Branch retinal vein occlusion (BRVO)

BRVO pathogenesis,clinical features, investigations and management including clinical trials

1. BRANCH RETINAL VEIN OCCLUSION (BRVO) NIKHIL GOTMARE @ eyeamnikhil

2. Central retinal vein occlusion (CRVO) Branch retinal vein occlusion (BRVO), Hemi-retinal vein occlusion (HRVO) Clinical features are present in all quadrants of the fundus in CRVO. Clinical features are present segmentally in BRVO Clinical features are present in either the superior or inferior two quadrants in HRVO Interruption of venous flow usually occurs at lamina cribrosa in case of CRVO Interruption of venous flow usually occurs at retinal arteriovenous intersection in case of BRVO Interruption of venous flow usually occurs at lamina cribrosa in case of HRVO Anterior segment NVI > NVD > NVE Location of neovascularization: posterior pole NVE > NVD > >NVI Post pole > ant segment NVE > NVD >NVI

3. Branch retinal vein occlusion (BRVO) Common cause of retinal vascular disease, second only to DR, 4 times as common as CRVO First described by Leber One of the branches of main vein are blocked – Superotemporal branch…66% – Inferotemporal branch…22-43% – Nasal branches…0.5-2.6% – Macular branch…24%

4. Pathogenesis - Multifactorial -Three mechanisms may be involved

5. Arteriovenous Crossing Koyanagi first described association btw A/V crossing & BRVO -Common adventitial sheath of retinal artery & vein provides settings for occlusion -Arteriosclerosis further aggravates the risk Zhao et al studied 106 eyes with BRVO… -They found artery anterior to vein in 99% cases -However, in approx 60% of normal…artery crosses anterior to vein without causing BRVO

6. Degenerative changes of vessel wall Jefferies et al showed that… The expected venous compression at A/V crossings doesn't exist, rather described– Bending of vein into nerve fiber layer at this point without compression Histological findings of venous lumen at A/V crossing suggested thrombus formation as to be a cause Seitz described– Alteration of venous endothelium & intima media as root of pathogenesis of BRVO

7. Abnormal hematological factors Some suggest relation btw BRVO & hyper-viscosity of blood Others suggest dysregulation of thrombosis-fibrinolysis balance

8. Hematological disorders Resistance to activated protein C Protein C or protein S deficiency Deficiency of Antithrombin III Genetic mutation in the prothrombin gene Anti-phospholipid antibodies Hyper- homocysteinemia Lupus erythematosus

9. Fundus findings Acute BRVO Dilated tortuous vein distal to occlusion Flame shaped hemorrhages respecting horizontal raphe Retinal edema Macular hemorrhage …macular BRVO Fluid leakage from distal vein Occasionally… subhyaloid hemorrhage Rarely…vitreous hemorrhage Cotton-wool spots…ischemia

10. Chronic BRVO Loss of retinal transparency Collaterals around area of occlusion Arteriolar narrowing & sclerosis Vascular sheathing Hard exudates CME & pigment clumps at macula NVD or NVE…in 36% eyes with nonperfusion > 5 DD Retinal detachment…rare Exudative / Tractional / Rhegmatogenous

11. Complications Macular complications – Chronic macular edema – Macular nonperfusion – Epiretinal membranes – Small foveal hemorrhages – Hard exudates Neovascularization & its sequel – NVD & NVE – Vitreous hemorrhage – NVI & NVA Retinal detachments – Rhegmatogenous – Tractional – Exudative

12. MANAGEMENT

13. Ocular Investigations Fluorescein angiography – Done with decreased vision despite hemorrhages have cleared…usually 3 months – In late stages…staining & leakage of dye from vessel – Macular edema & sensory detachment…dye leakage & pooling – Capillary non-perfusion… hypofluorescence – Collaterals & new vessels can be differentiated

14. Optical coherence tomography (OCT ) – Measure retinal thickness quantitatively – Useful in the follow-up of patients with macular edema secondary to BRVO

15. D/D of intra-retinal hemmorhages : - DR - CRVO - CNVM - Retinitis - Vasculitis D/D of Macular edema : - CRVO ruptured microaneurysm Radiation Retinopathy - Hypertensive retinopathy - Subfoveal Choroidal Neovascularisation D/D of VH: - Vitritis - Amylodosis - Lymphoma - Astroid Hyalosis - Vitreous degeneration - Leukemic vitreous infiltration

16. Ocular treatment Various modalities available for management of BRVO include: Laser photocoagulation Intravitreal & periocular steroids Intravitreal anti-VEGF   Surgical management of macular edema Systemic interventions  

17. Certain clinical trials need attention BVOS SCORE GENEVA RELATE BERVOLT BRIGHTER VIBRANT

18. Conventional Laser (Grid laser photocoagulation): The underlying principle of laser treatment is destruction of oxygen consuming photoreceptor cells causing (a) decreased oxygen consumption by outer retina allows oxygen to diffuse from the choroid to the inner retina, where it raises the oxygen tension and relieves hypoxia. (b)This also causes autoregulatory arteriolar constriction, which due to the law of Laplace, decreases hydrostatic pressure of venules, hence causing decreased edema by Starling’s rule.

19. Despite the established efficacy of grid laser photocoagulation, it carries the risk of anatomical and functional chorioretinal damage. Subthreshold Diode Micropulse Laser: The fundamental concept of SDM laser is based on the attempt to minimize laser damage to the neurosensory retina by reducing the duration of laser exposure and by using a subvisible clinical end point.

20. Title BVOS (1984) The Branch Vein Occlusion Study Purpose Scatter argon photocoagulation for prevention of NV and vitreous haemorrhage and improving visual acuity in eyes with macular edema reducing vision to 20/40 or worse No. of pateints 539   Inclusion criteria Major BRVO without NV Major BRVO with NV BRVO with macular edema and reduced vision Outcome measure Visual acuity and development of NV or vitreous hemorrhage Result/ conclusion Scatter argon photocoagulation prevents the development of NV and vitreous hemorrhage but should be applied after the development of NV. Argon laser improved visual outcome in eyes with BRVO and visual acuity reduced from macular edema to 6/12 or worse.

21. APPLICATION OF STEROIDS : It is postulated that intravitreal steroids can inhibit the arachidonic acid pathway and down-regulate the production of VEGF . Intravitreal triamcinolone also stabilizes the blood-retina barrier and reduces macular edema.

22. Title SCORE (2004) S tandard C are vs. C O rticosteroid for RE tinal Vein Occlusion Purpose Standard care vs intravitreal injection(s) of Triamcinolone Acetonide for macular edema of CRVO and BRVO No. of pateints 682 Inclusion criteria Centre-involving macular edema secondary to either CRVO or BRVO, <24 month old, VA ≥ 19 letters & ≤ 73 letters, retinal thickness > 250 microns in the central subfield Outcome measure Improvement by 15 or more letters from baseline in best-corrected ETDRS visual acuity score at the 12-month visit Result/ conclusion Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO but not in BRVO.   1-mg dose has a safety profile superior to that of the 4-mg dose

23. GENEVA Study The G lobal E valuatio N of Implantable d E xamethasone in Retinal V ein Occlusion with M A cular Edema evaluated the safety and efficacy of an intravitreal implant that delivers sustained levels of dexamethasone ( Ozurdex TM ). The study demonstrated that this slow-release device helped achieve a >15 letter improvement in BCVA in a significantly less time than sham and also in more percentage of patients compared to sham. The quantum of improvement was also better in the implants group. The major side effects associated with implants are IOP spikes and cataract progression.

24. INTRAVITREAL ANTI-VEGF AGENTS Vascular Endothelial Growth Factor and Interleukin-6 play major roles in the pathogenesis of macular edema in BRVO. Upregulation of VEGF has a correlation with the severity of macular edema.

25. Title BRAVO (2007) The RanibizumaB Injection in Patients with Macular Edema Secondary to BRAnch Retinal Vein Occlusion Purpose Intravitreal Ranibizumab vs sham injections(placebo) in patients with macular edema due to BRVO No. of pateints 397 Inclusion criteria Macular edema involving foveal center due to BRVO, CFT ≥ 250 μ m on OCT and BCVA of 20/40 to 20/400. Outcome measure Mean change in BCVA letter score at month 6 from Baseline Result/ conclusion Ranibizumab provided rapid and effective treatment for macular edema following BRVO with low rates of ocular and non-ocular safety events (good safety)

26. The BERVOLT study a retrospective study, looked at the efficacy and safety of bevacizumab in macular edema due to BRVO and CRVO. 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.

27. The RELATE trial R anibizumab Dos E Comparison (0.5 mg and 2.0 mg) and the Role of LA ser in the Managemen T of R E tinal Vein Occlusion was done (a) to compare 0.5 mg with 2.0 mg ranibizumab. (b)to determine whether scatter and grid laser photocoagulation adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) The trial enrolled patients with CRVO and BRVO. Conclusions : (a)no short-term clinically significant benefit from monthly injections of 2.0 mg versus 0.5 mg ranibizumab injections and (b) no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections obtained by addition of laser treatment to ranibizumab.

28. The BRIGHTER trial was done to compare the 6-month efficacy and safety profile of ranibizumab 0.5 mg with or without laser versus laser alone in patients with macular edema secondary to BRVO concluding that ranibizumab alone provides superior results compared to laser alone.

29. The VIBRANT trial was undertaken to compare the efficacy of Aflibercept with grid laser in cases of BRVO. After 6 monthly intravitreal injections (2mg), injections every 8 weeks maintained control of macular edema and visual benefits through week 52 Aflibercept has been evaluated in patients with CRVO ( COPERNICUS and GALILEO trials) and has been shown to be effective with an acceptable safety profile.

30. Other treatments Surgical treatment Arteriovenous Crossing Sheathotomy and Vitrectomy Systemic treatment Medical treatment is not effective. Various methods used… Anticoagulants Fibrinolytic agents Clofibrate capsules ( atromid -s) Carbogen inhalation Hemodilution

31. Case scenarios Condition 1 : Patient having BRVO with no macular edema or neovascularization. FFA shows <5DD of capillary nonperfusion . Rx; Follow up. Condition 2: Patient having macular edema but no neovascularization. FFA shows <5DD of capillary nonperfusion. Rx: Determine the cause of macular edema by fluorescein angiography. If leaking capillaries: but the vision is 6/9 or better, observation If the vision is worse than 6/12 or hampers patients activities, Anti-VEGF injection can be given. In chronic cases or in recalcitrant edema steroid in the form of Triamcinolone (SCORE trial) or dexamethasone (GENEVA trial) can be given. In cases of macular Ischemia, only observation can be done and the macular edema usually resolves within one year with gain of visual acuity..

32. Condition 3 : Patient having BRVO with no macular edema or neovascularization. FFA shows >5DD of capillary nonperfusion. Rx: more stringent follow-up, as the chances of developing neovascularization are more Condition 4: Patient having BRVO with no macular edema but with neovascularization present, either NVE or NVD. Rx: sectoral retinal photocoagulation Condition 5 : Patient having BRVO with macular edema and neovascularization. Rx: Determine the cause of macular edema as to ischemia or leakage. Laser of peripheral capillary nonperfusion areas. prior to that an anti-VEGF intravitreal injection may be considered to reduce macular edema in cases of leaking capillaries OCT should be done to document macular edema .

33. BVOS----- SCORE -----BRAVO THANK YOU GALILEO COPERNICUS BERVOLT BRIGHTER VIBRANT GENEVA-----------RELATE