Age-Related Macular Degeneration:

From One Medical Student to Another

Introduction
Age-Related Macular Degeneration (AMD) is the most common cause of blindness in the Western
world. Currently it is estimated that about 2 million Americans are affected by AMD and by the year
2020 it is projected to be closer to 3 million as life expectancy increases and the aging population
expands.[1] This is a critical issue involving a significant proportion of the elderly, as vision is essential
for maintaining independence and quality of life. A decline in visual acuity increases the risk for falls
and depression, both of which are significant sources of morbidity and mortality in the geriatric
population.
Risk factors for AMD include increasing age, smoking, family history, and race. AMD is rarely found
in individuals younger than 50 and has been reported in 30% of Americans over the age of 85.[1] A
family history of AMD does confer an increased risk, which is typically multifactorial in nature.
Polymorphisms in the complement factor H (CFH) gene, HTRA/ARMS2, and at other loci have been
shown to confer an increased risk of AMD among Caucasians.[2,3] CFH acts as an inhibitor of
complement, and this polymorphism is thought to weaken its ability to down-regulate complement
activity. This permits continued inflammation and pathogenic degeneration of the macula.[2] AMD is
most common in Caucasians; Hispanics and Asians have an increased prevalence compared to African
Americans.[ 1] Smoking is the most significant modifiable risk factor and cessation should be
encouraged at each visit to prevent continued vision loss. While current smokers are 2-4 times more
likely to be affected by AMD than nonsmokers of the same age, those who are smoke-free for 20 years
may decrease their risk of AMD to that of a non-smoker.[4] Other speculated risk factors for AMD
include obesity, hypertension, hyperlipidemia, hyperopia, light iris color, female gender, cardiovascular
disease, and nutritional deficiencies.[2,3]

Anatomy
The retina is the light-sensing portion of the eye, and is composed of different cell types arranged in
layers. The cell layers are described as inner and outer laminae in regards to where they are located
relative to the center of the eye. The photoreceptors comprise the outermost layer of the retina and are
located above the retinal pigment epithelium (RPE). The RPE is responsible for maintaining the
extracellular matrix and the activity of the photoreceptors. Beneath the RPE is Bruchs membrane,
which maintains the blood-ocular barrier. Bruchs membrane is composed of a central elastin core
sandwiched between layers of collagen. The choriocapillaris, the innermost layer of the choroid, lies
directly beneath Bruchs membrane and supplies most of the blood or oxygen to the outer one-third of
the retina. It also helps remove waste created from the photoreceptors and RPE activity. The short
posterior ciliary arteries supply the choriocapillaris. Together, the RPE, Bruchs membrane, and
choriocapillaris (Figure 1) maintain the health and function of the overlying photoreceptors and thus,
support vision.[5]
Figure 1. Diagram representing the layers of the eye important in AMD, with inner layers (nearer the center of
the eye) at the top and outer layers at the bottom.

The central retinal artery supplies blood to the inner two-thirds of the retina and enters the eye with the
optic nerve. These are the artery branches visible on the fundus exam. After entering the eye the artery
branches into a superior and an inferior arch that surrounds the macula.
The macula is the area of the retina that is responsible for central vision. It is used to do things such as
threading a needle, reading fine print, recognizing faces, and watching TV. In a normal exam, the fovea,
located at the center of the macula, appears to be darker than the surrounding retina (Figure 2).

Figure 2. Healthy fundus photograph of the right eye.

Classification
AMD can be classified as dry (a.k.a. atrophic or non-neovascular) or wet (a.k.a. neovascular or
exudative) form. Most cases of AMD are dry (80%) while the remaining 20% of cases are considered
wet. However, wet AMD accounts for 90% of cases with advanced stage disease and severe vision
loss.[5] The symptoms and treatments differ between classes and therefore will be described separately
in the following sections.
Dry AMD is identified on exam by diffuse or localized drusen and geographic atrophy. Geographic
atrophy can be defined as a loss of RPE and photoreceptors that appear as a well-demarcated yellowish
area often with choroidal vessels more evident on exam and symptomatically produce scotomas. Wet
AMD, by contrast, features newly-formed vessels known as choroidal neovascular membranes
(CNV). Similar to neovascularization that occurs in diabetic retinopathy, CNVs are immature and
leaky. Consequences of neovascularization include subretinal fluid, lipid deposition, hemorrhage,
pigment epithelial detachment (in which fluid separates the RPE from Bruchs membrane), and fibrotic
scarring all of which cause vision changes or loss.
The Age-Related Eye Disease Study (AREDS) defined categories based on the exam findings of drusen,
atrophy, and neovascularization; these categories are defined below.[3,6]
 No AMD: fewer than 5 small (<63 microns) drusen
Mild AMD: Multiple small drusen or some intermediate sized (63-124 microns) drusen.
Intermediate AMD: extensive intermediate sized drusen, more than one large (>125 microns)
drusen, or non-central geographic atrophy.
Advanced AMD: Central geographic atrophy or neovascularization causing vision loss (visual
acuity worse than 20/32) in one eye.

When estimating the size of funduscopic findings it is helpful to know that the average optic disc (optic
nerve head) is about 1500 microns in diameter and a vein width near the disc is about 120-150
microns. Therefore, a druse with a diameter the same width as a vein near the disc is considered large.

Pathophysiology
Basics
The macula is specifically affected in AMD and hence there is a loss of central and fine detailed
vision. The surrounding retina is mostly spared and therefore peripheral vision is generally intact.
Drusen are the clinical hallmarks of AMD and are typically the earliest exam finding. They are deposits,
comprised of extracellular matrix and inflammatory components (e.g. complement) located in Bruchs
membrane. Drusen appear pale and yellow and they can be categorized as hard or soft based on
appearance. Hard drusen are small, well-demarcated lesions and can be seen in the healthy, aging
population. Soft drusen are large and appear cotton-ball like (Figure 3). They are generally pathologic
and are not found in young, healthy populations.[7]

Figure 3. Fundus photograph of the right eye demonstrating hard and soft drusen.

The pathogenesis of AMD is not completely clear. Scientists feel that AMD is likely a pathological
extension of normal aging that occurs within the eye. It does not appear that there is one mechanism that
causes AMD, but that it stems from a collection of complex processes that combine to create the disease
state with age. However, it is clear that both genetics and the environment play a role in the
pathogenesis.

Advanced Discussion of Pathophysiology

Bruchs membrane plays a critical role in the pathogenesis of AMD. In young, healthy eyes, Bruchs
membrane functions as a structural support that is permeable to fluid and small molecules, such as
oxygen and glucose. It also acts as a barrier against neovascularization by containing molecules in the
elastin layer that are anti-angiogenic. As the RPE functions on a daily basis it creates vascular
endothelial growth factor (VEGF) that can pass through Bruchs membrane to the
choriocapillaris. However, the anti-angiogenic molecules within Bruchs membrane prevent growth of
neovascular capillaries from the choroid thus helping prevent wet AMD.
As we age, Bruchs membrane tends to accumulate debris in the elastin lamina and also drusen between
the collagen layer and RPE basal lamina. This debris accumulation causes a reduction in the
permeability of Bruchs membrane. This will hinder the pumping of waste from inside to outside of the
eye by the RPE and may cause pigment epithelial detachments. In addition, atrophy, as seen in dry
AMD, is thought to be caused by excess material deposited in Bruchs, thus hindering the connection to
the choroid for vascular supply and removal of waste.[8]
Aging is also associated with thinning and breakdown of the central elastin layer within Bruchs
membrane. Thinning of this layer increases the risk of neovascularization as it reduces the number of
bound anti-angiogenic proteins. In addition, elastin breakdown products (elastin-derived proteins) are
themselves angiogenic. Therefore, breakdown of elastin in Bruchs membrane not only causes a
reduction in the barrier to neovascularization, but also stimulates vessel growth.

Symptoms
Dry macular degeneration may initially be asymptomatic, or may present as blurred vision, decreased
contrast perception, difficulty adjusting from bright to dim lighting, or the need for brighter lighting or
more magnification when reading. Central scotomas (visual field defects) are present in the advanced
stage of non-neovascular age-related macular degeneration. These symptoms usually progress slowly,
over months to years.[2,3]
Wet macular degeneration may have symptoms of metamorphopsia (straight, linear objects appear wavy
or distorted) or central scotomas. Symptoms usually present as a sudden decline in vision and progress
rapidly over days to weeks.[2,3]

Examination/Testing
Amsler Grid
The Amsler grid is a pictorial tool used to identify the presence of metamorphopsia or scotomas. Dry
AMD may or may not have changes in visual acuity, while wet AMD is more likely to cause sudden
changes in visual acuity. However, both types can have changes on the Amsler grid. The grid can be
rechecked and recorded at each visit to help determine progression. A grid should also be given to each
patient for detection of changes at home, with instructions to check each eye separately. The earlier the
changes are detected, the higher the likelihood that a CNV can be detected at a treatable stage.[3]

Fundus exam
Small, hard drusen and larger soft drusen within the macula are characteristic of dry AMD. Atrophy of
the RPE may also be present and appears as a well-demarcated area of yellowing within the retina with
easy visualization of the choroidal vessels[3] (Figure 4). Drusen are also present in cases of wet AMD,
but CNV are inherent. Hemorrhage or subretinal fluid may also be visible (figure 5). CNV appear as a
well-demarcated graying of the retina.[3]
Figure 4. Fundus photograph of the left eye demonstrating geographic atrophy and drusen.

Figure 5. Fundus photograph of the left eye demonstrating subretinal hemorrhage in the presence of wet
AMD.

Fluorescein angiogram (FA)

This test entails the injection of fluorescein dye intravenously and the use of special filters on a fundus
camera to capture the fluorescent properties of the dye. Serial photos are taken over several minutes as
the choroid and retina are supplied with blood marked by the dye. An FA can demonstrate slow filling
of the choroid or retinal vessels (increased transit time), window defects caused by loss of RPE
(hyperfluorescence), blood vessel leakage (hyperfluorescence), or blocking lesions
(hypofluorescence).[9] An FA is indicated when an AMD patient complains of new metamorphopsia,
unexplained blurred vision, and/or when clinical exam reveals elevation of the retina, subretinal
hemorrhage, or hard exudates.[5] The results from the FA are mostly used to guide treatment, with
either lasers or intravitreal injections, and less so for diagnosis.
A patient with dry AMD and atrophy will have a window defect on FA. This window defect is from the
RPE atrophy that allows the fluorescence from perfusion of the choroid to show through, without the
RPE blocking the fluorescence from the camera. Therefore, this appears as an area of
hyperfluorescence. Drusen may appear as areas of punctate hyperfluorescence.[3]
Wet AMD may show leakage from CNV (hyperfluorescence) and/or blocking lesions from a subretinal
hemorrhage (Figure 6). Subretinal hemorrhage blocks the fluorescence of the choroid from the camera,
thus appearing black or hypofluorescent.[3]
Figure 6. Fluorescein angiogram photograph of the patient in Figure 5, demonstrating hypofluorescence of the
subretinal hemorrhage and hyperfluorescence of the leaky CNV.

Optical coherence tomography (OCT)

Geographic atrophy is demonstrated on OCT as an absence of the RPE layer and increased signal deep
to the RPE relative to adjacent areas where the RPE is intact. Drusen may be visible as elevations at the
level of the RPE[3] (Figure 7). OCT is used to determine if there is blood or fluid beneath the retina
(subretinal) or within the retinal layers (intraretinal). Fluid appears as black gaps or elevations and is
indicative of wet AMD. OCT is often used to determine if retreatment with anti-VEGF injections is
necessary or in cases where the fluorescein angiogram is equivocal.[3]

Figure 7. Optical coherence tomography (OCT) image demonstrating geographic atrophy as discontinuity of
the RPE (a) and increased signal deep to the level of the RPE (b) relative to adjacent areas where the RPE is
intact. Drusen (c) appear as solid elevations from Bruchs membrane.

Treatment/Prevention
Dry AMD
There is currently no treatment for dry AMD; however, recent attention has been given to AREDS
vitamins, so named because of the formulation used in the AREDS trial. It is recommended that patients
with intermediate or advanced stages supplement with high doses of antioxidants and specific vitamins
(vitamin C, vitamin E, beta-carotene, zinc, and copper) to decrease the risk for conversion to wet
AMD.[6] However, current or former smokers are discouraged from taking high doses of beta-carotene
due to an increased risk of lung cancer.[6] There is a supplement formulation available for current
smokers or those who have smoked in the last 10-15 years that substitutes lutein for beta-
carotene. Patients with rare drusen, mild AMD, or a strong family history can supplement with lower
doses of vitamins and antioxidants, such as those found in over the counter multi-vitamin
preparations. Patients should be encouraged to use the Amsler grid every day and counseled on low
vision aids as needed.[3] Smoking cessation should also be discussed and assistance with quitting
provided if necessary.[5]

Wet AMD
Anti-VEGF intravitreal injections have become the first line of treatment for all forms and locations of
CNV, but especially for treating subfoveal locations, as these injections are less likely than laser
photocoagulation to cause damage to the retina and loss of central vision. Anti-VEGF agents include
pegaptanib sodium (Macugen), bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept
(Eylea).[2,3] Currently, pegaptanib sodium, ranibizumab, and afibercept are FDA-approved for treating
wet AMD. It was previously thought that ranibizumab was more effective than bevacizumab, but a
pivotal treatment trial demonstrated similar efficacy and safety between the two.[10]
Focal laser photocoagulation is an effective neovascularization treatment that now has limited utility in
the anti-VEGF era. Photocoagulation can result in permanent visual field defects as it essentially
involves burning CNV membranes and surrounding retina. Therefore, it is not recommended for CNV
located within the macula.[2,3] Some physicians choose to continue using this therapy in extrafoveal
lesions such as in peripapillary CNVs (those that lie within one disc diameter of the nerve
head). However, anti-VEGF treatments, such as bevacizumab, have been shown to be as effective in
extrafoveal lesions and may actually be the better treatment option.[11]
Photodynamic therapy (PDT) consists of injecting a dye (verteporfin) intravenously that tends to
concentrate in new blood vessels and is activated by a laser beam. Activation causes localized
thrombosis and resolution of the CNV, but does not improve vision loss, as it causes damage to the
retina.[2] PDT is FDA-approved for wet AMD, but has also been largely replaced by the anti-VEGF
treatments. However, it may be effective when used in combination with anti-VEGF agents for patients
who do not respond or no longer respond to anti-VEGF injections alone.[12]
Low vision aids are strongly recommended for patients with macular degeneration who struggle with
activities of daily living and smoking cessation should be discussed to reduce further vision loss.[5]

AREDS Summary[6,13]
The Age-Related Eye Disease Study was designed to address the following question: Does zinc and
antioxidant supplementation slow vision loss associated with increasing age, such as AMD and
cataracts? It was composed of a clinical trial for supplementation in AMD and another trial for
cataracts. For AMD, each participant was staged using the category system mentioned above (see
Classification). They were then randomly assigned to one of four daily oral tablet supplementation
groups (zinc alone, antioxidants alone, zinc plus antioxidants, or placebo). Overall, they found that
those patients with intermediate AMD or those with advanced AMD in only one eye had a 25% lower
risk of progressing to advanced AMD in one or both eyes, respectively, when treated with zinc plus
antioxidants. Patients categorized as having no or early AMD did not show a benefit with the high dose
supplementation.

The current components of the AREDS formulation are as follows:

o 500 milligrams (mg) of vitamin C
o 400 international units (IU) of vitamin E
 o 15 mg of beta-carotene (or 25,000 IU of vitamin A)
o 80 mg of zinc oxide
o 2 mg of copper (as cupric oxide) to prevent copper deficiency anemia from zinc
intake

Smoking is the most important modifiable risk factor to prevent/reduce morbidity from AMD, and
cessation should be emphasized in these patients. However, if they choose to continue or if they have
smoked in the last 10-15 years they should not have beta-carotene supplementation as it increases the
risk of lung cancer. There is a special AREDS vitamin formulation for these individuals.
There is preliminary evidence that omega-3 fatty acids or fish oil and lutein supplements may be of
benefit to reduce the incidence of wet AMD.* This is currently being studied as a clinical trial,
AREDS2, which is projected to have results announced in 2013.

*Note added in proof: Please read the AREDS2 study results which concluded that adding
omega-3 fatty acids did not improve a combination of nutritional supplements commonly
recommended for treating age-related macular degeneration. It also concluded that lutein and
zeaxanthin also had no overall effect on AMD when added to the combination; however, they
were safer than the related antioxidant beta-carotene. For more information about AREDS2,
visit www.nei.nih.gov/areds2/ and www.areds2.org. or the related article in JAMA.[14]

Injections
See the primer on the intravitreal injection technique used at the University of Iowa.

Related Web Resources

EyeSmart. What is Age-Related Macular Degeneration? American Academy of Ophthalmology.
National Eye Institute. Age-related Macular Degeneration. National Institutes of Health.

References
1. Friedman DS, O'Colmain BJ, Muoz B, et al. Prevalence of age-related macular degeneration in the
United States. Arch Ophthalmol. 2004;122:564-572.
2. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358:2606-
2617.
3. Friedman NJ, Kaiser PK. The Massachusetts Eye and Ear Infirmary Illustrated Manual of
Ophthalmology. 3 ed: Saunders Elsevier; 2009.
4. McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR. Risk factors for age-related
maculopathy: the Visual Impairment Project. Arch Ophthalmol. 2001;119:1455-1462.
5. American Academy of Ophthalmology. Age-Related Macular Degeneration, Preferred Practice
Pattern. 2008.
6. 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.
7. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch
Ophthalmol. 2004;122:598-614.
8. Mullins RF, Sohn EH. Bruchs Membrane: The Critical Boundary in Macular Degeneration. In:
Ying GS, ed. Age Related Macular Degeneration The Recent Advances in Basic Research and
Clinical Care: InTech; 2012:300.
9. Wilson F. Practical Ophthalmology: A Manual for Beginning Residents. San Francisco: American
Academy of Ophthalmology; 2005.
10. The CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related Macular
Degeneration. N Engl J Med. 2011;364(20):1897-1909.
11. Davis A, Folk J, Russell S, et al. Intravitreal bevacizumab for peripapillary choroidal neovascular
membranes. Archives of Ophthalmology. 2012;130(8):1073-1075.
12. Tozer K, Roller A, Folk J, et al. Addition of Photodynamic Therapy for Treatment of Neovascular
AMD Refractory to Anti-VEGF Agents. Accepted for publication to Ophthalmology (2013)
13. National Eye Institute. Age-Related Eye Disease Study Results:
Background. http://www.nei.nih.gov/amd/background.asp. Retrieved January 30, 2013.
14. The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein/Zeaxanthin for the
Treatment of Age-Related Cataract: AREDS2 Randomized Trial Report No. 4. JAMA Ophthalmol.
2013 May 5:1-7. doi: 10.1001/jamaophthalmol.2013.4412. [Epub ahead of print] PubMed PMID:
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