Santosh C. Patel, M.D. Retina Specialists The Latest And Greatest in the Management of Retinal Diseases February 13, 2007 Retinal Diseases Majority of Blindness in Civilized World AMD Diabetic Retinopathy Vein Occlusions Retinal Detachments Retinitis Pigmentosa Macular Dystrophies Age-Related Macular Degeneration Most significant advances in all of ophthalmology in past 2 years Finally, treatments that improve vision Success is no longer defined as least letters lost Research on AMD treatment will transfer into other vascular diseases (Diabetic Retinopathy and Vein Occlusions) What Is AMD? AMD is a degenerative retinal disease that can cause central vision loss and blindness AMD is the leading cause of severe vision loss in people over 50 years of age in the western world There are 2 forms of AMD Non-neovascular (dry) AMD Affects 80% to 90% of patients Neovascular (wet) AMD Affects 10% to 20% of patients Approximately 90% of vision loss results from neovascular AMD Risk Factors for AMD Several risk factors, other than age, have been suggested Family history Gender Race Smoking Genetic factors High cholesterol Hypertension and cardiovascular disease Low intake of antioxidants/lutein AMD Is an Increasing Concern as the Population Ages US Population (millions) 80 60 40 20 0 US Population 65 years 1 34.8 39.7 53.7 2000 2010 2020 Year As the population ages, more people are at risk of developing AMD By 2020, up to 7.5 million people >65 years may suffer from AMD-related vision loss in developed countries 2
Dry Age Related Macular Degeneration treatment AREDS Antioxidants reduce the chance of visual loss from macular degeneration Zinc supplementation also reduces the risk of visual loss The combination of the two is even better Lutein 15-20 mg/day Omega- 3- Fatty Acids Fish oil or 2 or more servings of fish Antioxidant and Zinc Therapy for Non- Neovascular AMD: Results From AREDS Estimate of Risk Reduction in Developing Any Advanced AMD*: Intermediate AMD or Monocular Advanced AMD Antioxidants Zinc Antioxidants + Zinc 17% 21% 25% Recommendations From AREDS Consider using supplement of antioxidants plus zinc for patients with intermediate AMD, monocular advanced AMD, or vision loss due to AMD in 1 eye Patients who do not meet these criteria but may have a family history or are believed to be at risk for developing AMD should Maintain a diet rich in fruits and vegetables Supplement their diet with a multivitamin Undergo periodic ophthalmic exams for the development of intermediate or advanced AMD The Role of Lutein in Eye Health A carotenoid found in fruits and vegetables Antioxidant that protects cells from damage caused by free radicals Upon consumption, lutein deposits into areas of the body most prone to free radical damage One of the predominant antioxidants in the macula The macula is susceptible to damage from blue light, which in turn may contribute to AMD Lutein filters out blue light thereby preventing free radical damage in the eyes The Role of Lutein in Eye Health (cont) Some studies have suggested a possible link between lutein and decreased risk of eye disease The amount of lutein needed to provide a benefit is unknown Future studies are needed to elucidate the effects of lutein on AMD AREDS II Evaluating other micronutrients for AMD Lutein 10 mg Zeaxanthin 2 mg Omega-3 Fatty Acids (DHA/EPA) Weekly servings of fish Purified Fish Oil
AMD Damages the Macula Early AMD Retina Choroid Sclera Fovea Retina Choroid Sclera Macula RPE Bruch s Membrane Choriocapillaris Fundus photograph showing medium-sized drusen (63 124 µm) 1 Patients are usually asymptomatic and do not experience vision loss Examination reveals several small drusen or a few medium-sized drusen Can be followed yearly AREDS Vitamins not proven to work Figure courtesy of Novartis Pharmaceuticals Corporation. Intermediate AMD Fundus photographs showing numerous medium-sized drusen (left panel), and >1 large drusen (125 µm) [right panel] Examination reveals many medium-sized drusen or 1 large drusen Vision may be impaired AREDS Amsler Grid Advanced AMD: Non-Neovascular Fundus photograph depicting central geographic atrophy Vision impairment is more severe Follow fellow eye closely (every 3-4 months) if good vision May have difficulty recognizing faces from distance Examination reveals Presence of drusen Degeneration of RPE Incidence of Neovascular AMD in Elderly Persons in the United States Recent estimates were derived from random sample of Medicare beneficiaries aged 65 and older (N=1,041,009; between 1994 and 1998) 1 Incidence based on diagnosis codes associated with AMD and CNV 1 3-year incidence of AMD 9.4 to 11.4 per 1000 1 Estimates were consistent with the Beaver Dam and Framingham studies 1,2 Progression of Neovascular AMD: Normal Retina Photoreceptors RPE Choroid Photos courtesy of Novartis Pharmaceuticals Corporation.
Progression of Neovascular AMD: Development of Drusen Progression of Neovascular AMD: Formation of New Vessels Bruch s Membrane Drusen Choroidal Neovascular Lesion Bruch s membrane thickens (left panel) and drusen develop (right panel) New abnormal blood vessels proliferate and penetrate Bruch s membrane Photos courtesy of Novartis Pharmaceuticals Corporation. Photos courtesy of Novartis Pharmaceuticals Corporation. Progression of Neovascular AMD: Leakage of Fluid and Blood From CNV Current & Emerging Drug Therapy for Neovascular Macular Degeneration Visudyne (Photodynamic Therapy) Kenalog (Triamcinolone) Macugen (Pegaptanib) Lucentis (Ranibizumab) Avastin (Bevacizumab) New blood vessels leak blood and fluid Retaane (Anecortave Acetate) VEGF Trap Evizon (Squalamine) Photos courtesy of Novartis Pharmaceuticals Corporation. Visudyne In use since 2000 Photosensitizing drug Only available treatment for wet AMD until December 2004 (Macugen) Visudyne : Selective Accumulation in CNV Circulating Visudyne Complexes With LDL 1 Visudyne Accumulates in Neovascular Tissue, Which Is Rich in LDL Receptors 2
Visudyne Administration: A 2-Step Process Visudyne : Occlusion of CNV 1-3 Nonthermal Laser Activation of Visudyne Step 1: Infusion Reactive Oxygen Products Step 2: Nonthermal Laser Application Endothelial Cell Damage and Thrombus Formation 1 Selective Occlusion of Abnormal Vessels 3 Photos reprinted with permission from Novartis Pharmaceuticals Corporation. Visudyne (verteporfin for injection) prescribing information. Novartis Pharmaceuticals Corporation; April 2003. Visudyne Therapy Helps Slow the Rate of Vision Loss 2-Year Results in Predominantly Classic Lesions VA Letters Lost From Baseline (mean) 0-5 -10-15 -20 * -25 0 3 6 9 12 15 18 21 24 Months After Study Enrollment *P<.004. P<.001. Adapted with permission from Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol. 2002;120:1443-1454. Visudyne (n=159) Placebo (n=83) Sustained Benefit with Visudyne Therapy: VA Mean Change From Baseline (number of letters) VA = visual activity. Data on file, Novartis Pharmaceuticals Corporation. VA After 5-Years Use of Visudyne in Eyes With Predominantly Classic Lesions 0 Visudyne Placebo -5 (n=77) -10 (n=121) (n=121) Patients originally assigned to -15 placebo now receive Visudyne -20-25 (n=134) (n=132) (n=85) -30 0 3 6 9 1215182124273033363942454851545760 Time After Study Enrollment (months) PDT/Visudyne Frequency of usage significantly decreased with introduction of Anti-VEGF agents Still very good for Myopic Choroidal Neovascularization Only approved treatment for Myopia Triamcinolone (Kenalog) Intraocular injection of 4 mg (0.1 ml) Speculum Betadine Injected inferiorly (usually at 6 o clock) Anti-inflammatory and anti-vegf properties Used as monotherapy or in conjunction with PDT
Triamcinolone (Risks) Injection Risks Endophthalmitis Traumatic Cataract Retinal Detachment Vitreous Hemorrhage Steroid Risks Cataract Glaucoma Anti-VEGF Macugen (Pegaptanib) Vascular Endothelial Growth Factor Normal protein found in the blood system Various forms (different agents target different forms) Angiogenesis Elevated levels help tumors/cancers grow Elevated levels help fuel Choroidal neovascularization in AMD Neovascularization in Diabetic Retinopathy Cause of Neovascular AMD in combination with aging changes of the retina All of the new drug therapies are aimed against VEGF Treatments take from our Oncology colleagues Developed by Eyetech (Pfizer sponsored) Anti-VEGF Aptamer (Isoform 165) Chemically synthesized short strand of RNA FDA approved for all types of lesions (December 2004) Intravitreal injection every 6 weeks $1200/dose
Macugen
Anatomical Data Support Clinical Results Lucentis (Ranibizumab) Baseline Week 54 Total lesion size and leak intensity were significantly less in Macugen-treated patients compared with usual care controls Developed by Genentech Antibody directed against VEGF Binds all isoforms of VEGF Compared to Macugen which only targets isoform 165 Lucentis Lucentis FDA approval June 2006 Intravitreal injection every 4 weeks 90% of patients maintain or improve vision $2000/dose Taken from Lucentis.com Lucentis ANCHOR MARINA SAILOR FOCUS PIER
PIER study Lucentis monthly injections every month for 3 months Quarterly injections from then on Patients did well compared to sham Patients did better with monthly injections than quarterly ones Avastin Systemic Anti- VEGF agent developed by Genentech FDA approved for metastatic colorectal cancer February 2004 Phil Rosenfeld, MD PhD studied intravenous Avastin for AMD Bascom Palmer s 12 week results for 9 patients Systemic infusion 2 weeks apart with total of 2-3 treatments Vision improved in 1 week At 3 months, average vision improved over 2 lines in both eyes Avastin May 2005 Rosenfeld thought about injecting Avastin into the eye Genentech had thought Avastin s molecule was too large to penetrate the retina The drug worked better than any previous treatment Avastin usage spread throughout the world Avastin Has been used for AMD >2 years A year before Lucentis was available Excellent results (similar to Lucentis?) $75/dose Not FDA approved, but approved by Medicare Intravitreal injection every 4-6 weeks Drawbacks of Anti-VEGF Pan Anti-VEGF agents (Lucentis & Avastin) may have cardiovascular complications History of MI or Stroke in patients Multiple injections may be cumulative systemically Difficult to determine Anti-VEGF complications in these patients What is current treatment of AMD? Lucentis or Avastin 1 st Which one is better? Cost comes into play Patients choice comes into play Repeat at 4-6 weeks (usually necessary) Consider substituting Macugen Current trials underway
Lucentis vs. Avastin Lucentis vs. Avastin FDA approved for AMD Controlled trials with results and safety $2000/injection Not FDA approved for AMD, but covered by Medicare Large experience by retina specialists $75/injection Lucentis is smaller molecule Better penetration into retina? Cleared faster from blood stream so safer? Retaane (Anecortave Acetate) Developed by Alcon Steroid with the glucocorticoid cleaved off Prevents steroid associated IOP rises Given as juxtascleral depot every 6 months Anecortave Acetate New trial under way for the prevention of wet AMD Patients must have one eye with wet AMD and other eye with dry AMD
VEGF Trap Regeneron Pharmaceuticals Blocks action of VEGF Intravitreal injection Squalamine (Evizon) Systemic Anti- VEGF agent developed by Genaera Purified from tissue of dogfish shark MOA is to interrupt and reverse angiogenic process FDA has granted Fast Track designation Combination Therapy Combining PDT with Anti-VEGF agents Combining different Anti-VEGF agents Combining PDT, Steroids & Anti-VEGF Diabetic Retinopathy Vascular Diseases Branch Retinal Vein Occlusion Central Retinal Vein Occlusion Diabetic Retinopathy Macular Edema Neovascularization Vitreous Hemorrhage Tractional Retinal Detachment Diabetic Macular Edema Laser Intraocular Steroids Anti- VEGF Surgery
Diabetic Macular Edema laser treatment Laser treatment is the gold standard Laser destroys the leaking microaneurysms Laser also stimulates fluid resorption by the retina However, laser is not effective in penetrating significantly edematous retina Post laser fluorescein angiogram OCT before and after laser photocoagulaton Intraocular Steroids Intravitreal injection of 0.1 ml kenalog Often effective in reduction of retinal edema Effect may be transitory Often used in combination with laser Five months after laser photocoagulation for macular thickening Macular Edema Treated with Intraocular Kenalog Intraocular Kenalog risks Endophthalmitis (usually non-infectious) Vitreous Hemorrhage Retinal Detachment Cataract (most common) Glaucoma
Macular Edema Steroid Implants Macular Edema Steroid Implants Dissolvable Dexamethasone Implant Clinical Trials-Office based Long Acting Fluocinolone Implant Surgically implanted Diabetic Macular Edema Anti-VEGF treatment for cases not responsive to steroids Would eliminate cataract and glaucoma risks from steroids Cost an issue Diabetic Macular Edema Surgical Options Vitreous Traction? OCT is a valuable tool Vitrectomy Proliferative Retinopathy Proliferative Retinopathy
Neovascularization of Iris from Diabetic Retinopathy Treatment of Proliferative Retinopathy Pan retinal photocoagulation Theory Destroy ischemic retina Reduce proliferative factors Possibly increase oxygen levels in the retina Cause atrophy of neovascular tissue Treatment of Proliferative Retinopathy Tractional Retinal Detachment Anti-VEGF agent Macugen Avastin Lucentis Used in cases refractory to laser Can be used pre-op in Diabetics More Severe Proliferative Retinopathy Tractional Retinal Detachment treatment Pars Plana Vitrectomy Membrane Peel Panretinal Photocoagulation +/- Silicone Oil
Branch Retinal Vein Occlusion Branch Retinal Vein Occlusion macular edema Same treatment strategy as in Diabetic macular edema Laser treatment is gold standard Newer treatments include intraocular steroids and steroid implants Anti-VEGF treatment Current clinical trials underway Central Retinal Vein Occlusion Previous treatments included panretinal photocoagulation for neovascular glaucoma Newer treatments are aimed at visual improvement rather than prevention of glaucoma Central Retinal Vein Occlusion treatment Intraocular steroids for treatment of macular edema PRP for Neovascularization Anti-VEGF treatment Current clinical trials underway May help with both edema and prevention of neovascularization Sutureless Surgery 25 gauge vitrectomy (23 gauge) Xenon light sources Faster recovery No suture irritation No induced astigmatism from sutures Xenon Light Sources Halogen bulbs have been traditional light source Bright, white, safe light for improved visibility in surgery UV-Blue wavelength filtering designed to reduce phototoxic effects IR wavelength filtering added to reduce heat effects
High Speed Vitrectomy 25 Gauge Pars Plana Vitrectomy Previous vitrectomy units had cut rates of 600 cpm Latest vitrectomy units have cut rates of 2500 cpm Allows for less traction on retina Allows surgeon to get closer to retinal surface without complications Standard 20 Gauge Conjunctival incisions Larger incisions Sutures cause astigmatism Longer healing time Delayed visual recovery Patient discomfort Sutureless 25 Gauge Does not require conjunctival opening No sutures required Faster recovery No induced astigmatism Patients much more comfortable Retinal Tears/Detachments Lattice Degeneration Retinal Holes Retinal Tears Retinal Detachments Lattice Degeneration Found in 8-10% of general population Risk of RD low (0.1-0.7%) Risk of tear off lattice lesion 2.0% Atrophic Holes commonly found within lattice lesion Retinal Tears/Holes Horseshoe Tears Vitreous traction Usually symptomatic Need to be treated with laser Atrophic Holes Often asymptomatic Can lead to RD if holes within lattice lesion Usually not treated Peripheral Retinal Tears/Holes/Lattice (When to Treat?) Acute Symptomatic Retinal Tear Treat Asymptomatic Retinal Tear Asymptomatic Atrophic Holes Asymptomatic Lattice Degeneration Lattice Degeneration in fellow eye of RD Atrophic Holes in fellow eye of RD Lattice and Holes in Pre-LASIK Can observe without treatment Can observe without treatment Can observe without treatment Prophylactically treat Prophylactically treat Can observe without treatment
Retinal Detachment Repair Scleral Buckle Vitrectomy Pneumatic Retinopexy Selective cases Superior tears (between 10 and 2 o clock) No other retinal pathology (lattice, holes, etc.) Cooperative patient Pneumatic Retinopexy Cryo or laser tear Injection of 0.3 cc gas Local anesthesia Less complications Faster Recovery Less chance of cataract then vitrectomy Nevi Melanomas CHRPE Choroidal Lesions Choroidal Nevus Present in 6% of Caucasian Population 1 in 5000 Nevi will become Melanomas Risk Factors of Nevi becoming Melanomas Thickness > 2 mm (Ultrasound) Subretinal fluid Orange Pigment (as compared to drusen) Symptoms of flashes, floaters, va loss Margin of tumor < 3 mm to optic disc Nevus vs. Melanoma Treatment of Melanoma First, systemic work up for metastases Treatment of tumor Transpupillary Thermotherapy Plaque Radiation Charge particle irradiation Local resection Enucleation
Artificial Vision Artificial Vision Dual Chip System Silicone Chip Intraocular Silicone Chip Final Thoughts Anti- VEGF May cure all (AMD, Diabetic Retinopathy, Vein Occlusions) May have drawbacks (Cardiovascular consequences, financial restrictions) 25 Gauge Surgery Faster & Better Now available at Baylor Plano Imaging Devices The better we detect diseases, the faster we can treat (Optos, OCT, FA)