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*'''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 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.
*'''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 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 system|complement protein C3]]''': Two independent studies 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.<ref>{{cite journal | author = Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT | title = Complement C3 Variant and the Risk of Age-Related Macular Degeneration | journal = N Engl J Med.| volume = 357 | issue = 6| pages = 553–561 | year = 2007 | pmid = 17634448 | doi = 10.1056/NEJMoa072618}}</ref><ref>{{cite journal | author = Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM | title= Variation in Complement Factor 3 is Associated with Risk of Age-Related Macular Degeneration | journal = Nature Genetics | volume = 39 | issue = 10 | pages = 1200–1201 | year = 2007 | doi = 10.1038/ng2131 | pmid = 17767156 | issue = 10}}</ref> The authors of both papers consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.
*'''Arg80Gly variant of the [[complement system|complement protein C3]]''': Two independent studies 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.<ref>{{cite journal | author = Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT | title = Complement C3 Variant and the Risk of Age-Related Macular Degeneration | journal = N Engl J Med.| volume = 357 | issue = 6| pages = 553–561 | year = 2007 | pmid = 17634448 | doi = 10.1056/NEJMoa072618}}</ref><ref>{{cite journal | author = Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM | title= Variation in Complement Factor 3 is Associated with Risk of Age-Related Macular Degeneration | journal = Nature Genetics | volume = 39 | issue = 10 | pages = 1200–1201 | year = 2007 | doi = 10.1038/ng2131 | pmid = 17767156}}</ref> 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]].
*'''Hypertension''': Also known as [[high blood pressure]].
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== Genetic testing ==
== Genetic testing ==
{{Synthesis|date=June 2011}}
{{Synthesis|date=June 2011}}
A practical application of AMD-associated markers is in the prediction of progression of AMD from early stages of the disease to neovascularization.<ref>{{cite journal |author=Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J |title=Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration |journal= Proc Natl Acad Sci U S A |volume=107 |issue=16 |pages=7401–7406}}</ref><ref>{{cite journal |author=Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S |title=Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) |journal= Proc Natl Acad Sci U S A |volume=107 |issue=16 |pages=7395–7400}}</ref>
A practical application of AMD-associated markers is in the prediction of progression of AMD from early stages of the disease to neovascularization.<ref>{{cite journal |author=Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J |title=Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration |journal= Proc Natl Acad Sci U S A |volume=107 |issue=16 |pages=7401–7406 |doi=10.1073/pnas.0912702107 |pmid=20385819 |year=2010 |pmc=2867722}}</ref><ref>{{cite journal |author=Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S |title=Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) |journal= Proc Natl Acad Sci U S A |volume=107 |issue=16 |pages=7395–7400 |doi=10.1073/pnas.0912019107 |pmid=20385826 |year=2010 |pmc=2867697}}</ref>


Early work demonstrated that a family of immune mediators was plentiful in [[drusen]].<ref>{{cite journal |author= Mullins RF, Russell SR, Anderson DH, Hageman GS |title= Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease |journal= FASEB J |volume=14 |issue=7 |pages=835–46}}</ref> CFH is an important inhibitor of this inflammatory cascade and a disease-associated polymorphism in the complement [[factor]] H (CFH) gene strongly associates with AMD.<ref>{{cite journal |author= Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI |title= A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration |journal= Proc Natl Acad Sci USA |volume=102 |issue=20 |pages=7227–32}}</ref><ref>{{cite journal |author= Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK |title= Association of complement factor H polymorphisms with exudative age-related macular degeneration |journal= Mol. Vis |volume=12 |pages=1536–42}}</ref><ref>{{cite journal |author= Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP |title= Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration |journal= JAMA |volume=296 |issue=3 |pages=301–9}}</ref><ref>{{cite journal |author= Li M, Tmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS |title= CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration |journal= Nature Genetics |volume=38 |issue=9 |pages=1049–54}}</ref><ref>{{cite journal |author= Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P |title= Complement factor H variant increases the risk of age-related macular degeneration |doi=10.1126/science.1110359 |journal= Science |volume=308 |issue=5720 |pages=419–21}}</ref> Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced.<ref>{{cite journal |author= Rohrer B, Long Q, Coughlin B, Renner B, Huang Y, Kunchithapautham K |title= A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration |journal= Adv Exp Med Biol |volume=703 |pages=137–49}}</ref><ref>{{cite journal |author= Kunchithapautham K, Rohrer B |title Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive VEGF secretion in retinal pigment epithelium monolayers |journal= J Biol Chem | year=2011 |month = May |doi= 10.1074/jbc.M110.214593}}</ref> 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).<ref>{{cite journal |author= Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H |title= Complement C3 variant and the risk of age-related macular degeneration | year = 2007 |journal= NEJM |volume=357 | issue = 6 | pages=553–61}}</ref>
Early work demonstrated that a family of immune mediators was plentiful in [[drusen]].<ref>{{cite journal |author= Mullins RF, Russell SR, Anderson DH, Hageman GS |title= Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease |journal= FASEB J |volume=14 |issue=7 |pages=835–46 |pmid= 10783137 |year= 2000}}</ref> CFH is an important inhibitor of this inflammatory cascade and a disease-associated polymorphism in the complement [[factor]] H (CFH) gene strongly associates with AMD.<ref>{{cite journal |author= Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI |title= A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration |journal= Proc Natl Acad Sci USA |volume=102 |issue=20 |pages=7227–32 |doi= 10.1073/pnas.0501536102 |pmid= 15870199 |year= 2005 |pmc= 1088171}}</ref><ref>{{cite journal |author= Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK |title= Association of complement factor H polymorphisms with exudative age-related macular degeneration |journal= Mol. Vis |volume=12 |pages=1536–42 |pmid= 17167412 |year= 2006}}</ref><ref>{{cite journal |author= Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP |title= Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration |journal= JAMA |volume=296 |issue=3 |pages=301–9 |doi= 10.1001/jama.296.3.301 |pmid= 16849663 |year= 2006}}</ref><ref>{{cite journal |author= Li M, Tmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS |title= CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration |journal= Nature Genetics |volume=38 |issue=9 |pages=1049–54 |doi= 10.1038/ng1871 |pmid= 16936733 |year= 2006 |pmc= 1941700}}</ref><ref>{{cite journal |author= Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P |title= Complement factor H variant increases the risk of age-related macular degeneration |doi=10.1126/science.1110359 |journal= Science |volume=308 |issue=5720 |pages=419–21 |year= 2005 |pmid= 15761120}}</ref> Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced.<ref>{{cite journal |author= Rohrer B, Long Q, Coughlin B, Renner B, Huang Y, Kunchithapautham K |title= A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration |journal= Adv Exp Med Biol |volume=703 |pages=137–49 |pmid= 20711712 |year= 2010 |doi= 10.1007/978-1-4419-5635-4_10 |series= Advances in Experimental Medicine and Biology |isbn= 978-1-4419-5634-7}}</ref><ref>{{cite journal |author= Kunchithapautham K, Rohrer B |journal= J Biol Chem | year=2011 |month = May |doi= 10.1074/jbc.M110.214593 |title= Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive VEGF secretion in retinal pigment epithelium monolayers |volume= 286 |issue= 27 |pages= 23717–23724 |pmid= 21566137 |pmc= 3129152}}</ref> 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).<ref>{{cite journal |author= Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H |title= Complement C3 variant and the risk of age-related macular degeneration | year = 2007 |journal= NEJM |volume=357 | issue = 6 | pages=553–61 |doi= 10.1056/NEJMoa072618 |pmid= 17634448}}</ref>


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.<ref>{{cite journal |author= ^ Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP |title= Smoking and age-related macular degeneration: a review of association | year = 2005 |journal= Eye |volume=19 | issue =9 | pages=935–44}}</ref><ref>{{cite journal |author= Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD |title Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study |journal= Arch Ophthalmol | year=2004 |volume=122 | issue =5 | pages=750–7}}</ref><ref>{{cite journal |author Szaflik JP, Janik-Papis K, Synowiec E, Ksiazek D, Zaras M, Wozniak K |title DNA damage and repair in age-related macular degeneration |journal= Mutat Res | year=2009 |volume=669 | issue =1-2 | pages=167–176}}</ref> [[Mitochondrion|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.<ref>{{cite journal |author= Udar N, Atilano SR, Memarzadeh M, Boyer D, Chwa M, Lu S |title= Mitochondrial DNA Haplogroups Associated with Age-Related Macular Degeneration | year = 2009 |journal= Invest Ophthalmol Vis Sci |volume=50 | pages=2966–74 |doi= 10.1167/iovs.08-2646}}</ref><ref>{{cite journal |author= Canter JA, Olson LM, Spencer K, Schnetz-Boutaud N, Anderson B, Hauser MA |title = Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration |journal= PLoSONE | year=2008 |volume=3 | issue =5 | pages=e2091}}</ref>
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.<ref>{{cite journal |author= ^ Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP |title= Smoking and age-related macular degeneration: a review of association | year = 2005 |journal= Eye |volume=19 | issue =9 | pages=935–44 |doi= 10.1038/sj.eye.6701978 |pmid= 16151432}}</ref><ref>{{cite journal |author= Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD |journal= Arch Ophthalmol | year=2004 |volume=122 | issue =5 | pages=750–7 |title= Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study |doi= 10.1001/archopht.122.5.750 |pmid= 15136324}}</ref><ref>{{cite journal |journal= Mutat Res | year=2009 |volume=669 | issue =1–2 | pages=167–176 |author= Szaflik JP, Janik-Papis K, Synowiec E, Ksiazek D, Zaras M, Wozniak K |title= DNA damage and repair in age-related macular degeneration}}</ref> [[Mitochondrion|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.<ref>{{cite journal |author= Udar N, Atilano SR, Memarzadeh M, Boyer D, Chwa M, Lu S |title= Mitochondrial DNA Haplogroups Associated with Age-Related Macular Degeneration | year = 2009 |journal= Invest Ophthalmol Vis Sci |volume=50 | pages=2966–74 |doi= 10.1167/iovs.08-2646 |issue= 6 |pmid= 19151382}}</ref><ref>{{cite journal |author= Canter JA, Olson LM, Spencer K, Schnetz-Boutaud N, Anderson B, Hauser MA |title = Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration |journal= PLoSONE | year=2008 |volume=3 | issue =5 | pages=e2091}}</ref>


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.<ref>{{cite journal |author Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN |title = Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA DNA damage and repair in age-related macular degeneration |journal= NatGenet | year=2008 |volume=40 | issue =7| pages=892–896}}</ref><ref>{{cite journal | Kenealy SJ, Schmidt S, Agarwal A, Postel EA, De La Paz MA, Pericak-Vance MA |title = Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26 |journal=Mol Vis | year=2004 |volume=26 | issue =10| pages=57–61}}</ref> [[ARMS2]] protein may localize to the mitochondria and participate in energy metabolism, though much remains to be discovered about its function.
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.<ref>{{cite journal |title = Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA DNA damage and repair in age-related macular degeneration |journal= NatGenet | year=2008 |volume=40 | issue =7| pages=892–896 |author = Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN}}</ref><ref>{{cite journal |title = Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26 |journal=Mol Vis | year=2004 |volume=26 | issue =10| pages=57–61 |unused_data = Kenealy SJ, Schmidt S, Agarwal A, Postel EA, De La Paz MA, Pericak-Vance MA}}</ref> [[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]] (LIPC), cholesterol ester transferase (CETP), [[lipoprotein lipase]] (LPL) and the ABC-binding cassette A1 ([[ABCA1]]) correlate with disease progression, Early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome wide association studies <ref>{{cite journal |author Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J |title = Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration |journal= Proc Natl Acad Sci U S A | year=2010 |volume=107 | issue =16| pages=7401–6}}</ref><ref>{{cite journal |author Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S |title = Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) |journal= Proc Natl Acad Sci U S A. | year=2010 |volume=107 | issue =16| pages=7395–400}}</ref>
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]] (LIPC), cholesterol ester transferase (CETP), [[lipoprotein lipase]] (LPL) and the ABC-binding cassette A1 ([[ABCA1]]) correlate with disease progression, Early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome wide association studies <ref>{{cite journal |title = Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration |journal= Proc Natl Acad Sci U S A | year=2010 |volume=107 | issue =16| pages=7401–6 |author = Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J |doi = 10.1073/pnas.0912702107 |pmid = 20385819 |pmc = 2867722}}</ref><ref>{{cite journal |title = Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) |journal= Proc Natl Acad Sci U S A. | year=2010 |volume=107 | issue =16| pages=7395–400 |author = Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S |doi = 10.1073/pnas.0912019107 |pmid = 20385826 |pmc = 2867697}}</ref>


== Diagnosis ==
== Diagnosis ==
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== Further reading ==
== Further reading ==
{{refbegin | 1}}
{{refbegin | 1}}
* *{{Cite journal | doi =10.1038/eye.2011.37 | title =Complement in age-related macular degeneration: a focus on function | year =2011 | last1 =Bradley | first1 =D T | last2 =Zipfel | first2 =P F | last3 =Hughes | first3 =A E | journal =Eye | volume=25 | issue=6}}
* *{{Cite journal | doi =10.1038/eye.2011.37 | title =Complement in age-related macular degeneration: a focus on function | year =2011 | last1 =Bradley | first1 =D T | last2 =Zipfel | first2 =P F | last3 =Hughes | first3 =A E | journal =Eye | volume=25 | issue=6 | pages =683–693 | pmid =21394116}}
{{refend}}
{{refend}}


Revision as of 04:35, 17 August 2011

Macular degeneration
SpecialtyOphthalmology Edit this on Wikidata
Human eye cross-sectional view

Age-related macular degeneration is a medical condition which 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 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 all three layers of the eye, including the macula (the central part of the retina which surrounds the optic disc). 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 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 not approved for intra-ocular use, but is approved for other systemic indications. Pegaptanib (Macugen) has benefits in neovascular AMD and has approval for such use. 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. In the UK NICE institute issued guidelines for the treatment of wet AMD in the NHS. NICE only approved use of ranibizumab (trade name Lucentis) for wet AMD in the NHS in England. NHS hospitals and Primary Care Trusts in England are required to follow NICE guidance. Only about 10% of patients suffering from macular degeneration have the wet type.[5]

Photodynamic therapy has also been used to treat wet AMD.[6]

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) [7][8]
  • 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.[9] 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.[10]

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

The social psychologist Elliot Aronson, pictured here with his guide dog, continued to teach and write after losing his central vision to macular degeneration.[11][12]
  • 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.[13]
  • 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.[13] 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.[14]
  • Macular degeneration gene: The genes for the complement system proteins factor H (CFH), 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.[15][16]
    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 triphosphate (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.[17]
  • 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 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 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.[18][19] The authors of both papers consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.
  • 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[20] (at least twice weekly), rather than red meats, and eating any type of nuts may help macular degeneration patients.[21]
  • 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.[22][23]
  • 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.[24][25]
  • 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.[26] Other research, however, has shown that high-energy visible light (HEV) may contribute to age-related macular degeneration.[27][28][29]
  • 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."[30]
  • Deletion of CFHR3 and CFHR1: Deletion of the complement factor H-related genes CFHR3 and CFHR1 protects against age-related macular degeneration.[31][32]

Genetic testing

A practical application of AMD-associated markers is in the prediction of progression of AMD from early stages of the disease to neovascularization.[33][34]

Early work demonstrated that a family of immune mediators was plentiful in drusen.[35] CFH is an important inhibitor of this inflammatory cascade and a disease-associated polymorphism in the complement factor H (CFH) gene strongly associates with AMD.[36][37][38][39][40] Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced.[41][42] 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).[43]

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.[44][45][46] 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.[47][48]

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.[49][50] 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 (LIPC), cholesterol ester transferase (CETP), lipoprotein lipase (LPL) and the ABC-binding cassette A1 (ABCA1) correlate with disease progression, Early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome wide association studies [51][52]

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.

Management

Some evidence supports a reduction in the risk of age-related macular degeneration with increasing intake of two carotenoids, lutein and zeaxanthin,[53]

Consuming omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid) has been correlated with a reduced progression of early ARMD, and in conjunction with low glycemic index foods, with reduced progression of advanced ARMD.[54]

A 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,[55] a finding echoed by another review.[56] 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,[57] 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.[58]

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.

Adaptive devices can help people read. These include magnifying glasses, special eyeglass lenses, and computer screen readers such as JAWS for Windows. A desktop unit consisting of a closed-circuit television (CCTV) camera, monitor and a movable XY table is easy to use. The camera is aimed at a book and enables the user to zoom in and magnify the printed material to the size they can read. Desktop systems are perfect for extended periods of reading and writing. Accessible publishing 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 text of internet articles can be copied and pasted into a word processing program, then the font size increased and the background color of the document changed to black, and the font color to white. In Mac OS X, this kind of visual inversion can be enabled systemwide via the Universal Access panel of System Preferences (located under the Apple menu at the extreme left of all menubars). Text-to-speech and other assistive options are also available there.

Because peripheral vision is not affected, people with macular degeneration can learn to use their remaining vision to partially compensate.[59] Assistance and resources are available in many countries and every state in the U.S.[60] 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:[61] and watch an animation showing the Amsler grid with macular degeneration here:.[62]

Disability-adjusted life year for macular degeneration and other (sense organ diseases) per 100,000 inhabitants in 2004.[63]
  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

References

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Further reading

  • *Bradley, D T; Zipfel, P F; Hughes, A E (2011). "Complement in age-related macular degeneration: a focus on function". Eye. 25 (6): 683–693. doi:10.1038/eye.2011.37. PMID 21394116.

External links

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