| Macular degeneration |
|
Picture of the fundus showing intermediate age-related macular degeneration
|
| Classification and external resources |
| ICD-10 |
H35.3 |
| ICD-9 |
362.50 |
| DiseasesDB |
11948 |
| MedlinePlus |
001000 |
| eMedicine |
article/1223154 |
| Patient UK |
Macular degeneration |
| MeSH |
D008268 |
Human eye cross-sectional view
Macular degeneration, often age-related macular degeneration (AMD or ARMD), is a medical condition that usually affects older adults and 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 and visual impairment in older adults (>50 years), afflicting 30-50 million people globally.[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.
Although some macular dystrophies affecting younger individuals are sometimes rarely referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD).
The retina is a network of visual receptors and nerves. It lies on the choroid, a network of blood vessels that supply the retina with blood.
In the dry (nonexudative) form, cellular debris called drusen accumulates between the retina and the choroid, causing atrophy and scarring to the retina. In the wet (exudative) form, which is more severe, blood vessels grow up from the choroid behind the retina which can leak exudate and fluid and also cause hemorrhaging. It can be treated with laser coagulation, and more commonly with medication that stops and sometimes reverses the growth of blood vessels.[2][3]
Contents
- 1 Signs and symptoms
- 2 Causes and risk factors
- 3 Genetics
- 4 Pathophysiology
- 5 Diagnosis
- 6 Management
- 6.1 Dry AMD
- 6.2 Wet AMD
- 6.3 Drug Interventions
- 6.4 Nondrug interventions
- 6.5 Adaptive devices
- 7 Research directions
- 8 Notable cases
- 9 See also
- 10 References
- 11 Further reading
- 12 External links
Signs and symptoms
The same view with age-related macular degeneration (National Eye Institute)
Signs and symptoms of macular degeneration include:
- Drusen, tiny accumulations of extracellular material that build up on the retina
- Pigmentary changes
- Distorted vision in the form of metamorphopsia, in which a grid of straight lines appears wavy and parts of the grid may appear blank: Patients often first notice this when looking at things like miniblinds in their home or telephone poles while driving.
- Exudative changes: hemorrhages in the eye, hard exudates, subretinal/sub-RPE/intraretinal fluid
- Slow recovery of visual function after exposure to bright light (photostress test)
- Atrophy: incipient and geographic
- Visual acuity drastically decreasing (two levels or more), e.g.: 20/20 to 20/80
- Preferential hyperacuity perimetry changes (for wet AMD)[4][5]
- 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 (often caused by leakage and bleeding of abnormal blood vessels).
- Central scotomas (shadows or missing areas of vision)
- Trouble discerning colors, specifically dark ones from dark ones and light ones from light ones
- A loss in contrast sensitivity
- Straight lines appear curved in an Amsler grid
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, mainly peripheral. 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.[6] 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.[7]
The loss of central vision profoundly affects visual functioning. It is quite difficult, 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 six 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 any other condition affecting the macula, such as central serous retinopathy.
Causes and risk factors
Disability-adjusted life year for macular degeneration and other (sense organ diseases) per 100,000 inhabitants in 2004[8]
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
- Aging: About 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.[9]
- 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.[9] Researchers from the University of Southampton reported they had discovered six mutations of the gene SERPING1 that are associated with AMD. Mutations in this gene can also cause hereditary angioedema.[10]
- Macular degeneration gene: The genes for the complement system proteins factor H (CFH), factor B (CFB) and factor 3 (C3) are strongly associated with a person's risk for developing AMD. 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, another gene that has implications for the disease, called HTRA1 (encoding a secreted serine protease), was identified.[11][12]
The mitochondrial genome (mtDNA) in humans is contained on a single circular chromosome, 16,569 basepairs around, and each mitochondrion contains five to 10 copies of the mitochondrial chromosome. Several essential genes in mtDNA 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.
Specific diseases are associated with mutations in some of these genes. Below is one of the affected genes and the disease that arises from its mutation.
- Stargardt's disease (juvenile macular degeneration, STGD) 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 transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbor this 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.[13]
- Drusen: CMSD studies indicate 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 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.
- Arg80Gly variant of the complement protein C3: Two independent studies published in the New England Journal of Medicine and Nature Genetics in 2007 showed a certain common mutation in the C3 gene, which is a central protein of the complement system, is strongly associated with the occurrence of AMD.[14][15] The authors of both papers consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.
- Hypertension (high blood pressure) Individuals with high blood pressure are more likely to be affected by age-related macular degeneration. This is because high blood pressure, like smoking, leads to a constriction, or narrowing, of the blood vessels in the choroid which gives blood and oxygen to the retina. This constriction limits the amount of blood able to circulate and give blood and oxygen to the retina and therefore having a negative effect on its health.[medical citation needed]
- Cholesterol: Elevated cholesterol may increase the risk of AMD[16]
- Obesity: Abdominal obesity is a risk factor, especially among men[17]
- Fat intake Consuming high amounts of certain fats likely contributes to AMD, while monounsaturated fats are potentially protective.[18] In particular, ω-3 fatty acids may decrease the risk of AMD.[19]
- Oxidative stress: 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 AMD.[20][21]
- Fibulin-5 mutation: Rare forms of the disease are caused by genetic 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.[22][23]
- Exposure to sunlight, especially blue light: Evidence is conflicting as to whether exposure to sunlight contributes to the development of macular degeneration. A recent study on 446 subjects found it does not.[24] Other research, however, has shown high-energy visible light may contribute to AMD.[25][26][27]
- Vitamin D deficiency: higher vitamin D levels are associated with lower age-related macular degeneration risk in women[28]
- Smoking: Smoking tobacco increases the risk of AMD 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 "the literature review confirmed a strong association between current smoking and AMD. ... Cigarette smoking is likely to have toxic effects on the retina."[29]
- Deletion of CFHR3 and CFHR1: Deletion of the complement factor H-related genes CFHR3 and CFHR1 protects against AMD.[30][31]
Genetics
A practical application of AMD-associated markers is in the prediction of progression of AMD from early stages of the disease to neovascularization.[32][33]
Early work demonstrated a family of immune mediators was plentiful in drusen.[34] Complement factor H (CFH) is an important inhibitor of this inflammatory cascade, and a disease-associated polymorphism in the CFH gene strongly associates with AMD.[35][36][37][38][39] Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced.[40][41] Lending credibility to this has been the discovery of disease-associated genetic polymorphisms in other elements of the complement cascade including complement component 3 (C3).[42]
The role of retinal oxidative stress in the etiology of AMD by causing further inflammation of the macula is suggested by the enhanced rate of disease in smokers and those exposed to UV irradiation.[43][44][45] Mitochondria are a major source of oxygen free radicals that occur as a byproduct of energy metabolism. Mitochondrial gene polymorphisms, such as that in the MT-ND2 molecule, predicts wet AMD.[46][47]
A powerful predictor of AMD is found on chromosome 10q26 at LOC 387715. An insertion/deletion polymorphism at this site reduces expression of the ARMS2 gene though destabilization of its mRNA through deletion of the polyadenylation signal.[48][49] ARMS2 protein may localize to the mitochondria and participate in energy metabolism, though much remains to be discovered about its function.
Other gene markers of progression risk includes tissue inhibitor of metalloproteinase 3 (TIMP3), suggesting a role for intracellular matrix metabolism in AMD progression. Variations in cholesterol metabolising genes such as the hepatic lipase, cholesterol ester transferase, lipoprotein lipase and the ABC-binding cassette A1 correlate with disease progression. The early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome-wide association studies.[50][51]
Pathophysiology
Starting from the inside of the eye and going towards the outer surface, the three main layers at the back of the eye are the retina, which is light-sensitive tissue that is considered part of the central nervous system and is actually brain tissue; the choroid, which is made up of a web of blood vessels; and the sclera, which is the tough, white, outer layer of the eye.
Dry AMD
Age-related macular degeneration begins with characteristic yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) still have good vision. People with drusen may or may not develop AMD, in fact the majority of people over age 55 have drusen with no negative effects. The risk of developing symptoms is higher when the drusen are large and numerous and associated with disturbance in the pigmented cell layer under the macula. Large and soft drusen are thought to be related to elevated cholesterol deposits.
Central geographic atrophy, the "dry" form of advanced AMD, results from atrophy of 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.
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. The proliferation of abnormal blood vessels in the retina is stimulated by vascular endothelial growth factor (VEGF). Unfortunately, these new vessels are fragile, 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. Only about 10% of patients suffering from macular degeneration have the wet type.[citation needed]
Diagnosis
Super resolution microscopic investigation of human eye tissue affected by AMD
The major symptoms of macular degeneration:[52]
- When viewing an Amsler grid, some straight lines appear wavy and some patches appear blank
- When viewing a Snellen chart, at least 2 lines decline
- In dry macular degeneration, which occurs in 85-90 percent of AMD cases, drusen spots can be seen in Fundus photography
- In wet macular degeneration, using angiography we can see leakage of bloodstream behind the macula
- Using an electroretinogram, points in the macula with a weak or absent response compared to a normal eye may be found
- Visual acuity and color sensitivity should be similar for red, green and blue (RGB)
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 follow-up evaluation of the response to treatment by using either bevacizumab (Avastin) or ranibizumab (Lucentis), which are injected into the vitreous humor of the eye at various intervals.
Recently, structured illumination light microscopy using a specially designed super resolution microscope setup has been used to resolve the fluorescent distribution of small autofluorescent structures (lipofuscin granulae) in retinal pigment epithelium tissue sections.[53]
Management
Dry AMD
No medical or surgical treatment is available for this condition; however, the AREDS trial found benefits with some vitamin supplements along with high doses of antioxidants. The follow up study, AREDS2, showed that the antioxidants lutein and zeaxanthin also have benefits. These combinations of supplements have been suggested by the National Eye Institute and others to slow progression of the disease in people who have intermediate AMD, and those who have late AMD in one eye.[54] Though, the researchers stress that the AREDS formulation is not a cure, and will not restore vision already lost from AMD. The studies didn't prove that it helps people with early AMD, but it is reasonable to suggest that the benefits of the supplements also extend to those with early AMD. But, not all antioxidants are beneficial, higher beta-carotene intake was associated with an increased risk of AMD in addition to its association with increased lung cancers in smokers.[54][55]
Wet AMD
Due to the involvement by vascular endothelial growth factor (VEGF) in the development of new blood vessels, antiangiogenics or anti-VEGF agents can cause regression of the abnormal blood vessels and improve vision when injected directly into the vitreous humor of the eye. The injections must be repeated monthly or bimonthly initially, but the treatment may be stopped if the condition becomes stabilized. Several antiangiogenic drugs have been approved for use in the eye by the FDA and regulatory agencies in other countries.
The first angiogenesis inhibitor, a monoclonal antibody against VEGF-A, was bevacizumab, which is approved for use in several cancers. Ranibizumab is a smaller fragment, Fab fragment, of the parent bevacizumab molecule specifically designed for eye injections. A controversy in the UK involved the off-label use of cheaper bevacizumab over the approved, but expensive, ranibizumab.[56] A recent randomized control trial found that bevacizumab and ranibizumab had similar efficacy, and reported no significant increase in adverse events with bevacizumab[57] A 2014 Cochrane review with 3,665 patients indicated that the systemic safety of bevacizumab and ranibizumab are similar when used to treat neovascular AMD, except for gastrointestinal disorders.[58]
Other approved antiangiogenic drugs for the treatment of neo-vascular AMD include pegaptanib (Macugen) and aflibercept (Eylea).[59]
Photodynamic therapy has also been used to treat wet AMD.[60] The drug verteporfin is administered intravenously; light of a certain wavelength is then applied to the abnormal blood vessels. This activates the verteporfin destroying the vessels.
Drug Interventions
A Cochrane systematic review published in 2015 looked at randomized control trials (RCT's) that studied the effectiveness of statins compared with other treatments, no treatment or placebo in delaying the onset and progression of age related macular degeneration (ARMD). Two RCT's with a total population of 144 patients met the inclusion criteria. Both studies used simvastatin as the intervention and neither study showed a stastically significant difference between the statin use vs placebo in delaying the onset or progression of ARMD. The review article concluded that there is insufficient evidence from currently available RCT's to conclude that statins are efficacious in delaying the onset or progression of ARMD [61]
Nondrug interventions
A Cochrane Database Review of publications to 2012 found the use of vitamin and mineral supplements, alone or in combination, by the general population had no effect on AMD,[62] a finding echoed by another review.[63] A 2006 Cochrane Review of the effects of vitamins and minerals on the slowing of AMD found the 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, which also manufactured the supplements used in the study,[64] 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.[65] A Cochrane database review published in March 2012 did not find sufficient evidence to determine the effectiveness and safety of statins for the prevention or delaying the progression of AMD.[66]
Cell based therapies using bone marrow stem cells as well as Retinal pigment epithelial transplantation have been reported as experimental options in several patients.[67]
Saffron (Crocus sativus) is a spice containing the antioxidant carotenoids crocin and crocetin. Saffron has been known for its antioxidant, anti-inflammatory, and cell protective effects. The most important result for eye health benefits of saffron came from a recent double blind, placebo-controlled, cross-over clinical study. Results indicated that taking oral supplementation of saffron at 20 mg/day for three months induced a short-term and significant improvement of retinal function in early AMD. In this study cone-mediated ERG in response to high-frequency flicker (focal ERG, FERG) was employed as the main outcome variable. The effects, however, disappeared when patients stopped taking the saffron pills. No adverse side effects were reported in this study. According to Professor Silvia Bisti from the University of Sydney, who carried out the research, 'Patients' vision improved after taking the saffron pill’ (Falsini et al. 2010).[68]
In a 15-month follow up clinical study, the same researchers observed that patients continued to get the benefits of the supplement for as long as they took the saffron capsules. This study confirmed initial findings that saffron may hold the key for tackling vision loss in AMD.
According to this recent study, taking long term saffron supplement led to: "improvement in contrast and colour perception, reading ability, and vision at low luminances, all ultimately leading to a substantial improvement in the patients’ quality of life.". This new study showed that taking saffron supplementation for long term presents a safe natural solution to help prevent eyesight loss in old age, and as reported “no adverse systemic side effects were recorded” (Piccardi et al. 2012). Health Canada in 2012 approved Saffron 2020 for macular degeneration and cataracts. Saffron 2020 is made based on current clinical data on effect of saffron, resveratrol, lutein, zeaxanthin and vitamins in macular degeneration.[69]
Adaptive devices
Josef Tal, an Israeli composer who was affected by macular degeneration, checks a manuscript using a CCTV desktop unit.
Because peripheral vision is not affected, people with macular degeneration can learn to use their remaining vision to partially compensate.[70] Assistance and resources are available in many countries and every state in the U.S.[71] Classes for "independent living" are given and some technology can be obtained from a state department of rehabilitation.
Adaptive devices can help people read. These include magnifying glasses, special eyeglass lenses, computer screen readers, and TV systems that enlarge reading material.
Computer screen readers such as JAWS or Thunder work with standard Windows computers.
Video cameras can be fed into standard or special-purpose computer monitors, and the image can be zoomed in and magnified. These systems often include a movable table to move the written material.
Accessible publishing provides larger fonts for printed books, patterns to make tracking easier, audiobooks and DAISY books with both text and audio.
Research directions
Recent advancements within the field of stem cell research in the United States have led to the first human embryonic stem cell trial for dry AMD, which reports positive results.[72]
Notable cases
- Judi Dench[73]
- Joan Plowright[74]
- Peter Sallis[75]
See also
- Macular Disease Society
- Cherry-red spot
- Fuchs spot
- Micropsia
- Adeno associated virus and gene therapy of the human retina
- AMD Alliance International
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Further reading
- Copley, Caroline; Hirschler, Ben (April 24, 2012). Potter, Mark, ed. Novartis challenges UK Avastin use in eye disease. Reuters. Retrieved April 29, 2012
- John Sudhakar, Sundaram Natarajan, Periyasamy Parikumar, Mahesh Shanmugam, Rajappa Senthilkumar, David W Green, and Samuel JK Abraham (5 March 2013). "Choice of cell source in cell based therapies for retinal damage due to age related macular degeneration (AMD): A review". Indian Journal of Ophthalmology 2013: 1. doi:10.1155/2013/465169. Retrieved 23 March 2013.
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