Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity.
The Macular Disease Society (1) defined Age-Related Macular Degeneration (ARMD) as ''a primary disease of the Retinal Pigment Epithelium (RPE) with secondary degenerative effect upon the overlying retina and underlying choroidal vessel.'' Thus, it is a progressive disorder of the central part of the retina called the macula which leads to the gradual loss of central vision needed for reading, writing, driving, watching television, recognizing faces and doing other fine tasks (2, 3).
Macular degeneration develops differently in each person. Because it will affect regions of the macula differently from person to person, the symptoms tend to vary. Macular degeneration causes a progressive loss of central sight; however, it does not cause total blindness. Peripheral vision is unaffected, allowing a certain amount of mobility in normal surroundings.
The commonest early symptoms of ARMD include blurring of central vision. The person realizes that he/she needs more light than usual to read and perform other fine tasks. There is difficulty in recognizing faces unless they come closer (1, 2). A blind spot (scotoma) may appear in the center of the person's vision. This tends to increase as more rods and cones degenerate in the macular area. For wet ARMD, visual distortions / metamorphopsia would be the early sign and person starts perception of seeing the grid of straight lines as wavy, e.g. graph paper or the lines between wall tiles (1, 2). There is loss of color perception and contrast sensitivity, ability to trace colors and shadows. Specifically, there is difficulty in differentiating dark colors from dark colors and light ones from light ones (1, 2, 9). Then there is slow recovery of visual functions. This usually occurs after exposure to bright light (9).
Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden (4).
Globally, AMD ranks third as a cause of blindness after cataract and glaucoma. It is the primary cause in industrialized countries and in 2010 it was estimated to cost $340 billion to treat AMD. The costs are set to spiral over the next 20 years and really over burden the healthcare system unless people start to take preventative action.
ARMD can occur during the middle age but the risk increases with age. Studies show that people in their 50s have about 2% chance of developing ARMD, while those 60years and above, have 30% chance of getting it (2). Women are more at greater risk than men (1, 2). Significant vision loss accompanying more advanced forms of AMD increases from fewer than 1 percent among people in their 60s to more than 15 percent among people in their 90s, according to the Canadian Medical Association Journal (February 2004).
Age-related macular degeneration is the leading cause of legal blindness in people older than 55 years in the United States. Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the U.S. population, this number is expected to increase to almost 3 million by 2020. Because overall life expectancy continues to increase, age-related macular degeneration has become a major public-health concern.ARMD is emerging as one of the leading causes of blindness. Indeed, it is the leading cause of blindness in older North Americans, overtaking glaucoma and diabetic retinopathy combined. It has also been established as the leading cause of low vision in Americans (1, 5).
The Beaver Dam Eye Study has shown that 30%of individuals aged 75 and older have some form of ARMD, while 7%of those 75 and older have advanced form (6). Recent studies show that about 8million Americans are believed to be at risk of developing ARMD in the next five years, and 1.75million are currently affected with the advanced form of the disease (7,8) .Owing to the rapidly aging population, the number of persons having ARMD will increase by 50%to 2.95millionin 20207 .
In the United Kingdom, recent studies also show that ARMD is the commonest cause of severe visual impairment. About 1 in 100 people aged 65-75years and 1 in 8 people aged 85years and above, suffer from ARMD. The UK statistics also revealed that twice as many women over age of 75years suffer from ARMD compared to men of same age group (1).
And in Owerri, Nigeria, a recent clinic based survey revealed that 1 in 200 of the adult population aged 50years and above, suffer from one form of ARMD in one or both eye(s). The ratio of distribution was about 3 males to 4 females. The survey also showed that the older the person is, the more likely to develop ARMD. Out of Two thousand, four hundred and fifteen (2415) subjects aged 50 years and above, 6.90% of ARMD were seen in the 50-55 age-group, 13.03% in the 55-60, 18.01% in the 60-65, 27.20% in the 65-70 and 34.87% in the 70 and above age-groups The above clinical spectra may have been worse if this survey was conducted in a 'free-for service' rather than in a 'fee-for-service' clinic (6).
Macular degeneration, also called age-related macular degeneration (AMD or ARMD) or the now discarded term senile macular degeneration (SMD), describes a variety of pathologic but extremely common conditions that affect the macula (a portion of the retina of the eye) and, therefore, central vision.
The diagnosis of macular degeneration is becoming increasingly more common due to patient awareness, physician access, groundbreaking improvements in treatment, and the relentless graying of the population exponentially increases the percentage of the population at risk for this condition. Thus, macular degeneration is a formidable challenge to patients, their doctors, and the society as the costs for delivering state-of-the-art care increase.
Types of ARMD
There are two types, the Dry ARMD and the Wet ARMD. The Dry ARMD also known as the non- neovascular or non-exudative ARMD, is the commonest type and accounts for about 85-90%of all ARMD (2, 9). It is characterized by the gradual thinning, degeneration and eventual death of the Retinal Pigment Epithelium of the macula, leading to central visual loss as a result of the breakdown of the photoreceptors, the rods and cones (2, 9). The visual loss is gradual. About 20%of dry ARMD can progress to wet ARMD (1, 5, 9).Choroidal neovascularization (CNV), the underlying process causing wet AMD and abnormal blood vessel growth, is the body's misguided way of attempting to create a new network of blood vessels to supply more nutrients and oxygen to the eye's retina. Instead, the process creates scarring, leading to sometimes severe central vision loss.
Wet macular degeneration falls into two categories:
â€¢ Occult. New blood vessel growth beneath the retina is not as pronounced, and leakage is less evident in the occult CNV form of wet macular degeneration, which typically produces less severe vision loss.
â€¢ Classic. When blood vessel growth and scarring have very clear, delineated outlines observed beneath the retina, this type of wet AMD is known as classic CNV, usually producing more severe vision loss.
The wet ARMD, also known as the neovascular or exudative ARMD accounts forabout 10-15% of all cases of ARMD (2, 7). It is the most destructive and the onset can be very rapid. It causes loss of central vision within a short period of time (2, 9). Wet ARMD is caused by abnormal tiny blood vessels that grow in the choriocapillaris which break through the Bruch's membrane into the macular area, leading to blood and protein leakages below the macular. This ultimately results to irreversible damage to the photoreceptors of rods and cones. It is believed that the diseased (dead) retina stimulates the introduction of these new blood vessels in response to a decreased supply of nutrient and slow transport of wastes (2, 9). Ophthalmology Clinics of North America Journal reported in December 2003 that deteriorating, oxygen-starved cells within the retina likely help trigger neovascularization and accompanying damage in wet AMD. Neovascularization is activated by a protein called vascular endothelial growth factor (VEGF), targeted in macular degeneration treatments by anti-VEGF drugs.
Smokers are at risk 2-3 times compared to non-smokers. Smoking lowers the serum antioxidant level in the blood leading to nutritional deficiency at the cellular level. Passive smoking is equally just as bad (1, 2).Smoking is a major AMD risk factor and was found in one British study to be directly associated with about 25 percent of AMD cases causing severe vision loss. The British Journal of Ophthalmology in early 2006 also reported study findings showing that people living with a smoker double their risk of developing AMD.
ARMD is not a straightforward hereditary condition as some families may be affected while others may not. The lifetime risk of developing late-stage ARMD is 50% for people whose relatives have macular degeneration and 12% for people whose relatives do not have macular degeneration. In addition, people whoserelatives have late-stage ARMD also run the risk of developing the disease at a relatively young age (2,10).Columbia University Medical Center and other investigators found that variants of another gene complement factor B may be involved in development of AMD. Specific variants of one or both of these genes, which play a role in the body's immune responses, have been found in 74 percent of AMD patients who were studied. Also, variants of complement factor C3 have been associated with increased risk of developing AMD.Duke University and other researchers have noted a strong association between development of AMD and presence of a variant of a gene known as complement factor H (CFH). This gene deficiency is associated with almost half of all potentially blinding cases of macular degeneration.Recent studies have found that specific variants of different genes are present in most people who have macular degeneration. Studies of fraternal and identical twins may also demonstrate that heredity is a factor in who develops AMD and how severe it becomes.
Yellowish spots (Drusen) that form in the back of the eye or retina are an early sign of "dry" macular degeneration.Drusens are similar in molecular composition to plaques and deposits seen in other age-related diseases such as Alzheimer's disease and Atherosclerosis (11, 12). While Drusen deposits may be present in the retina without any visual loss, it has however been blamed for progressive loss of vision. Though the exact role of Drusen in the pathogenesis of ARMD is still unclear, it is believed that the lipid content of Drusen and its diffuse accumulation in the Bruch's membrane of the retina may be responsible for this loss of vision (7, 9). Recent researches suggest that large and soft Drusen are related to elevated cholesterol deposits (9).
Obese and people with elevated levels of blood cholesterol may be at higher risk (7). Obesity and syndrome X, or metabolic syndrome, are also associated with the condition. Sleep apnea may be associated with macular degeneration independent of the obesity risk factor.Overweight patients with macular degeneration had more than double the risk of developing advanced forms of macular degeneration compared with people of normal body weight, according to one study reported in Archives of Ophthalmology (June 2003). In the same study, those who performed vigorous activity at least three times weekly reduced their risk of developing advanced AMD, compared with inactive patients.
People who stay outdoors in the summer sun for more than 5 hours a day in both their teens and 30s are twofold more likely to develop early macular degeneration. Blue light and ultra violet rays have also been reported to increase macular degeneration (9,13). A small study reported in the British Journal of Ophthalmology (January 2006) found no correlation between the eye disease and sun exposure. No conclusive evidence as yet has linked excessive sun exposure to development of AMD.
People whose blood pressure was about 160/95 before being controlled and those with uncontrolled blood pressure of 160/95 and above, are at risk of developing wet macular degeneration two and three times respectively, compared with people with normal blood pressure. A high pulse pressure has also been associated with wet macular degeneration (1,2).Investigative Ophthalmology and Vision Science Journal reported the results of a European study demonstrating that high blood pressure may be associated with development of macular degeneration (September 2003).
Whites are much more at risk than Blacks (1). A small study in UK found no relation at all between lighter eye color, hair color and AMD. That finding is contradicted by several earlier studies indicating that lighter skin and eyes are associated with a greater prevalence of AMD.Because macular degeneration long has been thought to occur more often among Caucasian populations, particularly in people with light skin color and eye color, some researchers theorized that the extra pigment found in darker eyes was a protective factor against development of the eye disease during sun exposure.
Researchers at Singapore Eye Research Institute (SINGAPORE, June 2010) have found that, contrary to previous findings, Asians may be just as likely to develop age-related macular degeneration (AMD) as Caucasians. The researchers analyzed results of nine studies of populations in Japan, China, South Korea, India and Singapore and found that of people aged 40 to 79, 6.8 percent had early-stage AMD and .56 percent had late-stage, vs. 8.8 percent and .59 percent of Caucasians. The wet form of AMD was more prevalent in Asians with late-stage AMD than in Caucasians with late-stage. Asian men were more at risk for late AMD than Caucasian men and much more likely than Asian women to develop a late-stage form. Lead researcher Tien Yi Won, MD, MPH, PhD, said that further studies would need to determine whether there is such a thing as "Asian" forms of AMD. He added that many Asian men smoke, but the analysis could not include an adjustment for this known AMD risk factor.
Age-related accumulation of low-molecular-weight phototoxic, pro-toxic melanin oligomers within the lysosomes in the retinal pigment epithelium are suspected of decreasing the digestive rate of photoreceptors of the outer rod segments leading to lipofusion formation associated with macular degeneration (9). These include Macular degeneration gene, Stargardt's disease (Juvenile macular degeneration), and Fibulin-5 mutation among others (9).
Some medications like Fosamax for osteoporosis may predispose to macular degeneration. Some cases of macular degeneration can be induced from side effects of toxic drugs such as Aralen (chloroquine, an anti-malarial drug) or phenothiazine. Phenothiazine is a class of anti-psychotic drugs, including brand names of Thorazine (chlorpromazine, which also is used to treat nausea, vomiting and persistent hiccups), Mellaril (thioridazine), Prolixin (fluphenazine), Trilafon (perphenazine) and Stelazine (trifluoperazine).
High degrees of myopia may be associated with age-related macular degeneration or a similar condition called myopic degeneration. Family history is perhaps the most important risk factor other than age.
Taking Aspirin Frequently May Increase Macular Degeneration Risk. Astudy(AMSTERDAM, November 2011) calculated the odds ratio for age-related macular degeneration (AMD) based on frequency of aspirin use and found that AMD odds rose in people who took aspirin more often. For 4,691 people age 65 and older, researchers determined the presence of AMD and the frequency of low-dose aspirin use in the group.Early AMD and wet late AMD were associated with frequent aspirin use, and the odds of having these forms of AMD rose along with the frequency. In other words, those who took aspirin daily had greater odds for AMD than those who took it weekly or monthly.No reason was found for the odds increase. Also a study (January 2013) has found that regularly taking aspirin increases the risk of neovascular age-related macular degeneration (AMD).The study, led by Barbara E. K. Klein, MD, MPH, of the University Of Wisconsin School Of Medicine and Public Health, analyzed data from the Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin.Nearly 5,000 people participated at the baseline examination, ranging in age from 43 to 86. Examinations were performed every five years over 20 years, and participants were asked if they had regularly used aspirin at least twice a week for more than three months. The average duration of follow-up was 14.8 years.Over the course of the study, there were 512 cases of early AMD and 117 cases of late-stage AMD. The researchers found that regular aspirin use 10 years before the retinal examination was associated with late AMD (1.8 percent for aspirin users and 1.0 percent for non-users).One subtype of late AMD, neovascular AMD, had a significant association with aspirin use: 1.4 percent of aspirin users had neovascular AMD compared with 0.6 percent for non-users. There was no significant association for early AMD or geographic atrophy, the other subtype of late AMD.The findings of the study were found consistent with a small but statistically significant association between regular aspirin use and incidence of neovascular AMD, the research authors concluded.However, if further studies confirm the Beaver Dam Eye Study findings led by Dr. Klein, developing ways to slow the effect, especially for people who use aspirin to help prevent cardiovascular disease, will be of particular importance in the study and treatment of neovascular AMD.On another front, a previous study actually found a correlation between aspirin usage and a lack of AMD in women. The study report appeared online in September in Ophthalmology. No final conclusion has been reached on that, and further studies are being performed.
The American Academy of Ophthalmology notes that findings regarding AMD and risk factors have been contradictory, depending on the study. The only risk factors consistently found in studies to be associated with the eye disease are aging and smoking.
ARMD is usually detected during eye examination that involves (i) Visual acuity test (ii) Amsler grid test (iii) Dilated fundoscopy (iv) Fluorescein Angiography.Amsler Grid is a pattern of intersecting lines identical to a graph paper but with a black or red dot at the center. The central spot is the fixation point. For a normal eye, all lines surrounding the spot will look straight and evenly spaced. In the presence of any macular disease, the lines will look bent, distorted and or missing.
Dilated Fundoscopy may reveal any of the followings:
(a) Hard drusen- which are small, round, discrete, yellowish-white spots. Patients with hard drusen are at risk of developing geographic atrophy.
(b) Soft drusen- usually larger than hard drusen has indistinct edges. They increase the risk of developing exudative ARMD.
(c) Mixed drusen- refers to the eye with both hard and soft drusen.
(d) Calcified drusen- is a drusen with glistening appearance as a result of dystrophic calcification. They are usually associated with hard drusen.
(e) Basal laminar (nodular) Drusens- are innumerable, small, uniformly sized, discrete, round, slightly raised, sub-retinal lesions, and common in younger people.
If signs of macular degeneration are found, an ophthalmologist may take detailed pictures of the retina for future comparison. Tests may also include:
â€¢ Fluorescein Fundus Angiography (FFA): A special, extremely safe dye called fluorescein is injected into the arm. Then, an ophthalmologist or professional ophthalmic technician or photographer photographs the retina as the dye passes through the retina. This test determines the location of blood vessel or vascular damage and whether or not laser treatment could be potentially beneficial.Fluorescein angiography is essential to pinpoint the exact location of any planned laser treatment. Most importantly, this test determines whether or not there are leaking blood vessels (wet macular degeneration) which, if found, can be treated with lasers or injections.
â€¢ Indocyanine Green Fundus Angiography (ICG): This test uses a different intravenous dye coupled with infrared wavelength photography to view the retina. The test may help to identify signs and types of wet macular degeneration that cannot be seen with fluorescein angiography.
â€¢ Optical Coherence Tomography (OCT): This is a noninvasive examination technique that produces a cross-sectional image of the posterior retina in vivo. Although this method is now widely applied in the diagnosis of various macular disorders, its role in evaluation and follow-up of patients with age-related macular degeneration is only now becoming better established. OCT is particularly useful in determining the specific layers of retinal involvement as well as the presence of macular inflammation or swelling.
â€¢ Microperimetry using the Rodenstock scanning laser ophthalmoscope: This is used to quantify macular sensitivity and fixation pattern.
â€¢ Visual field testing or perimetry precisely tracks the location of lost or deficient retinal function. This important test requires reasonable patient cooperation and understanding. It is useful in a wide variety of conditions including glaucoma, macular degeneration, nerve problems, and other retinal problems.
In general, people older than 45 years should have a complete eye examination and then follow-up examinations every two years. People with age-related macular degeneration should check their vision daily or weekly with an Amsler grid and promptly notify their ophthalmologist of any changes in their vision. Timely treatment of early wet age-related macular degeneration can prevent further vision loss.
Smoking cessation is recommended for everyone in order to prevent or slow the progression of retinal disease. This is important for other ocular conditions as well including dry eye, cataract, diabetic retinopathy, and glaucoma. People with advanced irreversible age-related macular degeneration may benefit from low-vision aids.
People should be encouraged to use the remaining peripheral vision that is unaffected by the macular degeneration. An extremely useful standardized test that may indicate macular problems or worsening of age-related macular degeneration is the Amsler grid.
Presently, there is no known cure for dry ARMD, apart from taking dietary supplements. For wet ARMD, treatment may halt or delay the progression of vision loss. Indeed, most recent treatment regimens approved by the National Eye Institute (NEI) in USA seem to be able to reverse some of the visual losses caused by wet ARMD.
â€¢ Antioxidants: Deficiencies in antioxidants (specifically zinc and vitamins A, C, and E, selenium, copper, lutein, and zeaxanthine) have been noted in some people with age-related macular degeneration. Antioxidants may protect against age-related macular degeneration by preventing free radicals or unstable oxygen from damaging the retina.In a landmark prospective, randomized, controlled, masked national study conducted by the National Institutes of Health (NHS) and the National Eye Institute (NIH), people with moderate and advanced age-related macular degeneration were shown to have a significant benefit with regard to disease progression and preservation of visual acuity by taking dietary supplements containing high-dose antioxidants and zinc. This study, called the AREDS (age-related eye disease study), was the first ever to prove that dietary supplements can alter the natural progression and complications of a disease state.
The wet form of age-related macular degeneration is more likely than the dry form to cause significant vision loss. Different treatments of the wet form are available and may help decrease the amount of vision that is lost.
â€¢ Laser treatment: Clinical trials have demonstrated the value of laser treatment for some people with the wet form. Laser treatment may stop or lessen vision loss in early stages of the disease. It is performed with a specific wavelength designed to cauterize the abnormal blood vessels. Argon and krypton lasers are most commonly used for treating macular degeneration (1, 2, 8).A laser beam destroys existing blood vessels and may stop the growth of new ones. A scar forms after the laser treatment. This produces a permanent loss of vision in that area of the retina, sacrificed in order to preserve the rest of the eye layer. This is analogous to chopping down living trees in the path of a forest fire in order to stop the continued inevitable spread of that fire.Vision usually does not improve after laser treatment. It works in about half the cases, and only a small number of people meet the criteria for laser treatment. Its limitations have prompted a search for other forms of therapy.
â€¢ Photodynamic therapy: In April 2000, the U.S. Food and Drug Administration (FDA) approved this treatment. A light-activated drug called verteporfin (Visudyne) is given intravenously, and a specially designed laser is used to close the abnormal vessels while leaving the retina intact. The patient may need several treatments over one to two years because closed blood vessels can reopen within the treated area. Because Verteporfin is activated by light, exposure to sunlight must be avoided for five days after treatment. This laser treatment is vastly different from standard Argon laser treatment in that a broad beam of laser light covers the entire macula, while Argon laser treatment is precisely controlled by the ophthalmologist to cauterize specific leaking vessels under the biomicroscope (1, 2, 8).
â€¢ A variety of drugs that block vascular endothelial growth factor (VEGF) are being evaluated as a treatment option. These treatments for the first time have produced actual improvements in vision, rather than simply delaying or arresting the continued loss of vision characteristic of macular degeneration.
â€¢ Supplements: The AREDS researchers recommended that patients at risk of developing advanced age-related macular degeneration and those without contraindications, such as smoking, should consider taking antioxidant and zinc supplements. The AREDS formulation is specific and different from a regular daily multivitamin. Occuvite PreserVision (Bausch & Lomb), ICaps (Alcon), and Macular Protect Complete (Science Based Health) are some of the products that contain the AREDS formulation. Lower amounts of vitamin A should be used in patients who also smoke. Ophthalmologist should be consulted for the best recommendation.
â€¢ Anti-VEGF therapy: Vascular endothelial growth factor (VEGF) causes new blood vessels to develop and increases leakage and inflammation of blood vessels (1, 2, 8, 9). Most of these drugs are insoluble and therefore cannot be given as eye drops. Thus, the ideal form of administration is directly into the eye with a very fine needle. This can be safely accomplished through the pars plana, which is an accessible part of the eye without blood vessels about 3 millimeters behind the cornea. Thousands of these intravitreal injections are given every day in the United States with an outstanding efficacy and safety record. Nevertheless, these injection procedures are a form of surgical intervention and should be performed only by an ophthalmologist familiar with the technique, indications, contraindications, possible complications, and alternative therapies. Strict sterile protocols are necessary as with any surgical procedure.For example, out of the 716people treated in October, 2006 in New England with Ranibizumab, 9 in 10 people had slowed visual loss, while about a third had improved vision. The only limitation is that the injection could be painful. In addition, it has to be repeated monthly. The initial aim of treatment with Anti-VEGF was to prevent wet ARMD from getting worse. But this aim seems to have been surpassed, because in some cases these drugs have actually restored some of the vision that had earlier been lost.
â€¢ Surgery: A diversity of surgical treatments are being investigated for exudative age-related macular degeneration lesions that may not qualify for laser treatment, including macular translocation to a healthier area of the eye, displacement of sub-macular blood using gas, and removing membranes by surgery. Results of the Sub-macular Surgery Trial published in 2004 showed that surgery for hemorrhagic choroidal neovascular lesions did not increase the chance to stabilize or improve visual acuity, but it reduced the risk of severe vision loss.
â€¢ One of the more recent managements is the proton beam therapy. It is a good non invasive and pain less management of macular degeneration where by different doses of proton beam are given to patients with Wet macular degeneration. The follow up on visual stabilization and fluorescein angiography have been encouraging. The advantage of proton beam therapy is the ability to precisely localize the treatment to macula which is very sensitive. The other advantage to other therapies is the lateral damage to other tissues is minimal.
There have been several clinical trials where various doses of proton therapy have been applied to recruited patients and compared with controls. The results have been promising but certainly need much larger studies in different populations to see its benefit over other treatments. In most studies patients have been exposed to Therefore it would be critical to undertake a clinical trial in the middle east to see the results.