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macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among persons older than 65 years of age. Classification: 1) non-exudative or dry (90%) 2) exudative or wet Etiology: 1) unknown 2) risk factors [3,5] a) age b) atherosclerosis c) dyslipidemias d) hypertension (weak association) e) diabetes mellitus f) smoking: smoking cessation reduces risk [2] g) ultraviolet light exposure h) diet low in antioxidants i) obesity [13] j) aspirin increases risk of neovascular type late macular degeneration (RR = 1.7) [21,22] - data not strong enough to overturn use of aspirin for evidence-based indications [22] - low-dose aspirin neither beneficial nor harmful [46] Epidemiology: 1) prevalence increases with age a) 0.1% of population 43-54 years of age b) 30% of patients > 75 years of age have evidence of macular degeneration c) 18.34 million individuals in the US >= 40 years (11.6%) were living with early-stage macular degeneration and 1.49 million (0.94%) were living with late-stage macular degeneration in 2019 [42] 3) leading cause of irreversible blindness among persons > 65 years of age 4) more common in caucasian females 5) rare in blacks [7] 6) baby boomers less likely than previous generation to develop macular degeneration [33] - decrease coincides with a reduction in cardiovascular disease & dementia (both allegedly involve vascular & inflammatory factors) [33] Pathology: 1) retinal degeneration especially of the macula a) pigment mottling b) deposition of drusen c) beta-amyloid accumulates in the outer retina with increasing age & in eyes of patients with age-related macular degeneration [39] 2) three forms a) dry type, atrophic changes b) wet type 1] subretinal neovascular membrane (choroidal neovascularization) 2] fragile new vessels may leak fluid or hemorrhage, then scar 3] a chorioretinal artery* may be protective against choroidal neovascularization [34] 4] retinal edema [44] c) retinal pigment epithelium detachment with drusen * present in ~20% of the population [34] Genetics: 1) apolipoprotein E2 is a risk factor 2) polymorphism in region of complement factor H gene that binds heparin & C-reactive protein confers 7-fold increased risk [12] 3) defects in HMCN1 gene associated with ARMD1 4) defects in ABCA4 gene associated with ARMD2 5) defects in fibulin-5 gene associated with ARMD3 6) genetic variation in ERCC6 is associated ARMD5 7) defects in RAXL1 gene associated with ARMD6 8) polymorphism in HTRA1 gene associated with ARMD7 9) defects in ARMS2 gene associated with ARMD8 10) polymorphism in TLR4 gene associated with ARMD10 11) defects in RPGR associated with macular degeneration X-linked atrophic 12) polymorphism in complement C2, variant Asp-318 is associated with reduced risk of macular degeneration 13) risk alleles on chromosome 1 (CFH-CFHR5) & chromosome 10 (ARMS2/HTRA1) [41] Clinical manifestations: 1) dry type (most common {90%}) with gradual changes a) painless; may be asymptomatic b) metamorphopsia c) micropsia d) scotomas, central scotoma e) loss of fine central vision, color vision f) relative preservation of peripheral vision g) drusen seen on funduscopic examination 2) wet type with more acute changes* a) acute loss of central vision, may be severe - blind spot b) distorted vision (Amsler grid) c) blurry vision 3) conversion of dry type to wet type in 15% of cases * refer to ophthalmologist within 24 hours Laboratory: - fluorescein or indocyanine green angiography to identify neovascularization - see ARUP consult [18] Complications: 1) increased risk of stroke, absolute risk increase 2% [14] 2) conversion of dry type to wet type with rapid visual loss 3) prevalence of depression is 30% [7] 4) loss of central vision impairs ability of older drivers to see pedestrians [20] 5) glaucoma, cataracts, & age-related macular degeneration may increase risk of falls in the elderly [45] Management: 1) ophthalmologic referral (within 24 hours if acute changes) - within 1 week if within 24 hours not an option [7] 2) vascular endothelial growth factor inhibitor (VEGF inhibitor) intravitreal injection in conjunction with laser photocoagulation for exudative or wet form a) pegaptanib (Macugen) FDA-approved in 2004 b) ranibizumab (Lucentis) FDA-approved in 2006 c) bevacizumab (Avastin) off-label use (VAMC) as effective & less expensive than ranibizumab ($50 vs $2000 monthly) [17] e) aflibercept (Eylea) FDA-approved 2011 3) laser photocoagulation for selected patients with exudative or wet form [2] a) used in connection with fluorescein angiography b) target choroidal neovascularization outside the foveal avascular zone c) injection of photoactive dye followed by laser d) verteporfin (Visudyne) IV may used in conjunction with photocoagulation e) verteporfin as sensitizer selectively binds to LDL receptor sites in choroidal neovascularization f) red laser of wavelength 689 nm activates drug & releases free radicals resulting in damage to & closure of the abnormal blood vessels 4) neither VEGF inhibitor or laser photocoagulation of benefit for dry form [2] 5) daily self Amsler grid evaluation 6) prophylaxis a) dietary* b) management of dyslipidemia - HMG CoA reductase inhibitors (statins) of reported benefit [3] c) wear sunglasses d) antioxidants & zinc reduce risk/slow progression [2,13] e) folic acid, vit B6 & vit B12 supplements in combination may reduce risk [15] f) do not smoke - smoking cessation reduces risk/slows progression [2] g) vitamin D & omega-3 fatty acids of no benefit h) metformin for diabetes mellitus type-2 may reduce risk of age-related macular degeneration; later study found no association [37] i) low-dose aspirin neither beneficial nor harmful [46] 7) antioxidants plus zinc may have modest benefit on progression of disease [4] (Ocuvite PreserVision, AREDS) a) zinc (Zn+2) 80 mg b) vitamin C 500 mg c) vitamin E# 400 IU d) beta-carotene 15 mg 8) lutein & zeaxanthin may be of benefit [9,11,26] - addition of lutein + zeaxanthin, DHA + EPA, or both to AREDS formulation does not further reduce risk of progression [28] 9) retinal implants: semiconductor chips implanted into the retina to interface directly with the central visual pathways 10) referral to vision rehabilitation specialist for visual impairment & blindness [7] 11) use peripheral vision as much as possible to maintain function [7] 12) dopamine receptor agonists or L-dopa/dopa-decarboxylase inhibitor (Sinemet) used in treatment of Parkinson's disease increases dopamine-signaling via dopamine D2 receptors (DRD2) inhibiting choroidal neovascularization thus delaying neovascular (wet) age-related macular degeneration [47] 13) investigational - human embryonic stem cell-derived retinal pigment epithelium improved visual acuity in some patients [27] * dietary prophylaxis - a Mediterranean diet may reduce risk of macular degeneration [32] - lutein, zeaxanthin & nitrates in green leafy vegetable may play a role [43] - one study [1] found that a higher dietary intake of carotenoids, specifically lutein & zeaxanthin, which are enriched in dark green leafy vegetables (noted are spinach & collard greens) is associated with a lower risk of age-related macular degeneration [as much as 43% lower]. # NOT helpful alone [6] Comparative biology: - high-glycemic index diets worsen macular deneration in mice - low glycemic index diets arrest progession of macular deneration in mice - changes dependent on changes in the gut microbiome [31] - oligomeric Abeta1-42 injected into the eyes of wild-type mice induces age-related macular degeneration like pathology within 2 weeks [39]

Interactions

disease interactions

Related

Amsler grid (AG) drusen macula retinae, macula lutea, macula, area centralis or punctum luteum metamorphopsia micropsia scotoma

Useful

Ocuvite PreserVision; AREDS formulation

Specific

age-related macular degeneration/ABCR mutation associated bull's eye maculopathy (concentric annular macular dystrophy) Stargardt disease vitelliform macular dystrophy; Best macular dystrophy

General

retinal degeneration sign/symptom

Database Correlations

OMIM correlations MORBIDMAP 611313

References

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