AUTHOR AND EDITOR INFORMATION

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• Workup
• Treatment
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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Clinical
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• Workup
• Treatment
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• Follow-up
• Miscellaneous
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Background

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world. It 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 advanced nonexudative form of AMD is represented by the presence of atrophy that can be associated with severe central visual field loss.  The exudative form is associated with the development of choroidal neovascular membranes that result in the development of exudate, subretinal fluid, and hemorrhage.

Over 90% of patients diagnosed with AMD have nonexudative (dry) AMD; nonexudative (dry) AMD is generally associated with much slower (over decades), progressive visual loss, as compared to exudative (wet) AMD, which is generally associated with more rapid (over months) visual loss.  However, the more advanced cases of dry AMD can have as profound a visual loss as those suffering from 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), retinal pigment epithelium (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. At times, the step prior to the onset of visual loss has been classified as AMD if the patient has characteristic drusen and relevant family history.

The disease usually manifests itself 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 AMD is referred to as "wet," while the more prevalent form is known as "dry." 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. It can develop neovascularization and result in a more rapid loss of vision.

Antioxidant multivitamin therapy has been shown in a large clinical trail to be helpful in decreasing the risk of visual loss in this disorder. Additional therapies that have been tried include rheopheresis (apheresis) and laser to drusen. While these newer therapies may have a small benefit over the short term (1-3 y), they did not prove to have any significant benefit after that time.

Pathophysiology

Clinical pathophysiology

The clinical definition of early AMD varies with the source consulted. A 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.

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 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. The disease 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) with 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, recent data 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.  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 to 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 recent publication that indicates that choroidal levels of CRP are elevated in homozygote CFH polymorphic individuals.¹

Frequency

United States

AMD is the leading cause of blindness in the United States for people older than 50 years. Actual frequency of the disease depends on specific racial group studies. It is more prevalent in Caucasians 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 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% for those younger than 50 years, 2% at 70 years, and 6% at 80 years. In African Americans, dry AMD is noted to be approximately one half of the above incidence rate.

International

Incidence in Japanese and other Asian populations is lower than the Caucasian population in the United States, but recent reports suggest that incidence is increasing. The Inuit in Greenland have a significantly higher incidence as well as a distinctive phenotype. Most Africans and other pigmented races in general have a lower incidence of symptomatic macular degeneration. Similarly, it is evident that the lesions due to AMD in Asian populations are different from that in Caucasian 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.

Mortality/Morbidity

Significant visual morbidity resulting from AMD occurs. The presence of neovascularization results in a blurry central visual field. Even in dry AMD, with relatively good vision, patients often complain of 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).

It has also been noted that patients with AMD, especially the exudative variant, have a higher incidence of cerebrovascular accidents and cardiac disease.

Race

Incidence is higher in Caucasians compared to African Americans. Some studies report a rate that is about one half in African West-Indians in Barbados when compared to Caucasians in Baltimore. Incidence in Asians is between the above two rates, although it appears that incidence is increasing in this population.

Sex

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

Age

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

CLINICAL

Section 3 of 11  

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History

Patients 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.
• It is common for patients to report visual fluctuation (ie, they report days when their 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.

Physical

Funduscopic examination 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 AMD, these focal islands of atrophy coalesce and form large zones of atrophy with severely affected vision.
• Other signs of choroidal neovascularization include RPE elevation, exudate, or subretinal fluid. 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 AMD often has areas of drusen, as well as RPE mottling and atrophy.

Causes

Oxidative stress is believed to play a major role in the pathogenesis of AMD because of combined exposures of the retina to light and oxygen.  Additionally, it is now widely accepted that AMD is a genetically inherited disorder with late onset.

Recent 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 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.² In fact, 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 AMD.  In fact, 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 as to their relationship with AMD in the National Eye Institute–sponsored Age Related Eye Disease Study (AREDS). A recent report suggests dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with the development of neovascular AMD (though not nonexudative AMD).³ Similarly, those with higher fish consumption had a slightly lower incidence of developing neovascular AMD.
• Studying twins with AMD, Seddon and others arrived at some interesting conclusions.⁴ Current cigarette smoking increased the risk of developing AMD by 1.9-fold, and past smoking still increased the risk by 1.7-fold.  Both increased consumption of fish (>2 servings of fish per week) and a higher intake of omega-3 fatty acids 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.

DIFFERENTIALS

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Other Problems to be Considered

Sorsby dystrophy
Malattia leventinese
Doyne honeycomb dystrophy
North Carolina macular dystrophy
Cuticular drusen
Serpiginous choroidopathy

WORKUP

Section 5 of 11  

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Lab Studies

• Fluorescein angiography is of value if the 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 RPE elevation, subretinal hemorrhage, and/or presence of exudate.
• Fluorescein angiography is performed by injecting 3 cc 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 and 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.

Imaging Studies

• Dry AMD is followed best by accurate fundus photography.
• 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 GA progresses; unfortunately, it is almost impossible to discern these symptoms from the symptoms that occur when neovascularization has occurred. Therefore, a patient with 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.

Other Tests

• Recent reports 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.
• 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.

Procedures

• Amsler grid evaluation, slit lamp biomicroscopy, and fluorescein angiography
• • 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.

Histologic Findings

The earliest morphologic features of dry AMD 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 either 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.

TREATMENT

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Medical Care

Primary prevention

• Role of vitamins, antioxidants, risk of smoking, and hypertension: There is evidence that patients with early or moderate dry AMD 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. Specific data that suggest the benefit of antioxidant supplementation are provided below:
• • The first AREDS study was recently 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.
  • The Rotterdam Study (1990–1993) investigated whether regular dietary intake of antioxidants was associated with a lower risk of incident AMD in over 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 (AREDS 2) is currently underway. Its primary objective is to determine whether oral supplementation with macular xanthophylls (lutein at 10 mg/d plus zeaxanthin at 2 mg/d) or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs; DHA plus eicosapentaenoic acid at a total of 1 g/d) will decrease the risk of progression to advanced AMD, as compared with placebo. 
• 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. 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.
• Epidemiologic studies using a computer database previously indicated that the use of statins was protective against the development of AMD. However, a recent study, using rigorous systems and graded macular photographs, confirmed that the use of statins was not correlated with AMD incidence or progression.⁵
• 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, there are many risks in long-term treatment with zinc, vitamin A, or vitamin E.  Family members of patients with AMD are instead asked to do the following:
• • Avoid smoking or 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

Surgical Care

No accepted surgical alternative to dry AMD 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. The Complications Of Age-Related Macular Degeneration Prevention Trial (CAPT), a National Eye Institute sponsored study examining the visual benefit from such treatment, recently concluded. Preliminary results indicated 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 to those who did not get treated.  Additionally, at the end of the study, there was no significant visual benefit to those who were treated compared to those who did not get any laser treatment.

More recently, a few patients obtained retinal translocation surgery where the retina is rotated.  Many of these patients developed accelerated dry macular degeneration with RPE atrophy at the site of the new macula.  The procedure's benefits are questionable at this time.

Consultations

Serial general ophthalmologic examination, on a nonemergent basis, is indicated for patients with dry AMD. 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.

Diet

Recent evidence suggests that diet plays an important role in the prevention of dry AMD. Epidemiologic studies suggest that a diet containing green leafy vegetables is of benefit. Smoking cessation is of significant benefit.  Baked fresh fish are also beneficial due to the fatty acids provided; 1-2 servings a week are adequate.

Activity

No limitations exist. Each state has specific visual acuity criteria for driving with a private license. Commercial driving licenses typically require at least 20/40 in the worse eye and have other typical requirements for side vision.

MEDICATION

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Currently, no approved drug treatment of dry AMD is available. See Surgical Care  for the possible beneficial effects of laser therapy.

FOLLOW-UP

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Further Outpatient Care

• Patients with dry AMD 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.

In/Out Patient Meds

• No approved medications for the treatment of dry AMD are available.

Complications

• The major complication of dry AMD is the conversion to wet (or exudative/neovascular) AMD.

Prognosis

• Prognosis for this disease is significantly better than the prognosis for wet AMD. 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.

Patient Education

• Patients with 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 macular degeneration complain of 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. In fact, some of these patients have to scan the screen to be able to see the 20/400 character. In these patients, excess magnification would be detrimental, as 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.
• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Macular Degeneration.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Examining patients who report a new onset of symptoms in a timely manner is imperative. Patients should be examined for neovascular changes and treated appropriately.

MULTIMEDIA

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Media file 1:  A normal-appearing macula of the left eye. Note the even pigmentation of the retinal pigment epithelium and the absence of any yellow excrescences (drusen) in the fovea. The optic nerve has unrelated changes.
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Media file 2:  An angiogram of Media file 1. In angiography, fluorescein dye is passed through a peripheral vein and transmits through the vascular system. The dye fluoresces in the vasculature, as seen here. There are no vascular prominences in the macula or any areas of dye pooling or staining. The abnormal vessels in the optic nerve, however, do show dye leakage.
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Media type:  Photo

Media file 3:  Mild nonexudative age-related macular degeneration is shown with the presence of drusen (yellow deposits) in the macular region.
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Media file 4:  An angiogram of Media file 3, showing the staining of drusen. Drusen absorb dye and, in the late frames of the angiogram, show hyperfluorescence. This staining is distinguished from the leakage that occurs when the dye spreads outside the boundary of the lesion.
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Media type:  Photo

Media file 5:  A more advanced case of nonexudative age-related macular degeneration (AMD). This image shows drusen that are larger, more confluent, and soft. Soft drusen are defined as drusen that have indistinct borders. Such drusen are more likely to convert to wet AMD. There are a few areas of atrophy, where the retinal pigment epithelium (RPE) has lost pigmentation. The retinal cells overlying atrophic RPE are generally nonfunctional and result in a scotoma.
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Media type:  Photo

Media file 6:  An angiogram of Media file 5. The atrophic retinal pigment epithelium (RPE) demonstrates staining of the underlying choroidal vasculature. Normally, the intact RPE masks the presence of choroidal fluorescence. However, when the RPE atrophies, the underlying dye appears as an area of hyperfluorescence in the early stages of angiography. In the late stages, the drusen lose fluorescence in concert with (or with a small time lag) the rest of the retinal layers.
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Media type:  Photo

Media file 7:  A more advanced case of dry age-related macular degeneration. Several areas of atrophy are present as well as areas of significant pigment mottling in the macula. The large drusen inferior to fixation are poorly distinguished from each other.
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Media file 8:  An angiogram of Media file 7. The atrophic areas are easily distinguished by the hyperfluorescence of the retinal pigment epithelium (RPE) in the mid phase of the angiogram. There are areas where there is hypofluorescence of dye due to masking caused by the increased pigmentation. No areas of frank dye leakage or exudative age-related macular degeneration (AMD) are apparent. A "hot cross bun" pattern of dry AMD related pigment changes is evident near the fovea.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
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2. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. Sep 2006;38(9):1055-9. [Medline].
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13. Evans JR. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2006;(2):CD000254. [Medline].
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Article Last Updated: Sep 18, 2007