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Branch Retinal Vein Occlusion

Branch Retinal Vein Occlusion. Current understanding and approaches to treatment. Prescribing information can be found on the last two slides. About this slide deck.

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Branch Retinal Vein Occlusion

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  1. Branch Retinal Vein Occlusion Current understanding and approaches to treatment • Prescribing information can be found on the last two slides

  2. About this slide deck This slide deck is provided as a service to medicine by Bayer and is intended for educational use with healthcare professionals only Prescribing information for EYLEA(aflibercept solution for injection)is at the end of the slide deck, and is also available in accompanying material. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Bayer:Tel: 01635 563500; E-mail: pvuk@bayer.com

  3. Acknowledgements The contribution of the following in the development of this resource is gratefully acknowledged: Peter Addison, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust Sanjiv Bannerjee, Consultant Ophthalmologist, University Hospital Wales Michael Briggs, Consultant Ophthalmologist, Spire Liverpool Hospital Ben Burton, Consultant Ophthalmologist, James Paget University Hospital Louise Downey, Consultant Ophthalmologist, Hull Royal Infirmary SamerElsherbiny, Consultant Ophthalmologist, Birmingham and Midland Eye Centre Richard Gale, Consultant Ophthalmologist, York Teaching Hospital Praveen Patel, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust Adam Ross, Consultant Ophthalmologist, Bristol Eye Hospital Gavin Walters, Consultant Ophthalmologist, Harrogate District Hospital and York Hospital Yit Yang, Consultant Ophthalmologist, Wolverhampton Eye Hospital and Visiting Professor, Aston University

  4. Discussion topics BRVO = branch retinal vein occlusion. Definition of retinal vein occlusion Epidemiology of RVO Vision loss in BRVO Pathophysiology Natural history Clinical signs and imaging features Initial management Management of macular oedema Management of other complications

  5. Background and epidemiology of BRVO

  6. RVO is an obstruction of one of the veins that drains blood away from the retina BRVO Occlusion of a branch retinal vein CRVO Occlusion of the central retinal vein HRVO Occlusion of the superior/inferior branch ofthe central retinal vein The type of RVO depends on the location of the occlusion1 In the literature, HRVO is defined as an RVO that involves two retinal quandrants2,3 BRVO = branch retinal vein occlusion; CRV = central retinal vein; CRVO = central retinal vein occlusion; HRVO = hemiretinal vein occlusion; RVO = retinal vein occlusion. 1. Kiire CA, Chong NV. BMJ. 2012;344:e499; 2. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544;

  7. Common sites of retinal vein occlusion1 Blue arrow Point at which the central retinal vein exits the eye – a common site for CRVO Yellow arrow An arteriovenous crossing – a typical site for BRVO Image courtesy of Yit Yang. BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion. 1. Kiire CA, Chong NV. BMJ. 2012;344:e499.

  8. RVO is a major cause of vision loss RVO = retinal vein occlusion. 1. Laouri M, et al. Eye. 2011;25:981–988; 2. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015; 3. UK Government Driving Eyesight Rules. Available here: https://www.gov.uk/driving-eyesight-rules. Accessed March 2016. RVO is the second most common sight-threatening retinal vascular disorder (after diabetic retinopathy)1 • RVO is unilateral in most patients2 • Can be severe2 • Possible loss of vision to below driving standards3 • As a result, most patients are willing to undergo invasive treatments1 Sign of possible underlying systemic pathology2

  9. RVO puts a major burden on the patient’s life1 86%require monthly appointments 73%of these requirelong-term monthly appointments 1. Sivaprasad S, Oyetunde S. Clin Ophthalmol. 2016;10:939–946. 4.5 hours average appointment time 53% of patients need to take ≥1 day off work per appointment 71% of patients require a carer’s assistance for appointments

  10. Incidence of BRVO is greater than CRVO 1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518; 2. Cugati S, et al. Arch Ophthalmol. 2006;124:726–732. Beaver Dam Study (n = 4068):1 • 15-year incidence of BRVO was 1.8% versus 0.5% for CRVO • Incidence similar in men and women (1.5% versus 2.1%) Blue Mountains Eye Study (n = 3654):2 • 10-year incidence of BRVO was 1.2% versus 0.4% for CRVO • Incidence similar in men and women (2.0% versus 1.3%) There are no specific UK incidence data

  11. Incidence of RVO varies with age 15-year cumulative incidence of BRVO and CRVO BRVO CRVO Incidence, % Age, years 1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518.

  12. Symptoms of BRVO Fundus photograph of BRVO prior to treatment Image courtesy of Yit Yang. 1. American Academy of Ophthalmology. Branch Retinal Vein Occlusion Symptoms. Available here: http://www.aao.org/eye-health/diseases/branch-retinal-vein-occlusion-symptoms. Accessed March 2016. The main symptom of BRVO is blurring of central vision Can be sudden or gradual Normally painless

  13. Causes of vision loss in BRVO:Macular oedema1 OCT showing inferior temporal BRVO with secondary cystoid macular oedema Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion; OCT = optical coherence tomography. 1. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299.

  14. Causes of vision loss in BRVO:Intraretinal haemorrhage1 FFA mid phase showing supero-temporal BRVO with significant ischaemia and masking due to retinal haemorrhage (blue area). Arrow indicates likely point of occlusion Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion. 1. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299.

  15. Causes of vision loss in BRVO:Ischaemia and neovascularisation1,2 FFA of superior ischaemic (blue arrow) BRVO with neovascularisation (yellow arrow) Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013; 2. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299.

  16. BRVO can be ischaemic or non-ischaemic Colour fundus photograph and fluorescein angiography showing BRVO with macular ischaemia Fluorescein angiography showing BRVO with peripheral ischaemia Images courtesy of Peter Addison and Ben Burton. Ischaemia can be macular or peripheral

  17. Peripheral ischaemia can be defined in disc diameters or disc areas BRVO = branch retinal vein occlusion; 1. Hayreh SS, et al. Ophthalmology. 1983;90:488–506; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. No consensus on prevalence of BRVO with peripheral ischaemia because of varying definitions, measurement techniques, and patient samples1

  18. Background and epidemiology: Summary BRVO = branch retinal vein occlusion. BRVO is an occlusion of a branch retinal vein Main vision-threatening complications are macular oedema, retinal ischaemia, and neovascularisation and its sequelae Impact on vision depends on the location of the occlusion BRVO can be classified as ischaemic or non-ischaemic Incidence of BRVO is 1.2–1.8% • Patients are predominantly over the age of 55 years, but BRVO also affects the working-age population • There are no specific data for the UK

  19. Pathophysiology of BRVO

  20. Key risk factors for BRVO1 BRVO = branch retinal vein occlusion. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. Hypertension Diabetes Hyperlipidaemia Hyperhomocysteinaemia Blood coagulation disorders Systemic inflammatory disorders

  21. BRVO is considered to be the result of compression of a vein at an arteriovenous crossing • The following features of arteriovenous crossings contribute to the risk of venous occlusion: • Artery and vein share a common adventitial sheath1 • The artery lies anterior to the affected vein in 99% of eyes with BRVO2 • More than half of BRVO cases occur in the superotemporal quadrant3 Arteriole Bulge Compression Venule A Narrowing V BRVO = branch retinal vein occlusion. 1. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 2. Zhao J, et al. Ophthalmology. 1993;100:423–428;3. Klein R, et al. Arch Ophthalmol. 2008;126:513–518.

  22. Thrombus formation also plays a role in the pathogenesis of BRVO BRVO = branch retinal vein occlusion. 1. Browning DJ. Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer Science+Business Media; 2012.

  23. Hypothesised pathogenesis of BRVO1–3 Abnormal haematological factors Compression at an AV crossing Degenerative changes of vessel wall  cytokine production4 VEGF PlGF PDGF sICAM-1 MCP-1 IL-6, 8, 12, 13 RVO Stasis  Pressure Intraretinal haemorrhage  Permeability Ischaemia/hypoxia Macular oedema Neovascularisation Vitreous haemorrhage AV = arteriovenous; BRVO = branch retinal vein occlusion; IL = interleukin; MCP = monocyte chemotactic protein; PDGF = platelet-derived growth factor; PlGF = placental growth factor; sICAM-1 = soluble intercellular adhesion molecule; VEGF = vascular endothelial growth factor. 1. Karia N. Clin Ophthalmol. 2010;4:809–816; 2. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 3. Browning DJ. Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer Science+Business Media; 2012; 4. Noma H, et al. Invest Ophthalmol Vis Sci. 2014;55:3878–3885.

  24. Pathophysiology: Summary BRVO = branch retinal vein occlusion; VEGF = vascular endothelial growth factor. BRVO is considered to be the result of mechanical narrowing of a branch retinal vein lumen at an arteriovenous crossing Thrombus formation, as a result of Virchow’s triad, causes venous occlusion • Resulting occlusion leads to increased intraluminal pressure, retinal ischaemia, upregulation of inflammatory cytokines (including VEGF), vascular permeability and angiogenesis The resulting haemorrhage, neovascularisation, and macular oedema may all lead to vision loss, the main symptom in BRVO

  25. Natural history and clinical signs of BRVO

  26. BVOS provides information about the natural history of BRVO 1 2 3 BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VA = visual acuity. 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41. BVOS set out to answer three questions on the effectiveness of laser photocoagulation in BRVO1,2

  27. Natural history of BRVO from BVOS Fellow eye involvement1 94–95%of patients present with unilateral BRVO 10% of patients have fellow eye involvement over time Complications2 61%of patients with neovascularisation develop vitreous haemorrhage without treatment 22% of patients develop neovascularisation without treatment Visual outcome3 *p<0.0001 versus with treatment. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282.

  28. Clinical appearance of BRVO with fundus photography Colour fundus photograph of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion.

  29. Clinical appearance of BRVO with OCT OCT of infero-temporal BRVO with secondary cystoid macular oedema Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion; OCT = optical coherence tomography.

  30. Clinical appearance of BRVO with FA Early frame FA of long-standing BRVO Late frame FA of long-standing BRVO Images courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FA = fluorescein angiography.

  31. Signs of early-stage BRVO: Intraretinal haemorrhage Colour fundus photograph showing intraretinal haemorrhage (blue area) and cotton wool spots (yellow arrows) Image courtesy of Sanjiv Banerjee. BRVO = branch retinal vein occlusion. 1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013:1029–1338; 2. Optometry Today. Management & Investigation of Vascular Conditions. Module 13 Part 6: Clinical optometry. Intraretinal haemorrhages are generally characteristic of early-stage BRVO1 • Wedge-shaped distribution, with haemorrhage apex at occlusion site1,2 • Confined to one retinal quadrant; distribution determined by occlusion site1

  32. Signs of early-stage BRVO: Blot haemorrhage Colour fundus photograph of BRVO with blot haemorrhage (blue area) Image courtesy of Ben Burton.

  33. Signs of early-stage BRVO: Dilated, tortuous veins Colour fundus showing a dilated tortuous vein (blue arrow) downstream from the occlusion (yellow arrow) Image courtesy of Robin Hamilton. BRVO = branch retinal vein occlusion. 1. Browning DJ. In: Retinal Vein Occlusions. New York: Springer; 2012. Main clinical sign of BRVO Vein appears dilated before (upstream of) the occlusion, and threadlike after (downstream of) the occlusion1

  34. Collateral blood vessels form in long-standing BRVO1 FFA showing ghost vessels (yellow arrow) and retinal collaterals (blue arrow) in BRVO Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography; VEGF = vascular endothelial growth factor. 1. Henkind P. Aust J Ophthalmol. 1981;9:273–277; 2. Montero-Moreno JA, et al. Austin J Clin Ophthalmol. 2014;1(6):4. Compensatory blood vessels open up in long-standing BRVO1 • Bypass the occlusion, diverting blood to a non-occluded vessel • Seen as a positive development Differ from vessels formed as a result of neovascularisation:1 • Originate from capillaries and join obstructed and non-obstructed vessels • Do not usually leak on FA Development appears to be independent of VEGF,2 hence anti-VEGF therapy is unlikely to impede their development

  35. Complication of BRVO: Neovascularisation FFA showing disc neovascularisation (yellow arrow) and ischaemia (blue arrow) Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Shilling JS, et al. Br J Ophthalmol. 1976;60:810; 2. Henkind P. Aus J Ophthalmol. 1981;9:273–277; 3. Hayreh SS, et al. Ophthalmology. 1983;90:488–506. Neovascularisation is the development of fragile new vessels, prone to haemorrhage1,2 • Generally develop in ischaemic BRVO only3 • Can occur years after onset3

  36. Complication of BRVO: Vitreous haemorrhage Colour fundus photograph showing mild vitreous haemorrhage from neovascularisation in superotemporal BRVO Image courtesy of Yit Yang. BRVO = branch retinal vein occlusion. 1. Hayreh SS. Indian J Ophthalmol. 1994;42:109–132. Bleeding into the vitreous is a late-stage complication of BRVO, which often occurs secondary to neovascularisation1

  37. Long-standing BRVO Occlusion point Neovascularisation Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography.

  38. Long-standing BRVO Collateral vessels Vascular leakage Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography.

  39. Long-standing BRVO Neovascularisation Venous sheathing Collateral vessels Neovascularisation Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography.

  40. Natural history and clinical signs: Summary BRVO = branch retinal vein occlusion. Intraretinal haemorrhage, blot haemorrhage and macular oedema are signs of early-stage BRVO Neovascularisation is a complication of BRVO and can lead to vitreous haemorrhage Collateral vessels often open up in long-standing BRVO to compensate for the occlusion

  41. Initial management of BRVO

  42. Diagnosis of BRVO1 BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; IOP = intraocular pressure. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. Medical history Ocular investigations • BCVA • IOP Diagnostic imaging • Colour fundus photographs • Optical coherence tomography • Fundus fluorescein angiography Differential diagnosis

  43. Patients presenting with BRVO should receive tests to investigate the presence of underlying systemic pathology1 BRVO = branch retinal vein occlusion. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015.

  44. Management of macular oedema

  45. Milestones in the medical treatment of macular oedema secondary to BRVO* LaserPhotocoagulation Intravitreal corticosteroids Intravitreal anti-VEGF 2014 2011 2012 2013 2010 2009 2004 2015 2016 1977 1986 2007 GENEVA3 • VIBRANT7 BVOS1 SCORE2 BRAVO4 • HORIZON5 • RETAIN6 Treatment first used Trial data first published *Timeline excludes bevacizumab studies. BRVO = branch retinal vein occlusion. 1. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 2. Scott IU, et al. Arch Ophthalmol. 2009;127(9):1115–1128; 3. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 4. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 5. Heier JS, et al. Ophthalmology. 2012;119:802–809; 6. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219; 7. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544.

  46. Macular grid laser photocoagulation

  47. Macular grid laser photocoagulation for BRVO Technique Mechanism Side effects • Applied in a grid across the macula, avoiding the fovea • 50–100 µm spot size; 20–100 applications3 • Guided by fluorescein angiography2 • Avoid areas of intraretinal haemorrhage2 • Improves tight junctions in the retinal pigment epithelium1 • Efficacy demonstrated in the Branch Vein Occlusion Study2 • Scarring4 • Loss of central vision4 FFS showing laser scars (arrow) arising from laser photocoagulation Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Stefansson E. Eur Ophthal Rev. 2009;2:76–79; 2. Branch Vein Occlusion Study Group. Am J Ophthalmol.1984;98:271–282; 3. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015;4. Dowler J. J R Soc Med. 2003;96:277–279.

  48. BVOS: Significant improvement in VA with grid laser photocoagulation in patients with macular oedema1 Treated Cumulative proportion of eyes gaining ≥2 lines on two consecutive visits, % Control Follow-up, years 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282.

  49. Intravitreal corticosteroids

  50. Intravitreal corticosteroids for BRVO Mechanism Postulated to be downregulation of cytokine expression (including VEGF) to inhibit vascular permeability1 Important side effects include increased intraocular pressure and cataract formation2,3 Side effects • Intravitreal dexamethasone implant (approved in the UK for the treatment of macular oedema secondary to BRVO and CRVO) • Triamcinolone acetonide (not currently approved for use in BRVO) • Fluocinolone acetonide (not approved for use in BRVO) BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; VEGF = vascular endothelial growth factor. 1. Coscas G, et al. Ophthalmologica. 2011;226:4–28; 2. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128; 3. Haller JA, et al. Ophthalmology. 2011;118:2453–2460.

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