Macular Degeneration (Age-related)

OVERVIEW

Age-related macular degeneration (AMD) is a condition characterized by the deterioration of the macula portion of the eye. 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 in reading, driving, seeing fine detail, and recognizing facial features, for example. 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. More Americans are affected by AMD than are affected by cataracts and glaucoma combined. Approximately 85–90% of the cases of AMD are the dry type. Although atrophic AMD accounts for most 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 in blacks, and has 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; 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. Early detection of atrophic AMD is important to stave off the more debilitating neovascular AMD.6

In neovascular AMD, blood vessels below the retina undergo abnormal growth into the retina beneath 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 take place over years, neovascular AMD can progress in mere months or even weeks.8

Genetics
Research has shown that age-related macular degeneration is a disease with multiple risk factors. Studies of families with age-related macular degeneration showed some genetic component and inheritance pattern to the disease.9,10 Identical twins with age-related macular degeneration 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

Recently, research has identified a gene responsible for age-related macular degeneration.69-71 This genetic abnormality is present in approximately 50% of patients with age-related macular degeneration. The responsible genes affect the body’s ability to suppress inflammation. The specific defect is of the “complement system” of the inflammatory pathway. This defect allows the body to mount an abnormally exuberant inflammatory response, especially in the retina. Over many years, inflammation is thought to cause damage and degeneration to the retina, thereby affecting vision.

Currently, there is no widely available test for this gene mutation. Nevertheless, genetic testing may become available in the near future.

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—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 the release of proteins and lipids extracellularly, forming 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 choroids—causing calcification and fragmentation. This, coupled with an increase in vascular endothelial growth factor (VEGF), allows the growth of choriocapillaries into the retina that have passed through the fractured Bruch’s membrane.14

The depositing 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. As one ages, there is an increase in the number of drusen and the amount of confluence of drusen—i.e., aggregation. After age 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 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 the 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 Prolonged treatment of hypertension with a thiazide diuretic, however, was associated with a more significant incidence of neovascular AMD.22

Nutrient Deficiencies Deficiencies in the carotenoids lutein, zeaxanthin, and meso-zeaxanthin are linked to AMD. Lutein, zeaxanthin, and meso-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), which showed improvement in several symptoms accompanying AMD.24

High Fat Intake Higher intake of specific types of fat rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid (an omega-6) was low.25

ANATOMY AND PHYSIOLOGY (STRUCTURE AND FUNCTION)

The Retina and the Choroid
The retina is the innermost layer of the eye and is comparable to the film inside a camera. It is composed of nerve tissue that senses light entering the eye. This complex system of nerves sends impulses through the optic nerve to the brain, which translates these messages into the images 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 the brain, the cones and rods that 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 choriocapillaries, 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 made up predominantly 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 the macula. The rods detect motion as well as 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 nine (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-cell 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 the 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—one unable 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 the abnormal growth of very tiny blood vessels in the choroid, known as choriocapillaries, which grow into the retina beneath 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 because of the growth 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: The normally smooth macula becomes bumpy and contains blank spots in central vision. The onset can be very rapid compared with atrophic AMD, and more debilitating, with almost the 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 that accumulate and crosslink, forming glycation end-products.30 The deterioration of macular cones is a possible underlying cause for AMD.31

PHARMACOLOGY

Historically, there has been little within conventional medicine to restore eyesight lost to either form of the disease. Several new therapies are showing promise, however.

Hydergine
Hydergine is a mild vasodilator used to stimulate mental functioning and 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 neovascularization 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.

Anti-VEGF Medications: Macugen®, Lucentis®, and Avastin®
Anti-VEGF medications are a new treatment for wet macular degeneration. VEGF is an acronym for vascular endothelial growth factor. VEGF is a small molecule that acts as a signal to cause human cells to act in certain ways. There are many types of VEGF molecules normally found in the human body. VEGF’s main role is to induce new blood vessel formation. It also functions to increase inflammation and cause fluid to leak out of blood vessels. In wet macular degeneration, VEGF stimulates the formation of abnormal blood vessels in the macular area of the retina. These blood vessels are abnormally porous and can bleed, which can lead to loss of vision.

All the anti-VEGF medications work in a similar fashion. They chemically bind to and inhibit (or prevent) the biologic activity of VEGF. By preventing VEGF’s action, they effectively reduce and prevent the formation of abnormal blood vessels. They also reduce the amount of leakage and therefore reduce swelling in the macula. These actions lead to preservation of the vision in patients with macular degeneration.

There are three types of anti-VEGF medications currently being used. The first agent is called pegaptanib, or Macugen®. It selectively binds to a specific type of VEGF called VEGF 165, one of the dangerous forms of VEGF.72 Macugen® has been approved by the Food and Drug Administration (FDA) for treatment of wet AMD. It is administered via intraocular injection given every six weeks.

Lucentis®, or ranibizumab, is also FDA-approved for the treatment of wet macular degeneration. As opposed to Macugen®, Lucentis® inhibits all forms of VEGF. Lucentis® is administered via monthly intraocular injection.

A third anti-VEGF agent currently in use is Avastin®, or bevacizumab. Avastin® is chemically similar to Lucentis® and works via the same mechanism to inhibit all forms of VEGF. This drug is commonly used but is not approved by the FDA. The cost of Avastin® is approximately 90% less than the other two agents. There is a clinical trial underway sponsored by the National Eye Institute. This study is evaluating the safety and efficacy of Avastin® over against Lucentis®. The results will not be available for years.

Untreated, most patients with wet macular degeneration will get worse and lose their central vision.73 Although the mechanisms of action of the anti-VEGF agents are similar, the success rates between the treatments vary. Macugen® was the first anti-VEGF treatment on the market. Macugen® was shown to allow patients a better chance of keeping their vision. Seventy percent of patients taking Macugen® did not have further severe visual loss.73 In other words, Macugen® patients were found to lose less vision. Macugen® has not been found to improve vision.

Lucentis® improved on the results of Macugen®. Ninety-five percent of Lucentis® patients kept their vision, and nearly 40% of Lucentis® patients improved. Forty percent of patients completed one year of treatment with vision of 20/40 or better.74

Avastin® has not been as thoroughly investigated as either Lucentis® or Macugen®.75 Many retina specialists believe that Avastin®’s efficacy parallels that of Lucentis®.76 Rigorous clinical trials for Avastin® are underway and are being performed by the National Eye Institute.

Lucentis®, Macugen®, and Avastin® are all administered by intraocular injection—in other words, these medications are injected directly into the eye. The injections are given after the surface of the eye has been cleansed and sterilized. Some doctors will give antibiotic drops prior to the injection. Some form of anesthesia is usually administered. This can be given in the form of drops or as a very small injection of anesthetic around the eye. The actual injection takes a few seconds.

Possible adverse effects of intraocular injections occur at a rate of fewer than 1 per 100 injections.74 When adverse effects occur, however, they can be very serious and sight-threatening. One possible adverse reaction is a serious eye infection known as endophthalmitis. Other possible complications are a retinal detachment and the development of a cataract. High ocular pressure usually follows the injection but generally resolves within the hour.

It is rare to have a systemic side effect after an intraocular injection. Yet there is some evidence that there may be a slight increased risk of a stroke after Lucentis® injections.77 Further data is currently being collected and analyzed. Unlike Macugen® and Lucentis®, Avastin® has not had extensive formal testing for side effects and complications.

From a patient’s point of view, it is very important to understand certain concepts of wet macular degeneration and its treatment in order to be able to discuss a therapeutic plan with his or her doctor. A specific treatment plan should be tailored to each patient’s needs and disease activity. Review all the treatment options for wet macular degeneration: conventional laser, photodynamic therapy, and anti-VEGF treatments. Each treatment has a different risk/benefit profile. Some of the treatments can be used in combination to produce an effect greater than an individual treatment alone.78 The anti-VEGF treatments have been a breakthrough in terms of better outcomes for patients with wet macular degeneration.

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 neovascularization. LP is limited to the treatment of well-defined, or "classic," subretinal neovascularization; present in only 15% 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 the 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

Surgery Subretinal surgery has been attempted for age-related macular degeneration. Some surgeries were geared toward the removal of blood and the subretinal neovascular membrane. Another type of surgery tried to physically displace the macula and move it onto a bed of healthier tissue. Overall, research studies show that the results of surgery are disappointing.79 Vision has generally not improved after surgery.80 Additionally, the frequency and severity of surgical complications were generally thought to be unacceptably high.