Understanding Age-Related Macular Degeneration

The Medical Practice of Ray M. Balyeat, MD: Limited to Medical & Surgical Management
of Diseases of the Macula, Retina & Vitreous

For patients and family members who desire a brief overview of AMD--read the black print;
for patients and family members who desire a more complete understanding of AMD--read
the black and the blue print

Age-related macular degeneration or "AMD" is the most common cause of blindness
in individuals over the age 65 years in North America, Western Europe and Australia.
The prevalence of this condition increases dramatically when evaluating the aging
American population by "decades of life". Often senior citizens and their children
comment “it seems as though AMD is becoming more common". Perhaps so, as the
ability of physicians to diagnose AMD has become easier and more sophisticated
and since Americans and Europeans are living longer. Since it is likely that
environmental factors such as high fat diets and cigarette smoking influence the
development of AMD, the number of affected individuals per age bracket may very
well be on the rise. The lay press' fascination with the reporting of AMD and AMD
research (regrettably inaccurately in many cases) also increases the feeling that
AMD used to be a rare condition but is now quite common.

(source: National Institutes of Health)

The retina is a multilayered structure th

lines the interior

the

eye. It has been

likened to film in the back of a

camera, a

somewhat inaccurate and overused

analogy

but still useful for

individuals unfamiliar with the anatomy

of the eye. The

center

of the retina is known as the

macula

; it is

located adjacent to

the optic nerve head.

macula

is oval in shape,

with its long

axis oriented

horizontally, and has an average

diameter of 5.5

millimeters, which

correspond

approximately

to the

central

degrees of

visual field. The central

portion of

the macula is

called the fovea and to varying degrees

(depending upon

the

individual) has a yellowish sheen.

The

yellow color of this zone

may be caused

by the

presence of

pigments (lutein and

zeathanthin). The

pinpoint center of the

macula (known to

ophthalmologists

and biologists as the

foveola) is only 150

microns in

thickness; beyond the foveola

the macula is still

only 200

to 275 microns.

The surface area of

the macula

represents about 15% of the total surface area of

the

retina.

The cells of the macula are specially "wired"

together to

provide us with the

ability to read and see

small

objects in great

detail. The remaining 85% of the

retina,

the

peripheral retina,

provides us with coarser

peripheral vision,

enhances our ability

to see in lower light

conditions and assists

the brain in the

prevention of

double

vision.

xternal to (or beneath) t

macula and

peripheral retina is a layer of pigmented

cells

called

the

retinal pigment epithelium or RPE. The RPE aids in

removal

of waste

material creating by the very active, high

energy

consuming retina.

External to (or beneath)

the

RPE

lies the

choroid, a

blood vessel network, which

presumably helps to

carry away

such waste materials and

to provide nutrients and

oxygen to

the RPE and to the

retina adjacent to the RPE. So, in

order to

understand

AMD, we have to consider

these three

anatomic

parts of

the eye: the macula (which also has many

"sub

layers

its own), the RPE and the

choroid. The retina,

the

RPE,

and the choroid are very thin, flat

structures that lie on

top

of each other like

layers of lasagna.

They represent the

inner lining of the eye. The center of the eye

filled with a

gel-

like substance called vitreous. The watch

crystal front

part of

the eye

is called the cornea. The iris (the

“colored”

part of the

eye) and the lens (behind the

iris

) work

with the

cornea to focus

light onto the macula. The macula and

peripheral

retina are

stimulated by light and send an

electrochemical impulse to the

brain via

the optic nerve.

As we get older all parts of our bodies age including the eye. The retina also ages
including the macula. Individuals don’t think about their retina getting older since
we can’t directly examine our own retinas. Skin of the aging face develops wrinkles;
hair turns gray, and the macula acquires spots called drusen. Drusen are tiny
yellowish white deposits located beneath the RPE and represent waste products
that have been incompletely degraded by the RPE. The appearance and thickness
of the RPE also change with advancing age. Drusen may gradually become more
numerous and larger; the RPE becomes more irregularly pigmented and thinner
(thinning of the RPE is called “geographic atrophy” by ophthalmologists) Lay
individuals refer to this process of multiplying drusen and altered pigmentation of
the RPE as ”dry” macular degeneration. (Ophthalmologists describe this condition
as “non-exudative” macular degeneration.) Ophthalmologists and medical
scientists know from many studies, particularly the Age-related Eye Disease Study
(AREDS) published in October, 2002, that as drusen become larger and more
numerous and as RPE atrophy progresses in severity, the following occurs:

•

he likelihood of the central vision loss from AMD substantially increases

•

he probability of developing “wet” AMD increases

Wet AMD arises as a complication of pre-existing dry macular degeneration. Many
lay people do not understand this. They think that AMD affected individuals lose
their vision from either dry AMD or from wet AMD. The vast majority of patients who
develop wet AMD had moderately severe or severe dry AMD before “going wet”.
Wet AMD usually implies that new, abnormal blood vessels (a condition
ophthalmologists call “choroidal neovascularization”—literally, new vessels arising
from the choroid) are present. In the early stages of wet or exudative AMD, a thin
layer of fluid forms beneath the macula usually accompanied by a small amount of
blood (see picture below: the fluid is shaded in yellow). It is at this stage that current
drug therapies and sometimes focal thermal laser treatment (photocoagulation) are
likely to be of greatest benefit. If treatment is delayed or ineffective, scar tissue forms
beneath the macula (submacular fibrosis) during the next 6 to 18 months. Once
submacular fibrosis has developed, loss of central vision is permanent.

Ophthalmologists also use the terms “neovascular” AMD or “exudative” AMD to
describe what lay people call wet AMD. About 1 in 6 patients who lose substantial
central vision to AMD do so because of the development of exudative AMD. Thus,
for patients with exudative or wet AMD, central vision loss is truly the summated
effect of pre-existing dry or non-exudative changes PLUS the effect of wet or
exudative changes.

Dry or non-exudative AMD may take decades to create measurable vision loss.
Patients are sometimes astounded to learn that the diagnosis of AMD is based upon
the presence of changes in the macula identifiable by examining physicians and not
based upon measured vision loss. Symptoms may not be present or may include
blurring, missing or “floating” letters when trying to read, blind spots within the
center of vision, and distortion. Patients with AMD often feel as though they need a
lot of light in order to read. As dry AMD progresses in severity, symptoms often
mimic those of wet AMD. Sometimes, patients with dry AMD may enjoy useful
central vision which suddenly deteriorates. More typically, the development of wet
AMD causes what patients describe as abrupt loss of central vision which
deteriorates over a matter of days to weeks. It is not unusual for patients in the early
stages of wet AMD to suddenly wake up with loss of central vision in an affected
eye. If their pre-existing dry AMD did not create significant loss of vision immediately
prior to the development of choroidal neovascularization, such individuals are
usually quite dismayed to discover that they have an advanced eye disease. Wet or
exudative AMD typically causes the development of a dark spot, sometimes a
darkish red spot, within the central field of vision. This symptom is usually
accompanied by distortion, i.e. “wavy lines”. With the passage of time, the dark spot
grows in size and depth. It is very important to understand that although AMD can
cause severe loss of central vision, only in very rare cases does AMD threaten loss
of all or nearly all vision. In other words, even severely affected AMD patients
typically maintain peripheral or “ambulatory” vision.

Most patients with AMD want to know why they have developed this condition. What
did they do wrong? Why me? Despite intense scientific investigation and the
discovery of many tantalizing clues as to why and how AMD develops in the human
eye, the fact remains that medical scientists and ophthalmologists do not know what
causes AMD. Actually, AMD is probably not a single disease entity (such as
Parkinson’s disease or Lou Gehrig’s disease) but rather a degenerative condition
influenced by more than 50 different genes and a number of environmental factors.
It is therefore hereditary. Individuals may inherit a single, a few, or many genes
which when defective place them at minimal or great risk for developing what looks
and behaves like AMD. Ophthalmologists have identified the following risk factors:

• Age itself is a risk factor for AMD. In fact, people between the ages of 65

and 74 have a 1-in-5 chance of developing the disease. Over the age of 75, the

chance increases to nearly 1-in-3.

• Studies have shown links between cigarette smoking and increased risk

of both wet and dry

AMD.

Current heavy smoking is associated with at

least a

fold increased risk of AMD with vision loss.

• As indicated above, family history appears to play a role in AMD.

Children

of affected individuals should be screened for AMD beginning around 50 years

of age.

• Some studies (not all) have suggested a link between exposure to

sunlight

and

age-related macular degeneration (AMD) and cataracts.

• AMD is somewhat more common in women than in men.

Caucasians are

more susceptible to AMD than are people of other races.

•

Poor nutrition can play a role in the development of a variety of eye

diseases. Population studies have demonstrated that diets rich in leafy green

vegetables and certain types of fish and low in cholesterol and

polyunsaturated fatty acids appear to be protective against the development of

AMD. It is not clear, however, whether or not a 70 year old patient with AMD can

significantly influence the progression of their condition by radically altering

their diet alone. Nevertheless, The Age-related Eye Disease Study (AREDS)

demonstrated a 25 to 30% reduction in the progression

moderately severe

non-exudative (dry) AMD to exudative (wet) AMD for patients

who took high

dose vitamins A, C, E and zinc during the

year life of the

study

Dr. Balyeat

recommends that his non-cigarette smoking patients with moderately severe

dry

AMD in one or both eyes use PreserVision Gelcaps, 2 by mouth daily

(Bausch & Lomb).

This study

did not demonstrate a protective benefit for

patients with no

or mild non-

exudative AMD during the life of the study.

Currently, there is no

indisputable

evidence that substances such as lutein,

Omega 3, or bilberry

offer any

protective benefit. However, lutein and Omega 3

saturated

fatty acid

are under

investigation in the AREDS II (which began

enrollment of

patients in

summer,

2006).

• Obesity has been linked to the progression of intermediate stage

AMD to

advanced AMD

• Elevated serum cholesterol levels have been shown to increase the risk of

AMD.

• Hypertension is also a risk factor associated with

wet

AMD.

Patients with moderately severe non-exudative AMD have a 10 to 50% risk of
developing severe AMD with potentially severe loss of vision over an 6 year time
frame. The terms "mild", "moderately severe" and "severe" to describe the
appearance of affected maculas were defined by the AREDS. Physicians who deal
with AMD patients should understand these definitions and know how to apply them
to their patients during counseling.

There is no known cure for AMD. Current treatment strategies aim to prevent or
control new blood vessel growth (choroidal neovascularization) beneath the
macula. If an AMD patient has vision loss attributable to a combination of dry AMD
features PLUS wet AMD features, suppressing their wet features will not completely
restore their central vision since there is no proven treatment strategy to reverse or
to prevent loss of central vision from dry AMD. There are some dry AMD treatment
strategies in early research stages but they are many years away from becoming
clinical reality as of the time of this writing. The treatment for wet AMD consists of
the following:

•

Focal thermal laser photocoagulation

for the rare patient who has a well-

defined choroidal neovascular lesion far enough away from the center of the

macula so that the laser induced scar will not preclude useful central vision

•

Macugen

(pegaptanib)

injections

. Macugen is a drug injected directly into

the central vitreous gel of the eye. It is given every 6 weeks for up to 2 years

depending upon the response of the patient. Macugen works by binding to

and inactivating vascular endothelial growth factor (VEGF). VEGF is a protein

present in wet AMD eyes. VEGF is critical in stimulating the growth of abnormal

blood vessels from the choroid which leak and cause fluid build-up beneath

the macula.

•

Lucentis

(ranibizumab) and

Avastin

(bevacizumab)

injections

. Lucentis

and Avastin are also injected into the central vitreous gel of the eye. They are

administered every 4 weeks for up to 1 to 2 years depending upon the

response of the patient.

Avastin

, an antibody,

and

Lucentis

, an antibody

fragment,

also work by

binding to and

inactivating VEGF. Their activity against

VEGF

ppears to be

more potent than

that of Macugen. Lucentis and Avastin

are both made by

Genentech, a

California based pharmaceutical company.

Lucentis and Avastin

are not the

same drug but act similarly against VEGF.

Lucentis is FDA

approved for use

inside the eye; Avastin is FDA approved to

treat colon and

breast cancer.

However, Avastin can be formulated by licensed

compounding

pharmacies

into a preparation for use inside the eye.

•

Visudyne

(verteporfin) and

photodynamic therapy (PDT)

. Visudyne is a

medication that is injected into the bloodstream and then “activated” using a

long wavelength (“infrared”) laser. PDT with Visudyne is performed on

average every 3 months for 12 to 18 months in order to maximize the effect of

this procedure. Strictly speaking, PDT with Visudyne is not “laser treatment for

AMD” but rather

drug therapy activated by a laser

. The infrared laser

energizes

the Visudyne molecules which bind to the abnormal blood vessels

growing

beneath the macula. In doing so, Visudyne injures these vessels

causing

microscopic blood clots. This causes the abnormal blood vessels

(choroidal

neovascular membranes) to shrink and leak less.

• Triamcinolone injections. Triamcinolone is a corticosteroid medication

that has been around for a long time. It is most commonly used as an adjunct

to treatment with Visudyne. Visudyne/PDT with triamcinolone injections in

number of

studies seems to produce better and longer lasting results

than

Visudyne alone

• Retaane (Anecortave Acetate) injections. This medication is not yet FDA

approved for clinical use outside monitored treatment trials. Early study

results, however, are encouraging. Retaane is injected behind the eye every 6

months. This drug may prove to be useful in preventing wet AMD in patients

who are at high risk for developing neovascular AMD.

At present ophthalmologists who treat AMD are trying to formulate treatment
strategies which will optimize the effect of the above mentioned drugs. Not all wet
AMD eyes are alike; some types of wet AMD may respond well to repeated treatment
with Visudyne, Macugen or Lucentis (or Avastin) and some types may respond best
to some form of combination therapy, e.g., Visudyne/PDT PLUS Lucentis (or
Avastin). Many patients ask “how long will treatment last or how many injections or
PDT sessions will I have to undergo?” Some individuals may respond quite well to
less than 9 Macugen or less than 12 Lucentis injections but may require repeated
injections at a later date should their wet AMD return. Some patients may develop
severe scarring beneath their macula (submacular fibrosis) while undergoing
therapy at which point further treatment may be inadvisable. Some patients may
literally require frequent and regularly scheduled injections and/or PDT sessions for
more than 2 years.

Patients with wet AMD should remember that laser photocoagulation, PDT and drug
injections are not curative and that improvement in vision from treatment may not
last owing to recurrent choroidal neovascularization or from progression in dry AMD
features. Patients with wet AMD should be encouraged to discuss the risks and
benefits of any treatment plan with their ophthalmologist.

October, 2006

*The specific daily amounts of antioxidants and zinc used by the AREDS study
researchers were 500 milligrams of vitamin C; 400 International Units of vitamin E; 15
milligrams of beta-carotene (often labeled as equivalent to 25,000 International Units
of vitamin A); 80 milligrams of zinc as zinc oxide; and two milligrams of copper as
cupric oxide. Copper was added to the AREDS formulations containing zinc to
prevent copper deficiency anemia, a condition associated with high levels of zinc
intake. Special note: patients who smoke cigarettes should avoid the use of high
dose vitamin A since smoking and vitamin A consumption has been linked to lung
cancer.

Prevalence of AMD in USA.pdf

What is Age-related Macular Degeneration (AMD)?

What Causes Age-related Macular Degeneration?

Treatment for AMD

Click to see data and chart in PDF:

Age-related Macular Degeneration (AMD)

The Basics and an Anatomy Lesson

retinal pigment epithelium (RPE)

choroid

abnormal new vessels beneath the RPE

(fluid beneath the macula in yellow)

color photo of a normal macula
(as viewed through the pupil)

cross sectional diagram of the eye

Watch a video animation of the time lapse development of AMD.
You may need a video program such as Quicktime by Apple to
view this animation. Note: the development of drusen (the yellow
spots, then the development of blood beneath the macula (in red)
and finally the development of scarring (submacular fibrosis).

Click to download
Quicktime by Apple:

Click "AMD Video":
(source: National Institutes of
Health)

(source: macula.org)

multiple cell layers of the retina
(photoreceptor cells in light purple)

choroidal vessels (the choroid)

RPE

Click to download Adobe
PDF Reader:

optic
nerve-
head

fovea

simple diagram of the macula cut in cross section
(front of the eye would be oriented toward the top of the page)

color photographs of maculae with AMD at various stages of development:

Moderately severe dry
AMD (the yellow spots
are called "drusen")

Moderately severe dry AMD
(the light colored patches are
areas of RPE degeneration, ie,
"geographic atrophy")

Severe dry AMD (note the many
drusen and geographic atrophy
in the central macula)

Wet or neovascular AMD (note
the subtle grayish green
discoloration in the central
macula and faint spot of blood)

Wet AMD with massive bleeding
beneath the entire macula (the
yellow spots are protein and
cholesterol deposits)

Advanced, chronic wet AMD (note
the yellowish gray area beneath
the macula--this is "submacular
fibrosis"--a scar)