Controversies in the Management of Vitreoretinal Diseases An

Controversies in the Management of Vitreoretinal Diseases An Update on Retinal Care in 2019 Elias C. Mavrofrides, M. D. Florida Retina Institute

Denotes Slide with Key Information

Background u 35 yo Hispanic Female u Worsening vision over 10 days u Severe headaches u Seen in ER and had Neuroimaging u Vision is 20/200 OD and 20/400 OS

Diagnosis u Vogt-Koyanagi-Harada’s Autoimmune condition v Uveitis v Headaches v Alopecia and Poliosis v Hearing loss v

Treatment u Start oral Prednisone at 40 mg per day u Start topical Prednisolone qid OU u Arrange for Rheumatology evaluation to plan steroid sparring medication

Background u Vision is 20/20 u Laser assisted-cataract extraction with premium intraocular lens u “Vision is horrible and I can barely see!”

Vitrectomy for Floaters “Floaterectomy”

“Floaters” u Age v related changes within the vitreous gel Myopia – earlier and more severe u Inflammation u Post-surgical (esp. after YAG capsulotomy) u Vitreous Hemorrhage u Pigmentation (usually from retinal tear)

Age Related Vitreous Opacities u Part of the natural liquification of the vitreous gel u Usually noticed in late teens and early 20 s u Significant increase when Posterior Vitreous Detachment (PVD) actually occurs (40 -80 years of age)

Treatment Options u Live with them u Homeopathic meds u YAG laser u Vitrectomy

Floaterectomy? Why even consider this?

Vitrectomy for Floaters u Many are unable to “ignore” floaters u Increased expectations v Advancements in LASIK and Cataract surgery u Tremendous vision financial investment in

Floaterectomy? Too dangerous or Reasonable?

Vitrectomy for Floaters u Advances in vitrectomy techniques Small gauge, sutureless vitrectomy v Valved cannulas v High speed vitrectomy cutters v Improved fluid dynamics v

Small Gauge Vitrectomy u Newer technique using smaller incisions v 0. 5 mm or 0. 7 mm vs. 0. 9 mm u Still use 3 ports Trocars inserted directly through the conjunctiva and sclera v Smaller incisions usually do NOT require suturing v

Floaterectomy Effectiveness u Patients at the retina specialist are rarely happy! v AMD, Diabetes, Retinal Detachment, Retinal Degenerations, Trauma u Floaterectomy v patients LOVE the results My happiest patients by far!

Floaterectomy Effectiveness u “I feel like I can see in HD” u “My vision is better than when I was 20” u “One of the best medical decisions I have ever made”

Floaterectomy Complications u Iatrogenic break during surgery u Retinal detachment after surgery u Cystoid macular edema (CME) u Vitreous hemorrhage u Endophthalmitis

VERY IMPORTANT SLIDE Selection Criteria is Key Choose the Right Patients!!

Floaterectomy Selection Criteria u True PVD u Pseudophakic u Open posterior capsule u Symptoms persist for 6 months

Floaterectomy Disclaimer u Floaterectomy is NOT for everyone u Young patients without a true PVD need to wait u Must have cataract surgery first

Age-Related Macular Degeneration

Age-Related Macular Degeneration u. Leading cause of legal blindness in Americans over 60 years old u. Wet Macular Degeneration 10% of all cases v 90% of those with severe vision loss v

Dry Macular Degeneration u Drusen develop in the macula u Retinal Pigment Epithelium (RPE) eventually atrophies u Overlying retina also thins and weakens v Vision loss ensues

How Can We Treat Dry Macular Degeneration ?

Dry Macular Degeneration u There are NO treatments available to reverse Dry Macular Degeneration changes

Latest Research for Dry Macular Degeneration Can we do better than just Vitamins?

Dry Macular Degeneration Treatment u Oral v Medications Modulate visual pathway u Injections u Novel therapies

Wet Macular Degeneration

Wet Macular Degeneration u Choroidal Neovascularization (CNV) – Abnormal blood vessels develop under the retina

Wet Macular Degeneration u Growth of new blood vessels originating from the choroid u Growth under the RPE or into the subretinal space

Wet Macular Degeneration u These abnormal blood vessels leak fluid and bleed u Eventually these blood vessels form a scar in the macula

How Can We Treat Wet Macular Degeneration ?

CNV Tx: An Unmet Medical Need vs. . . Desperate Search Surgical/ Laser Therapies Laser Photocoagulation PDT: Visudyne. TM, Sn. ET 2 Surgery Removal Translocation 360° retinotomy vs. . . limited Transpupillary Thermotherapy Feeder Vessel Treatment Radiation RPE Transplantation ■Effective ■Ineffective Pharmacological Therapies Anti-VEGF agents (intravitreous) Pegaptanib, Rhu. FAB Anecortave (post juxtascleral) Triamcinolone (intravitreous) Squalamine (intravenous) Prinomastat (oral) Thalidomide (oral) Interferon alfa (subcutaneous) Combination strategies PDT + Triamcinolone (intravit) ■Ongoing study

It’s All about the Injections!!

Vascular Endothelial Growth Factor (VEGF) u Mediator of developmental and pathological vascularization u Angiogenic and vascular permeability properties VEGF-A 165 Receptor binding site

VEGF Inhibitors u Avastin u Lucentis u Eyelea X VEGF-A 165 Receptor binding site

Avastin® (bevacizumab, Genentech Inc. ) First anti-VEGF therapy approved by the FDA Avastin® Bevacizumab MW 150 k. D FDA approved as a first line therapy for metastatic colorectal cancer on February 26, 2004

Avastin® (Bevacizumab, Genentech Inc. ) u Full-length, Avastin® Bevacizumab MW 150 k. D humanized, mouse monoclonal antibody activity against VEGF u Approved for metastatic colorectal cancer on February 26, 2004

Lucentis™ (ranibizumab) is derived from Avastin® (bevacizumab) Avastin-Fab MW 48 k. D Avastin® Bevacizumab MW 150 k. D Lucentis™ Ranibizumab MW 48 k. D 140 X higher affinity for VEGF

Lucentis (Genentech) u Recombinant humanized antibody “fragment” binds to VEGF v Targets all isoforms of VEGF u Gained FDA approval June 30, 2006

Eylea (VEGF Trap) for Wet AMD u Eylea (VEGF Trap) by Regeneron

Eylea (VEGF Trap) for Wet AMD u Fusion protein that inhibits Vascular Endothelial Growth Factor (VEGF-A) and Placental Growth Factor (Pl. GF) u Portions of human VEGF receptors domains fused to the Fc portion of human Ig. G 1

VEGF Inhibitors u REVOLTIONIZED HOW WE TREAT WET MACULAR DEGENERATION X VEGF-A 165 Receptor binding site

VEGF Inhibitors u HOW BAD WAS IT BEFORE VEGF INHIBITORS? ? X VEGF-A 165 Receptor binding site

Before the Injections… …There was Phtodynamic Therapy (PDT)

With PDT Treatment, Average Outcome is a Loss of Vision… Follow-up visit (months) 0 0 3 6 9 12 15 18 21 24 -5 Classic -10 -15 Occult–No Classic -20 -25 Predominantly classic treated (n=159) Occult no classic* treated (n=123) -30 Mean visual acuity loss (letters) *VA 20/50 -1 or lesion size 4 MPS DA TAP Study Group 2001; VIP Study Group 2001

… But Less Loss Than With No Treatment Follow-up visit (months) 0 -5 0 3 6 9 12 15 18 21 24 Predominantly classic placebo (n=83) Occult no classic* placebo (n=64) -10 -15 Treated -20 -25 Not Treated -30 Mean visual acuity loss (letters) *VA 20/50 -1 or lesion size 4 MPS DA TAP Study Group 2001; VIP Study Group 2001

With the Injections… We Can Do Much Better!!

Average VA – Usual Care UC Baseline Day 98

Average VA with Lucentis rhu 500 rhu 300 UC Baseline Day 98

Secondary Endpoint: Mean Change in Visual Acuity Over Time Sham (n=238) Ranibizumab 0. 3 mg (n=238) ETDRS letters 10 +7. 2 +6. 5 5 0 Ranibizumab 0. 5 mg (n=240) 17. 6 letter difference* 2 4 6 8 10 12 16. 9 letter difference* -5 -10 – 10. 4 -15 Month Note: Vertical bars are ± one standard error of the mean. *P< 0. 0001

Secondary Endpoint: Mean Change in Visual Acuity Over Time Sham (n=238) Ranibizumab 0. 3 mg (n=238) ETDRS letters 10 +7. 2 5 0 Ranibizumab 0. 5 mg (n=240) +6. 6 +5. 4 +6. 5 2 4 6 8 10 12 14 16 18 20 22 21. 4 letter difference* 24 -5 20. 3 letter difference* -10. 4 -10 -15 -14. 9 Month Note: Vertical bars are ± one standard error of the mean. *P<0. 0001

Lucentis for AMD u Amazingly effective compared to previous treatments v Significant visual improvement possible u BUT, some patients will not improve visually v Subretinal fibrosis or RPE atrophy

Lucentis – Benefits Approx 90% chance of stabilization u Approx 40% chance of significant visual u v First AMD treatment resulting in improved visual acuity

Anti-VEGF Therapy Issues u Which one is the best? u Do the injections need to be monthly? u Expense of Lucentis and Eylea u Compounding Avastin

Anti-VEGF Therapy Issues u. Which u Do one is the best? the injections need to be monthly? u Expense of Lucentis and Eylea u Compounding Avastin

Avastin vs. Lucentis u NEI/NIH to sponsor head-to-head trial u Complications of Age-Related Macular Degeneration Treatment Trial (CATT)

Avastin vs. Lucentis CATT Trial u 1200 patients randomized Lucentis with 4 week dosing v Avastin with 4 week dosing v Lucentis with variable dosing based on OCT v Avastin with variable dosing based on OCT v

Avastin vs. Lucentis CATT Trial u Similar v Visual Acuity Results Gained 5. 9 letters with Avastin versus 6. 8 letters with Lucentis u Injecting as needed based on OCT findings gave similar results to injecting every month

Avastin vs. Lucentis CATT Trial u BUT, there were some slight differences Fluid on OCT – Lucentis better than Avastin v Leakage on Angiogram – Lucentis better than Avastin v

Avastin vs. Lucentis CATT Trial u One Big Difference – COST $595 for one year of Avastin v $23, 000 for one year of Lucentis v

Clinical Trials Avastin vs. Lucentis u CATT (US) n=1, 185 u IVAN (UK) n=610 u MANTA (Austria) n=321 u GEFAL (France) n=501

Eylea for Wet AMD Has NOT been compared to Avastin or Lucentis for AMD

Anti-VEGF Therapy Issues Which one is the best? ?

Anti-VEGF Therapy Issues u Which one is the best? u. Do the injections need to be monthly? u Expense of Lucentis and Eylea u Compounding Avastin

Anti-VEGF Therapy u Continuous Therapy – treat every 4 -8 weeks indefinitely u Treat and Extend – gradually increase interval between injections u As Needed – treat based on OCT

Anti-VEGF Therapy Issues u Which one is the best? u Do the injections need to be monthly? u. Expense of Lucentis and Eylea u Compounding Avastin

Anti-VEGF Therapy u Avastin - $50 to $200 per treatment u Lucentis – approx. $2, 000 per treatment v $1. 4 Billion sales United States in 2017 u Eylea v - approx. $2, 000 per treatment $5. 9 Billion sales World Wide in 2017

Anti-VEGF Therapy Issues What is Step Therapy?

Anti-VEGF Therapy Issues u Which one is the best? u Do the injections need to be monthly? u Expense of Lucentis and Eylea u. Compounding Avastin

Silicone Oil Droplets If you or a loved one received Avastin Eye Injections and later experienced: • Silicone Oil Floaters • Particles in the Eye You may be entitled to significant compensation from the

Retina Specialist Dilemma

Retina Specialist Delimma u Cost to the “system” u Cost to the patient u Overall effectiveness u Frequency of treatment

Other Therapies for Wet AMD u PDT still used on rare occasions u Steroids for AMD v Periocular or Intraocular injection v Concern for IOP issues v Newer Steroid implants NOT approived

Future Therapies for Wet AMD u Brolucizumab Injections - “the BRO” Anti-VEGF from Novartis v Longer interval between injections v Maybe even more effective than others v Release sometime in 2019 u New

Future Therapies for Wet AMD u Topical v Drops Poor Penetration into Eye u Stem Cell Transplant How to get them where we need them v Organization issues v u Tissue v Transplant How to get the tissue where we need it u Electronic chips

Background u 69 yo WM referred for macular evaluation OS u Patient went for new glasses u He did NOT notice any significant problem

Vitreoretinal Interface Disorders u Epiretinal Membrane (ERM) u Vitreomacular Attachment and Traction (VMA or VMT) u Macular Hole

Vitreoretinal Interface Disorders u Epiretinal Membrane (ERM) When to refer v When do we operate v

Epiretinal Membrane Surgery u Snellen v Visual Acuity There is NO specified number • Some 20/25 ERMs need surgery • Some 20/70 ERMs should be left alone

Epiretinal Membrane Surgery u Appearance on Exam and OCT does NOT dictate the need for surgery

Epiretinal Membrane Surgery u The degree of visual symptoms is most important !!

Epiretinal Membrane Surgery u Cataract surgery is NOT necessary before ERM surgery v But, always access degree of cataract or other visual pathology when assess visual symptoms

Epiretinal Membrane Surgery u Membrane is peeled manually after a standard vitrectomy u The ERM and ILM are usually both removed u Air bubble often injected v But, not longer gases and NO face down positioning needed

Vitreoretinal Interface Disorders Vitreomacular Attachment and Traction (VMA or VMT)

Macular Hole Surgery u Peel the Internal Limiting Membrane (ILM) u Gas Bubble – C 3 F 8 versus SF 6 u Face Down Positioning – Duration?

Macular Hole Surgery u Peel the Internal Limiting Membrane (ILM) improves hole closure

Macular Hole Surgery u Gas v bubble is key to closing hole Surface tension u Air is NOT as effective as other gases SF 6 is short acting and good for most holes v C 3 F 8 lasts much longer and better for larger, more severe holes v

Macular Hole Surgery u Face down positioning helps increase hole closure 80% closure with NO face down positioning v Better closure rates with 3 -5 days of positioning v One or more weeks NOT necessary v

Retinal Tears and Retinal Detachment

Background u 67 yo WM with new onset floaters OD u Seen 2 days earlier by general ophthalmologist with PVD u Today notices increased symptoms

Retinal Detachment Repair u Scleral buckle procedure u Pneumatic retinopexy u Vitrectomy with laser and gas u Combined scleral buckle with vitrectomy

Retinal Detachment Repair u Scleral buckle procedure Still used frequently today v Especially effective in younger patients v

Retinal Detachment Repair u Scleral buckle procedure

Retinal Detachment Repair u Pneumatic retinopexy Done in office v Patient selection is key v • Superior tear • Multiple tears must be clustered v Can result in excellent outcomes

Retinal Detachment Repair u Pneumatic retinopexy https: //www. myriverside. com/eye-clinic/eye-conditions-procedures/detached-and-torn-retina/

Retinal Detachment Repair u Vitrectomy with laser and gas Very common now that vitrectomy techniques have improved v Treat greater range of pathology including inferior detachments v Combined scleral buckle used much less frequently now v

Retinal Detachment Repair u Vitrectomy with laser and gas http: //www. medicaloptics. ie/retinal-detachment/

Retinal Detachment Repair u Proliferative Vitreo. Retinopathy (PVR) Biggest concern of retinal detachment repair v Scar tissue reaction that can re-deatch the retina v Occurs about 10% of retinal detachments v Usually results in worse visual outcomes v

Retinal Detachment Repair u Proliferative Vitreo. Retinopathy (PVR) No medications available to prevent this from developing v Timing of surgery and surgical technique not a significant factor v Patient compliance often NOT a factor v

Retinal Detachment Repair u Proliferative v Vitreo. Retinopathy (PVR) Risk factors • Younger patients • Healthier patients • Ethnic and Racial

Retinal Detachment Repair u Proliferative Vitreo. Retinopathy (PVR)

Retinal Detachment Repair u Proliferative Vitreo. Retinopathy (PVR)

Retinal Detachment Repair u Proliferative Vitreo. Retinopathy (PVR)

Diabetic Macular Edema u Focal laser therapy u Intravitreal Anti-VEGF agent v Avastin, Lucentis, Eylea u Periocular and Intavitreal Steroids Triamcinolone v Intravitreal Steroid Implants – Ozurdex or Iluvein v

Proliferative Diabetic Retinopathy u Intravitreal v Anti-VEGF agent Avastin, Lucentis, Eylea u Pan. Retinal Photocoagulation (PRP) u Vitrectomy Surgery

Proliferative Diabetic Retinopathy u Intravitreal v Anti-VEGF agent Significant benefit seen in numerous studies u PRP laser Still has an important role v Often combined with intravitreal Anti. VEGF injection v

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