Macular degeneration

Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness in the elderly (>50 years). Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life.

The inner layer of the eye is the retina, which contains nerves that communicate sight, and behind the retina is the choroid, which contains the blood supply to the retina. In the dry (nonexudative) form, cellular debris called drusen accumulate between the retina and the choroid, and the retina can become detached. In the wet (exudative) form, which is more severe, blood vessels grow up from the choroid behind the retina, and the retina can also become detached. It can be treated with laser coagulation, and with medication that stops and sometimes reverses the growth of blood vessels.

Although some macular dystrophies affecting younger individuals are sometimes referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD).

Age-related macular degeneration

Age-related macular degeneration begins with characteristic yellow deposits in the macula (central area of the retina which provides detailed central vision, called fovea) called drusen between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) have good vision. People with drusen can go on to develop advanced AMD. The risk is considerably higher when the drusen are large and numerous and associated with disturbance in the pigmented cell layer under the macula. Recent research suggests that large and soft drusen are related to elevated cholesterol deposits and may respond to cholesterol lowering agents.

Researchers from the University of Southampton reported October 7, 2008 that they had discovered six mutations of the gene Serping1 that are associated with AMD. Their findings were reported in the British medical journal The Lancet.

Advanced AMD, which is responsible for profound vision loss but never total blindness, has two forms: dry and wet. Central geographic atrophy, the “dry” form of advanced AMD, results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. While no treatment is available for this condition, vitamin supplements with high doses of antioxidants, lutein and zeaxanthin, have been demonstrated by the National Eye Institute and others to slow the progression of dry macular degeneration and, in some patients, improve visual acuity.

Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth in the choriocapillaries, through Bruch's membrane, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated.

Until recently, no effective treatments were known for wet macular degeneration. However, new drugs, called anti-angiogenics or anti-VEGF (anti-Vascular Endothelial Growth Factor) agents, when injected directly into the vitreous humor of the eye using a small, painless needle, can cause regression of the abnormal blood vessels and improvement of vision. The injections frequently have to be repeated on a monthly or bi-monthly basis. Examples of these agents include Lucentis, Avastin (a close chemical relative of Lucentis) and Macugen. Only Lucentis and Macugen are FDA-approved as of April 2007. Macugen has been found to have only minimal benefits in neovascular AMD and is no longer used. Worldwide, Avastin has been used extensively despite its "off label" status. The cost of Lucentis is approximately US$2000 per treatment while the cost of Avastin is approximately US$150 per treatment. Both drugs are made by Genentech.

Risk factors

• Aging: Approximately 10% of patients 66 to 74 years of age will have findings of macular degeneration. The prevalence increases to 30% in patients 75 to 85 years of age.
• Family history: The lifetime risk of developing late-stage macular degeneration is 50% for people who have a relative with macular degeneration, versus 12% for people who do not have relatives with macular degeneration, a fourfold higher risk.
• Macular degeneration gene: The genes for the complement system proteins factor H (CFH) and factor B (CFB) have been determined to be strongly associated with a person's risk for developing macular degeneration. CFH is involved in inhibiting the inflammatory response mediated via C3b (and the Alternative Pathway of complement) both by acting as a cofactor for cleavage of C3b to its inactive form, C3bi, and by weakening the active complex that forms between C3b and factor B. C-reactive protein and polyanionic surface markers such as glycosaminoglycans normally enhance the ability of factor H to inhibit complement . But the mutation in CFH(Tyr402His) reduces the affinity of CFH for CRP and probably also alters the ability of factor H to recognise specific glycosaminoglycans. This change results in reduced ability of CFH to regulate complement on critical surfaces such as the specialised membrane at the back of the eye and leads to increased inflammatory response within the macula. In two 2006 studies at Yale Department of Epidemiology and Public Health and the Department of Ophthalmology and Visual Sciences, Moran Eye Center at the University of Utah School of Medicine, another gene that has implications for the disease, called HTRA1 (encoding a secreted serine protease), was identified.

The mitochondrial genome (mtDNA) in humans is contained on a single circular chromosome 16,569 basepairs around, and each mitochondrion contains 5 to 10 copies of the mitochondrial chromosome. There are several essential genes in mtDNA that are involved in replication and translation, along with some genes that are crucial for the machinery that converts metabolic energy into ATP. These include NADH dehydrogenase, cytochrome c oxidase, ubiquinol/cytochrome c oxidoreductase, and ATP synthase, as well as the genes for unique Ribosomal RNA and Transfer RNA particles that are required for translating these genes into proteins.

There are specific diseases associated with mutations in some of these genes. Below is one of the affected genes and the disease which arises from its mutation.

Mutation of the ATP synthase gene: Retinitis Pigmentosa (RP) is a genetically linked dysfunction of the retina and is related to mutation of the Adenosine Tri-Phosphate (ATP) Synthase Gene 615.1617

Stargardt’s disease (STGD, also known as Juvenile Macular Degeneration) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbor the STGD gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM.

• Drusen

CMSD studies indicate that drusen are similar in molecular composition to plaques and deposits in other age-related diseases such as Alzheimer's disease and atherosclerosis.

While there is a tendency for drusen to be blamed for the progressive loss of vision, drusen deposits can, however, be present in the retina without vision loss. Some patients with large deposits of drusen have normal visual acuity. If normal retinal reception and image transmission are sometimes possible in a retina when high concentrations of drusen are present, then even if drusen can be implicated in the loss of visual function, which indicates there must be at least one other factor that accounts for the loss of vision. Retinitis Pigmentosa (RP) is a genetically linked dysfunction of the retina and is related to mutation of the ATP Synthase Gene 63.

• Arg80Gly variant of the complement protein C3 A genetic study published in the New England Journal of Medicine in 2007 showed that a certain, common mutation in the C3 gene which is a central protein of the complement system is strongly associated with the occurrence of Age-related Macular Degeneration. The authors consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.
• Hypertension: Also known as high blood pressure.
• Cardiovascular status — high cholesterol, obesity.
• High fat intake is associated with an increased risk of macular degeneration in both women and men. Fat provides about 42% of the food energy in the average American diet. A diet that derives closer to 20-25% of total food energy from fat is probably healthier. Reducing fat intake to this level means cutting down greatly on consumption of red meats and high-fat dairy products such as whole milk, cheese, and butter. Eating more cold-water fish (at least twice weekly), rather than red meats, and eating any type of nuts may help macular degeneration patients.
• Oxidative stress: It has been proposed that age related accumulation of low molecular weight, phototoxic, pro-oxidant melanin oligomers within lysosomes in the retinal pigment epithelium may be partly responsible for decreasing the digestive rate of photoreceptor outer rod segments (POS) by the RPE. A decrease in the digestive rate of POS has been shown to be associated with lipofuscin formation - a classic sign associated with macular degeneration.
• Fibulin-5 mutation Rare forms of the disease are caused by geneic defects in fibulin-5, in an autosomal dominant manner. In 2004 Stone et al performed a screen on 402 AMD patients and revealed a statistically significant correlation between mutations in Fibulin-5 and incidence of the disease. Furthermore the point mutants were found in the Calcium binding sites of the cbEGF domains of the protein. there is no structural basis for the effects of the mutations.
• Race Macular degeneration is more likely to be found in whites than in blacks.
• Exposure to sunlight especially blue light. There is conflicting evidence as to whether exposure to sunlight contributes to the development of macular degeneration. A recent study in the British Journal of Ophthalmology on 446 subjects found that it does not. Other research, however, has shown that High-energy visible light (HEV) may contribute to age-related macular degeneration.

Signs

• Drusen
• Pigmentary alterations
• Exudative changes: hemorrhages in the eye, hard exudates, subretinal/sub-RPE/intraretinal fluid
• Atrophy: incipient and geographic
• Visual acuity drastically decreasing (two levels or more) ex: 20/20 to 20/80.

Symptoms

• Blurred vision: Those with nonexudative macular degeneration may be asymptomatic or notice a gradual loss of central vision, whereas those with exudative macular degeneration often notice a rapid onset of vision loss.
• Central scotomas (shadows or missing areas of vision)
• Distorted vision (i.e. metamorphopsia) - A grid of straight lines appears wavy and parts of the grid may appear blank. Patients often first notice this when looking at mini-blinds in their home.
• Trouble discerning colors; specifically dark ones from dark ones and light ones from light ones.
• Slow recovery of visual function after exposure to bright light

The Amsler Grid Test is one of the simplest and most effective methods for patients to monitor the health of the macula. The Amsler Grid is essentially a pattern of intersecting lines (identical to graph paper) with a black dot in the middle. The central black dot is used for fixation (a place for the eye to stare at). With normal vision, all lines surrounding the black dot will look straight and evenly spaced with no missing or odd looking areas when fixating on the grid's central black dot. When there is disease affecting the macula, as in macular degeneration, the lines can look bent, distorted and/or missing. See a video on how to use an Amsler grid here:

Macular degeneration by itself will not lead to total blindness. For that matter, only a very small number of people with visual impairment are totally blind. In almost all cases, some vision remains. Other complicating conditions may possibly lead to such an acute condition (severe stroke or trauma, untreated glaucoma, etc.), but few macular degeneration patients experience total visual loss. The area of the macula comprises about 5% of the retina and is responsible for about 35% of the visual field. The remaining 65% (the peripheral field) remains unaffected by the disease.

The loss of central vision profoundly affects visual functioning. It is not possible, for example, to read without central vision. Pictures which attempt to depict the central visual loss of macular degeneration with a black spot do not really do justice to the devastating nature of the visual loss. This can be demonstrated by printing letters 6 inches high on a piece of paper and attempting to identify them while looking straight ahead and holding the paper slightly to the side. Most people find this surprisingly difficult to do.

Similar symptoms with a very different etiology and different treatment can be caused by Epiretinal membrane or macular pucker or leaking blood vessels in the eye..

Diagnosis

Fluorescein angiography allows for the identification and localization of abnormal vascular processes. Optical coherence tomography is now used by most ophthalmologists in the diagnosis and the followup evaluation of the response to treatment by using either Avastin or Lucentis which are injected into the vitreous of the eye at various intervals.

Prevention

The Age-Related Eye Disease Study showed that a combination of high-dose beta-carotene, vitamin C, vitamin E, and zinc can reduce the risk of progressing from early to advanced AMD by about 25 percent. A followup study, Age-Related Eye Disease Study 2, to study the potential benefits of lutein, zeaxanthine, and fish oil, is underway.

Anecortave acetate (Retanne), an anti-angiogenic drug that is given as an injection behind the eye, is currently being studied for reducing risk of neovascular (wet) AMD in high-risk patients.

Studies are underway at Harvard, with the goal of reducing lipofuscin accumulation.

In 2007, a study at the National Eye Institute, Maryland found that Lutein and zeaxanthin (nutrients in eggs and green vegetables) protect against macular degeneration.

Studies found that antioxidants disrupt the link of two processes that cause macular degeneration and extend the lifetime of irreplaceable photoreceptors and other retinal cells.

Juvenile macular degeneration

Juvenile macular degeneration is not a term in standard usage at this time. The preferred term for conditions that affect the macula in younger individuals related to genetics is macular dystrophy. Examples of these include:

• Best's disease
• Doyne's honeycomb retinal dystrophy
• Sorsby's disease
• Stargardt's disease

The first genetic link to juvenile macular degeneration was discovered at the Cleveland Clinic.

Impact

Macular degeneration can advance to legal blindness and inability to drive. It can also result in difficulty or inability to read or see faces.

Adaptive devices can help people read. These include magnifying glasses, special eyeglass lenses, desktop and portable electronic devices, and computer screen readers such as JAWS for Windows.

Accessible publishing also aims to provide a variety of fonts and formats for published books to make reading easier. This includes much larger fonts for printed books, patterns to make tracking easier, audiobooks and DAISY books with both text and audio.

References

External links

• Macular Degeneration Research
• Information and support for AMD patients
• Age Related Macular Degeneration Support
• 'Robo' Gene Fights Macular Degeneration
• Age related macular degeneration caused by immune system, summary of peer review article
• Artificial Retina Project - U.S. Department of Energy Office of Science