Download to view and/or an annotated lecture on macular

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email address.
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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.
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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.
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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.
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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.
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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.
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This is a scanning electron micrograph of the RPE and adjacent
photoreceptors.
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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.
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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.
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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.
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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 AgeRelated 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.
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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.
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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
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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
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The picture on the left show what small, diffuse drusen look like on
exam.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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
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.
Page 25
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.
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.
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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
Page 27
Bressler NM. Early detection and treatment of neovascular age-related macular degeneration. J Am Board Fam Pract.
2002;15:142-152.
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 lowvision 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.
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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
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.
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9. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol.
1997;123:199-206.
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.
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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.
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%
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,
Page 33 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, placebocontrolled 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
Page 34
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%
Age-Related Eye Disease Study Research Group. A randomized,
placebo-controlled, clinical trial of high-dose
Page 35
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.
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.
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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.
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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,
Page
38 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
Page Group.
39 Ophthalmology. 2005;112:1759-1766.
Next we will discuss the more exciting treatment options, available for
wet AMD.
Page 40
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
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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.
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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.
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These are images of fluorescein angiography that demonstrate the effect
of PDT.
Page 45
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.
Page 46
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.
Page 47
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.
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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 shamtreated 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.
Page 49
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.
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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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52
This is a patient as baseline in the PRONTO study.
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53
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.
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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.
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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.
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These are some potential things to look forward to in the next few
decades.
Page 61
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.
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Other treatment options are being
explored, including radiation
therapy to the CNV membrane.
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Just like cancer treatment, the best option is probably going to be a
combination of different medications and modalities.
Page 65
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.
Page 66
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.
Page 67
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.
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Another stem cell treatment is the implantation of cells that should
release factors that prevent GA from progressing.
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This shows the sophisticated system for implanting these cells.
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This is an animation of that process in the actual lecture.
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And this is a movie of that process in the actual lecture.
Page 73
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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This%is%a%picture%of%the%telescope%in%a%pa1ent’s%eye.%
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75!
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The%telescope%minimized%the%blind%spot,%and%can%enable%be:er%vision.%
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