Macular degeneration

Macular degeneration
Classification and external resources
Picture of the fundus showing intermediate age-related macular degeneration.
ICD-10	H35.3
ICD-9	362.50
DiseasesDB	11948
MedlinePlus	001000
eMedicine	article/1223154
MeSH	D008268

Human eye cross-sectional view

Age related macular degeneration is a medical condition which usually affects older adults that 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 visual impairment in older adults (>50 years).^[1] 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; behind the retina is the choroid, which contains the blood supply to the macula (the central part of 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.^[2][3]

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 begins with characteristic yellow deposits in the macula (central area of the retina, which provides detailed central vision, called the 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.

Classification

Dry AMD

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. No medical or surgical treatment is available for this condition, however vitamin supplements with high doses of antioxidants, lutein and zeaxanthin, have been suggested by the National Eye Institute and others to slow the progression of dry macular degeneration and, in some patients, improve visual acuity.^[4]

Beta-carotene was not protective^[4]. See also Nutritional supplements (below).

Wet AMD

Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, 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, can cause regression of the abnormal blood vessels and improvement of vision when injected directly into the vitreous humor of the eye. The injections have to be repeated on a monthly or bi-monthly basis. Examples of these agents include ranibizumab (trade name Lucentis), bevacizumab (trade name Avastin, a close chemical relative of ranibizumab) and pegaptanib (trade name Macugen). Only ranibizumab and pegaptanib are approved by the FDA for AMD as of April 2007. Bevacizumab is approved, but for other indications. Pegaptanib (Macugen) has been found to have benefits in neovascular AMD. Worldwide, bevacizumab has been used extensively despite its "off label" status. The cost of ranibizumab (Lucentis) is approximately US$2000 per treatment while the cost of bevacizumab (Avastin) is approximately US$150 per treatment. Both drugs are made by Genentech. The UK NICE institute has issued guidelines for their use within the NHS.

Photodynamic therapy has also been used to treat wet AMD.^[5]

Signs and symptoms

Normal vision (B&W)

The same view with age-related macular degeneration (B&W)

• 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.
• Preferential hyperacuity perimetry changes (for wet AMD) ^[6][7]

• 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
• A loss in contrast sensitivity.

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.^[8] The area of the macula comprises only about 2.1% of the retina, and the remaining 97.9% (the peripheral field) remains unaffected by the disease. Interestingly, even though the macula provides such a small fraction of the visual field, almost half of the visual cortex is devoted to processing macular information.^[9]

The loss of central vision profoundly affects visual functioning. It is not possible, for example, to read without central vision. Pictures that 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 difficult to do.

There is a loss of contrast sensitivity, so that contours, shadows, and color vision are less vivid. The loss in contrast sensitivity can be quickly and easily measured by a contrast sensitivity test performed either at home or by an eye specialist.

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.

Cause

• 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.^[10]
• Family history: The lifetime risk of developing late-stage macular degeneration is 50% for people that have a relative with macular degeneration, versus 12% for people that do not have relatives with macular degeneration, a fourfold higher risk.^[10] 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. Mutations in this gene can also cause hereditary angioedema.^[11]
• Macular degeneration gene: The genes for the complement system proteins factor H (CFH) and factor B (CFB) and factor 3 (C3) 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 activecomplex 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.^[12][13]
  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 that 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.^[14]

• 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, 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 Two independent genetic studies from two groups published in the New England Journal of Medicine and Nature Genetics 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.^[15][16] The authors of both papers 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^[17] (at least twice weekly), rather than red meats, and eating any type of nuts may help macular degeneration patients.^[18]

• 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.^[19][20]

• 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 Caucasians than in people of African descent.^[21][22]

• 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.^[23] Other research, however, has shown that High-energy visible light (HEV) may contribute to age-related macular degeneration.^[24][25][26]

• Smoking Smoking tobacco increases the risk of macular degeneration by two to three times that of someone who has never smoked, and may be the most important modifiable factor in its prevention. A review of previous studies found that "the literature review confirmed a strong association between current smoking and AMD. ... Cigarette smoking is likely to have toxic effects on the retina." ^[27]

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

There is a method called Alta Eficacia Method, that helps to prevent the aged-related macular degeneration by a filter. This filter prevents passage of part of the spectrum of blue and violet light, to protect the user against avoidable blindness.^[28]

The violet light of the visible spectrum has been related to the physiopathogenesis of age-related macular degeneration (AMD), which is the leading cause of irreversible and avoidable blindness in the developed world.^[29]

Alta Eficacia Tecnología is the owning firm of the patent Therapeutic Contact Lens for Pseudophakic Eyes and/or Eyes Suffering Neurodegeneration, which hypothetically provides protection against avoidable blindness, developed by Celia Sánchez-Ramos.^[30]

Management

Some evidence supports a reduction in the risk of age-related macular degeneration with increasing intake of two carotenoids, lutein and zeaxanthin^[31] and a large clinical trial is running from 2008 to 2014 to see if they can influence the progression of this disease.^[32]

Consuming omega-3 fatty acids (DHA & EPA) has been correlated with a reduced progression of early ARMD, and in conjunction with low glycemic index foods, with reduced progression of advanced ARMD.^[33]

An earlier, Cochrane Database Review of publications to 2007 found that the use of vitamin and mineral supplements, alone or in combination, by the general population had no effect on age-related macular degeneration,^[34] a finding echoed by another review.^[35] A 2006 Cochrane Review of the effects of vitamins and minerals on the slowing of ARMD found that positive results mainly came from a single large trial in the United States (the Age-Related Eye Disease Study, with funding from the eye care product company Bausch & Lomb who also manufactured the supplements used in the study^[36]), and questioned the generalization of the data to any other populations with different nutritional status. The review also questioned the possible harm of such supplements, given the increased risk of lung cancer in smokers with high intakes of beta-Carotene, and the increased risk of heart failure in at-risk populations who consume high levels of vitamin E supplements.^[37]

Prognosis

Josef Tal, an Israeli composer who has been affected by macular degeneration, checks a manuscript using a CCTV desktop unit.

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, and computer screen readers such as JAWS for Windows. One of the simplest to use assistive technology for low vision is known as a desktop unit. Desktop systems are perfect for extended periods of reading and writing. These units consist of a CCTV, monitor and a movable XY table. The camera is aimed at a book and enables the user to zoom-in and magnify the printed material to the size he can read. 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.

With internet text easily cut-and-pasted into other applications, a very simple process can make reading far easier for patients with ARMD. Inverting the text (changing black-on-white to white-on-black) almost eliminates the problem of excessive bright light surrounding the letters, while increasing font size further reduces it. The author of this paragraph routinely reads internet articles by doing this, as follows:

1. Click "select all" (Ctrl-A) in Windows, to highlight the article or text.
2. Copy (Crtl-C) and-paste (Ctrl-V) the article into Notepad, to reduce the article to plain text, for easy copying.
3. Copy the text again in Notepad, then paste it into Microsoft Word, or similar application.
4. Increase the font size, say to 24-point type.
5. Change the background color of the document to black, and the font color to white. Using a special "template" document for this purpose eliminates the step of having to reformat each new document.

Another alternative that achieves the same result is squinting, as it also reduces the surrounding bright light. Individuals who find it impossible to read normal text can extend the life of their ability to read by many years, with this simple adjustment.

Because the peripheral vision is not affected, people with macular degeneration can learn to use their remaining vision to continue most activities.^[38] Assistance and resources are available in many countries and every state in the U.S.^[39] Classes for "independent living" are given and some technology can be obtained from a state department of rehabilitation.

Amsler Grid Test

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, in essence, 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: [1] and watch an animation showing the Amsler grid with macular degeneration here: [2]. A copy of an Amsler grid that is suitable for printing can be downloaded here:[3].

Epidemiology

Disability-adjusted life year for macular degeneration and other (sense organ diseases) per 100,000 inhabitants in 2004.^[40]

     no data      less than 100      100-114      114-128      128-142      142-156      156-170      170-184      184-198      198-212      212-226      226-240      more than 240

See also

• Cherry-red spot
• Fuchs spot
• Micropsia

External links

• Macular Degeneration Foundation
• Macular Degeneration Support
• National Eye Institute
• Neovascularization analysis in ocular pathologies
• English Site of German organization SOS Eye Sight e.V.

References