BRVO MANAGEMENT 2016

INTRAVITREAL INJ & LASER

DR DINESH MITTAL DR SONALEE MITTAL

DRISHTI EYE HOSP VIJAYNAGAR INDORE

BRVO• Branch retinal vein occlusion (BRVO) is a common cause of

retinal vascular disease. The Beaver Dam Study estimated the 15-year cumulative incidence of retinal vein occlusions (RVO) at 2.3% in the population, with a majority of these (78%) being BRVO. BRVO affects males and females equally and occurs most frequently between the ages of 60 and 70. The pathologic interruption of venous flow in these eyes almost always occurs at a retinal arteriovenous intersection, where a retinal artery crosses over a retinal vein. Systemic vascular diseases such as hypertension and arteriosclerosis are risk factors for BRVO, probably because they lead to thickening of the retinal artery.

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PATHOGENESIS• Because BRVO mostly occurs at arteriovenous crossings, underlying arterial disease may play a causative role. In 99% of 106 eyes with BRVO, the artery was located anterior to the vein at the obstructed site. Histopathologically, the retinal artery and vein share a common adventitial sheath, and in some cases, a common medium. The lumen of vein may be compressed up to 33% at the crossing site.

VISION loss from RVOs is typically due to• macular ischemia, • macular edema,• or complications from neovascular disease

CLINICAL FEATURES Symptoms

• Patients with BRVO present with sudden painless loss of vision or a visual field defect. Subclinical presentations may occur if a tributary distal to the macula or a nasal retinal vein is involved. Rarely, patients with BRVO will present with floaters from a vitreous hemorrhage if the initial vein occlusion was unrecognized and retinal neovascularization has occurred.

CLINICAL FEATURES Signs

• Patients typically present with a wedge-shaped distribution of intraretinal hemorrhage that is less marked if the occlusion is perfused (or nonischemic), and more extensive if the occlusion is nonperfused (or ischemic) and associated with retinal capillary nonperfusion. The Branch Vein Occlusion Study Group defined ischemic BRVO as those with greater than a total of five disc diameters of nonperfusion on fluorescein angiography (FA).

CLINICAL FEATURES Signs

• The location of the venous blockage determines distribution of intraretinal hemorrhage; if venous obstruction is at the optic nerve head, two quadrants of the fundus may be involved, whereas if the occlusion is peripheral to the disc, one quadrant or less may be involved with intraretinal hemorrhage. The most common location for BRVOs is in the superotemporal quadrant.

BRVO

BRVO• Over time the intraretinal hemorrhage may completely resorb. Without the characteristic segmental distribution of intraretinal Hemorrhage, the ophthalmoscopic diagnosis may be more difficult, but the segmental distribution of retinal vascular abnormalities that occurred during the acute phase will persist and be apparent on FA. In many cases, macular edema may also be detected by OCT .

BRVO• Consequently, in chronic phase of disease, after intraretinal hemorrhage absorption, diagnosis may depend on detecting a segmental distribution of retinal vascular abnormalities that may include capillary non perfusion, dilation of capillaries, microaneurysms, telangectatic vessels, and collateral vessel formation. Nonocular signs such as systemic hypertension have been associated with BRVOs. Thus, systemic blood pressure may be elevated.

B/L BRVO

• In bilateral cases or cases involving young patients, systemic manifestations of infectious disease, inflammatory or autoimmune conditions, neoplasm, or hypercoagulable states may be present.

Complications

• There are three common vision-limiting complications of BRVO: • (1) macular edema;• (2) macular ischemia; and • (3) sequelae of neovascularization. During the acute phase, extensive intraretinal hemorrhages may obscure macular ischemia and macular leakage on FA. Under these circumstances it is impossible to evaluate the perfusion status by FA because the hemorrhage itself blocks the view of the vasculature. In addition, the hemorrhage in the foveal center may reduce visual acuity independently of any macular edema or ischemia.

Complications

• Since this reduction in visual acuity may recover completely if there is no other cause for visual loss, such as macular edema or macular capillary nonperfusion, observation in these cases can be considered. When there is extensive foveal hemorrhage, OCT is an important test to look for macular edema. Although it may be difficult to provide a prognosis in acute phase, it is helpful to recognize that about one-third to one-half of patients with BRVO have a return of vision to 20/40 or better without any therapy.

Complications

• Retinal and iris neovascularization, vitreous hemorrhage, traction retinal detachment, and neovascular glaucoma are complications that manifest late in the course of the disease due to ischemia. With the exception of macular ischemia, these complications can largely be treated or prevented. Thus, it is important that patients with BRVO be closely followed. From the Branch Vein Occlusion Study, 31–41% of patients with ischemic BRVO (defined as >5 disc diameters of nonperfusion on FA) developed neovascularization or vitreous hemorrhage, compared with 11% of patients with nonischemic BRVO.

CLINICAL EVALUATION

• A complete ophthalmic examination should be performed, paying particular attention to history of glaucoma and signs of intraocular inflammation, since these are risk factors for BRVO. Careful examination of iris and angle should be performed in appropriate cases to monitor for early signs of rubeosis or neovascular glaucoma. Initially, when risk of macular edema and neovascularization is higher, patients should be followed every month. Once stable, and if visually significant macular edema and other complications are not present, follow-up can be extended.

Fluorescein angiography

• To help verify the diagnosis and evaluate for complications, FA should be obtained to delineate retinal vascular characteristics that may have prognostic significance: macular leakage and edema, macular ischemia, and large segments of capillary nonperfusion that may portend eventual neovascularization. FA will accurately define capillary abnormalities in BRVO . The characteristic finding on FA is delayed filling of occluded retinal vein. capillary nonperfusion, blockage from intraretinal hemorrhages, microaneurysms , telangiectatic collateral vessels, and dye extravasation from macular edema or retinal neovascularization are other features encountered.

Fluorescein angiography

• In chronic cases, when hges have resolved, microvascular changes on FA may provide the only clues of a previous BRVO. When FA demonstrates macular leakage and edema with cystoid involvement of the fovea, but no capillary nonperfusion, it is presumed that the macular edema is the cause of vision loss. Under these circumstances, about one-third of patients will spontaneously regain some vision. However, patients who have had decreased vision for over 1 year as a result of macular edema are much less likely to regain vision spontaneously

Fluorescein angiography• . When macular edema is present ophthalmoscopically within the

first 6 months after a BRVO and there is little or no leakage on FA, macular ischemia may be the cause of the macular edema. In such circumstances, the edema almost always spontaneously resorbs in the first year after the occlusion, often with return of vision. Unfortunately, acute BRVOs with dense intraretinal hges may make FA interpretation challenging due to blockage of fluorescence by the hemorrhages. Thus, it is advisable to obtain FA only after the intraretinal hemorrhages have cleared significantly from the macula. Other diagnostic tests, such as OCT, can be obtained in the acute phase to aid in the diagnosis of macular edema.

Optical coherence tomography

• OCT has become the most important imaging modality in the treatment of patients with BRVO and macular edema. OCT offers a noninvasive and rapid method of quantitatively measuring macular edema. OCT is frequently used to monitor the response to treatment of macular edema and has been used in place of FA in some treatment trials for BRVO. Unlike FA, intraretinal hemorrhages have a minimal effect on the interpretation of OCT, making this imaging modality helpful, even in the acute setting with foveal hemorrhage.

OCT• The characteristic findings of BRVO on OCT are cystoid edema,

intraretinal hyper reflectivity from hemorrhages, shadowing from edema and hemorrhages, and occasionally subretinal fluid . In chronic cases, photoreceptor inner-segment–outer-segment junction abnormalities from long-standing macular ischemia and macular edema may also be seen .

BVO Study for neovascularization

• A separate group of patients in the BVOS were randomized to receive PRP to prevent neovascular complications. The BVOS demonstrated that prophylactic PRP can lessen subsequent neovascularization NV and, if NV already exists, that PRP can lessen subsequent vitreous hemorrhage. Only eyes with the type of BRVO that shows large areas (>5 disc diameters) of retinal capillary nonperfusion are at risk for developing NV . About 40% of these eyes develop NV , and of this 40%, about 60% will experience periodic vitreous hemorrhage

BVO Study for neovascularization

• NVE OR NVD , or both, may develop at any time within the first 3 years after an occlusion but are most likely to appear within the first 6–12 months after the occlusion. If PRP is applied in eyes with large areas of nonperfusion, the incidence of NV can be reduced from about 40% to 20%. However, if one were to treat prophylactically, many eyes (60%) that would never develop NV would receive PRP . For this reason, it is recommended that PRP be applied only after NV is observed.

Recommendations of BVOS

summary recommendations• The summary recommendations for management of acute branch vein

occlusion from BVOS emphasize waiting at least 3–6 months before considering laser therapy. If the vision is reduced to 20/40 or worse, wait 3–6 months for sufficient clearing of retinal hemorrhage to permit high-quality FA and then evaluate for macular edema and macular ischemia. If perfused macular edema accounts for visual loss, and vision continues to be 20/40 or worse without spontaneous improvement, consider grid macular photocoagulation.

For Macular edema, 6/12 or worse

• • Wait for clearance of retinal hemorrhages to allow adequate fluorescence angiography

• • Determine if decreased visual acuity is caused by macular edema (versus macular nonperfusion – on FFA)

For Macular edema, 6/12 or worse

• If macular edema explains vision loss, and no spontaneous improvement occurred by 3 months, grid macular laser photocoagulation is recommended

• • If capillary non perfusion explains decreased visual acuity, laser treatment is not advised

For neovascularization

• • Good quality of FFA has to be obtained after retinal hemorrhages have cleared sufficiently.

• • If more than five disc diameters of capillary nonperfusion are present, the patient should be followed at 4 month intervals to see development of neovascularization

For neovascularization

• • If neovascularization develops, panretinal photocoagulation to the involved sector should be applied using green laser to achieve medium white burns to cover entire involved segment

• Vitrectomy • Indicated in complicated cases of Vitreous hemorrhage, TRD and CRD.

summary recommendations•However, this conclusion needs to be balanced against the improvements in vision seen with recent anti-vascular endothelial growth factor (VEGF) agents. If macular ischemia accounts for the visual loss, no laser treatment is recommended to improve vision.

SECTORAL LASER

Retinal neovascularization• NVI is a rare complication of BRVO. Retinal neovascularization is

particularly difficult to recognize in BRVO because the collaterals that develop frequently may mimic NV . Arising from pre-existing capillaries, these collaterals occur as vein-to-vein channels around the blockage site, across the temporal raphe, and in other locations to bypass the blocked retinal segment. These collaterals frequently become quite tortuous, mimicking the appearance of NV if they are evaluated by ophthalmoscopy alone. When it is unclear whether an abnormal vascular pattern represents collateral formation or true NV , the FA can be helpful because leakage from NV is more prominent than from collateral vessels.

WHEN TO DO SECTORAL LASER• The BVOS data strongly suggest that photocoagulation after the

development of NV is as effective in preventing vitreous hemorrhage as is photocoagulation before the development of neovascularization. When neovascularization is unequivocally confirmed by FA, PRP can reduce the likelihood of vitreous hemorrhage from about 60% to 30%. PRP can be applied with argon blue green laser to achieve “medium” white burns (200–500 μm in diameter) spaced one burn width apart and covering the entire area of capillary nonperfusion, as defined by FA, but extending no closer than two disc diameters from the center of the fovea and extending peripherally at least to the equator.

BRVO

BRVO WITH MACULAR ODEMA INVOLVING CENTRE OF RETINA

NOOBSERVATION

YES INTRAVITREAL AVASTIN

FA

OBSERVATION FOR NVE ESP IF CNP AREA MORE THAN 5 DD AREA

NO NVENVE PRESENT

VITREOUS HGESECTORAL LASER

GRID LASER

40 %

VITREOUS HAEMORRHAGE• Of patients who develop neovascularization, 60% experience

episodes of vitreous hemorrhage if the condition is left untreated. In some cases, the hemorrhage may be mild or may clear spontaneously without causing permanent visual impairment. However, in some patients, vitreous hemorrhage from neovascularization can lead to prolonged visual disability in the affected eye. When hemorrhage is dense, B-scan USG may help rule out an associated TRD . Most eyes can be observed. If the vitreous hemorrhage does not spontaneously clear in a few months, a pars plana vitrectomy with sector endolaser photocoagulation should be considered.

Steroid treatment

• Macular edema results from increased vascular permeability mediated at least in part by an increase in VEGF. Corticosteroids have been shown to inhibit the expression of VEGF and therefore reduce macular edema in animal models. The antiinflammatory effects of corticosteroids may further potentiate its anti-VEGF effects and help attenuate macular edema. Intraocular corticosteroids, however, have significant side-effects, including cataract formation and glaucoma. IN (SCORE) BRVO study, the effectiveness and safety of intravitreal triamcinolone acetate (IVTA) for the treatment of macular edema from BRVO were evaluated.

Steroid treatment• Three-year results from 128 patients suggested that the laser

group maintained a significantly greater average increase in vision (12.9 letters) compared with the two IVTA groups (4.4 letters, 1 mg and 8.0 letters, 4 mg). Significant side-effects from IVTA included cataract formation and elevation of IOP requiring treatment. Both side-effects were dose-dependent. As a result of this study, IVTA is not recommended as first-line therapy for macular edema in BRVO. However it can be considered in patients where macular grid laser or other therapies are ineffective, as treatment was found to be relatively safe, especially in pseudophakic eyes.

GENEVA (dexamethasone implant) study• GENEVA (dexamethasone implant) study The Global Evaluation of

implantable dexamethasone in RVO with macular edema (GENEVA) study evaluated a sustained-release, biodegradable, dexamethasone intravitreal implant (Ozurdex, Allergan, Irvine, CA) for treatment of macular edema in CRVO and BRVO patients. Ozurdex is a biodegradable copolymer of poly (D,L-lactide-co-glycolide) acid (PLGA) containing micronized dexamethasone. It is injected intravitreally through a pars plana route using a 23-gauge custom injector, and it gradually releases total dose of dexamethasone over several months via Krebs cycle breakdown of the PLGA into lactic and glycolic acid, and finally into water and carbon dioxide.

GENEVA (dexamethasone implant) study

• A major difference between the GENEVA study and other recent BRVO studies is the absence of a macular grid laser group, or rescue laser treatment for the sham group. The GENEVA study showed that the dexamethasone implant is an alternative treatment to macular grid laser in the appropriate patient population (i.e., no glaucoma, pseudophakic) and is approved by the Food and Drug Administration (FDA) for this indication.

Anti-VEGF treatment

• Macular edema results from increased vascular permeability as a response to retinal nonperfusion. In patients with BRVO,retinal ischemia leads to the secretion of VEGF, which leads to increased vascular permeability, vasodilation, migration of endothelial cells, and neovascularization. Increased vascular permeability and perhaps vasodilation lead to retinal edema. Thus, inhibition of VEGF is an attractive treatment for macular edema from BRVO. There are several anti-VEGF agents currently being investigated for use in treatment of RVOs. We will discuss the use of ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea). Bevacizumab is a full-length, humanized monoclonal antibody that binds all VEGF-A isoforms and is FDA-approved for colorectal cancer, but is used off-label in the eye.

Anti-VEGF (Avastin/Lucentis) • Intravitreal injection of anti - VEGF agents is the most widely

practiced mode of therapy during early stages of BRVO these days.

• The edema disappears within 48-72 hours in most cases. The disappearance of edema is so dramatic in most cases that non-response raises doubt about efficacy of the vial used! But the effect is short-lasting. Repeat injections are needed at 2-4 month intervals to maintain whatever benefit the patient gets after first injection.

• There is no difference among the two agents in terms of efficacy.

Ranibizumab• Ranibizumab is an affinity-purified, humanized monoclonal

antibody fragment (Fab) that binds all VEGF-A isoforms. The BRAVO study showed that ranibizumab is superior to traditional laser treatment for macular edema from BRVO with little risk of adverse events. The current recommendation is therefore to treat patients diagnosed with macular edema from BRVO with monthly 0.5 mg ranibizumab. If treatment fails after 3 months (<5 ETDRS letter gain, or improvement of <50 μm in central subfield thickness), then traditional grid macular laser should be performed.

Anti-VEGF• The BRAVO study showed that PRN treatment did not adversely

affect the visual outcome after five scheduled monthly injections. However, the timing of when to switch to PRN treatment was not evaluated in the BRAVO study and thus the decision to switch to PRN dosing should be based on factors such as improvement in visual acuity, residual macular edema on OCT imaging, success of prior injections, and expectations of the patient.

FOLLOW-UP

• The major complications that can lead to vision loss in patients with BRVO include macular edema, macular ischemia, and neovascularization. Treatment is available for macular edema and neovascularization and follow-up should be tailored to monitor the development of these complications adequately. Initially, patients should be followed closely every month or 2 months for the development of macular edema and/or neovascularization. Anti-VEGF therapy with or without macular laser should be initiated for patients with macular edema without spontaneous improvement

FOLLOW-UP

• Once macular edema has stabilized or has resolved, the follow-up interval can be extended to 3–6 months or even longer for stable chronic cases. Patients with previously untreated retinal nonperfusion measuring >5 disc diameters should be followed at closer intervals (3 months) due to increased risk for neovascular complications. In patients where anti-VEGF therapy and/or laser is not showing sufficient therapeutic efficacy, steroids can be considered, particularly in pseudophakic patients. Only after failure of medical therapy should surgery be considered.

CONCLUSIONS• BRVO is a common cause of vision loss, but many treatment options are

available and emerging therapies are under investigation. Current treatments for macular edema include macular grid laser and intravitreal anti-VEGF injections and intraocular corticosteroids. All have side-effects. Anti-VEGF therapy typically lasts 4–6 weeks, necessitating frequent reinjections, and corticosteroids can induce vision-limiting side-effects such as glaucoma and cataract. However, due to its longer duration of action, corticosteroids may play an important role in pseudophakic patients or in patients who do not respond to laser and antiVEGF agents. Alternate delivery methods, including topical,local depot injections, or perhaps even systemic delivery, will likely emerge. Combination therapy with anti-VEGF agents acting to reduce macular edema rapidly, and therapy aimed at restoring blood flow such as vitrectomy with or without sheathotomy for BRVO may merit future investigation to limit the need for chronic pharmacotherapy.

BRVO

BRVO WITH MACULAR ODEMA INVOLVING CENTRE OF RETINA

NOOBSERVATION

YES INTRAVITREAL AVASTIN

FA

OBSERVATION FOR NVE ESP IF CNP AREA MORE THAN 5 DD AREA

NO NVENVE PRESENT

VITREOUS HGESECTORAL LASER

GRID LASER

40 %

THANK YOU

DR DINESHDR SONALEE