MACULAR DEGENERATION (AGE-RELATED)
OVERVIEW
Age-related macular degeneration (AMD) is a condition characterized by the
deterioration of the macula. Macular is derived from the Latin word, macula,
meaning spot. The macula is the central and most vital area of the retina,
providing the clearest, most distinct vision needed, for example, in seeing
fine detail, reading, driving, and recognizing facial features. There are two
forms of macular degeneration: atrophic (dry) and neovascular (wet). Both forms
of the disease may affect both eyes simultaneously. Vision can become severely
impaired, with central vision rather than peripheral vision affected. The ability
to see color is generally not affected, and total blindness from the condition
is rare.
EPIDEMIOLOGY AND GENETICS
Prevalence
AMD is the leading cause of irreversible visual impairment and blindness among
Americans 65 and older, affecting more Americans than cataracts and glaucoma
combined. Approximately 85-90% of the cases of AMD are the dry type. Although
atrophic AMD accounts for most of all diagnosed cases, neovascular AMD is responsible
for nearly 80-90% of significant visual disability associated with the disease.1 The
average age of onset of visual loss is 75 years, but after the age of 50 the
incidence steadily increases, with more than one third of people over the age
of 90 affected.2 The eye-health organization
Prevent Blindness America estimates that 13 million Americans have evidence
of macular degeneration, while the Macular Degeneration Partnership places
the number at closer to 15 million. It is equally common in men and women,
with a higher incidence in whites than blacks, and a heritable nature.3,4
Symptoms and Disease Progression
The atrophic (dry) type of macular degeneration progresses more slowly than
the neovascular (wet) type, with vision lost painlessly. In atrophic AMD, a
thinning of the macula may initially produce blurry vision or distortion, and
then in more advanced cases will result in blank spots in the central visual
field as the macula degenerates. Decreased reading ability, especially in dim
light, and difficulty in adapting to dim light and the dark are common symptoms.5 A
vision test sometimes reveals physical deterioration before symptoms occur.
The importance of early detection of atrophic AMD is due to a high risk of
developing the more debilitating neovascular AMD.6
In neovascular AMD, blood vessels below the retina undergo abnormal growth
into the retina underneath the macula. These newly formed blood vessels frequently
bleed, causing the macula to bulge or form a mound, often surrounded by small
hemorrhages and tissue scarring.7 The
results are a distortion in central vision and the appearance of dark spots.
While the progression of atrophic AMD may last for years, neovascular AMD can
progress in months or even weeks.8
Genetics
The extent to which heredity can be considered a part of the pathogenesis
of AMD is not clear but evidence points to a family of genes connected with
the disease.9,10 Nearly one fourth
of parents, siblings, and offspring of patients who have AMD manifest the disease
concurrently. Identical twins with AMD and common environmental and dietary
influences show a strikingly similar appearance and degree of visual loss (89-100%).
Fraternal twins reared in a shared environment show less visual loss (46%).11
ETIOLOGY AND MECHANISMS OF ACTION
General Causes
The causes of AMD are currently unknown. One theory postulates that abnormalities
in the enzymatic activity of aged retinal pigment epithelium (RPE) cells lead
to accumulation of metabolic byproducts. When the RPE cells become engorged,
their normal cellular metabolism is obstructed, resulting in extracellular
excretions that produce pigment deposits, i.e. drusen, and lead to neovascularization.12
A more recent theory suggests an alteration in the dynamics of the choroidal
blood circulation as an important pathophysiological mechanism. The choroid
is the system of blood vessels adjacent to the retina; the retina itself contains
no blood vessels. Blockages within the choroidal blood vessels lead to increased
ocular rigidity and decreased efficiency in the choroidal blood circulation
system. Specifically, the increased capillary resistance due to blockages causes
elevated hydrostatic pressure, resulting in release of proteins and lipids
extracellularly, basal deposits, primarily as drusen.13 Along
with drusen formation, there may be deterioration in the elastin and collagen
in Bruch’s membrane, i.e., the barrier between the retina and the choroid,
causing calcification and fragmentation. This, coupled with an increase in
vascular endothelial growth factor (VEGF), allows growth of choriocapillaries
into the retina that have passed through the fractured Bruch’s membrane.14
The deposition of drusen is generally believed to be the precursor lesion
for AMD when they are “soft” or “indistinct” (>=
63 µm). Small drusen (< 63 µm) are extremely common with approximately
80% of the general population over 30 manifesting at least one. With age, there
is an increase in the number of drusen and the amount of confluence of drusen,
i.e., aggregation. After the age of 70, 26% of individuals have soft drusen
and 17% have confluent drusen.15
Contributing Causes
Cigarette Smoking
It is widely believed that cigarette smoking is associated with AMD. Cigarette
smoking among women increases the risk of macular degeneration by 2.4-fold.
Those who quit smoking still have a twofold increased risk. Among those who
quit smoking for 15 years, little reduction in risk was shown. Cigarette smoking
is an independent and avoidable risk factor for age-related macular degeneration
among women.16
Oxidative Stress
Oxidative stress that reduces blood flow to the eye and increases the level
of free radicals is a contributing factor to both wet and dry macular degeneration.
This occurs when naturally occurring antioxidants are present in decreased
concentrations. Diminished levels of glutathione occur during aging, which
makes the lens nucleus susceptible to oxidative stress-induced clouding.17 Decreased
vitamin C, normally highly concentrated in the aqueous humor and corneal epithelium,
is less effective in helping absorb ultraviolet radiation and preventing cataracts
than when present in high concentration.18 Deficiencies
in L-carnosine and vitamin E also mitigate oxidative stress and free-radical
damage.
Inflammation
Retinal pigment epithelium (RPE) and, possibly, choriocapillary injury and
inflammation lead to formation of an abnormal extracellular matrix, which causes
an altered and abnormal diffusion of nutrients to the retina and RPE, possibly
precipitating further RPE and retinal damage.19
Phototoxicity
Another risk factor for AMD is phototoxicity caused by exposure to blue and
ultraviolet radiation which adversely affects the functioning of RPE cells.
Blue light irradiation destabilizes certain membrane structures in RPE cells.20 Exposure
to sunlight without protective sunglasses is a risk factor for AMD.
Arterial Hypertension
Men with a history of hypertension are at greater risk for developing AMD.21 However,
prolonged treatment of hypertension with a thiazide diuretic was associated
with a more significant incidence of neovascular AMD.22
Nutrient Deficiencies
Deficiencies in the carotenoids, lutein, and zeaxanthin, are linked to AMD.
Lutein and zeaxanthin are present in the retina and positively affect macular
pigment density. Lutein and zeaxanthin are important in the prevention of AMD
by maintaining denser macular pigment; this results in less retinal tearing
or degeneration.23 The therapeutic
efficacy of lutein and zeaxanthin in AMD is significant according to the Lutein
Antioxidant Supplementation Trial (LAST) that showed improvement in several
symptoms accompanying AMD.24
High Fat Intake
Higher intake of specific types of fat—including vegetable, monounsaturated,
polyunsaturated fats, and linoleic acid—rather than total fat intake
are associated with a greater risk for advanced AMD. Conversely, diets high
in omega-3 fatty acids and fish reduced the risk for AMD when intake of linoleic
acid was low.25
ANATOMY AND PHYSIOLOGY (STRUCTURE AND FUNCTION)
The Retina and Choroid
The retina is the innermost layer of the eye and is comparable to the film
inside of a camera. It is composed of nerve tissue which senses light entering
the eye. This complex system of nerves sends impulses through the optic nerve
to the brain, which translates these messages into images that we see. (We “see” with
our brains; our eyes merely collect the information to do so.)26
The retina is composed of numerous layers (10 in all), including (from the
innermost layer next to the vitreous humor) nerve cells that connect the eye
to the optic nerve and brain, the cones and rods which contain photoreceptors,
and a retinal pigment epithelium (RPE) layer. Beneath the RPE are another four
layers: closest to the RPE is Bruch’s membrane which separates the RPE
from the choroid; then the choroid itself which is made up of a system of blood
vessels and pigment cells. There are two layers of the choroid: the tiny capillaries
closer to the RPE, called the choriocapillaris, and the larger blood vessels.
Outside the choroid is the sclera, the white part of the eye.27
In the central part of the retina is the macula. The macula is predominated
by cone cells containing photoreceptors most sensitive to light, color, and
visual detail. The other type of photoreceptors, the rods, is found on the
periphery of the macula, with many occupying the space outside of the macula.
The rods detect motion, dim, and night light.13
Visual Pathways
Light entering the eye is converged first by the cornea, then by the crystalline
lens. The light rays intersect at a point just behind the lens (inside the
vitreous humor) and diverge from that point back to the retina. The diverging
light passes through 9 (clear) layers of the retina and, ideally, is brought
into focus in an upside-down image on the first (outermost) retinal layer (pigmented
epithelium). The image is reflected back onto the adjacent second layer, where
the rods and cones are located. Rods and cones actually face away from incoming
light, which passes by these photoreceptors before being reflected back onto
them. Light causes a chemical reaction with “iodopsin” in cones
and with “rhodopsin” in rods, beginning the visual process that
continues by transmission through nerve cells complexes to the optic nerve
and the brain.13,26
PATHOPHYSIOLOGY
The pathophysiological mechanisms causing AMD are not well understood. Normal
aging results in changes in the macula including a reduction in light-sensitive
cone and rod cells (photoreceptors) and granules of pigment in the retinal
pigment epithelium (RPE).29 The pigment
granules of the RPE absorb incoming light and reflect it back to the cones
and rods. Progression of these processes is more rapid and severe in AMD than
in healthy eyes and usually is accompanied by increased waste products in the
RPE that adversely affect the retina. The barrier between the retina and choroid,
known as Bruch’s membrane, which is normally elastic, becomes laden with
debris deposited from the adjacent RPE. This causes a fragile and fractured
Bruch’s membrane, due to its inability to assimilate incoming debris.7
These pathophysiological changes result in production of larger and less well-demarcated
drusen; the pigmented deposits occurring under the macula. These larger drusen
are in contrast to the smaller and better demarcated drusen found in healthy
eyes of people over 30. Large drusen
(>= 63µm) are characteristic of atrophic AMD in which this drusen
causes thinning of macular tissue, experienced as blurry or distorted vision
with possible blank spots in central vision.15
Changes in the retina can result in abnormal growth of very tiny blood vessels
in the choroid, known as choriocapillaries, which grow into the retina underneath
the macula. This process of choroidal neovascularization, is the essential
mark of more severe and debilitating neovascular AMD, in which abnormal bulges
appear in the macula due to the ingrowth of blood vessels in the retina. The
condition frequently worsens because these blood vessels leak and form scar
tissue.29 Neovascular AMD is characterized
by distorted vision because the normally smooth macula becomes bumpy and contains
blank spots in central vision. The onset can be very rapid compared to atrophic
AMD and more debilitating, with almost complete loss of central vision in some
cases.12
The underlying pathophysiological changes of AMD may be a breakdown in normal
enzymatic activity of aging retinal pigment epithelium (RPE) cells or dysfunction
of the choroidal vascular system that results in increased ocular rigidity
and decreased efficiency in the choroidal blood circulation. The aging eye
may fail to break down and remove old proteins which accumulate and crosslink
forming glycation end products.30 The
deterioration of macular cones is a possible underlying cause for AMD.31
PHARMACOLOGY
There is little that can be done within conventional medicine to restore lost
eyesight with either form of the disease.
Hydergine
Hydergine is a mild vasodilator used to stimulate mental functioning shown
effective in treating dry macular degeneration in doses of 4-5 mg per day and
higher.32
Thalidomide
Several new antiangiogenesis drugs that inhibit neovacularization have been
developed that demonstrate the beneficial effects of thalidomide and prednisolone.
Thalidomide, in particular, may be the most promising in counteracting the
progression of neovascularization in wet AMD patients by inhibiting VEGF.33 It
is legal for doctors to prescribe thalidomide to treat wet macular degeneration
even though it is only officially approved and indicated to treat leprosy.
Thalidomide causes severe birth defects and must not be used by pregnant women
or women who may become pregnant.
Current AMD Treatments
Laser Photocoagulation
Laser photocoagulation (LP) is effective in the treatment of eyes with exudative
disease; but has not worked well on atrophic AMD due to the development of
neovascularization. LP is limited to the treatment of well-defined, or "classic," subretinal
neovascularization; present in only 15 percent of those with exudative disease.34 Most
patients have subretinal neovascularization that is "occult" (i.e.,
covered by blood or thick subretinal fluid). In eligible eyes, LP can reduce
the risk of further vision loss, but it does not restore lost vision. After
successful treatment of bleeding vessels, choroidal neovascularization can
recur and cause further vision loss.7
Photodynamic Therapy
Photodynamic therapy is the newer and more widely preferred treatment that
takes advantage of certain unique properties of subretinal neovascular vessels.
Compared with normal blood vessels, neovascular tissue appears to retain the
dye used in photodynamic therapy. After dye has been injected in a peripheral
vein, it is "excited" with laser light. This activated dye then forms
reactive free radicals that close down the leaky subretinal vessels. Because
normal retinal vessels retain very little dye, the abnormal subretinal vessels
are selectively "damaged."35
In some studies, one dye, verteporfin (Visudyne) was shown to preserve vision
in a significant number of patients with the wet form of AMD. Researchers have
reported that Visudyne has prevented vision loss in 61% of wet AMD patients
receiving it in experimental trials.36 Visudyne
therapy is approved for the treatment of classic subforeal choroidal neovascularization
(CNV) lesions. The lesion size must measure less than 5400 mcm at the time
of treatment.37
Experimental Surgery
Subretinal surgery and macular translocation are two experimental surgical
procedures currently being investigated for the treatment of age-related macular
degeneration. Subretinal surgery is performed to remove abnormal subretinal
neovascularization in patients with exudative disease. In macular translocation
surgery, the macula is surgically detached and moved from a more diseased area
of retinal pigment epithelium to a less diseased area. The success rates for
these surgical procedures are unknown.7
NUTRITIONAL THERAPY
Recommended Foods
Foods Containing Lutein and Zeaxanthin
The phytochemicals that protect against wet macular degeneration are lutein
and zeaxanthin.38-43 Lutein is a
pigment found in dark green leafy vegetables, including spinach, kale, broccoli,
and collard greens. Zeaxanthin is found in fruits and vegetables with yellow
hues such as corn, peaches, persimmons, and mangoes.
Due to the fact that lutein and zeaxanthin have the tissue-specific characteristic
of all carotenoids, their natural tendency is to concentrate in the macula
and retina. Consumption of foods rich in these substances is especially important
because they have a direct effect on macular pigment density. The denser the
pigment, the less likely a retinal tear or degeneration will occur. Some improvement
has been seen in subjects after only one month of supplementation.23,43
Soy
Soy contains the phytochemical genistein that has antiangiogenesis properties.44 This
property of inhibiting blood vessel growth is important in limiting abnormal
ingrowth of choroidal blood vessels. Those with neovascular macular degeneration
may take two Ultra Soy Extract capsules 2 times per day to obtain enough genistein
to possibly inhibit blood vessel growth in the eye.
Oily Fish
Oily fish like salmon, tuna, and mackerel are important sources of omega-3
fatty acids essential for protection against macular degeneration and other
diseases.25,45 More frequent consumption
of fish protects against late age-related macular degeneration. The greatest
benefit was seen in those who ate one serving a week; more fish did not offer
more protection.45 |