Retina Imaging Conference Tala Kassm DO April 14, 2016 University of Louisville Department of Ophthalmology and Visual Sciences

Subjective CC: “I can’t see from my left eye over 2-3 months.” CC: “I can’t see from my left eye over 2-3 months.” HPI: 47 year old white male presents with progressive vision loss in his left eye over 2-3 months. He initially thought it was something wrong with his glasses which he only uses to read. Denied eye pain, flashes or floaters. HPI: 47 year old white male presents with progressive vision loss in his left eye over 2-3 months. He initially thought it was something wrong with his glasses which he only uses to read. Denied eye pain, flashes or floaters.

History POH: None PMH: Gastroesophageal reflux disease, anxiety, no hypertension Family Hx: Noncontributory Meds: Clonazepam, Fluoxetine, Omeprazole Allergies: NKDA Social history: denies alcohol, tobacco or illicit drug use Review of Systems: denies recent trauma, joint pain, easy bruising, or blood clots/DVT’s.

Clinical Exam OD OS OD OS VA(cc,D): 20/20 20/50 ( x160) ( x159) Pupils: 3->2 3->2 no RAPD IOP:1614 EOM:FULL FULL CVF:FULL FULL A/S: Unremarkable OU, No NVI

Clinical Exam Dilated Fundus Exam: OD – Unremarkable OS OS ON c/d- 0.5 hyperemic, shunt vessel temporally MaculaMA’s and dot blot heme (DBH), hard exudates Vessels Dilated and tortuous veins mild diffuse arterial hyalinization mild diffuse arterial hyalinization PeripheryMA’s and DBH diffusely, No NVE

Photo - IR Right Eye – Normal Anatomy Left Eye – dilated and tortuous veins

FA - OD Late phase 2:20 - normal findings

FA OS Normal Arterial filling 0:17 sec AV phase, no enlargement of FAZ 0:23 sec

FA - OS Delayed venous perfusion 0:35 seconds Late venous phase 0:29 sec

FA - OS Late in recirculation phase 5:06 Petalloid cystoid macular edema

OCT Retina Intact retinal layers with normal foveal pit Severe CME with central subretinal fluid

Assessment 47 year old male with progressive, painless vision loss of left eye 47 year old male with progressive, painless vision loss of left eye Diagnosis: Non-ischemic central retinal vein occlusion with severe cystoid macular edema OS in a patient less than 50 years of age Diagnosis: Non-ischemic central retinal vein occlusion with severe cystoid macular edema OS in a patient less than 50 years of age Differential also includes: Differential also includes: Hyperviscosity Retinopathy Hyperviscosity Retinopathy Ocular Ischemic Syndrome Ocular Ischemic Syndrome

Plan Hypercoagulable work up Hypercoagulable work up Protein C, protein S, antithrombin III, homocysteine level Protein C, protein S, antithrombin III, homocysteine level Complete blood count and lipid panel as well Complete blood count and lipid panel as well Follow up in four to six weeks Follow up in four to six weeks Possible injection at that time Possible injection at that time

Labs Complete blood count and metabolic panel WNL Complete blood count and metabolic panel WNL Lipid panel: Total of 221, TG 295 Lipid panel: Total of 221, TG 295 LDL of 125 LDL of 125 Protein S Free: >150 (normal 150 (normal<124) Protein S total: 135 Protein S total: 135 Homocysteine: 19.7 (normal <15) Homocysteine: 19.7 (normal <15) Antithrombin III: 112 Antithrombin III: 112 Protein C Ag: 90 Protein C Ag: 90 Antithrombin activity: 109 Antithrombin activity: 109 Antiphospholipid and Factor V Leiden pending Antiphospholipid and Factor V Leiden pending

Follow Up 4 weeks later 4 weeks later VA OS decreased to 20/70, no NVI VA OS decreased to 20/70, no NVI Worsening of CME OS on OCT with CMT of 857 Worsening of CME OS on OCT with CMT of 857 First Eylea injection OS First Eylea injection OS 6 weeks later 6 weeks later VA improved to 20/25, no NVI VA improved to 20/25, no NVI CME improved OS, CMT of 237 on OCT CME improved OS, CMT of 237 on OCT Second Eylea injection OS Second Eylea injection OS Hematology consult – anticoagulation not indicated Hematology consult – anticoagulation not indicated

Follow Up 4 weeks 4 weeks 6 weeks 6 weeks

Central Retinal Vein Occlusion Venous occlusive disease is the second most common retinal vascular disorder Venous occlusive disease is the second most common retinal vascular disorder Incidence of all RVO’s over a year period is 1.6 – 2.3% Incidence of all RVO’s over a year period is 1.6 – 2.3% Prevalence is 0.8 per 1000 persons for CRVO Prevalence is 0.8 per 1000 persons for CRVO Increases with age Increases with age No gender predilection No gender predilection Risk factors: older age, hypertension, hyperlipidemia, atherosclerotic cardiovascular disease, open angle glaucoma, hypercoagulability Risk factors: older age, hypertension, hyperlipidemia, atherosclerotic cardiovascular disease, open angle glaucoma, hypercoagulability

Pathogenesis First described by Leibreich in 1855 First described by Leibreich in 1855 However still not completely understood However still not completely understood Occlusion due to a thrombus in the central retinal vein at, or posterior to, the lamina cribrosa. Occlusion due to a thrombus in the central retinal vein at, or posterior to, the lamina cribrosa. Arteriosclerosis of the neighboring central retinal artery causes turbulent venous flow and endothelial damage Arteriosclerosis of the neighboring central retinal artery causes turbulent venous flow and endothelial damage

Ischemic vs. Non-Ischemic Represents a continuum of severity of retinal perfusion Represents a continuum of severity of retinal perfusion Based on total area of nonperfusion on fluorescein angiography - 10 disc areas or more of retinal capillary nonperfusion of posterior pole is ischemic Based on total area of nonperfusion on fluorescein angiography - 10 disc areas or more of retinal capillary nonperfusion of posterior pole is ischemic Can help predict subsequent ocular neovascularization and identification of patients who have a poorer visual prognosis Can help predict subsequent ocular neovascularization and identification of patients who have a poorer visual prognosis

Prospective, observational case series to investigate if hypercoagulability plays a role in thrombus formation in patients with CRVO less than 56 years of age Prospective, observational case series to investigate if hypercoagulability plays a role in thrombus formation in patients with CRVO less than 56 years of age Homocysteine, protein C, protein S, antithrombin III activity, antiphospholipid antibodies, anticardiolipin antibodies Homocysteine, protein C, protein S, antithrombin III activity, antiphospholipid antibodies, anticardiolipin antibodies Hyperhomocysteinemia and circulating antiphospholipid antibodies were significantly more common in CRVO patients compared with age-matched controls Hyperhomocysteinemia and circulating antiphospholipid antibodies were significantly more common in CRVO patients compared with age-matched controls

2 year prospective case-control study 2 year prospective case-control study Patients 20 to 40 years with a diagnosis of CRVO in the absence of any other systemic disease Patients 20 to 40 years with a diagnosis of CRVO in the absence of any other systemic disease 86 subjects – 29 included 86 subjects – 29 included Hyperhomocysteinemia (Hhcys) >15 Hyperhomocysteinemia (Hhcys) >15 Of the 29, 15 had Hhcys (51.7%) Of the 29, 15 had Hhcys (51.7%) Mean homocysteine level of Mean homocysteine level of Hhcys is a risk factor for CRVO with an OR 1.9 Hhcys is a risk factor for CRVO with an OR 1.9

Cross sectional population survey >49 years of age, 2872 participants Cross sectional population survey >49 years of age, 2872 participants Prevalence of RVO was 1.6% Prevalence of RVO was 1.6% Participants with Hhcys >15 were three times more likely to have RVO Participants with Hhcys >15 were three times more likely to have RVO Odds ratio of 2.92 (95% CI, 1.57 – 5.44) Odds ratio of 2.92 (95% CI, 1.57 – 5.44) Other studies: Other studies: OR 3.0, OR 1.3, OR 8.9 (95% CI, 5.7 – 13.7) OR 3.0, OR 1.3, OR 8.9 (95% CI, 5.7 – 13.7)

Complications Neovascularization of Iris and Angle Neovascularization of Iris and Angle In nonperfused CRVO: 45-80% In nonperfused CRVO: 45-80% Greatest predictors of anterior segment neovascularization – visual acuity worse than 20/200 or degree of nonperfusion Greatest predictors of anterior segment neovascularization – visual acuity worse than 20/200 or degree of nonperfusion Early treatment with PRP – resolution of NVI in 2/3 cases Early treatment with PRP – resolution of NVI in 2/3 cases Neovascular glaucoma Neovascular glaucoma 90 day glaucoma (onset typically within 3 months) 90 day glaucoma (onset typically within 3 months) Occurs in 20 to 63% of CRVO’s Occurs in 20 to 63% of CRVO’s

Management of CRVO Medical treatment and workup Medical treatment and workup Laser photocoagulation – CVOS Laser photocoagulation – CVOS Prophylactic PRP decreases the risk of iris neovascularization compared to untreated eyes – not statistically significant Prophylactic PRP decreases the risk of iris neovascularization compared to untreated eyes – not statistically significant PRP more likely to result in prompt regression of NVI in previously untreated group vs. prophylactically treated group PRP more likely to result in prompt regression of NVI in previously untreated group vs. prophylactically treated group Frequent follow-up exams during early months, prompt PRP if NVI develops to reduce risk of NVG Frequent follow-up exams during early months, prompt PRP if NVI develops to reduce risk of NVG

Management of CRVO Intravitreal corticosteroids Intravitreal corticosteroids SCORE study – patients treated with 1 mg and 4 mg of triamcinolone SCORE study – patients treated with 1 mg and 4 mg of triamcinolone At one year 27% and 26% respectively had improvement of 15 ETDRS letters At one year 27% and 26% respectively had improvement of 15 ETDRS letters Dexamethasone injectable intravitreal implant Dexamethasone injectable intravitreal implant Improved visual acuity outcomes over a 6–month period Improved visual acuity outcomes over a 6–month period

Management of CRVO Intravitreal Anti- VEGF Therapy Intravitreal Anti- VEGF Therapy Ranibizumab and aflibercept both FDA approved Ranibizumab and aflibercept both FDA approved Bevacizumab used off-label Bevacizumab used off-label Used in practice as monthly dosing, as-needed treatment or treat-and-extend approach for macular edema Used in practice as monthly dosing, as-needed treatment or treat-and-extend approach for macular edema May also be used to reduce iris neovascularization and treat neovascular glaucoma in the short term May also be used to reduce iris neovascularization and treat neovascular glaucoma in the short term

Course and Outcome Prognosis depends on subtype of CRVO Prognosis depends on subtype of CRVO Of ischemic, 10% achieve vision better than 20/400 Of ischemic, 10% achieve vision better than 20/400 Usually predicted based on visual acuity at initial evaluation Usually predicted based on visual acuity at initial evaluation Presenting VA >20/40, maintained in 65% of people Presenting VA >20/40, maintained in 65% of people Presenting VA <20/200, remained at that level in 80% Presenting VA <20/200, remained at that level in 80% Nonischemic CRVOs experience full recovery of vision in less than 10% of cases Nonischemic CRVOs experience full recovery of vision in less than 10% of cases

References Scott IU, Ip MS, Van Veldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard of care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009; 127(9): Scott IU, Ip MS, Van Veldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard of care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009; 127(9): BCSC: Retina and Vitreous pages BCSC: Retina and Vitreous pages Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8): Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8): Klein R, Moss SM, Meuer SM, Klein BE. The 15 – year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4): Klein R, Moss SM, Meuer SM, Klein BE. The 15 – year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4): Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology. 2013;120(2) Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology. 2013;120(2) Gunther, J. Scott IU, Ip Michael. Retinal Venous Occlusive Disease. Albert & Jakobiec’s Principles & Practice of Ophthalmology. 2000, 1994(132): Gunther, J. Scott IU, Ip Michael. Retinal Venous Occlusive Disease. Albert & Jakobiec’s Principles & Practice of Ophthalmology. 2000, 1994(132): Goldman DR, Shah CP, Morley MG, Heier JS. Venous Occlusive Disease of the Retina. Ophthalmology. 2014; 6.19, e1 Goldman DR, Shah CP, Morley MG, Heier JS. Venous Occlusive Disease of the Retina. Ophthalmology. 2014; 6.19, e1

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