basis to monitor for the development of these complications. After initial presentation, the typical follow up should be every month or two months to monitor the development of macular edema and/or neovascularization. If macular edema develops, treatment with anti-VEGF therapy with/without laser should be initiated and monitored for resolution. Once edema has resolved or stabilized, the follow up interval can be extended to three to six months or longer for stable chronic cases. Patients with nonperfused BRVO (> 5 disc diameters), that has not been treated with laser should be monitored every three months due to increased risk of neovascularization.

Complications

The most common cause of decreased vision in BRVO is macular edema. Other complications include ischemic maculopathy, retinal neovascularization, macroaneurysmal formation, retinal telangiectasia, retinal detachment and vitreous hemorrhage.

Macular edema occurs in 90% of BRVO cases. Reduced blood flow to the macula results in increased upregulation of endothelin-1, inflammatory cytokines, and VEGF, which results in increased endothelial permeability leading to macular edema and exudates. Macular edema can be divided into perfused and nonperfused, with better visual acuity prognosis with nonperfused macular edema. [24][48][49]

Vitreous hemorrhage occurs in 3.9% of BRVO cases.[50] Chronic retinal nonperfusion results in increased levels of VEGF, which stimulates neovascularization. Disk hemorrhages are less common in BRVO, but have been noted in normal tension glaucoma patients with BRVO.[51] Neovascular glaucoma rarely occurs in BRVO cases .[52]

Serous retinal detachments occur in up to 20% of BRVO cases and it is more common in major BRVO cases than in macular BRVO (45).[48][53] Retinal breaks occur in 3% of BRVO cases and rhegmatogenous retinal detachment occur in 1.3% of BRVO cases.[54]

Prognosis

BRVO has good visual prognosis with 50-60% of patients have a final visual acuity ≥ 20/40 even without treatment. The natural course of BRVO depends on the type of occlusion, degree of occlusion and development of collaterals. Poor prognostic indicators are chronic macular edema, macular BRVO, and NV resulting in VH. [5][52][55][56]

In untreated symptomatic BRVO the initial VA ranges from 20/40 to less than 20/200. VA improves in 1/3 to 3/4 of patients by at least 2 lines. On average VA improves by 1 letter at 3 months to 15 letters at 18 months in untreated eyes. Patients presenting with macular edema, on average18% resolve without treatment by 4.5 months, and 41% resolve at 7.5 months.[57]

Patients presenting with VA ≤ 20/200 have a higher rates of final VA ≤ 20/200 (33-83%) regardless if they underwent treatment or not. Eyes on initial presentation with VA ≥ 20/50 without treatment have poorer prognosis with lower chance of final VA ≤ 20/200 (0-25%).  Patients with initial VA ≥ 20/50 without treatment have better prognosis with majority of eyes with final VA ≥ 20/50 (56-90%). [19] However, even though there is improvement in visual acuity without treatment, significant visual acuity improvement beyond 20/40 is uncommon.[57]

To clarify the natural prognosis of BRVO without treatment, Hayreh et al reviewed 216 cases of BRVO (consisting of major and macular BRVO) that were followed for a median of 3 years. After resolution of macular edema, 76% of eyes with major BRVO and 58% of eyes with macular BRVO have improvement by ≥ 3 lines on Snellen chart. The median resolution of BRVO consisting of resolution of both macular edema and retinal hemorrhages is 21 months in major BRVO and 18 months in macular BRVO.[57]

On initial presentation temporal major BRVO present with VA ≥ 20/60 in 51% of cases, with no difference between superior or inferior temporal arcade involvement on VA. In macular BRVO initial VA is ≥ 20/60 in 74% of cases, with no difference between inferior and superior macular BRVO. In major BRVO with initial VA ≥ 20/60, 75% improve (gain of 3 lines on Snellen chart) or remain stable. Eyes with initial VA ≤ 20/70, 69% improve by 3 lines on Snellen chart.[5]

Developing BRVO in one eye increases the risk of BRVO in the fellow to 7-10%.[6][7][52][57][58] The Beaver Dam Eye Study showed no association of increased all-cause mortality or ischemic heart disease death, after controlling for age, in subjects with BRVO.[4]

Summary of Studies

BVOS Group – 1984 and 1986[6][7]

  • Goal to assess if photocoagulation can: (1) prevent neovascularization, (2) prevent vitreous hemorrhage, and (3) improve vision in eyes with macular edema with ≤ 20/40 from BRVO.
  • Total patients: 319+ 82+139
  • Duration: mean of 3.1 years
  • Groups
    1. Eyes with ≥ 5 disk diameters of nonperfusion without NV treated with either scatter laser or no laser
    2. Eyes with NV treated with either scatter laser or no laser
    3. Eyes with BRVO and macular edema and visual acuity of ≤ 20/40 randomized to grid laser or no laser
  • Results
    1. 319 eyes recruited. 12% in treated eyes developed NV and 22% in non-treated eyes developed NV. However, no change in visual acuity from baseline. 36% of non-treated eyes developed NV
    2. 82 eyes recruited. 29% of treated eyes developed VH and 61% of non-treated eyes developed VH. 12% of eyes that developed VH had vision loss.
    3. 139 eyes recruited. 65% of treated eyes gained two or more lines from baseline, compared with 17% of non-treated eyes. Overall, treated eyes gained 1.33 lines compared to non-treated eyes gained 0.23 lines of vision.
  • Conclusion
    1. Eyes randomized to grid laser had visual acuity gain.


Study was not powered to determine if laser treated should be applied before or after NV to prevent VH. BVOS group recommended use of grid laser for BRVO with macular edema and VA ≤ 20/40. It also recommended following nonperfused eyes at 4 months intervals and use of scattered laser once NV develops.

GENEVA – 2010[34]

  • Total patients: 830 patients with BRVO and macular edema for 6 weeks to 12 months, and 437 patients with CRVO and macular edema for 6 weeks to 9 months.
  • Duration: 6 months
  • Objective: evaluate efficacy and safety of dexamethasone intravitreal implant (DEX implant, OZURDEX) in CRVO and BRVO with macular edema.
  • Randomized to sham procedure, 0.35mg DEX implant, or 0.7mg DEX implant
  • Results were not separated by BRVO and CRVO and analyzed as a single group.
    1. At 30 to 90 days DEX implant groups had a higher percentage of eyes with BCVA gain ≥ 15 letters
    2. A lower percentage of eyes had a loss ≥ 15 letters in DEX implant groups compared to sham group at all time points
  • Summary: DEX implants can improve the speed of visual improvement in eyes with macular edema due to BRVO or CRVO. The study was limited by the absence of rescue laser for treatment of the sham group.

SCORE-BRVO – 2009[33]

  • Total patients: 411 patient with macular edema due to BRVO
  • Duration: 12 months
  • Objective: compare efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid laser)
  • Randomized to 1mg, or 4mg preservative-free intravitreal triamcinolone or macular grid laser
  • Results: all three groups had equivalent percentage of patients with gain of ≥ 15 letters from baseline at 12 months. The rate of elevated intraocular pressure and cataracts were similar between the grid laser and 1-mg groups; however, both adverse effects were significantly higher in the 4-mg group. Of note, volume of all injections was 0.05 mL.
  • Summary: There is no difference in visual acuity gained at 12 months but grid laser and triamcinolone; however, there is higher rates of cataracts and elevation of intraocular pressure with the use of triamcinolone 4-mg.

BRAVO – 2011[36][37]

  • BRAVO (The RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety)
  • Total patients recruited: 397 with BRVO and macular edema diagnosed within 12 months
  • Duration: 12 months
  • Randomized to Ranibizumab 0.3mg, Ranibizumab 0.5mg, and sham/Ranibizumab 0.5mg (with Ranibizumab administered during observation period based on specific criteria) 
  • Protocol: Treatment period (first 6 months) monthly injection with possible rescue laser at 3 month time point based on specific criteria. Observation period (second 6 months) patients assessed monthly and given PRN ranibizumab if vision ≤ 20/40 or mean central foveal thickness ≥ 250 .  Grid laser photocoagulation allowed once at 3 and 9 months if met specific criteria.
  • Results: At 6 months, the mean letter gain was 16.6 and 18.3 in the 0.3mg and 0.5mg ranibizumab groups and 7.3 in the sham group. 54.5% of sham group received rescue laser compared with 18.7% and 19.8% in the 0.3mg and 0.5mg ranibizumab groups. At 12 months, the mean letter gain was 16.4 and 18.3 in the 0.3mg and 0.5mg groups, and 12.1 in the sham/0.5mg group.
  • Summary: ranibizumab had better vision improvement than grid laser at 6 months. As needed ranibizumab is able to maintain the benefits achieved after monthly scheduled injections of ranibizumab with macular edema from BRVO.  

HORIZON – 2012[38]

  • Total patients: 304 BRVO patients and 304 CRVO patients from BRAVO and CRUISE trials, respectively.
  • Duration: every 3 months for 12 months
  • Objective of study was to evaluate efficacy and safety of ranibizumab in RVO patients
  • Patients were extension from prior trials (BRAVO and CRUISE) and monitored every 3 months and given ranibizumab 0.5mg if they met pre-specified criteria.
  • Results for BRVO subjects: number of injections in 0.3/0.5mg and 0.5mg ranibizumab groups and the sham/0.5mg group were 2.4, 2.1, 2.0 respectively. The mean BCVA gains achieved at month 12 of the BRAVO study were reduced by 2.0 (0.3/0.5mg) and 1.7 (0.5mg), and increased by 2.4 (sham/0.5mg). 9-13% of BRVO patients required rescue laser in this 12 month period. 
  • Summary: Despite the reduced frequency of injections in the second year after the BRAVO study, patients were able to cement their gains with reduced frequency of injections.

VIBRANT – 2015[39][40]

  • Total patients: 181 eyes with either BRVO or hemi-RVO with foveal center-involved macular edema
  • Duration: every 4 weeks for 52 weeks
  • Randomized to IAI every 4 weeks for the first 20 weeks or grid laser at baseline followed by a single rescue grid laser from weeks 12 through 20. After 24 weeks, the IAI group received IAI every 8 weeks, while the grid laser group received sham injections. Patient in the grid laser group that qualified for rescue laser were given 3 monthly IAI followed by IAI every 8 weeks. The IAI group was assessed for rescue laser at 36 weeks and given grid laser if qualified.
    • Rescue treatment criteria included > 50µm increase in central subfield thickness compared with lowest previous measurements, loss of ≥ 5 letters compared with best previous measurement in conjunction with any increase in central subfield thickness, or presence of new or persistent cystic retinal changes, subretinal fluid or persistent diffuse edema.
  • Results: at 24 weeks the mean change of BCVA was 17.0 in IAI group compared to 6.9 in grid laser group. At 52 weeks the mean change of BCVA was 17.1 in IAI group compared to 12.2 in grid laser group. In the IAI group, 10% of eyes received rescue laser and in the laser/IAI group, 80% of eyes received rescue IAI. At baseline, both groups had similar percentage of nonperfused BRVO. At 24 weeks there was significant reduction in number of nonperfused BRVO in the IAI group compared with laser group. At 52 weeks there was no difference in nonperfused BRVO between the two groups.
  • Summary: monthly IAI for 6 months followed by IAI every 8 weeks resulted in maintained control of macular edema and sustained improvement in BCVA for 52 weeks.

BERVOLT Study – 2015[43]

  • Total patients: 87 eyes with BRVO
  • Duration: mean follow up of 24.4 months 
  • Retrospective, non-comparative case series of BRVO of patients who received ≥ 1 intravitreal injection of bevacizumab 
  • Results: there was significant improvement of visual acuity with mean change of BCVA of 0.25 logMAR (13 letters) at 2 years with an average of 7.6 injections.
  • Summary: bevacizumab is an alternative to other anti-VEGF therapies for BRVO with macular edema. The letter gain equivalent is around 15, which is similar to findings in BRAVO/HORIZON studies. However, the study is limited by the retrospective protocol, lack of randomization, 14 month delay between diagnosis and treatment, and variable protocolled use of bevacizumab.

Other Studies

==== RELATE – In the * RanibizumabDosE Comparison (0.5mg and 2.0mg) and the Role of LAser in the ManagemenT of REtinal Vein Occlusion - A Pharmacodynamic Approach(RELATE), patients were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to PRN ranizumab plus laser or ranibizumab alone. Patients with CRVO and BRVO were included. No short-term clinically significant benefit was found with 2.0-mg versus 0.5-mg ranibizumab injections. In addition, there was no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections needed with the addition of laser treatment to ranibizumab. Campochiaro PA, Hafiz G, Mir TA, Scott AW, Solomon S, Zimmer-Galler I, Sodhi A, Duh E, Ying H, Wenick A, Shah SM, Do DV, Nguyen QD, Kherani S, Sophie R. Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion: The RELATE Trial. Ophthalmology. 2015;122(7):1426-37.

==== BRIGHTER – In 2016, the * Efficacy and Safety of Ranibizumab With or Without Laser in Comparison to Laser in Branch Retinal Vein Occlusion (BRIGHTER) study has shown that ranibizumab with or without laser is better than laser alone. Visual acuity results were superior for the ranibizumab treated arms of the study than for the laser arm: 14.8 letter gain for ranibizumab arms vs. 6 letter gain for the laser arm at 6 months (primary endpoint. Tadayoni R, Waldstein SM, Boscia F, Gerding H, Pearce I, Priglinger S, Wenzel A, Barnes E, Gekkieva M, Pilz S, Monés J; BRIGHTER study group. Individualized Stabilization Criteria-Driven Ranibizumab versus Laser in Branch Retinal Vein Occlusion: Six-Month Results of BRIGHTER. Ophthalmology. 2016;123(6):1332-44. At 24 months, ranibizumab arms continued to do better than the laser arm. Addition of laser did not decrease the number of anti-VEGF injections. No new safety signals were noted. Tadayoni R, Waldstein SM, Boscia F, Gerding H, Gekkieva M, Barnes E, Das Gupta A, Wenzel A, Pearce I; BRIGHTER Study Group. Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion: 24-Month Results of the BRIGHTER Study. Ophthalmology. 2017;124(12):1778-1787.

Additional Resources

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