eMedicine Specialties > Ophthalmology > Retina

ARMD, Nonexudative

Author: Raj K Maturi, MD, Clinical Associate Professor, Department of Ophthalmology, Indiana University School of Medicine
Contributor Information and Disclosures

Updated: Sep 18, 2007

Introduction

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

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.

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