Nonexudative (dry) age-related macular degeneration (ARMD) (see the image below) comprises more than 90% of patients diagnosed with ARMD. ARMD is the most common cause of irreversible vision loss in the developed world; this condition is associated with the presence of drusen, without visual loss early in the disease, and often progresses to retinal atrophy and central retinal degeneration with associated loss of central vision. Generally, nonexudative ARMD has a much slower (over decades), progressive visual loss relative to exudative (wet) ARMD (over months).
Signs and symptoms
Signs and symptoms of ARMD 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, but it may be present as the atrophy slowly progresses
See Clinical Presentation for more detail.
Funduscopic examination in patients with suspected ARMD includes the following findings:
AMRD: Significant for the presence of drusen, usually confluent with significant pigment changes and pigment accumulation in the posterior pole; retinal pigment epithelium (RPE) often appears atrophic, with easier visualization of the underlying choroid plexus
Advanced stages of nonexudative ARMD: Coalescence of focal islands of atrophy and formation of large zones of atrophy with severely affected vision
Choroidal neovascularization: RPE elevation, exudate, or subretinal fluid
Fluorescein angiography: Has value in patients with AMRD who note a recent onset or worsening of vision associated with metamorphopsia
Amsler grid evaluation: Cornerstone of evaluation of nonexudative AMRD
Biopsy and histologic examination
Fundus photography: Best modality to follow nonexudative ARMD
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.
Prevention is the best treatment for nonexudative ARMD, because no satisfactory method exists to treat this condition. Accumulated evidence suggests that ARMD is a genetic disease.
Management of nonexudative ARMD may include the following  :
Intravitreal injection with ranibizumab, bevacizumab, or pegaptanib sodium
Photodynamic therapy with verteporfin
Thermal laser photocoagulation surgery
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 ARMD
Age-related macular degeneration (ARMD) is the most common cause of irreversible vision loss in the developed world. ARMD is associated with the presence of drusen, without visual loss early in the disease, and often progresses to retinal atrophy and central retinal degeneration with associated loss of central vision. The intermediate form 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 ARMD is characterized by the presence of atrophy that can be associated with severe central visual-field loss. In all forms of dry ARMD, peripheral visual acuity is preserved. Exudative ARMD is associated with the development of choroidal neovascular membranes that result in the development of exudate, subretinal fluid, and hemorrhage.
Greater than 90% of patients diagnosed with ARMD have nonexudative (dry) ARMD; nonexudative ARMD is generally associated with much slower (over decades), progressive visual loss compared with exudative (wet) ARMD, which is generally associated with more rapid (over months) visual loss. However, patients with the more advanced cases of dry ARMD can have as profound a visual loss as those with exudative ARMD.
ARMD 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 ARMD. At times, the step prior to the onset of visual loss has been classified as ARMD if the patient has characteristic drusen and relevant family history.
ARMD usually manifests after age 50 years. The disease is often bilateral, and patients report a significant history of disease in family members who have lived to later years of their life. Many patients develop a more rapid form of visual loss secondary to the development of neovascularization from the choroid that develops either below or above the RPE; this form of ARMD is referred to as wet, while the more prevalent form is known as dry. When the dry form of ARMD progresses with larger areas of RPE atrophy, the condition is referred to as geographic atrophy (GA). GA usually is bilateral but not necessarily symmetrical. It can develop neovascularization and 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 trail, the Age-Related Eye Diseases Study (AREDS), to be helpful in decreasing the risk of visual loss with nonexudative ARMD. Most of the decrease in visual loss appeared to be due to a reduced risk of conversion to wet ARMD. The AREDS notably did not show any benefit with the use of these vitamins in very early ARMD or in those subjects without ARMD at baseline.
The Women's Antioxidant and Folic Acid Cardiovascular Study looked at a cohort of women without any evidence of ARMD. 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 ARMD by approximately 40%. The study also demonstrated a reduced risk of developing nonvisually significant ARMD by a similar amount. 
A phase I study demonstrated visual benefit and decreased progression of ARMD in subjects with advanced dry ARMD who were provided with an intravitreal implant that secreted ciliary neurotrophic factor (CNTF).
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.
The clinical definition of early age-related macular degeneration (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 ARMD by the use of 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 ARMD, while those with 1 risk factor had a 3.1% move to advanced ARMD. However, when eyes had 2, 3, or 4 risk factors, the rate of advanced ARMD conversion (either large geographic atrophy or neovascularization) increased to 12%, 26%, and 47% respectively. 
Because the above matrix is a simple and powerful tool to determine the persons who will develop advanced ARMD, 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 ARMD. 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) ARMD is said to occur.
Dry ARMD is an inherited autosomal dominant disease that appears to be affected by nutrition and environmental factors. Nonexudative ARMD 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 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 ARMD.
In 2006, two other genes were identified that increased the risk similarly. The CFH polymorphism that was most significantly associated with ARMD 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. 
Some studies have dileneated 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 ARMD 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 inflammosome), which activates a cascade of molecular responses that lead to RPE cell death. [8, 9]
Age-related macular degeneration (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. ARMD is more prevalent in whites and likely has a more severe course in patients who have light-colored eyes. A liberal definition of ARMD 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 ARMD is noted to be approximately half the incidence rate stated above.
The incidence of age-related macular degeneration (ARMD) 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 ARMD in Asian populations are different from those in white populations. This is in agreement with the most accepted theory regarding ARMD: that it is a multigenic inherited condition. The background and the specific gene affected would affect the phenotype.
Age-related macular degeneration (ARMD) results in significant visual morbidity. The presence of neovascularization results in a blurry central visual field. Even in dry ARMD, 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).
ARMD 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.  Additionally, 3000 subjects in the AREDS trial were subject to a battery of cognitive tests. Among subjects with ARMD, those with poorer vision had worse cognition.  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 ARMD.  Given the higher rate of impaired cognitive function in patients with dry ARMD, it is important for the clinician to consider cognitive function when assessing low vision options and treatments.
The incidence of age-related macular degeneration (ARMD) 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.
No known difference exists between males and females in the incidence of age-related macular degeneration (ARMD).
As implied by its name, the incidence of age-related macular degeneration (ARMD) 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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