Venous Occlusive Diseases

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Wilfrid Mosley
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1 Venous Occlusive Diseases Bruce R. Saran, MD Adjunct Assistant Clinical Professor of Medicine Scheie Eye Institute University of Pennsylvania School of Medicine Philadelphia, PA -a division of:

2 RVO Demographics } prevalence of RVOs worldwide is about 0.5% } estimated to affect more than 16 million people worldwide in 2008 } BRVO occurs 6-7 times more than CRVO } African Americans have a similar incidence of CRVO to white Americans

3 RVO Demographics } 2.14 cases/1000 > 40 years } 5.36 cases/1000 > 64 years } males slightly > females } No racial preference } Second eye 7-11%

4 RVO Risk Factors } CRVO in one eye has a 1% risk per year of CRVO developing in the fellow eye } CRVO is associated with glaucoma } Risk of BRVO is more likely associated with local vascular factors (arterial-venous crossing changes) rather than local ocular factors

5 RVO Risk Factors for BRVO } Arterial hypertension } Hyperlipidemia } Diabetes } Coronary artery disease

6 CRVO-risk factors Lower Risk } Increased physical activity } alcohol } exogenous estrogens

7 CRVO-medical workup: } Blood pressure } Erythrocyte sedimentation rate (ESR) } Full blood count (FBC) } Random blood glucose } Random total and HDL cholesterol } Urea, electrolytes and creatinine (renal disease in association with hypertension) } Thyroid function tests (associated with dyslipidemia) } EKG (left ventricular hypertrophy secondary to hypertension)

8 CRVO-medical workup: patients<50 or bilateral } Chest X-ray (sarcoidosis, tuberculosis) } C-reactive protein (CRP) } "Thrombophilia screen" (thrombin time, prothrombin time and activated partial thromboplastin time, antithrombin functional assay, protein C, protein S, activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation; anticardiolipin antibody, lupus anticoagulant) } Autoantibodies (RF, ANA, anti-dna antibody) } Serum angiotensin-converting enzyme (ACE) } Fasting plasma homocysteine level } Treponemal serology } Carotid duplex imaging

9 CRVO: differential diagnosis } A. Diabetic retinopathy } B. Radiation retinopathy } C. Conditions leading to anemia or low platelets, i.e., blood dyscrasias such as leukemia } D. Ocular ischemia from carotid disease } E. Malignant Hypertension

10 CRVO-classification Non-ischemic } venous stasis retinopathy Ischemic } hemorrhagic retinopathy } CVO study P } CVO study N } visual acuity typically 20/200 or better } visual acuity typically 20/400 or worse

11 CRVO- Non-ischemic classification } may present with good vision } few retinal hemorrhages } Few or no cotton-wool spots } no APD } Fluorescein angiography shows preserved perfusion } may resolve or progress to ischemic

12 CRVO-Ischemic classification } severe visual loss 20/400 or worse } extensive retinal hemorrhages & cotton-wool spots } Positive APD } Fluorescein angiography shows poor perfusion } Extinguished /depressed ERG } neovascular glaucoma and/or proliferative retinopathy

13 RVO Treatment: guided by clinical trials } Laser studies } 1980s Branch Vein Occlusion Study (BVOS) } 1990s Central Vein Occlusion Study (CVOS) } 2009 Steroid studies } SCORE Study } Ozurdex Trials: Geneva } 2010 Anti-VEGF Ranibizumab studies } BRAVO and CRUISE } 2012 Anti-VEGF Aflibercept studies } Copernicus and Galileo

14 CVOS Central Vein Occlusion Study Group - established guidelines for treating CRVO } 725 patients, followed for 3 years } Visual outcome = dependent on initial vision } 65% had VA > 20/40

15 CVOS Central Vein Occlusion Study Group intermediate VA (20/50-20/200) VA < 20/200 } 19% improved >20/50 } 44% stayed in group } 80% chance of not changing VA whether perfused or nonperfused } 37% decreased < 20/200

16 CVOS Central Vein Occlusion Study Group } First 4 months: 15% ischemic } Next 32 months:19% ischemic = 34% at 3 years } INV/ANV occurred in 16% total-35% in non-perfused on fluorescein angiography and only 10% perfused } poor VA and non-perfusion on fluorescein angiography associated with INV/ANV Rule of 3rds: 1/3 gets better, 1/3 same, 1/3 worse

17 Non-ischemic Central Retinal Vein Occlusion } optic disc edema may be present } conversion to ischemic 5%-34% } Late visual loss from CME & pigmentary changes

18 Non-ischemic Central Retinal Vein Occlusion } IVFA leakage from veins, disc and macular edema } ERG is normal } IOP may be low } OCT with edema in Henle s layer (OPL) and INL with SRF in acute disease

19 Non-Ischemic CRVO 42 y WF PPLOV VA=20/200 OD

20 intravitreal Avastin given 1 month s/p Avastin VA=20/40

21 Ischemic Central Retinal Vein Occlusion } sudden, painless decrease in VA } 20/400 or worse } x=68.5 years (older) } Blurred/obscured disc margin, dilated precapillary arterioles

22 Ischemic Central Retinal Vein Occlusion } confluent retinal hemorrhages, flame shaped } dilated, tortuous veins } cotton-wool spots } macular edema or macular hemorrhage pronounced

23 Ischemic-CRVO general course (pre anti-vegf era) } 58 % iris neovascularization } 47 % angle neovascularization } 33 % neovascular glaucoma } 8 % NVE

24 Ischemic Central Retinal Vein Occlusion- IVFA } CVO study : VA < 20/200 or non-perfusion predictive of NVI } NVG 10% with 10 DD nonperfusion } NVG 50% % with 80 DD or more

25 Ischemic Central Retinal Vein Occlusion } NVI highly associated with NVG } non-perfusion or NVI requires aggressive PRP and anti-vegf treatments } follow-up interval is increased *this is the classic 90 day glaucoma associated with CRVO

26 CRVO treatment: laser } Focal laser ineffective: reduces anatomic macular edema with little effect on visual acuity } Panretinal photocoagulation effective for ischemia and NVI / ANV

27 CRVO treatment: new paradigm } Avastin } Lucentis } Eylea } Ozurdex

28 CRVO treatment: Ranibizumab (Lucenits) [Cruise Study] } 0.5-mg Ranibizumab gained a mean of 14.9 letters } 0.8 letters in the sham group } 47.7% of ranibizumab gained 15 letters, >3 lines compared with 16.9% of sham } rapid improvement in BCVA with rapid reduction in central foveal thickness after treatment with ranibizumab at day 7 compared with no reduction in the sham group

29 CRVO treatment: Aflibercept (Eylea) [Copernicus/Galileo Study] } 2 mg Aflibercept gained a mean of 18 letters } 3.3 letters in the sham group } % of ranibizumab gained 15 letters, >3 lines compared with % of sham } rapid improvement in BCVA with rapid reduction in central foveal thickness after treatment with ranibizumab at day 7 compared with no reduction in the sham group

30 OZURDEX 0.7 mg (700 µg) (dexamethasone) Intravitreal Implant [Geneva Study] } NOVADUR solid polymer delivery system through 22 gauge needle } 30% achieved 15 or more letters of improvement after 60 days } 28% gained 15 or more letters at 2 months } 45% at 6 months } 39% at 1 year } 32% achieved 15 or more letters of improvement 60 days after 2 nd TX improvement (3 lines of vision) occurred 1-2 weeks after implantation in 20-30% } duration of effect persisted 1-3 months after onset

31 CRVO CASE STUDY : Acute VA=20/400

32 CRVO s/p Lucentis X 1 CRVO CASE STUDY : Acute VA=20/80

33 CASE STUDY 2: Bilateral VA 20/150 reduced to CF-treated with Avastin then Eylea. Ozurdex offered

34 2009 VA=CF 2011 VA=20/150 CRVO s/p Ozurdex X 1 CASE STUDY : post tx VA=20/150 at 6 weeks

35 HRVO

37 HRVO } CRVO with two trunks behind lamina cribosa (20%) } Thought to be variant of CRVO but with complications and findings of both types of vein occlusions } Also divided into ischemic and nonischemic

38 CRVO Anatomy

39 Anatomy of HRVO

40 HRVO/CRVO Similarities } Hayreh found BRVO artery crosses over vein in 91% whereas in HRVO only 1/3 showed this and >1/3 had no crossing } Collateral vessels in BRVO feed at crossing whereas in CRVO they form at disc or more posterior as found in HRVO } In HRVO about 1/3 showed increased IOP as did CRVO unlike BRVO where increased IOP not > general population } ON edema seen in HRVO/CRVO but not usually in BRVO

41 Treatment Implications } HRVO (ischemic) 13% NVI (Hayreh): NVI > BRVO but < CRVO } Non-ischemic showed no neovascularization } NVD 29% and NVE 42% in ischemic: HRVO > CRVO and BRVO

43 BRVO

44 Branch Retinal Vein Occlusion-BRVO } Leber occlusion at the A/V crossing } 3/4 in the superior retina } share a common adventitial sheath } venous lumen diminished by atherosclerosis } artery caliber increases with arterial media thickening

45 Branch Retinal Vein Occlusion-BRVO } collaterals develop as vein-to-vein channels } maybe only indicator of old disease } do not leak on IVFA

46 BRVO-risk factors Increased } Hypertension } Glaucoma } CAD Decreased } higher HDL levels } alcohol consumption } Hyperopia } higher levels Alpha-2 globulin

47 BRVO- classification } non-ischemic } Indeterminate } ischemic > 5 DD capillary non-perfusion

48 BRVO- characteristics } unilateral and segmental distribution nerve fiber hemorrhages } intraretinal hemorrhages } cotton-wool spots } retinal edema

49 BRVO- characteristics } 41% visual acuity of 20/20 to 20/50 } 25% VA of 20/60 to 20/200 } 32% VA of 20/200 or worse } 60%-100% have macular edema at some point in their clinical course } 30% with persistent macular edema after 1 year, can improve over 6-12 months

50 BRVO- characteristics retinal hemorrhages and venous tortuousity } gradually decrease 6- to 12-month } microaneurysms characteristic of acute recovery } narrowed arterioles with venous occlusion/sheathing

51 BRVO- characteristics late changes } RPE proliferation } residual macular edema } macular cysts and holes } macular pucker } persistent macular hemorrhages and microaneurysms

52 BRVO- characteristics late changes } subretinal fibrosis } neovascularization of the disc and retina

53 BRVO: differential diagnosis } A. Diabetic retinopathy } B. Radiation retinopathy } C. Hemi central retinal vein occlusion } D. Juxtafoveal telangiectasia } E. Epiretinal membrane } H. Hypertensive retinopathy

54 BRVO: treatment } Initial observation for MANY patients } ischemic type of BRVO, NVE or hemorrhage would warrant scatter photocoagulation (in distribution of BRVO) } observation 3-6 months, patients with persistent macular edema and/or visual acuity 20/40 or worse, should consider focal laser or intravitreal medication } 1. Good blood pressure control } 2. Treatment of dyslipidemia } 3. Treatment of diabetes mellitus, if present

55 BRVO- Treatment from BVOS FOCAL LASER } 65% treated gained 2 or more lines -compared to 37% controls } 60% treated eyes had VA > 20/40 -compared to 34% controls } 12% treated eyes had VA < 20/200 -compared to 23% controls } 12% treated lost 2 or more lines -compared to 17% controls

56 BRVO- Treatment from BVOS sectoral PRP* to prevent the retinal neovascularization } reduced neovascularization from 22% to 12% } ischemic occlusion more than 5 disc diameters of capillary nonperfusion

57 New Treatments: BRVO Anti-VEGF Surgery } Avastin } Lucentis } Arterial-Venous Delamination } Eylea Steroids: } Ozurdex } Kenalog

SCORE : IVTA BRVO } 1mg 29% } 4mg 26% } STD 27% achieved vision endpoint } rates of elevated IOP & cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group }

58 SCORE : IVTA BRVO } 1mg 29% } 4mg 26% } STD 27% achieved vision endpoint } rates of elevated IOP & cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group } Conclusions NO difference identified in visual acuity at 12 months for the standard care group compared with the triamcinolone groups } rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group

59 Ozurdex + Avastin for Macular Edema Due to BRVO } 23% lasted to 6 months without additional therapy } +10 letters at 2 weeks } +14 letters at month 1 and 2 } +12 letters at month 4 } > +3 line VA in 28% at week 2 to 45%, at months 4

60 Lucentis (Ranibizumab) for BRVO BRAVO study } Efficacy } Ranibizumab treatment groups } Rapid improvement in visual and OCT by Day 7 and sustained through Month 6 with monthly treatment } With initiation of PRN treatment at Month 6, gains in BCVA were maintained, on average, through Month 12 } 18.3 letter gain with ranibizumab vs. 7.3 letter gain in shame } 54.5% of the sham group requiring rescue laser } only 19.8% ranibizumab required rescue laser

61 Eylea (Aflibercept) for BRVO: Vibrant Study } Eylea } mean change of BCVA was 17.1 letter gain with Eylea vs 12.2 in grid laser group at 52 weeks } rescue treatment was required in 10% of drug group and in 80% eyes in the laser/drug group Avastin (Bevacizumab): BERVOLT and multiple studies } BERVOLT retrospectively studied efficacy and safety of bevacizumab for macular edema due to BRVO and CRVO } Efficacy similar to Eylea and Lucentis

62 Case 1 PPLOV X 3 months VA 20/60

64 1 month s/p intravtreal Lucentis

65 1 month s/p intravtreal Lucentis VA 20/60 to 20/25

66 Case 2 BRVO VA 20/200 s/p Lucentis 6 months previous

67 Case 2 BRVO VA 20/200 s/p Lucentis 6 months previous

68 Case 2 BRVO VA 20/200 s/p Lucentis 6 months previous

70 Case 2

71 BRVO VA 20/200 s/p Lucentis 6 months previous

72 3 months s/p Lucentis and peripheral PRP VA 20/40

73 Pre tx 2010 VA = 20/200 3 months post tx2010 VA = 20/40

74 6 months s/p Lucentis and peripheral PRP VA 20/30

75 2011 VA = 20/30

76 Macular Branch Retinal Vein Occlusion } small venous tributary } subgroup of BRVO } patients with macular branch vein occlusion complain of blurring or distortion of vision

77 Macular Branch Retinal Vein Occlusion } superior macular more common } 85% macular edema } small areas capillary nonperfusion in 20% } neovascularization typically is not seen

78 40 yo WM with PPLOV OD: 20/70 OS: 20/50

79 40 yo WM 3 months later OD: 20/20 OS: 20/20

80 Summary Ocular Complications Type NVD NVE NVI NVG % % % CRVO % Ischemic 15% HRVO (I) 11 (-29)% BRVO 10.6% Macular- 0% BRVO 8% 58% 33% 9 (-42)% 9 (-13)% 3% 20.7% 1.6% 0.8% 0% 0% 0%

81 Retinal Vein Occlusion Practice Guidelines } Symptoms <2 months without CME on OCT or loss of vision: observe monthly for 3 months and then quarterly } Symptoms> 2 months, CME, RPE changes, VA >20/40 consider treatment } Medical work up to PMD } Follow all patients monthly for first 3 months and then quarterly

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