feel free to contact me with any questions at the above ... free to contact me with any questions at...

Feel free to contact me with any questions at the above email address.

This is a picture of me with my son, the first time he saw Mickey Mouse. He was so excited, he was holding his hands up to his ears and screaming like a teenage girl at a Justin Bieber concert. To me this is a testament to how important vision is, and how much its loss can affect our lives.

We like to describe the eye like a camera. Light comes in through the front, first passing through the clear cornea (1), then through the pupil which is the black circle surrounded by the colored iris, then passing through the lens, which is what is replaced during cataract surgery, then passing through the large vitreous cavity before hitting the retina. Just like a camera, the lens and cornea help to focus light onto the retina to produce a clear image. Like film, the image is collected by the retina and sent to the brain via the optic nerve for interpretation. The retina is very thin and delicate, about 2-3 sheets of paper in thickness, and lines the back wall of the eye like wallpaper on a wall.

Here is a color photograph of a right retina. You can see the optic nerve on the right side, which has blood vessels emanating from and exiting the eye in its center. These blood vessels supply the inner layers of the retina with oxygen. You can see the large vessels surrounding the middle of the retina to the left. The area of the retina surrounded bythese vessels is called the macula with the fovea in the very center.

The macula has the highest density of photoreceptors (rods and cones) and therefore gives us our best vision. The fovea even more so. Underneath the color photograph of the retina above is a cross section of the retina and underlying layers at a cellular level. You can see the multiple layers of the retina. The green arrow points to the photoreceptors. Directly underneath the retina is a single layer of cells called the retinal pigment epithelium, or RPE (red arrow). Underneath the RPE is a layer of blood vessels called the choroid. Both layers are very important and play an central role in macular degeneration. A thin layer called Bruchs’ membrane separates the RPE and choroid, and acts as a barrier.

The RPE is very important to the health of the overlying retina. It serves many housekeeping functions, including controlling the delivery of oxygen and nutrients from the underlying choroid, helping to remove waste from the overlying retina, which is constantly producing waste as it functions, pumping fluid out of the retina and space under the retina, absorbing heat and excess light, among others. If the RPE is unhealthy, the retina will not function properly, and as a result your vision will not be normal.

This is a scanning electron micrograph of the RPE and adjacent photoreceptors.

In addition to providing visual chromophore to the retina, the RPE also maintains the health of the retina by internalizing and digesting cellular debris from photoreceptor cells (termed, lipofuscin) in a process called phagocytosis. In healthy ocular tissue, the cellular debris which is shed from the retina is efficiently degraded within the RPE and poses no threat to vision.

During a workup for macular degeneration we use several diagnostic studies, in addition to an examination. These images are black and white photographs of the retina during a study called fluorescein angiography. This starts with an injection of sodium fluorescein dye into a vein in the arm. The dye travels to the eye within 15 seconds or so, and as it travels through the retinal vessels photographs are taken. The above images are from a “normal” eye. The image on the left is about 1 minute after the dye was injected, and the image on the left is about 5 minutes after the dye was injected. The dye first appears in the choroidal vessels (the background mottled gray), followed by the retinal arteries (brighter vessels in the image on the left), followed soon thereafter by the retinal veins. You can see that in this normal study that the dye remains confined to the vessels, and that the fovea is dark and free of vessels. Fluorescein angiography is very good at detecting the abnormal vessels that define wet AMD – they are irregular and leak the dye profusely. These are usually performed at the first visit, upon diagnosis, and once or twice a year thereafter.

The second important study we use for AMD is optical coherence tomography. This study is similar to an ultrasound, but uses light instead of sound waves. The light is reflected off the back wall of the eye and the reflectance of the different tissue is measured (eg. clear liquid does not reflect and appears black, dense tissue such as the RPE reflects a lot of light and appears bright or red). In a normal retina (top right) the retina is flat on the RPE with an even contour and a small dip at the fovea. In wet AMD, fluid can be seen in the retina (ME = macular edema), under the retina (SRF = subretinal fluid), and/or under the RPE (pigment epithelial detachment). These findings are a sign of “active” disease, and can be used to follow the course of the disease during treatment. This test is typically done at every visit.

What Is AMD? AMD is a degenerative disease of the retina that can result in central vision loss

and blindness AMD is the leading cause of irreversible impairment of vision in people >50

years of age. By the year 2030, AMD will be the cause of more blindness in the United States than diabetic retinopathy and glaucoma combined

Approximately 25% of individuals >70 years of age, or about 3.6 million elderly persons, are affected by early or late-stage AMD

Among individuals >70 years of age, AMD occurs more often in women than in men and in white individuals more often than in black individuals

AMD occurs in 2 forms, non-neovascular (dry) AMD and neovascular (wet) AMD. Approximately 80% to 90% of cases are non-neovascular AMD and 10% to 20% are neovascular AMD

Neovascular AMD is responsible for approximately 90% of severe vision loss from AMD

By 2030, AMD will be the cause of more blindness in the USA than diabetic retinopathy and glaucoma combined

1. Friedman DS, Congdon NG, Kempen J, et al. Vision Problems in the U.S.: Prevalence of Adult Vision Impairment and Age-Related Eye Disease in America. 4th ed. Schaumburg, Ill: Prevent Blindness America; 2002:1-36.

2. Desai M, Pratt LA, Lentzner H, Robinson KN. Trends in Vision and Hearing Among Older Americans. Aging Trends No. 2. Hyattsville, Md: National Center for Health Statistics; 2001:1-8. Available at: www.cdc.gov/nchs/data/agingtrends/02vision.pdf. Accessed in March 26, 2004.

3. Hyman L. Epidemiology of AMD. In: Hampton GR, Nelson PT, eds. Age-Related Macular Degeneration: Principles and Practice. New York, NY: Raven Press; 1992:1-35.

4. Ferris FL III, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102:1640-1642.

These are color pictures of the left retina is two different eyes showing the two causes of severe vision loss in AMD. Ninety percent of severe vision loss is due to the “wet” form of AMD, which will be discussed later, and 10% of severe vision loss is due to the dry form. On the left is a picture of geographic atrophy. Note the whiter area in the macula with irregular borders. This is actually loss of the RPE layer in this area. Once the RPE is lost the overlying retina and photoreceptors cannot survive, causing a permanent, large blind spot in the vision. On the right is an eye with bleeding and swelling in the retina due to new blood vessels, what we call choroidal neovascularization, or CNV. These vessels grow like weeks in the macula and can easily bleed as well as leak fluid. The retina acts like a sponge, absorbing this fluid, and a swollen retina or a retina with blood cannot function properly. Fortunately, we have good treatment options to attack this CNV, and the retina in this situation can repair itself somewhat.

Normal Anatomy of the Retina The next series of slides describe the pathophysiology underlying the

2 forms of advanced AMD: geographic atrophy and choroidal neovascularization (CNV).

This first slide depicts the normal retina, as shown on the left in a cross section histology sample. The boxed area is shown on the right in an artist�s rendering.

The choriocapillaris is an extensive network of capillaries that make up the choroidal circulation. These vessels nourish the outer retina, as opposed to the retinal blood vessels seen earlier.

The retinal pigment epithelium (RPE) forms a barrier beneath the retina, and acts as an important source of nutrients in the maintenance of a normal retina. Each RPE cell contacts multiple photoreceptors. The RPE performs a lot of the housekeeping tasks for the retina, and without it the retina cannot survive.

Bruch�s membrane separates the RPE from the choriocapillaris, acting as a physical and chemical barrier to vascular invasion of the subretinal space.

Campochiaro. J Cell Physiol. 2000;184:301

Drusen Formation The presence of drusen is one of the first clinical features of AMD, and

defines dry AMD. They are very common, seen in about 25% of all people over the age of 70.

Drusen are made up of metabolic byproducts derived from the RPE, neural retina, and choriocapillaris.

The development of drusen leads to thickening of Bruch�s membrane. This alteration in the membrane disrupts the flow of nutrients between the choroid layer and the RPE.

Drusen may be visualized ophthalmoscopically as yellow-white deposits and are classified morphologically as either hard or soft. Hard drusen are small in diameter (< 63 �m) and appear as punctate dots, whereas soft drusen are larger (≥ 63 �m) with �softer,� or more poorly demarcated, edges.

Drusen do not cause visual loss unless they are large, but their presence may be associated with difficulty with dark adaptation and poor contrast sensitivity.

Campochiaro. J Cell Physiol. 2000;184:301

The picture on the left show what small, diffuse drusen look like on exam.

Geographic Atrophy Geographic atrophy (GA) refers to RPE cell death and loss of the

overlying photoreceptors. GA in the central macular region may lead to significant loss of vision.

Although the mechanisms underlying these alterations are not well understood, they may involve oxidative damage or loss of growth factor support.

Ophthalmoscopically, areas of GA appear as diffuse, irregular patches in which there is better visualization of the underlying choroidal circulation.

Ambati et al. Surv Ophthalmol. 2003;48:257. Zarbin. Arch Ophthalmol. 2004;122:598.

These pictures demonstrate the two findings of dry AMD, compared to a “normal” eye.

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These findings can be a progressive spectrum. This series of photos over 11 years demonstrates a patient who had drusen in 1993 that became more numerous several years later, with the development of geographic atrophy in 1999 that subsequently enlarged. Unfortunately, this GA involved the fovea (the center of the macula), resulting in a significant central blind spot. We currently have no medications to prevent or reverse this progression, but a healthy lifestyle and high doses of antioxidant vitamins can slow it down and decrease the risk of severe vision loss.

Choroidal Neovascularization Budding Through Bruch�s Membrane This cartoon depicts the development of neovascular, or wet AMD. This is

defined by the development of choroidal neovascularization, or new blood vessels that arise from the choroid. These vessels are very unhealthy and can penetrate through Bruch’s membrane and damage the overlying RPE and retina. Importantly, these vessels rely on a growth factor known as vascular endothelial growth factor (VEGF) to survive. This provides a therapeutic target, which will be discussed later.

As CNV progresses, further displacement of the RPE may occur, as shown in this artist�s rendering and the following images.

Choroidal Neovascularization Budding Through Bruch�s Membrane (cont�d) Accumulation of fluid under and in the retina from the leaking CNV membrane

can be seen on exam, by optical coherence tomography (OCT), or by leakage on fluorescein angiography.

Chronic fluid can lead to photoreceptor death and RPE loss.

Campochiarro. J Cell Physiol. 2000;184:301.

Choroidal Neovascularization Budding Through Bruch�s Membrane (cont�d) Formation of a scar is the end-stage of persistent CNV. The scar comprises

vascularized tissue and fibrocytes that may exist in the subretinal and sub-RPE space. A scar is permanent, with severe and permanent loss of central vision.

Campochiarro. J Cell Physiol. 2000;184:301.

These images show the progression of wet AMD without treatment. On the left are a color photo and an image from fluorescein angiography showing an active CNV membrane. As discussed, if untreated this will progress to a permanent scar involving most of the macula.

Early AMD This fundus photograph shows small and medium-sized drusen (63-124 µm)

In the early stages of AMD, patients are usually asymptomatic and do not experience vision loss

Examination of the retina reveals small drusen (<63 µm) or a few medium-sized drusen (63-124 µm)

Drusen appear as focal yellow-white lesions that are buried deep in the retina and are varied in distribution, size, shape, and number. They are usually clustered in the macula but are found at other sites in the retina, as well

Small- and medium-sized drusen may disappear, and new ones may form at other sites in the macula

These drusen may cause loss of reading speed, impaired contrast sensitivity, and mild distortion, but usually do not cause loss of vision

Risk of CNV with small drusen is 10%, compared to 30% to 46% in patients with large drusen

1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

2. Martidis A, Tennant MTS. Age-related macular degeneration. In: Yanoff M, Duker JS, Augsburger JJ, et al, eds. Ophthalmology. 2nd ed. St. Louis, Mo: Mosby; 2004:925-933.

1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

2. Bressler SB, Maguire MG, Bressler NM, et al. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Degeneration Study Group. Arch Ophthalmol. 1990;108:1442-1447.

3. National Eye Institute Web site. Age-related macular degeneration: what you should know. Available at: www.nei.nih.gov/health/maculardegen/armd_facts.htm. Accessed December 17, 2003.

Intermediate AMD These fundus photographs show numerous medium-sized drusen (63-124 µm) in

the left panel and ≥1 large drusen (125 µm) in the right panel

These drusen are associated with a 3-fold greater risk of developing CNV

Vision may be impaired in patients with intermediate AMD

These fundus photographs illustrate advanced AMD, which may be neovascular, meaning CNV or disciform scar, or non-neovascular, meaning geographic atrophy involving the center of the macula.

Bressler NM. Early detection and treatment of neovascular age-related macular degeneration. J Am Board Fam Pract. 2002;15:142-152.

Symptoms of AMD Patients who develop neovascular AMD experience a number of visual

disturbances

Distortion of central vision (metamorphopsia) or loss of central vision with scotoma often cause patients to see a distorted view of objects that have lines, such as door posts and/or frames

Many patients also report problems with light glare, differences in size or color of objects seen by each eye, reduced contrast sensitivity, clouding of the visual field, floaters, flickering or flashing lights, and/or formed hallucinations

Neovascular AMD can lead to severe central vision loss, which has a significant impact on patients.

Patients with a visual acuity between 20/30 and 20/60 have difficulty reading printed materials, and often need either strong reading lenses, bifocals, or magnifiers to read normal-size print. In addition, if their best corrected visual acuity falls below 20/40, in most states they cannot obtain an unrestricted driver�s license.

Patients with a visual acuity between 20/80 and 20/160 have difficulty reading large-print materials, even with a magnifier and must rely on low-vision optical and electronic devices for reading.

Patients with a visual acuity between 20/200 and 20/400 have extreme difficulties recognizing facial features and road signs, and must rely on prescriptive low-vision and electronic devices for reading.

1. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology.

1995;102:205-210. 2. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia: the Blue Mountains Eye Study.

Ophthalmology. 1995;102:1450-1460. 3. Desai M, Pratt LA, Lentzner H, Robinson KN. Trends in Vision and Hearing Among Older Americans. Aging Trends

No. 2. Hyattsville, Md: National Center for Health Statistics; 2001:1-8. Available at: www.cdc.gov/nchs/data/agingtrends/02vision.pdf. Accessed in March 26, 2004.

4. Snellen ELM, Verbeek ALM, van den Hoogen GWP, et al. Neovascular age-related macular degeneration and its relationship to antioxidant intake. Acta Ophthalmol Scand. 2002;80:368-371.

5. Christen WG, Glynn RJ, Manson JE, et al. A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA. 1996;276:1147-1151.

6. Hammond CJ, Webster AR, Snieder H, et al. Genetic influence on early age-related maculopathy: a twin study. Ophthalmology. 2002;109:730-736.

7. Klein ML, Mauldin WM, Stoumbos VD. Heredity and age-related macular degeneration: observations in monozygotic twins. Arch Ophthalmol. 1994;112:932-937.

8. Meyers SM, Greene T, Gutman FA. A twin study of age-related macular degeneration. Am J Ophthalmol. 1995;120:757-766.

9. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997;123:199-206.

Risk Factors for AMD The greatest risk factor for developing AMD is advancing age

Genetics, race, gender, and behavioral and multiple environmental factors have been suggested as other causes of AMD

Currently it is thought that AMD is caused by a combination of genetic and environmental factors

Current smokers have an increased risk of AMD compared to people who never smoked

Strategies for Preventing Progression to Advanced AMD Early detection, diagnosis, and treatment of AMD are essential to maximize

preservation of central vision. Lesions left untreated may enlarge and damage more of the macula. Consequently, patients with smaller lesions benefit the most from treatment

Findings from clinical studies suggest that lifestyle modifications may help slow the progression of AMD

Smoking cessation: smoking is a strong risk factor for all types of AMD Exercise: regular exercise reduces the rate of progression of AMD by 25%

Maintain healthy weight: a high body mass index (>25) increases the relative risk of AMD progression by approximately 2.3-fold

Maintain normal blood pressure: hypertension is more common in patients with large drusen or extensive intermediate drusen and neovascular AMD

Maintain proper nutrition: in 1 study the risk of AMD was reduced by 46% in

1. Ferris FL III, Fine ST, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol.1984;102:1640-1642.

2. Bressler NM. Early detection and treatment of neovascular age-related macular degeneration. J Am Board Fam Pract. 2002;15:142-152.

3. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology. 2001;108:697-704.

4. Seddon JM, Cote J, Davis N, Rosner B. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol. 2003;121:785-792.

5. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case control study in the age-related eye disease study: age-related eye disease study, report number 3. Ophthalmology. 2000;107:2224-2232.

6. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.

7. Cho E, Hung S, Willett WC, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001;73:209-218.

1. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.

2. Head KA. Natural therapies for ocular disorders, part one: diseases at the retina. Altern Med Rev. 1999;4:342-359. 3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose

supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

Strategies for Preventing Progression to Advanced AMD (cont) Studies have shown that good nutrition can help to prevent AMD from

progressing to advanced stages

In a case-control dietary study in patients with AMD, a high dietary intake of carotenoids decreased the risk of AMD by 43%

The greatest benefit was achieved by consuming at least 2 to 4 servings per week of dark green leafy vegetables

Other colorful fruits and vegetables that are rich in carotenoids include carrots, sweet potatoes, grapes, cantaloupe, and oranges. Several of these have been shown to reduce the risk of AMD

Dietary supplements containing the antioxidants vitamin C, vitamin E, and beta carotene, plus zinc, have been shown to reduce the risk of progression to advanced AMD by 43%

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

The Age-Related Eye Disease Study AREDS was a prospective, randomized, multicenter, double-masked, placebo-

controlled clinical trial that was conducted between 1992 and 2001. Patients enrolled in the study were treated for 7 years (average follow-up 6.3 years) and received an eye examination at least once every 6 months

Patients eligible for enrollment included those with early AMD, intermediate AMD, advanced AMD with monocular vision, or pigment abnormalities or noncentral geographic atrophy in 1 or both eyes

The study was designed to determine whether active treatment with antioxidants and/or zinc could reduce the risk of progression to advanced AMD and loss of visual acuity

Patients 55 to 80 years of age (N=3640) were randomized to 1 of 4 treatments

Placebo

Antioxidants (500 mg vitamin C, 400 IU vitamin E, and 15 mg beta carotene

Zinc 80 mg as zinc oxide with 2 mg of copper as cupric oxide (copper was added to prevent potential anemia)

Antioxidants plus zinc

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.

AREDS Rate to Advanced AMD With Supplements Data are shown for the probability of progression to advanced AMD in ≥1 eye in

patients with intermediate AMD in the 4 treatment groups: placebo, antioxidants, zinc, or antioxidants plus zinc and advanced monocular AMD (category 3 and 4)

Patients on antioxidants plus zinc had nearly 30% lower risk of progression to wet AMD than patients on placebo

The probabilities of progression to advanced AMD within 5 years in each group were

Placebo: 28%

Antioxidants: 23%

Zinc: 22%

Antioxidants plus zinc: 20%

AREDS2 was a follow-up study on AREDS and looked at a modified AREDS formulation with a lower dose of zinc (80 – 25mg) and eliminating beta-carotene as well seeing if zeaxanthine, lutein, and omega3 fatty acids were of any benefit.

Omega-3 fatty acids supplements had no effect on AMD progression. Lutein/zeaxanthin did demonstrate reduction of risk of AMD progression.

There were no differences in risk of AMD progression with elimination of beta-carotene or lowering the zinc dose.

Management of Patients With Early AMD Management of early AMD focuses on lifestyle intervention measures

and regular eye examinations to monitor for signs of disease progression.

Smoking is one of the most consistent risk factors for AMD. Therefore, patients with early AMD should be encouraged to stop smoking.

Specific recommendations for comprehensive medical eye evaluations from the Preferred Practice Patterns Committee are every 2 to 4 years for patients between ages 40 and 64 and every 1 to 2 years for patients ≥ 65 years.

The use of antioxidant vitamins and minerals was not shown in the Age-Related Eye Disease Study (AREDS) to reduce the progression of early AMD to intermediate AMD. Thus, there is currently no evidence to support the use of vitamin supplementation for patients who have less than intermediate AMD. However, physicians may want to consider the use of a multivitamin.

Preferred Practice Patterns Committee. Age-Related Macular Degeneration. Limited Revision. American Academy of Ophthalmology Retina Panel, 2005.

Management of Patients With Intermediate AMD

Patients with intermediate AMD should be educated about methods of detecting new symptoms of CNV, including regular self-monitoring and prompt notification to an ophthalmologist who can confirm signs of disease progression.

These patients should receive ophthalmic re-examinations every 6 to 24 months, with fundus photography as appropriate and fluorescein angiography if edema or other signs of CNV are evident.

In AREDS, the combination of antioxidant vitamins and zinc significantly reduced the rate of losing visual acuity and the rate of development of advanced AMD by about 25% in patients with intermediate and advanced AMD.2 Supplementation as recommended in the AREDS is thus recommended for patients with intermediate AMD.

1. Preferred Practice Patterns Committee. Age-Related Macular Degeneration. Limited Revision. American Academy of Ophthalmology Retina Panel, 2005.

2. Age-Related Eye Disease Study Research Group. Arch Ophthalmol. 2001;119:1417-1436. 3. Preferential Hyperactivity Perimetry Research Group. Ophthalmology. 2005;112:1759-1766.

Next we will discuss the more exciting treatment options, available for wet AMD.

Until recently, neovascular AMD treatments could, at best, slow the loss of VA in AMD patients. Today, however, the treatment landscape has changed significantly.

But let�s review quickly the evolution of AMD treatment over the last 2 decades.

The first treatment for neovascular AMD was laser photocoagulation in the early 1980s. Its efficacy was first demonstrated in a randomized clinical trial with the Senile Macular Degeneration Study, published in 1982.

In the late 1990s, the TAP study demonstrated that the light-activated drug verteporfin—used with a nonthermal laser—could slow VA loss in patients with predominantly classic lesions.

The VISON trials demonstrated that the intravitreally administered anti-VEGF treatment Macugen slowed VA loss compared to sham-treated patients.

The MARINA and ANCHOR trials demonstrated that Lucentis, an anti-VEGF antibody, is effective for maintaining and even restoring VA in some patients.

Finally, the VIEW trials have demonstrated that aflibercept is essentially as effective as monthly Lucentis

Laser photocoagulation involved destroying the CNV membrane with a thermal laser. This is currently only rarely used, and only for lesions that do not involve the fovea.

Photodynamic therapy was a significant advance, that used a dye given through the vein that allowed the laser to target the neovascular tissue with minimal collateral damage to the retina.

These are images of fluorescein angiography that demonstrate the effect of PDT.

PCT was a definite advance. This graphs shows LESS vision loss over time in patients treated with PDT than those who were not. However, patients still lost vision.

The discovery of a molecule called vascular endothelial growth factor (VEGF) was a major breakthrough. This molecule acts like fertilizer for growing blood vessels, including CNV membranes. Following its discovery, medications that counteract its effect were developed, including Lucentis (ranibizumab), Avastin (bevacizumab), Macugen (pegaptanib), and Eylea (aflibercept). These medications can be injected directly into the eye and are the current standard of care for wet AMD.

These images show a fluorescein angiogram and OCT of a patient before and after Lucentis injection. Note the substantial leakage and retinal swelling in the images on the left, and reduction in the images on the right.

MARINA and ANCHOR were the pivotal studies that showed the amazing effect of these medications over two years for wet AMD patients. For the first time, patients were actually gaining vision. We saw that on average the sham-treated patients lost 10.4 letters by month 12 and 14.9 letters by month 24. The Lucentis treatment group demonstrated significant average vision gains - 7.2 letters by month 12, an increase that was sustained at 6.6 letters by month 24, resulting in an overall difference of 21.4 letters between the sham- and LUCENTIS-treated groups at month 24.

The injections in MARINA and ANCHOR were given monthly. PIER was a subsequent study that examined whether we could maintain the effect but only give the injection every 3 months.

Unfortunately, the answer was no. You can see that the lines for vision improve initially, but then fall.

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The PRONTO study showed that injections given “as needed” with signs of activity (that is, fluid on the OCT), were nearly as effective as mandated, monthly injections.

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This is a patient as baseline in the PRONTO study.

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These OCT images depict the subject�s response to Lucentis treatment. At the baseline treatment, the subject�s visual acuity was 20/200 and her foveal retinal thickness was 465 microns. One month later, the subject�s visual acuity had improved to 20/50 and her foveal retinal thickness had decreased to 258 microns. At the third monthly injection, the subject�s VA had improved further to 20/40 and her foveal retinal thickness had decreased to 172 microns. In November, 2 months after the last LUCENTIS injection, the subject�s VA had increased to 20/30 and her foveal retinal thickness was 219 microns. At this time, she declined further LUCENTIS injections despite a recommendation by the physician.

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Several months later, after the subject was hospitalized and not able to receive LUCENTIS injections, her visual acuity had declined to 20/400 and her foveal retinal thickness increased to 501 microns. At this time, she received another LUCENTIS injection. One month later, the subject�s visual acuity had increased to 20/50 and her foveal retinal thickness was 153 microns, at which time the subject received another LUCENTIS injection. Finally, approximately 6 weeks later, the subject�s VA had declined slightly to 20/80 and her foveal retinal thickness had increased to 316 microns.

Treat and extend is the newest treatment regimen. It is based on giving monthly injections until the fluid is completely gone, and then trying to slowly increase the time between injections by two weeks at each visit, as long as the patient stays dry. So, a patient might start at getting injections every 4 weeks until the fluid is gone, and once it is gone then coming back in 6 weeks for another injection. If the fluid is still gone at this 6 week timepoint the next visit is in 8 weeks, and so on. An injection is given at every visit, but the time between visits is varied based on the activity of the disease.

This is a series of OCT images from a patient demonstrating a potential course.

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This slide compares many of our recent studies on the VEGF inhibitor medications. You can see that patients tend to do quite well, with about 95% maintaining vision and 30-40% gaining a substantial amount of vision with treatment. This was never seen before the anti-VEGF medications.

These are some potential things to look forward to in the next few decades.

Treatment for AMD is a big market, and there are many medications being studies that promise more efficacy or a longer duration of action.

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People are looking at devices that we might implant into the eye that slowly release medication for a long period of time.

Other treatment options are being explored, including radiation therapy to the CNV membrane.

Just like cancer treatment, the best option is probably going to be a combination of different medications and modalities.

We still lack an effective treatment for dry AMD or geographic atrophy. The MAHALO study is looking at an oral medication that appears to slow the growth of GA.

We know that AMD is a complicated genetic disease and we can identify high-risk genes in individuals with genetic testing. This might help to identify those at high risk, as well help us to tailor treatment based on a patient’s genetic profile.

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Stem cells are also being actively explored, including cells that release healthy, growth factors from an implant.

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Believe it or not, we can grow retinas and eyes in the lab, but we do not know how to incorporate these in living tissue.

Another stem cell treatment is the implantation of cells that should release factors that prevent GA from progressing.

This shows the sophisticated system for implanting these cells.

This is an animation of that process in the actual lecture.

And this is a movie of that process in the actual lecture.

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We have a miniature telescope that can be implanted for patients with a large scar or GA in the macula, but there are very strict criteria for who can receive them.

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feel free to contact me with any questions at the above ... free to contact me with any questions at...

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