Risk factors associated with AMD include increasing age, cigarette smoking, and white race. Older age is the most significant risk factor with the prevalence of AMD increasing with age. According to the Beaver Dam Eye Study, 30% of patients age 75 years and older have some form of the disease.6 Smoking is the environmental factor that is most strongly associated with AMD, and has been demonstrated in many large population studies of white, Latino, and Asian patients.1 Smoking cigarettes increases the risk of atherosclerosis that can affect the choroidal vessels of the eye. Nicotine also promotes inflammation and angiogenesis through the upregulation of vascular endothelial growth factor (VEGF).5 Patients who smoke cigarettes are twice as likely to develop AMD as nonsmokers; if they quit, the risk remains elevated for 15 to 20 years after smoking cessation.5 Smokers who already suffer from AMD will have a much greater risk of developing advanced disease (geographic or wet AMD). Patients being treated for wet AMD with VEGF inhibitors also have demonstrated a poorer response to therapy when continuing to smoke.5 Although all ethnicities show an increase in AMD frequency with age, prevalence is highest in whites, followed by Asians and Hispanics, and lowest in blacks.7
Multiple other risk factors also have an association with AMD, with differing levels of evidence to support their significance in the development of disease: genetics, female sex, family history, high body mass index, cardiovascular disease, increased sunlight exposure, systemic inflammation, and low antioxidant levels.8
The retina undergoes many changes as part of the natural aging process. AMD is a complex disease characterized by pathologic changes in the retinal pigment epithelium and the Bruch membrane, the extracellular matrix that lies between the retinal pigment epithelium and the choroidal vasculature. The pathogenesis of AMD, especially geographic AMD, is not completely understood. However, evidence indicates that the key contributors to the development of disease include lipofuscin/drusen accumulation, chronic inflammation, oxidative damage, and mutations in the complement system.5
The retinal pigment epithelium supports the function of the retinal photoreceptor cells by removing metabolic wastes and transporting them through the Bruch membrane to the choroidal vasculature. As the retinal pigment epithelium cells age, they accumulate lipofuscin, which are products of incomplete metabolism of external segments of the photoreceptors. Structural changes also occur in the Bruch membrane, affecting its permeability. This leads to an accumulation of material (lipofuscin, A2-E) that deposits between the retinal pigment epithelium and Bruch membrane and eventually forms drusen.
Drusen are the focal yellow deposits of acellular debris that can be seen through an ophthalmoscope. Hard drusen commonly are associated with normal aging of the eye; soft drusen indicate increased risk and progression of AMD. Drusen play a role in inhibiting the transport of metabolites to the choroid vessels. These deposits and their molecular components also initiate inflammation through the complement cascade.9 This, in turn, damages the retinal pigment epithelium, photoreceptor cells, and choroidal vessels and may lead to geographic atrophy. Continued damage to the retinal pigment epithelium leads to further dysfunction of the Bruch membrane. In some patients, changes to the Bruch membrane are accompanied with a rise in VEGF, which results in the growth of new vessels under the retinal pigment epithelium and the retina. These new vessels are fragile and will leak and cause fluid buildup under the retina, resulting in detachment of cones and pigment cells and sudden vision loss. Eventually, the vessels involute and a disciform scar forms in the macula, characterizing the end stage of wet AMD.
Oxidative stress also appears to contribute to the development of AMD.10 Because of their complex metabolic processes, retinal tissues are among the most demanding tissues in terms of oxygen consumption. The macula is in a constant state of stress from light exposure and high oxygen consumption.10 For antioxidative processes to function correctly, patients need substantial amounts of vitamins (including vitamins C and E); minerals such as zinc, selenium, copper, and manganese; antioxidants such as glutathione; and carotenoids such as lutein and mezoxantine. Although studies about the protective effects of nutritional supplementation on the eyes have been ambiguous, researchers agree that patients with AMD are in a metabolically altered state of oxidation reduction and antioxidant supplementation is convenient and promotes health.5
The main genetic abnormalities associated with AMD occur in the genes that regulate inflammation, such as the complement factor H gene.1 Many complement factor H polymorphisms have been described in patients with both early and late AMD.9 Chronic subclinical local inflammation in the eyes can trigger or even sustain continual damaging processes. Many studies have investigated the role of genetic variants, such as the complement factor H gene and the age-related maculopathy susceptibility gene 2 (ARMS2), on the development and progression of AMD.11 While studies are ongoing, the genetics associated with AMD are very complex. The complement pathway continues to be considered a potential therapeutic target. The goal is to develop ways to enhance or disrupt the complement system at appropriate stages to prevent retinal damage.9
Although AMD is broken down into two types according to the pathophysiology, it also can be separated into three stages based on clinical manifestations: Patients with early and intermediate disease have dry AMD; those with advanced disease have progressed to geographic or wet AMD.
Patients in early-stage AMD usually are asymptomatic. When visual changes do occur, the patient most likely has intermediate to advanced disease. Early detection and referral to an ophthalmologist is critical to preserve vision because prompt treatment is associated with more successful outcomes in patients with wet AMD.8 For this reason, primary care providers should know the risk factors, clinical manifestations, and age groups affected by AMD.
The American Academy of Ophthalmology recommends the following frequency for comprehensive eye examinations in adults with no risk factors for AMD or signs of disease:
- Under age 40 years: every 5 to 10 years.
- Ages 40 to 54 years: every 2 to 4 years.
- Ages 55 to 64 years: every 1 to 3 years.
- Age 65 and older: every 1 to 2 years.12
Patients should have a comprehensive medical eye evaluation with an ophthalmologist at age 40 years if they have not previously had one.12 Occasionally patients with monocular visual loss are unaware of any deficits in their vision when sight in the contralateral eye is still good.8 Therefore, the proper administration of the Snellen examination may give evidence of any monocular vison loss. Symptomatic patients or those in whom risk factors have been identified merit closer follow-up, and decisions on the frequency of their visits should be made on an individual basis.12
Findings of macular drusen may be an incidental funduscopic finding that will prompt primary care providers to refer patients with significant risk factors to an ophthalmologist. The appearance of drusen alone does not indicate that a patient has or will develop AMD. Small hard drusen are a normal consequence of aging and can be found in most patients over age 50 years.
Patients with symptomatic dry AMD initially present with complaints of gradual onset of blurred vision in one or both eyes. They will describe having difficulties with activities that require fine visual acuity such as driving or reading. They may even talk about the need to use brighter lights or possibly need to use a magnifying lens for specific tasks. Patients also may describe the appearance of new scotomas in their vision.
Patients with wet AMD may present with complaints of an acute onset of visual distortion in one eye or complete loss of unilateral central vision, which occurs with a sudden subretinal hemorrhage. Disease usually already exists in both eyes, but most frequently only presents in one. Straight lines will appear wavy and distorted, a symptom referred to as metamorphopsia. Patients also may complain that the edges of windows or doors appear curved.
Obtain a thorough history of symptomatic patients to assess the onset of visual symptoms, whether one or both eyes are affected, and if the vision loss involves far vision, near vision, or both. The physical examination should include visual acuity, visual fields by confrontation, external eye and lid assessment, pupillary function, extraocular movement, and a funduscopic evaluation. All patients with visual loss should be referred to an ophthalmologist and timing of that referral is determined by the time frame in which symptoms have presented. Any sudden loss of vision (days up to a week) should be evaluated within 48 hours; visual changes occurring over weeks to months should be assessed nonurgently at the next available appointment.8
An ophthalmologist will perform a slit-lamp examination of the patient's retina to assess for drusen, abnormalities in the retinal pigment epithelium, geographic atrophy, choroidal neovascularization, subretinal fluid, and hemorrhage.
Early AMD is characterized by small drusen, few medium drusen, and minimal or no retinal pigment epithelial changes. Intermediate AMD is characterized by extensive medium drusen or one or more large drusen in one or both eyes. At this point, the patient is considered to be at risk for progression to advanced AMD.
Advanced AMD is defined as either progression to choroidal neovascularization or geographic atrophy involving the center of the macula. Examination will reveal focal atrophy of the retinal pigment epithelium over the macula in patients with geographic AMD. These patients also have cell death in the adjacent areas of the retinal pigment epithelium. In patients with wet AMD, new vessels from the choroidal or retinal circulation will be visible in the subretinal space, often with a collection of blood and/or fluid beneath the retina.
The diagnosis of AMD usually is made clinically based on the patient's history, symptoms, and confirmation with a dilated eye examination using a slit lamp. However, various imaging tests can be used to gain a better understanding of AMD and to monitor progress before and after therapy.
Optical coherence tomography (OCT) is a noninvasive imaging technique that provides high-resolution, cross-sectional images of the retina, retinal nerve fiber layer, and the optic nerve head.13 OCT has significantly improved the understanding of retinal diseases and can help differentiate AMD from other retinal disorders. Newer-generation OCT, including spectral domain OCT, can determine the presence of subretinal fluid and retinal thickening and is used to monitor progression and therapeutic responses to therapy in patients with wet AMD.2
Fluorescein angiography should be performed on patients suspected of having choroidal neovascularization based on symptoms or physical examination findings. This includes patients complaining of new metamorphopsia or unexplained blurred vision, those with findings of macular edema, subretinal blood, elevation of the retinal pigment epithelium on physical examination, or those with OCT-detected fluid. Patients being considered for treatment with either photodynamic therapy or laser photocoagulation should have angiography to guide therapy and to evaluate recurrences post-treatment. The dye is injected IV as a bolus and a sequence of photographs are taken. Newly formed choroidal vessels leak fluorescein; normal retinal vessels do not.2
Fundus autofluorescence is a newer imaging technique that can identify areas of geographic atrophy and can be used to monitor these areas for disease progression. This test also allows for identification of lipofuscin accumulation in the retinal pigment epithelium, a sign of cellular metabolism and aging.2
All patients with AMD should be educated about healthful lifestyle choices; including regular exercise; smoking cessation; wearing protective eyewear in the sun; and including fruits, vegetables, fish, and nuts in their diet. Providers also need to address patients' psychosocial needs because depression and anxiety may develop as a result of disability. Patients may benefit greatly from antidepressant medication, psychologic counseling, or referral to a support group. Once a patient's visual acuity has reached the point in which self-care becomes difficult, referral to a low-vision rehabilitation specialist becomes a vital part of their care.8 Primary care providers can monitor this on a regular basis.
No approved treatment exists for early AMD. Patients may be given an Amsler grid (Figure 1) to self-evaluate on a weekly basis for any changes in vision, such as missing areas of the grid or distorted/wavy lines. Providers also can ask patients to test their vision in each eye by regularly covering one eye at a time and reading, noting any new changes in vision. Follow-up should be arranged anywhere from 6 to 24 months, with the understanding that patients should return promptly if they experience any new symptoms.
Two benchmark studies sponsored by the National Institutes of Health, the Age-Related Eye Disease Study 1 and 2 (AREDS 1 and 2), provided evidence supporting the claim that nutritional supplements can reduce patients' risk of progression to advanced AMD.11 Based on the results from AREDS 1 and 2, patients with intermediate AMD, noncentral AMD, advanced AMD, or vision loss in one eye due to AMD are advised to take a combination of antioxidant supplements and zinc. Nonsmokers and former smokers can follow the regimen outlined in AREDS 1: vitamin C, vitamin E, beta-carotene, and zinc. AREDS 2 replaced beta-carotene with lutein and zeaxanthin with similar risk reduction. Smokers are advised to follow this regimen due to a heightened risk of lung cancer with beta-carotene supplementation. Patients should follow up with their ophthalmologist every 6 to 18 months or sooner if any new symptoms develop.
For patients with wet AMD, first-line therapy is intravitreal injections with VEGF inhibitors, which limit the destructive effects of neovascularization on retinal tissue. These injections can stabilize or possibly reverse vision loss.5 Large randomized clinical trials have found similar results in efficacy with the use of both ranibizumab and bevacizumab, the standard drugs of treatment.14 A newer medication, aflibercept, has had comparable results, but with a longer duration of action. Ranibizumab and bevacizumab are injected every 4 weeks and aflibercept every 8 weeks. Therapy should be initiated at the first signs and symptoms of neovascular disease. Any delay in therapy (more than 21 weeks) is associated with poorer vision outcomes.15
Photodynamic therapy typically is used in patients who fail to respond to initial treatment with VEGF inhibitors, and can be used alone or in combination with anti-VEGF medications. A photosensitizing dye is injected IV and a photoactivating laser is applied through the eye immediately afterward. Neovascular tissue retains more dye than other vessels; the dye forms reactive free radicals that damage the vascular endothelium and cause thrombosis of these new vessels. Unfortunately, vessels may reopen, which would necessitate repeat therapy. The use of photodynamic therapy has decreased significantly with the increased use of anti-VEGF therapy.
Thermal laser photocoagulation is a therapy that is rarely recommended.16 This treatment can cause vision loss due to enlargement of current scotoma or development of a new scotoma. Any use of this treatment should be limited to areas outside the macula.
Although treatment of dry AMD is lacking at this time, the search for therapies targeting the pathways involved in the pathogenesis continues. Some studies have used medication to target the inflammation associated with AMD. Others have looked at therapies that reduce the effects of oxidative stress. Researchers also have considered stem cell-based therapies to regenerate damaged photoreceptors and retinal pigment epithelium.17
AMD can seriously impair patient quality of life. Central vision loss increases the risk of falls and injury and may result in the inability to drive, read, prepare meals, or to recognize loved ones' faces. The number of people affected by AMD is expected to grow as the population ages. Primary care providers can be the first to recognize symptoms and the need for referral to ophthalmology in this population. Early recognition and coordinated care between primary care providers and vision specialists will lead to timely management, which may decrease the incidence of permanent blindness due to AMD.
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/preferred-practice-pattern/comprehensive-adult-medical-eye-evaluation-2015. Accessed November 16, 2016.
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14. Solomon SD, Lindsley K, Vedula SS, et al Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev
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Keywords:Copyright © 2017 American Academy of Physician Assistants
age-related macular degeneration; AMD; blindness; primary care; eye condition; retinal disease