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The Latest And Greatest in the Management of Retinal Diseases
February 13, 2007
Santosh C. Patel, M.D.Retina Specialists Retinal Diseases
Majority of Blindness in Civilized WorldAMDDiabetic RetinopathyVein OcclusionsRetinal DetachmentsRetinitis PigmentosaMacular Dystrophies
Age-Related Macular Degeneration
Most significant advances in all of ophthalmology in past 2 yearsFinally, 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 blindnessAMD is the leading cause of severe vision loss in people over 50 years of age in the western worldThere 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 fromneovascular AMD
Risk Factors for AMDSeveral risk factors, other than age, havebeen suggested
Family historyGenderRace
SmokingGenetic factorsHigh cholesterolHypertension and cardiovascular diseaseLow intake of antioxidants/lutein
34.839.7
53.7
0
20
40
60
80
2000 2010 2020
US
Popu
latio
n (m
illio
ns)
US Population ≥65 years1
Year
AMD Is an Increasing Concern as the Population Ages
As the population ages, more people are at risk of developing AMDBy 2020, up to 7.5 million people >65 years may suffer from AMD-related vision loss in developed countries2
2
“Dry” Age Related Macular Degenerationtreatment
AREDS Antioxidants reduce the chance of visual loss from macular degenerationZinc supplementation also reduces the risk of visual lossThe combination of the two is even better
Lutein15-20 mg/day
Omega- 3- Fatty AcidsFish oil or 2 or more servings of fish
Estimate of Risk Reduction inDeveloping Any Advanced AMD*:
Intermediate AMD or Monocular Advanced AMD
Antioxidants ZincAntioxidants
+ Zinc
17% 21% 25%
Antioxidant and Zinc Therapy for Non-Neovascular AMD: Results From AREDS
RecommendationsFrom AREDS
Consider using supplement of antioxidants plus zinc for patients with intermediate AMD, monocular advanced AMD, or vision loss due to AMD in 1 eyePatients 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 vegetablesSupplement their diet with a multivitaminUndergo periodic ophthalmic exams for the development of intermediate or advanced AMD
The Role of Luteinin Eye Health
A carotenoid found in fruits and vegetables
Antioxidant that protects cells from damage causedby 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 Luteinin Eye Health (cont)
Some studies have suggested a possible linkbetween lutein and decreased risk of eye diseaseThe amount of lutein needed to provide a benefitis unknownFuture studies are needed to elucidate the effectsof lutein on AMD
AREDS II
Evaluating other micronutrients for AMDLutein 10 mgZeaxanthin 2 mgOmega-3 Fatty Acids (DHA/EPA)
Weekly servings of fishPurified Fish Oil
3
AMD Damages the Macula
Retina
ChoroidSclera
RetinaChoroid
Sclera
Macula
Fovea
RPE
Bruch’s Membrane
Choriocapillaris
Figure courtesy of Novartis Pharmaceuticals Corporation.
Fundus photograph showing medium-sized drusen
(63–124 µm)1
Early AMD
Patients are usually asymptomatic and do not experience vision lossExamination reveals several small drusen or a few medium-sized drusenCan be followed yearlyAREDS Vitamins not proven to work
Fundus photographs showing numerous medium-sized drusen (left panel), and >1
large drusen (125 µm) [right panel]
Intermediate AMD
Examination reveals many medium-sized drusen or ≥1 large drusen Vision may be impairedAREDSAmsler Grid
Fundus photograph depictingcentral geographic atrophy
Advanced AMD: Non-Neovascular
Vision impairment ismore severeFollow fellow eye closely (every 3-4 months) if good vision
May have difficulty recognizing faces from distance
Examination revealsPresence of drusenDegeneration 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 CNV1
3-year incidence of AMD ≈9.4 to ≈11.4 per 10001
Estimates were consistent with the Beaver Dam and Framingham studies1,2
Photoreceptors
Choroid
RPE
Photos courtesy of Novartis Pharmaceuticals Corporation.
Progression of Neovascular AMD: Normal Retina
4
Bruch’s membrane thickens (left panel)and drusen develop (right panel)
Bruch’sMembrane
Drusen
Photos courtesy of Novartis Pharmaceuticals Corporation.
Progression of Neovascular AMD: Development of Drusen
ChoroidalNeovascularLesion
Photos courtesy of Novartis Pharmaceuticals Corporation.
Progression of Neovascular AMD: Formation of New Vessels
New abnormal blood vessels proliferateand penetrate Bruch’s membrane
New blood vessels leak blood and fluid
Photos courtesy of Novartis Pharmaceuticals Corporation.
Progression of Neovascular AMD: Leakage of Fluid and Blood From
CNVVisudyne (Photodynamic Therapy)Kenalog (Triamcinolone)
Macugen (Pegaptanib)Lucentis (Ranibizumab)Avastin (Bevacizumab)
Retaane (Anecortave Acetate)VEGF TrapEvizon (Squalamine)
Current & Emerging Drug Therapy for Neovascular Macular Degeneration
Visudyne
In use since 2000Photosensitizing drugOnly available treatment for “wet” AMD until December 2004 (Macugen)
Circulating VisudyneComplexes With LDL1
Visudyne Accumulates inNeovascular Tissue, Which Is Rich in LDL Receptors2
Visudyne®: Selective Accumulation in CNV
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Step 1:Infusion
Step 2:Nonthermal
LaserApplication
Photos reprinted with permission from Novartis Pharmaceuticals Corporation.Visudyne® (verteporfin for injection) prescribing information. Novartis PharmaceuticalsCorporation; April 2003.
Visudyne® Administration:A 2-Step Process
Reactive Oxygen Products
Selective Occlusion of Abnormal Vessels3
Nonthermal Laser Activation of Visudyne
Endothelial Cell Damageand Thrombus Formation1
Visudyne®: Occlusion of CNV 1-3
2-Year Results in Predominantly Classic Lesions
*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.
-25
-20
-15
-10
-5
0
3 6 9 12 15 18 21 24
Months After Study Enrollment
VA L
ette
rs L
ost F
rom
Bas
elin
e (m
ean)
*
††
Visudyne (n=159)Placebo (n=83)
Visudyne Therapy Helps Slow the Rate of Vision Loss
0
VA = visual activity.Data on file, Novartis Pharmaceuticals Corporation.
VA After 5-Years’ Use of Visudyne®
in Eyes With Predominantly Classic Lesions
-30
-25
-20
-15
-10
-5
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60Mea
n C
hang
e Fr
om B
asel
ine
(num
ber o
f let
ters
)
Time After Study Enrollment (months)
VisudynePlacebo
Sustained Benefit with Visudyne Therapy: VA
(n=121)
(n=134) (n=132)
(n=121) Patients originally assigned to placebo now receive Visudyne
(n=77)
(n=85)
PDT/Visudyne
Frequency of usage significantly decreased with introduction of Anti-VEGF agentsStill very good for Myopic Choroidal Neovascularization
Only approved treatment for Myopia
Triamcinolone (Kenalog)
Intraocular injection of 4 mg (0.1 mL)SpeculumBetadineInjected inferiorly (usually at 6 o’clock)
Anti-inflammatory and anti-VEGF propertiesUsed as monotherapy or in conjunction with PDT
6
Triamcinolone (Risks)
Injection RisksEndophthalmitisTraumatic CataractRetinal DetachmentVitreous Hemorrhage
Steroid RisksCataractGlaucoma
Anti-VEGF
Vascular Endothelial Growth FactorNormal protein found in the blood systemVarious forms (different agents target different forms)AngiogenesisElevated levels help tumors/cancers growElevated levels help fuel
Choroidal neovascularization in AMDNeovascularization in Diabetic Retinopathy
Cause of Neovascular AMD in combination with aging changes of the retinaAll of the “new” drug therapies are aimed against VEGFTreatments take from our Oncology colleagues
Macugen (Pegaptanib)
Developed by Eyetech (Pfizer sponsored)Anti-VEGF Aptamer (Isoform 165)Chemically synthesized short strand of RNAFDA approved for all types of lesions (December 2004)Intravitreal injection every 6 weeks$1200/dose
7
Macugen
8
Baseline Week 54
Anatomical Data Support Clinical Results
Total lesion size and leak intensity were significantly less in Macugen-treated patients compared with usual care controls
Lucentis (Ranibizumab)
Developed by GenentechAntibody directed against VEGFBinds all isoforms of VEGF
Compared to Macugen which only targets isoform 165
Lucentis
FDA approval June 2006Intravitreal injection every 4 weeks90% of patients maintain or improve vision$2000/dose
Lucentis
Taken from Lucentis.com
Lucentis
ANCHORMARINASAILORFOCUSPIER
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Lucentis
PIER studymonthly injections every month for 3 monthsQuarterly injections from then onPatients did well compared to shamPatients did better with monthly injections than quarterly ones
Avastin
Systemic Anti- VEGF agent developed by GenentechFDA approved for metastatic colorectal cancer February 2004Phil Rosenfeld, MD PhD studied intravenous Avastin for AMD
Bascom Palmer’s 12 week results for 9 patientsSystemic infusion 2 weeks apart with total of 2- 3 treatmentsVision improved in 1 weekAt 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 treatmentAvastin usage spread throughout the world
Avastin
Has been used for AMD >2 yearsA year before Lucentis was available
Excellent results (similar to Lucentis?)$75/doseNot FDA approved, but approved by MedicareIntravitreal injection every 4-6 weeks
Drawbacks of Anti-VEGF
Pan Anti-VEGF agents (Lucentis & Avastin) may have cardiovascular complicationsHistory of MI or Stroke in patientsMultiple injections may be cumulative systemicallyDifficult to determine Anti-VEGF complications in these patients
What is current treatment of AMD?
Lucentis or Avastin 1st
Which one is better?Cost comes into playPatients choice comes into play
Repeat at 4-6 weeks (usually necessary)Consider substituting Macugen
Current trials underway
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Lucentis vs. Avastin
FDA approved for AMD
Controlled trials with results and safety$2000/injection
Not FDA approved for AMD, but covered by MedicareLarge experience by retina specialists$75/injection
Lucentis vs. Avastin
Lucentis is smaller moleculeBetter penetration into retina?Cleared faster from blood stream so safer?
Retaane (Anecortave Acetate)
Developed by AlconSteroid with the glucocorticoid cleaved off
Prevents steroid associated IOP risesGiven as juxtascleral depot every 6 months
Anecortave Acetate
New trial under way for the prevention of “wet” AMDPatients must have one eye with “wet” AMD and other eye with “dry” AMD
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VEGF Trap
Regeneron PharmaceuticalsBlocks action of VEGFIntravitreal injection
Squalamine (Evizon)
Systemic Anti- VEGF agent developed by GenaeraPurified from tissue of dogfish sharkMOA is to interrupt and reverse angiogenic processFDA has granted Fast Track designation
Combination Therapy
Combining PDT with Anti-VEGF agentsCombining different Anti-VEGF agentsCombining PDT, Steroids & Anti-VEGF
Vascular Diseases
Diabetic RetinopathyBranch Retinal Vein OcclusionCentral Retinal Vein Occlusion
Diabetic Retinopathy
Macular EdemaNeovascularizationVitreous HemorrhageTractional Retinal Detachment
Diabetic Macular Edema
LaserIntraocular SteroidsAnti- VEGFSurgery
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Diabetic Macular Edemalaser treatment
Laser treatment is the “gold” standardLaser destroys the leaking microaneurysmsLaser also stimulates fluid resorption by the retinaHowever, laser is not effective in penetrating significantly edematous retina
Post laser fluorescein angiogram
OCT before and after laser photocoagulaton
Five months after laser photocoagulation for macular thickening
Intraocular Steroids
Intravitreal injection of 0.1 ml kenalogOften effective in reduction of retinal edema Effect may be transitoryOften used in combination with laser
Macular Edema Treated with Intraocular Kenalog
Intraocular Kenalogrisks
Endophthalmitis (usually non-infectious)Vitreous HemorrhageRetinal DetachmentCataract (most common)Glaucoma
13
Macular Edema Steroid Implants
Dissolvable Dexamethasone ImplantClinical Trials-Office based
Macular Edema Steroid Implants
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 steroidsCost an issue
Diabetic Macular Edema
Surgical OptionsVitreous Traction?OCT is a valuable toolVitrectomy
Proliferative RetinopathyProliferative Retinopathy
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Neovascularization of Iris from Diabetic Retinopathy
Treatment of Proliferative Retinopathy
Pan retinal photocoagulationTheory – Destroy ischemic retinaReduce proliferative factorsPossibly increase oxygen levels in the retinaCause atrophy of neovascular tissue
Treatment of Proliferative Retinopathy
Anti-VEGF agentMacugenAvastinLucentis
Used in cases refractory to laserCan be used pre-op in Diabetics
Tractional Retinal Detachment
More Severe Proliferative Retinopathy Tractional Retinal Detachment
treatment
Pars Plana VitrectomyMembrane PeelPanretinal Photocoagulation+/- Silicone Oil
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Branch Retinal Vein OcclusionBranch Retinal Vein Occlusion
macular edema
Same treatment strategy as in Diabetic macular edemaLaser treatment is “gold” standardNewer treatments include intraocular steroids and steroid implantsAnti-VEGF treatment
Current clinical trials underway
Central Retinal Vein Occlusion
Previous treatments included panretinal photocoagulation for neovascular glaucomaNewer treatments are aimed at visual improvement rather than prevention of glaucoma
Central Retinal Vein Occlusiontreatment
Intraocular steroids for treatment of macular edemaPRP for NeovascularizationAnti-VEGF treatment
Current clinical trials underwayMay help with both edema and prevention of neovascularization
Sutureless Surgery
25 gauge vitrectomy (23 gauge)Xenon light sourcesFaster recoveryNo suture irritationNo induced astigmatism from sutures
Xenon Light Sources
Halogen bulbs have been traditional light sourceBright, 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
16
High Speed Vitrectomy
Previous vitrectomy units had cut rates of 600 cpmLatest vitrectomy units have cut rates of 2500 cpm
Allows for less traction on retinaAllows surgeon to get closer to retinal surface without complications
25 Gauge Pars Plana Vitrectomy
Standard 20 GaugeConjunctival incisionsLarger incisionsSutures cause astigmatismLonger healing timeDelayed visual recoveryPatient discomfort
Sutureless 25 GaugeDoes not require conjunctival openingNo sutures requiredFaster recoveryNo induced astigmatismPatients much more comfortable
Retinal Tears/Detachments
Lattice DegenerationRetinal HolesRetinal TearsRetinal Detachments
Lattice Degeneration
Found in 8-10% of general populationRisk 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 TearsVitreous tractionUsually symptomaticNeed to be treated with laser
Atrophic HolesOften asymptomaticCan lead to RD if holes within lattice lesionUsually not treated
Peripheral Retinal Tears/Holes/Lattice(When to Treat?)
Can observe without treatmentLattice and Holes in Pre-LASIK
Prophylactically treatAtrophic Holes in fellow eye of RD
Prophylactically treatLattice Degeneration in fellow eye of RD
Can observe without treatmentAsymptomatic Lattice Degeneration
Can observe without treatmentAsymptomatic Atrophic HolesCan observe without treatmentAsymptomatic Retinal Tear TreatAcute Symptomatic Retinal Tear
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Retinal Detachment Repair
Scleral BuckleVitrectomyPneumatic Retinopexy
Selective casesSuperior tears (between 10 and 2 o’clock)No other retinal pathology (lattice, holes, etc.)Cooperative patient
Pneumatic Retinopexy
Cryo or laser tearInjection of 0.3 cc gasLocal anesthesiaLess complicationsFaster RecoveryLess chance of cataract then vitrectomy
Choroidal Lesions
NeviMelanomasCHRPE
Choroidal Nevus
Present in 6% of Caucasian Population1 in 5000 Nevi will become MelanomasRisk Factors of Nevi becoming Melanomas
Thickness > 2 mm (Ultrasound)Subretinal fluidOrange Pigment (as compared to drusen)Symptoms of flashes, floaters, va lossMargin of tumor < 3 mm to optic disc
Nevus vs. Melanoma Treatment of Melanoma
First, systemic work up for metastasesTreatment of tumor
Transpupillary ThermotherapyPlaque RadiationCharge particle irradiationLocal resectionEnucleation
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Artificial Vision
Dual Chip System
Artificial Vision
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 SurgeryFaster & BetterNow available at Baylor Plano
Imaging DevicesThe better we detect diseases, the faster we can treat (Optos, OCT, FA)
Recommended