Nonexudative (Dry) Age-Related Macular Degeneration (AMD)

Practice Essentials

Nonexudative (dry) age-related macular degeneration (AMD or ARMD) (see the image below) comprises more than 90% of patients diagnosed with AMD. AMD is the most common cause of irreversible vision loss in the developed world. Drusen can be detected early in this disease without visual loss. As dry AMD progresses to retinal atrophy and central retinal degeneration, loss of central vision is often observed. Generally, nonexudative AMD has a much slower (over decades), progressive visual loss relative to exudative (wet) AMD (over months).

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Moderate nonexudative age-related macular degeneration is shown with the presence of drusen (yellow deposits) in the macular region.

Signs and symptoms

Signs and symptoms of dry AMD include the following:

• Difficulty with night vision and with changing light conditions (specifically, changes in Amsler grid self-evaluation and trouble with reading)
• Visual fluctuation (ie, some days, vision is poor; other days, vision appears improved)
• Difficulty with reading and making out faces
• Metamorphopsia (distortion of visual images): Not a major patient complaint for dry AMD, but it may be present as the atrophy slowly progresses. However, rapid onset of metamorphopsia is concerning for the development of wet AMD.

See Clinical Presentation for more detail.

Diagnosis

Funduscopic examination in patients with suspected AMD includes the following findings:

• Early to intermediate nonexudative AMD: Significant for the presence of multiple drusen for early AMD. For intermediate AMD, drusen may appear confluent with significant pigment changes and pigment accumulation in the posterior pole. In addition, the retinal pigment epithelium (RPE) often appears atrophic, with easier visualization of the underlying choroid vascular plexus
• Advanced stages of nonexudative AMD: Coalescence of focal islands of atrophy and formation of large zones of atrophy with severely affected vision
• Advanced AMD (wet): Choroidal neovascularization: RPE elevation, exudate, subretinal fluid or hemorrhage

Procedures

• Fluorescein angiography: Has value in patients with AMD who note a recent onset or worsening of vision associated with metamorphopsia
• Amsler grid evaluation: Cornerstone of evaluation of nonexudative AMD
• Ocular coherence tomography (OCT) of the retina
• Ocular coherence tomography angiography (OCTA) of the retina
• Slit-lamp biomicroscopy
• Biopsy and histologic examination

Imaging studies

• Fundus photography and fundus autofluorescence: Best modality to follow nonexudative AMD
• Optical coherence tomography (optional; may be used to follow disease progression): To examine retinal thickness
• Multifocal electroretinography (optional; may be used to follow disease progression): To evaluate functional response of retinal rods and cones

See Workup for more detail.

Management

Prevention is the best treatment for nonexudative AMD, because no satisfactory method exists to treat this condition. Accumulated evidence suggests that AMD is a genetic disease.

Management of exudative AMD may include the following^[1] :

• Intravitreal injection with ranibizumab, bevacizumab, aflibercept, or pegaptanib sodium
• Photodynamic therapy with verteporfin
• Thermal laser photocoagulation surgery

Nonpharmacotherapy for both wet and dry AMD

• Antioxidant vitamin and mineral supplements (vitamin A, vitamin E, zinc, and lutein)^{[2, 3, 4, 1]}
• Screening for impaired visual acuity
• Wraparound shades (eg, orange-tinted, blue blocker lenses): Effective solution for delayed dark adaptation and to protect eyes from direct sunlight
• Avoidance/cessation of tobacco use
• Frequent follow-up for risk assessment of conversion to exudative AMD

See Treatment and Medication for more detail.

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Background

Age-related macular degeneration (AMD or ARMD) is the most common cause of irreversible vision loss in the developed world. AMD is associated with the presence of drusen, without visual loss early in the disease. However, the disease often slowly progresses over years to retinal atrophy and central retinal degeneration with associated loss of central vision. The early form of dry AMD is characterized by small to intermediate sized drusen, without significant vision loss. The intermediate form of dry AMD is associated with loss of retinal pigment epithelium (RPE) and the overlying retinal layers (atrophy), with loss of contrast sensitivity, loss of reading speed, and difficulty with adaptation to changing light conditions. The advanced, nonexudative form of AMD is characterized by the presence of atrophy that can be associated with severe central visual-field loss. In all forms of dry AMD, peripheral visual acuity is preserved. Exudative AMD is associated with the development of choroidal neovascular membranes that result in the development of exudate, subretinal fluid, and hemorrhage, as well as relatively rapid central vision loss and visual distortion.

Greater than 90% of patients diagnosed with AMD have nonexudative (dry) AMD; nonexudative AMD is generally associated with much slower (over decades), progressive visual loss compared with exudative (wet) AMD, which is generally associated with more rapid (over months) visual loss. However, patients with the more advanced cases of dry AMD can have as profound a visual loss as those with exudative AMD.

AMD describes a collection of inherited diseases (multifactorial) that share common features, including age predilection, positive family history, presence of yellow-gray material in the Bruch membrane (ie, drusen), RPE changes (eg, atrophy, clumping, RPE detachments) in the posterior pole or periphery, and visual disturbances (eg, abnormal reading, stereo and/or color vision disturbances, dark/light adaptation disturbances).

RPE degeneration is accompanied by variable loss of both the overlying photoreceptors and the underlying choroidal perfusion. When the appropriate age and clinical findings are accompanied by the loss of visual acuity, visual field, or other visual functions, the condition is often classified as AMD. Early AMD may be diagnosed prior to the onset of visual loss if the patient has characteristic drusen and relevant family history.

AMD usually manifests after age 50 years. The disease is often bilateral and may be asymmetrical, and affected patients report a significant history of disease in family members who have lived to later years of their life. Approximately 10% of patients develop a more rapid form of visual loss secondary to the development of neovascularization from the choroid (CNV), wet AMD. The abnormal vessels may be located either below (type 1) or above (type 2) the RPE. Dry, or nonexudative, AMD is the most prevalent form of this disease. When the dry form of AMD progresses with larger areas of RPE atrophy, the condition is referred to as geographic atrophy (GA). GA usually is bilateral but not necessarily symmetrical. GA can also develop neovascularization and can result in a more rapid loss of vision.

Antioxidant multivitamin therapy (consisting of vitamin A at 25,000 IU, vitamin C at 500 mg, zinc at 80 mg, copper at 2 mg, and vitamin E at 400 mg) has been shown in a large clinical trial, the Age-Related Eye Diseases Study (AREDS), to be helpful in decreasing the risk of visual loss with nonexudative AMD. Most of the decrease in visual loss appeared to result from a reduced risk of conversion to wet AMD. The AREDS notably did not show any benefit with the use of these vitamins in very early AMD or in subjects without AMD at baseline. AREDS also showed a relative increased risk of lung cancer among smokers who used high-dose vitamin A. The AREDS2 study showed that a formulation that replaced vitamin A/beta-carotene with a combination of lutein and zeaxanthin was safer and likely more effective at preventing AMD progression than the initial AREDS formula.

The Women's Antioxidant and Folic Acid Cardiovascular Study looked at a cohort of women without any evidence of AMD. The randomized, double-blind, placebo-controlled trial included 5442 female healthcare professionals and noted that a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) reduced the relative risk of developing visually significant AMD by approximately 40%. The study also demonstrated a reduced risk of developing non–visually significant AMD by a similar amount.^[5]

A phase I study demonstrated visual benefit and decreased progression of AMD in subjects with advanced dry AMD who were provided with an intravitreal implant that secreted ciliary neurotrophic factor (CNTF). Current molecules under investigation aim to inhibit GA progression via various mechanisms, including reducing toxic byproduct generation and accumulation, slowing the visual cycle, and inhibiting the complement pathway, which have all been shown to be involved in the pathogenesis of AMD. Targeting the alternate complement pathway has shown the most promise to date for dry AMD treatment. More specifically, complement factor H mutations have been linked to dry AMD, and smoking, a known risk factor for AMD progression, alters activity of complement factor H. There are both phase 2 and 3 trials underway to address the potential role of complement inhibitors to treat nonexudative AMD.

Additional therapies that have been tried include rheopheresis (apheresis) and laser to drusen. While these therapies demonstrated a small benefit over the short term (1-3 y), they did not prove to have any significant benefit after that time. In fact, the Complications of Age-related Macular Degeneration Prevention Trial (CAPT) has demonstrated that laser to drusen is ultimately not beneficial and may potentially be harmful.

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Pathophysiology

Clinical pathophysiology

The clinical definition of early age-related macular degeneration (AMD or ARMD) varies with the source consulted. A clinically useful guideline is when drusen in the posterior pole are greater than 5 in number and at least 63 µm in size. With time, drusen enlarge and result in shallow elevation of the RPE that overlies the Bruch membrane. These deposits may merge over time, and they can be associated with pigmentation change visible on ophthalmoscopy.

Evaluation of the AREDS results provided a clinically useful method of determining risk of advanced AMD using simple criteria: (1) presence of large drusen (greater than 125 µm in size) and (2) the presence of pigment abnormalities. Thus, one eye having both large drusen and pigment abnormalities has a score of 2 (1 for each criterion), and if both eyes have each risk factor, the score is 4. Using this simplified criteria, the AREDS found that over 5 years, eyes with a risk factor score of 0 had only a 0.4% move to advanced AMD, while those with 1 risk factor had a 3.1% move to advanced AMD. However, when eyes had 2, 3, or 4 risk factors, the rate of advanced AMD conversion (either large geographic atrophy or neovascularization) increased to 12%, 26%, and 47% respectively.^[6]

Because the above matrix is a simple and powerful tool to determine the persons who will develop advanced AMD, it is useful to recollect the criteria when performing a clinical examination. For example, the presence of a large druse (125 µm in size) would be most easily remembered by looking for drusen whose shortest diameter is approximately 125 µm (or as large as the diameter of a retinal vein at the optic disc margin). Only drusen within 2 disc diameters of the center were used during the analysis. Pigment abnormalities included any areas of hyperpigmentation or hypopigmentation, as well as noncentral areas of geographic atrophy.

Visual acuity loss or visual-field loss occurs when the RPE atrophies and results in secondary loss of the overlying photoreceptor cells that it supplies. The variety of fundus changes described above defines dry AMD. When the damaged RPE results in the development of choroidal neovascularization with late leakage on fluoresce in angiography and a decrease in vision and metamorphopsia, exudative (wet) AMD is said to occur.

Molecular pathophysiology

Dry AMD is an inherited autosomal dominant disease that appears to be affected by nutrition and environmental factors. Nonexudative AMD is characterized by the degeneration of the retina and the choroid in the posterior pole due to either atrophy or RPE detachment. The atrophy is generally preceded (or coincident in some cases) by the presence of yellow extracellular deposits adjacent to the basal surface of the RPE called drusen.

Drusen are composed of vitronectin (a multifunctional plasma and extracellular matrix protein), lipids, immune and inflammatory related proteins, amyloid associated proteins, as well as other poorly characterized substances. While drusen were thought to be the result of accumulated waste material from subretinal tissues, data now suggest that the accumulation is due to the presence of inflammation in the subretinal space. This extracellular material in the Bruch membrane is composed of various substances, including vitronectin and proteinaceous material. The products of oxidative stress also trigger chronic low-grade inflammation (pathophysiological parainflammation) process in patients with AMD. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. Inappropriate activation of the complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD.

The complement system is an alternative system (ie, independent of antibodies) of defense against infection. Complement factor H (CFH) is a robust anti-inflammatory agent, in that it protects host cells from complement-mediated damage by binding to the activated complement component C3b.

In 2005, four separate groups reported that a common variation in the CFH (complement factor H) gene increased susceptibility to dry AMD.

In 2006, two other genes were identified that increased the risk similarly. The CFH polymorphism that was most significantly associated with AMD is a T→C substitution that results in a tyrosine-to-histidine substitution of the CFH protein. Thus, it appears that in affected individuals, RPE cells may undergo damage via the complement system because of their inability to inhibit the complement cascade as effectively. Additional indirect evidence in support of this chain of events is noted by a publication that indicates that choroidal levels of C-reactive protein are elevated in homozygote CFH polymorphic individuals.^[7]

Some studies have delineated a molecular pathway leading to geographic atrophy and visual loss. This pathway indicates that RPE death leads to secondary photoreceptor loss and consequent visual loss over time. Ambati et al found that RPE cells in patients with dry AMD have low levels of a RNA-cleaving enzyme, DICER1. Low levels of this enzyme lead to decreased breakdown of RNA-Alu molecules. Overabundance of cytoplasmic RNA-Alu molecules (non-coding sequences of RNA) activates inflammatory proteins (NLRP3 inflammasome), which activates a cascade of molecular responses that lead to RPE cell death.^{[8, 9]}

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Frequency

United States

Age-related macular degeneration (AMD or ARMD) is the leading cause of blindness in the United States for people older than 50 years. The actual frequency of the disease depends on specific racial group studies. AMD is more prevalent in whites and likely has a more severe course in patients who have light-colored eyes. A liberal definition of AMD that includes all patients with significant drusen in the posterior pole, with or without visual loss, estimates the prevalence at greater than 20% of the population older than 60 years. A more rigorous, population-based survey with a definition that requires the presence of either late atrophy and/or choroidal neovascularization results in an incidence of 0% at age 50 years or younger, 2% at 70 years, and 6% at 80 years. In African Americans, dry AMD is noted to be approximately half the incidence rate stated above.

International

The incidence of AMD in Japanese and other Asian populations is lower than the white population in the United States, but reports suggest that the incidence is increasing. The Inuit people in Greenland have a significantly higher incidence, as well as a distinctive phenotype. Most black Africans and other people with darker-pigmented skin in general have a lower incidence of symptomatic macular degeneration. Similarly, it is evident that the lesions resulting from AMD in Asian populations are different from those in white populations. This is in agreement with the most accepted theory regarding AMD: that it is a multigenic inherited condition. The background and the specific gene affected would affect the phenotype.

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Mortality/Morbidity

Age-related macular degeneration (AMD or ARMD) results in significant visual morbidity. The presence of neovascularization results in a blurry central visual field. Even in dry AMD, with relatively good vision, patients often report trouble adjusting to varying light conditions. Often, these patients note difficulty when initially placed in a dark environment from a relatively lighted one (eg, entering a restaurant from bright sunlight).

AMD patients, especially those with the exudative variant, have a higher incidence of cerebrovascular accidents and cardiac disease.

Geographic atrophy may also be associated with cognitive impairment, as assessed by mini-mental status exams and other similar tests. One case control study demonstrated a 3x increased odds for mild cognitive impairment in geographic atrophy subjects when compared to normal controls even when controlled for age, visual acuity and education level.^[10] Additionally, 3000 subjects in the AREDS trial were subject to a battery of cognitive tests. Among subjects with AMD, those with poorer vision had worse cognition.^[11] Participants in the Cardiovascular Health Study underwent cognitive testing as well as mini-mental state testing and those with poorer cognition were at a slightly higher risk of having dry AMD.^[12] Given the higher rate of impaired cognitive function in patients with dry AMD, it is important for the clinician to consider cognitive function when assessing low vision options and treatments.

Race

The incidence of AMD is higher in whites compared with African Americans. Some studies report a rate of approximately half in African West Indians in Barbados compared with whites in Baltimore, Maryland. The incidence in Asians is between the above 2 rates, although it appears that the incidence is increasing in this population.

Sex

No known difference exists between males and females in the incidence of AMD.

Age

As implied by its name, the incidence of AMD is related to the age of the patient. The incidence increases with each decade of life, with a significant rise in patients aged 70 years or older.

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Prognosis

Prognosis for this disease is significantly better than the prognosis for wet age-related macular degeneration (AMD or ARMD). Patients likely will have steadily but slowly deteriorating visual acuity. It also is common to have other visual dysfunction (eg, loss of ability to quickly adapt to changing lighting conditions, loss of contrast sensitivity). Variability of vision from day-to-day is common.

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Patient Education

Patients with geographic atrophy (GA) may have a variety of visual dysfunction. The location of atrophy often suggests the type of visual dysfunction that will be experienced by the patient. Many patients with age-related macular degeneration (AMD or ARMD) report difficulty in adjusting to changing light conditions; specifically, they take a significantly longer time to adjust to indoor lighting after being outside in bright sunlight. Wrap-around outdoor sunglasses that have an orange tint work for some patients.

Patients who primarily have central atrophy often note trouble with reading and performing fine motor tasks. Magnification and increased contrast (via a monitor or increased illumination) are the best solutions for such visual dysfunction.

In contrast, other patients have GA that spares the foveal center but affects the entire perifoveal region. These patients often can see 20/20, but they are unable to navigate due to the small area of good visual acuity. Some of these patients must scan the screen to be able to see the 20/400 character. In these patients, excess magnification would be detrimental, because it would effectively decrease their limited visual field. Increased contrast and minification, by way of increased illumination and reverse telescopes respectively, may be beneficial for these patients.

Referral to comprehensive vision rehabilitation is indicated early in the disease process. The American Academy of Ophthalmology (AAO) recommends referral for vision rehabilitation when acuity is less than 20/40 or when a loss of contrast sensitivity, scotoma, or field loss is noted. The aim of early referral is to prevent the many negative consequences of vision loss. For example, when acuity is reduced to 20/50 or worse, patients have twice the risk of falling, 3 times the risk of depression, and 4 or greater times the risk of hip fracture. Rehabilitation aims to maximize patients’ use of their partial vision and to provide practical adaptation to reduce disability. Comprehensive rehabilitation addresses the “whole person,” as outlined in the AAO’s booklet of Vision Rehabilitation for Adults. Barriers to low-vision therapy access include poor insurance coverage and transportation.^[13]

For patient education resources, see the Eye and Vision Center, as well as Macular Degeneration.

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History

Patients with age-related macular degeneration (AMD or ARMD) usually report a family history of decreased vision late in life.

They often report difficulty with night vision and with changing light conditions. Specifically, patients report changes in Amsler grid self-evaluation and trouble with reading.

Commonly, AMD patients report visual fluctuation (ie, days when vision is poor and other days when it appears improved).

Patients report difficulty with reading and making out faces.

Metamorphopsia is not a major complaint, but it may be present as the atrophy slowly progresses.

An association between AMD and Alzheimer disease has been reported.^[14]

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Physical

Funduscopic examination in age-related macular degeneration (AMD or ARMD) is significant for drusen in the early stages of disease. These drusen usually are confluent with significant pigment changes and accumulation of pigment in the posterior pole. RPE often appears atrophic with an easier visualization of the underlying choroidal plexus.

In advanced stages of dry ARD, these focal islands of atrophy coalesce and form large zones of atrophy with severely affected vision.

Signs of choroidal neovascularization include RPE elevation, exudate, or subretinal fluid. The presence of these symptoms may indicate that neovascularization is occurring and that fluorescein angiography may be indicated to evaluate the retina.

The periphery of patients with ARMD often has areas of drusen, as well as RPE mottling and atrophy.

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Causes

Oxidative stress is believed to play a major role in the pathogenesis of age-related macular degeneration (AMD or ARMD) because of combined exposures of the retina to light and oxygen. Additionally, AMD is now widely accepted as a genetically inherited disorder with late onset.

Groundbreaking studies in the genetics of AMD have changed the way in which most specialists perceive the disease. Specifically, a majority of the risk of developing AMD is determined by variations in 3 specific genes, as follows:

• CFH gene (chromosome 1)
• BF (complement factor B) gene and C2 (complement component 2) gene (chromosome 6)
• LOC gene (chromosome 10)

Maller and others showed that polymorphisms in the above 3 genes independently raise the risk of AMD.^[15] The above genetic factors contribute to approximately 50% of the sibling risk of developing AMD.

• Smoking and a higher body mass index are 2 of the most common other environmental factors that contribute independently to the increase in the risk of developing AMD. Smoking has been clearly identified as increasing the risk of AMD by 2 times.
• Large studies have not shown hypertension or heart disease to increase the odds of developing AMD.
• Serum lipids were extensively studied regarding their relationship with AMD in the National Eye Institute–sponsored AREDS. One report suggests dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with the development of neovascular AMD (although not nonexudative AMD).^[16] Similarly, individuals with higher fish consumption had a slightly lower incidence of developing neovascular AMD.
• A study looking at whether the regular consumption of omega-3 fatty acids and fish may affect the onset of AMD in women found that incidence of the disease was significantly decreased among women who ate 1 or more servings of fish per week.^[17]
• Studying twins with AMD, Seddon and others arrived at some interesting conclusions.^[18] Current cigarette smoking increased the risk of developing AMD by 1.9-fold, and past smoking still increased the risk by 1.7-fold. Increased consumption of fish (>2 servings of fish per week) and a higher intake of omega-3 fatty acids both were protective and reduced the odds of developing AMD by 0.55-fold.

These studies have generally been performed in individuals from the United States of European descent. Thus, the results may not apply to individuals of other races.

Blue light emitted from device screens (eg, smartphones, laptops) also causes vision damage and hastens blindness. Ratnayake et al (2018) found that blue light interacts with retinal, resulting in creation of toxic molecules within photoreceptor and nonphotoreceptor cells, which can cause macular degeneration.^[19]

Patients with glaucoma should be asked about cognitive status, since an association between Alzheimer disease and glaucoma has been found.^[14]

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Complications

The major complication of dry age-related macular degeneration (AMD or ARMD) is the conversion to wet (or exudative/neovascular) AMD.

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Laboratory Studies

Fluorescein angiography is of value if the age-related macular degeneration (AMD or ARMD) patient notes a recent onset or worsening of vision associated with metamorphopsia. Metamorphopsia may indicate the onset of choroidal neovascularization. Clinical evidence for neovascularization includes retinal pigment epithelium (RPE) elevation, subretinal hemorrhage, and/or the presence of exudate.

Fluorescein angiography, as shown in the images below, is performed by injecting 3 mL of 25% sodium fluorescein in a peripheral vein, followed by a rapid sequence of angiography images. Fluorescein is a vegetable-based dye that is activated by light at a particular wavelength, which causes emission at a higher wavelength. Using the appropriate blocking and transmission filters, the photographer is able to capture an image of the dye in the blood vessels and, later, as the dye leaks, images of the retina and the choroid.

Some complications of fluorescein angiography may occur. The dye is relatively safe. Occasionally (< 5%), patients may have nausea or vomiting shortly after dye injection. Infrequently, patients may develop an allergic reaction to the dye and have hives, angioedema, venous dilation, and, very rarely, death (< 1/250,000). No cross-reactivity occurs between this dye and iodine. The dye is cleared by renal excretion and is safe in patients on dialysis. Note the images below.

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In angiography, fluorescein dye is passed through a peripheral vein and transmits through the vascular system. The dye fluoresces in the vasculature, ....

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Staining of drusen. Drusen absorb dye and, in the late frames of the angiogram, show hyperfluorescence. This staining is distinguished from the leakag....

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The atrophic retinal pigment epithelium (RPE) demonstrates staining of the underlying choroidal vasculature. Normally, the intact RPE masks the presen....

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The atrophic areas are easily distinguished by the hyperfluorescence of the retinal pigment epithelium (RPE) in the mid phase of the angiogram. Hypofl....

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Fluorescein angiogram 4 minutes after injection of dye on 67-year-old woman showing pigment epithelial detachments.

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A later frame of the angiogram demonstrating the absence of dye leakage outside the lesion, with staining of the areas of atrophy (window defects) in ....

Indocyanine green (ICG) angiography uses ICG, which is a water-soluble tricarbocyanine dye, rather than fluorescein. ICG is almost completely protein-bound and is retained in the choroidal circulation after intravenous injection, making it useful for imaging choroidal circulation.

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Imaging Studies

Dry age-related macular degeneration (AMD or ARMD) is followed best by accurate fundus photography, images of which are shown below.

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A normal-appearing macula of the left eye. Note the even pigmentation of the retinal pigment epithelium and the absence of any yellow excrescences (dr....

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Moderate nonexudative age-related macular degeneration is shown with the presence of drusen (yellow deposits) in the macular region.

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A more advanced case of nonexudative age-related macular degeneration (ARMD). This image shows drusen that are larger, more confluent, and soft. Soft ....

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A more advanced case of dry age-related macular degeneration. Several areas of atrophy are present, as are areas of significant pigment mottling in th....

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Fundus photo showing drusen in a 67-year-old woman with dry age-related macular degeneration.

Performing tests (eg, fluorescein angiography) on a routine basis is not necessary.

The physician is sometimes at a quandary when a patient describes loss of vision or new onset of metamorphopsia. The patient sometimes notes such changes as geographic atrophy (GA) progresses; unfortunately, it is almost impossible to discern these symptoms from the symptoms that occur when neovascularization has occurred. Therefore, a patient with a new onset of metamorphopsia or a sudden decrease in vision may require a fluorescein angiogram to distinguish exudative AMD versus the indeterminable progression of GA.

Recently, optical coherence tomography (OCT) has advanced to permit noninvasive visualization of the retinal and superficial choroidal vessels within the macula via OCT angiography. OCT angiography uses complex mathematical computation in a subtraction analysis to image these small vessels noninvasively with high resolution so that no dye injection is required. OCT angiography may be helpful in both detection of early conversion to wet AMD or to follow response of wet AMD to treatment.

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Spectral domain optical coherence tomography (SD-OCT) analysis: OCT B-scans show the presence of pigment epithelial detachment bilaterally in a patien....

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Fluorescein angiography: Fundus angiography in the same patient shows staining of drusen and window defects only in each eye. No active neovasculariza....

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Optical coherence tomography (OCT) shows an active neovascular network in the right eye as opposed to the nonvascularized pigment epithelial detachmen....

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Optical coherence tomography (OCT) shows an active neovascular network in the right eye as opposed to the nonvascularized pigment epithelial detachmen....

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Other Tests

Reports on age-related macular degeneration (AMD or ARMD) have examined the thickness of the retina with optical coherence tomography (OCT). This study has shown decreased reflectance at the level of the rod-cone layer indicating that atrophy is present in this layer. Note the images below.

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High-definition optical coherence tomography scan of a 67-year-old woman showing retinal pigment epithelium mottling and pigment epithelial detachment....

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High definition optical coherence tomography right eye demonstrating retinal pigment epithelium atrophy and changes in the deeper layers of retina. Th....

Multifocal electroretinography (MERG) may be performed on the retina to evaluate the functional response of rods and cones.

The above 2 tests are not required in the evaluation of AMD, but they have been performed by various authors to follow the progression of disease.

Fundus autofluorescence (FAF) is a noninvasive retinal imaging modality used in clinical practice to provide a density map of lipofuscin, the predominant ocular fluorophore, in the retinal pigment epithelium.

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Procedures

Amsler grid evaluation, slit-lamp biomicroscopy, and fluorescein angiography in age-related macular degeneration

The cornerstone of evaluation of dry AMD consists of visual acuity measurement and evaluation by Amsler grid. The biggest treatable risk of visual loss in dry AMD is the development of neovascularization. Studies have shown Amsler grid evaluations, if performed properly, are quite sensitive in detecting change. The specificity of this test is somewhat limited. Patients with dry AMD often note Amsler grid changes that are temporary, and good observers can detect progression of their dry AMD on the grid.

New metamorphopsia is a good indication for performing fluorescein angiography. This test is the most sensitive and specific way to evaluate for choroidal neovascularization.

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Histologic Findings

The earliest morphologic features of dry age-related macular degeneration (AMD or ARMD) consist of the accumulation of 2 kinds of lesions (ie, basal laminar deposits, basal linear deposits) just beneath the RPE layer. The accumulation of these deposits is often uneven and associated with RPE hyperplasia and migration. This condition is clinically evident as pigment clumping. As these deposits slowly increase, they can be seen as soft drusen and/or localized RPE detachments.

As these drusen enlarge, they can cause the development of new blood vessels (wet AMD) and/or the slow demise of the overlying photoreceptor cells. Photoreceptor cell loss can be accompanied by the thinning (atrophy) of RPE cells, as well as underlying choroidal circulation. The end stage of these changes is the presence of a very thin choroidal layer with the absence of small choroidal vessels underlying an area of atrophic RPE. The rod-cone layer overlying this zone is atrophied, and the middle retinal layers show signs of degeneration. This end stage gradually enlarges and is seen clinically as GA.

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Staging

Dry AMD has multiple clinical features that include drusen, alterations in the retinal pigment epithelium (RPE) resulting in hyperpigmentation or hypopigmentation of the macula, and RPE atrophy. The most frequently used classification system for dry AMD was described in the Age-Related Eye Disease Study (AREDS) and includes 4 categories.^[11]

• Category 1: No AMD characterized by no or few small drusen (< 63 microns)
• Category 2: Early AMD characterized by multiple small drusen, few intermediate drusen (63-124 microns), or mild RPE abnormalities
• Category 3: Intermediate AMD characterized by multiple intermediate drusen, at least one large druse (>124 microns), or geographic atrophy (GA) not involving the center of the fovea
• Category 4: Advanced AMD characterized by GA involving the foveal center

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Medical Care

No approved medications for the treatment of dry age-related macular degeneration (AMD or ARMD) are available.

Role of vitamins, antioxidants, risk of smoking, and hypertension ^{[2, 3, 20, 4]}

Evidence shows that patients with early or moderate dry age-related macular degeneration (AMD or ARMD) should consume adequate quantities of antioxidants, including vitamin A, vitamin E, zinc, and lutein. Prevention is the best treatment in this case because no satisfactory method exists to treat dry AMD. Accumulated evidence suggests that AMD is a genetic disease. Therefore, children of patients who have lost vision to AMD are the best candidates for a primary prevention trial.

The first Age-Related Eye Diseases Study (AREDS) has concluded, and its results are illuminating. In this study, patients with very mild or moderate forms of dry AMD were given antioxidant supplementation (15 mg of beta-carotene, 500 mg of vitamin C, 400 IU of vitamin E, 80 mg of zinc, plus 2 mg of copper). These patients had a small but definite decrease in their progression to advanced AMD. Interestingly, the data showed benefit in preventing the conversion of dry AMD to neovascular AMD.

A study by Millen et al examined the relationship between serum 25-hydroxyvitamin D (25[OH]D) levels and the prevalence of AMD.^[21] The study determined that high concentrations of 25(OH)D protected against early AMD in women younger than 75 years.

The Rotterdam Study (1990–1993) investigated whether regular dietary intake of antioxidants was associated with a lower risk of developing AMD in more than 4000 persons aged 55 years or older in The Netherlands. In this study, a high dietary intake of beta-carotene, vitamins C and E, and zinc was also associated with a substantially reduced risk of AMD in elderly persons.

Some evidence indicates that multivitamins with antioxidants and lutein may be of benefit. Clear evidence shows that smoking accelerates the disease process. It is recommended that patients who have a family history of AMD, and specifically those patients whose first-degree relative has lost vision due to AMD, should take a multivitamin with lutein each day. It is advised that patients stop smoking and consider supplemental oral antioxidants if they are unable to stop smoking.

Controversy exists over the exact vitamin combination that may be beneficial. Zinc and vitamin E are commonly touted as providing the best benefits. One study reports the beneficial effects of zinc, while another study shows a worse outcome with large doses of zinc. Therefore, it would be prudent to take a multivitamin containing a moderate dose of these vitamins.

To further refine the specific benefits of antioxidants, a randomized controlled clinical trial, Age-Related Eye Disease Study 2 (AREDS2), was performed. This study determined that oral supplementation with macular xanthophylls (lutein at 10 mg/d plus zeaxanthin at 2 mg/d) was superior to lutein alone at slowing dry AMD progression, while omega-3 long-chain polyunsaturated fatty acids (LCPUFAs; DHA plus eicosapentaenoic acid at a total of 1 g/d) did not decrease the risk of progression to advanced AMD, as compared with placebo.

Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of AMD. The objective of the Women’s Antioxidant and Folic Acid Cardiovascular Study was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride, and cyanocobalamin.^[5] The trial included 5442 female healthcare professionals aged 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. The randomized trial data for the large cohort of women at high risk of cardiovascular disease indicated that daily supplementation with folic acid (2.5 mg/d), pyridoxine 50 mg/d) and cyanocobalamin (1 mg/d) may reduce the risk of AMD.

The purpose of the Cardiovascular Health and its Association with Prevalence and Progression of Age-Related Macular Degeneration (CHARM) study was to determine if cardiovascular health, as determined by novel noninvasive techniques, was associated with prevalent AMD or AMD progression.^[22] The results were unexpected in that better cardiovascular health was associated with increased risk of prevalent AMD and progression. Inconsistent findings between the prevalence and progression components could be due to truly different disease etiologies or to spurious findings, as can occur with inherent biases in case control studies of prevalence. Further investigation of these noninvasive methods of characterizing the cardiovascular system should be undertaken because they may help to further elucidate the role of the cardiovascular system in the etiology of prevalent AMD and progression.

Epidemiologic studies using a computer database previously indicated that the use of statins was protective against the development of AMD. However, a 2007 study, using rigorous systems and graded macular photographs, confirmed that the use of statins was not correlated with AMD incidence or progression.^[23]

Early symptoms

Prolonged darkness (delayed dark adaptation) upon entering a restaurant from bright sunlight is one of the earliest symptoms, with patients noting this phenomenon prior to the presence of any significant atrophy. One effective suggestion for patients with this symptom is to use wrap-around shades. Some low-vision specialists suggest the use of orange-tinted, blue-blocker lenses.

Patients with dry AMD often have a visual function that is much poorer than suggested by their Snellen acuity. The presence of large areas of atrophy, usually in a perifoveal zone, results in large scotomas near the center of the visual field. These scotomas prevent patients from performing simple tasks (eg, recognizing faces, reading). Low-vision specialists often prescribe magnifiers with a line marker so that patients do not lose their place while reading.

Family members of patients with AMD

While it would seem logical that the same vitamins used to treat patients with AMD would be of benefit prior to the development of AMD in family members, in the AREDS, supplements did not show any significant benefit with treatment over the 7-year follow-up when the disease was very mild. Additionally, many risks are associated with long-term zinc, vitamin A, and vitamin E supplementation. Instead, family members of patients with AMD should do the following:

• Do not smoke and avoid second-hand smoke.
• Protect eyes from direct sunlight using either dark glasses or a wide-brimmed hat.
• Eat a well-balanced diet high in natural antioxidants.
• Eat fresh baked fish (1-2 servings) daily.
• Eat green leafy vegetables (eg, spinach, kale) daily.
• Consider a supplement consisting of folic acid (2.5 mg/d), pyridoxine (50 mg/d), and cyanocobalamin (1 mg/d).^[5]

Family members should be specifically requested NOT to take the AREDS supplement vitamins because the risk associated with long-term supplementation with these vitamins may not overcome the benefits of taking them. For example, in subjects with 1 risk factor in the AREDS, the race of progression of disease at 5 years was minimally different from that of the placebo-treated subjects. This also held true at 10 years. Subjects with more risk factors (2-4) had progressively increased levels of benefit with supplementation.

Clinical guideline summaries

American Academy of Ophthalmology Retina/Vitreous Panel - Age-related Macular Degeneration

US Preventive Services Task Force - Screening for impaired visual acuity in older adults: U.S. Preventive Services Task Force recommendation statement

National Institute for Health and Clinical Excellence (NICE) - Ranibizumab and pegaptanib for the treatment of age-related macular degeneration

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Surgical Care

No accepted surgical alternative to dry age-related macular degeneration (AMD or ARMD) is available.

It is possible that the drusen present in dry AMD can be ameliorated by the performance of a very light grid laser therapy.^[24] The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT), a National Eye Institute–sponsored study examining the visual benefit from such treatment, has concluded. Preliminary results indicate that focal laser therapy in a light grid pattern causes drusen resorption and improved visual acuity in the short term. However, the procedure was associated with a slightly higher risk of developing choroidal neovascularization in the short term compared with no laser treatment. Additionally, at the end of the study, no significant visual benefit was observed in those who were treated compared with those who did not receive laser treatment.

More recently, a few patients underwent retinal translocation surgery during which the retina is rotated. Many of these patients developed accelerated dry macular degeneration with retinal pigment epithelium (RPE) atrophy at the site of the new macula. Interestingly, the area of atrophy that developed at the new site resembled almost identically the area of atrophy that was preexistent prior to the translocation. This provides clinical evidence that the RPE layer is the source of disease pathophysiology and that the retinal atrophy that results is a response to diseased RPE.

A phase II study using encapsulated, genetically modified cells that secrete ciliary neurotrophic factor indicated the retinal thickening occurred in a dose-dependent, statistically significant manner. Treated subjects also had a higher percentage of preserved vision. Additional studies are required prior to approval by the US Food and Drug Administration (FDA).

Isolated reports of both embryonic and adult-derived stem cells being placed in the subretinal space have been noted. These are small reports whose primary purpose was to determine the feasibility of such an endeavor. In the near future, RPE cell repair via external transplantation of stem cells may provide a reasonable method of treatment for those patients with severe disease.

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Consultations

Serial general ophthalmologic examination, on a nonemergent basis, is indicated for patients with dry age-related macular degeneration (AMD or ARMD). If these patients have an acute loss of vision, retina consultation with fluorescein angiography is indicated in a timely manner to rule out the possibility of conversion to wet AMD.

Patients who have significant AMD changes, with or without vision loss, may wish to have their children evaluated by an ophthalmologist once the children reach age 50 years.

A neurologist should be consulted for patients with AMD who exhibit signs of cognitive dysfunction, since an association with Alzheimer disease has been found.^[14]

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Diet

Evidence suggests that diet plays an important role in the prevention of dry age-related macular degeneration (AMD or ARMD).^[25] Epidemiologic studies suggest that a diet containing green leafy vegetables is of benefit. Smoking cessation is of significant benefit. Consumption of baked fresh fish also is beneficial, owing to the fatty acids provided; 1-2 servings a week are adequate.

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Activity

No limitations are noted for age-related macular degeneration (AMD or ARMD). Each state has specific visual-acuity criteria for driving with a private license. Commercial driving licenses typically require at least 20/40 vision in the worse eye and have other typical requirements for side vision.

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Long-Term Monitoring

Patients with dry age-related macular degeneration (AMD or ARMD) should be observed frequently. Their follow-up care should be determined by the extent of disease and by the ophthalmologist's assessment of risk of conversion to wet AMD.

Daily Amsler grid evaluation is necessary, with immediate reports to the ophthalmologist of any changes are noted.

Recently, an alternate home visual field monitoring device to detect metamorphopsia (ForeseeHome device, Notal Vision Ltd, Tel Aviv, Israel) has been developed and demonstrated to provide earlier detection of wet AMD development.

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Medication Summary

Currently, no approved pharmacologic drug treatment of dry age-related macular degeneration (AMD or ARMD) is available. See Surgical Care for the possible beneficial effects of laser therapy.

Antioxidant multivitamin therapy (consisting of vitamin A at 25,000 IU, vitamin C at 500 mg, zinc at 80 mg, copper at 2 mg, and vitamin E at 400 mg) has been shown in a large clinical trial, the Age-Related Eye Diseases Study (AREDS), to be helpful in decreasing the risk of visual loss with nonexudative AMD. The AREDS2 study showed that a formulation that replaced vitamin A/beta-carotene with a combination of lutein and zeaxanthin was safer and likely more effective at preventing AMD progression than the initial AREDS formula. However, both AREDS and AREDS2 notably did not show any benefit with the use of these vitamins in very early AMD or in subjects without AMD at baseline.

Although no pharmacologic treatments have been approved to treat dry AMD, many compounds are in the latter stages of clinical trials, most notably, lampalizumab, a complement inhibitor that is administered by intraocular injection.

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