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1.  Prevalence of Age-Related Macular Degeneration in Nakuru, Kenya: A Cross-Sectional Population-Based Study 
PLoS Medicine  2013;10(2):e1001393.
Using digital retinal photography and slit lamp examination in a population-based sample in the Nakuru District of Kenya, Andrew Bastawrous and colleagues determined the prevalence of age-related macular degeneration in adults 50 years and older.
Background
Diseases of the posterior segment of the eye, including age-related macular degeneration (AMD), have recently been recognised as the leading or second leading cause of blindness in several African countries. However, prevalence of AMD alone has not been assessed. We hypothesized that AMD is an important cause of visual impairment among elderly people in Nakuru, Kenya, and therefore sought to assess the prevalence and predictors of AMD in a diverse adult Kenyan population.
Methods and Findings
In a population-based cross-sectional survey in the Nakuru District of Kenya, 100 clusters of 50 people 50 y of age or older were selected by probability-proportional-to-size sampling between 26 January 2007 and 11 November 2008. Households within clusters were selected through compact segment sampling.
All participants underwent a standardised interview and comprehensive eye examination, including dilated slit lamp examination by an ophthalmologist and digital retinal photography. Images were graded for the presence and severity of AMD lesions following a modified version of the International Classification and Grading System for Age-Related Maculopathy. Comparison was made between slit lamp biomicroscopy (SLB) and photographic grading.
Of 4,381 participants, fundus photographs were gradable for 3,304 persons (75.4%), and SLB was completed for 4,312 (98%). Early and late AMD prevalence were 11.2% and 1.2%, respectively, among participants graded on images. Prevalence of AMD by SLB was 6.7% and 0.7% for early and late AMD, respectively. SLB underdiagnosed AMD relative to photographic grading by a factor of 1.7.
After controlling for age, women had a higher prevalence of early AMD than men (odds ratio 1.5; 95% CI, 1.2–1.9). Overall prevalence rose significantly with each decade of age. We estimate that, in Kenya, 283,900 to 362,800 people 50 y and older have early AMD and 25,200 to 50,500 have late AMD, based on population estimates in 2007.
Conclusions
AMD is an important cause of visual impairment and blindness in Kenya. Greater availability of low vision services and ophthalmologist training in diagnosis and treatment of AMD would be appropriate next steps.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, 39 million people are blind, and 246 million people (mainly living in developing countries) have moderate or severe visual impairment. The third leading global cause of blindness (after cataracts and glaucoma) is age-related macular degeneration (AMD). This group of conditions is characterized by lesions in the macular (central) region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. AMD, which affects older people, destroys the sharp central vision that is needed for reading or driving, leaving only dim, blurred images or a black hole at the center of vision. AMD can be diagnosed by examining digital photographs of the retina or by examining the retina directly using a special magnifying lens (slit lamp biomicroscopy). There is no cure for AMD, although injections into the eye of certain drugs, such as bevacizumab, that block the activity of vascular endothelial growth factor can slow the rate of vision loss caused by some forms of AMD.
Why Was This Study Done?
Most investigations of the prevalence (the proportion of a population with a disease) of AMD and of risk factors for AMD have studied people with European or Asian ancestry. Very little is known about AMD in African populations, and the data that are available mainly come from African populations living outside Africa. It is important to know whether AMD is an important cause of visual impairment and blindness in Africa, so that informed decisions can be made about the need for AMD programs in African countries. In this cross-sectional population-based study, the researchers investigate the prevalence of AMD among people aged 50 years or older living in Nakuru District (an ethnically diverse region of Kenya) and look for predictors of AMD in this population. In a cross-sectional population-based study, researchers observe a representative subset of a population at a single time point.
What Did the Researchers Do and Find?
The researchers randomly selected 100 clusters of 50 people aged 50 years or older for their study. Between January 2007 and November 2008, study participants had a comprehensive eye examination and completed a standardized interview that included questions about their age, gender, other demographic details, medical history, and exposure to possible risk factors for AMD. Based on digital retinal images, the prevalences of early and late AMD among the study population were 11.2% and 1.2%, respectively. The prevalences of early and late AMD judged by slit lamp biomicroscopy were 6.7% and 0.7%, respectively. After controlling for age, women had a higher prevalence of both early and late AMD than men. The overall prevalence of AMD rose with age: compared to the youngest age group, the oldest age group had a three-fold higher risk of developing late AMD. Of the people with any grade of AMD, 25.6% had some visual impairment and 2.5% were blind. Overall, 9.9% of the blindness seen in the study was attributable to AMD.
What Do These Findings Mean?
These findings identify AMD as an important cause of visual impairment and blindness in Nakuru District, Kenya. Extrapolation of these findings to the whole of Kenya suggests that 283,900 to 362,800 Kenyans had early AMD and 25,200 to 50,500 had late AMD in 2007. The accuracy of these findings is limited by the inability to obtain digital retinal images from all the participants (often because of electricity failures) and by other aspects of the study design. Moreover, because the methodology used in this study differed from some other studies of AMD, the prevalence of AMD reported here cannot be compared directly to those found in other studies. Nevertheless, these findings have several important implications. In particular, although recent evidence suggests that bevacizumab is likely to be both effective and affordable in Africa, the infrastructure required to deliver an adequate AMD service is currently prohibitively expensive in most African countries. Thus, these findings suggest that it is essential that research is undertaken to support the development of AMD treatment programs that are affordable and deliverable in Africa, and that low vision resources are provided for individuals with vision impairment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001393.
The US National Eye Institute provides detailed information about age-related macular degeneration
The UK National Health Service Choices website also provides information about age-related macular degeneration, including personal stories about the condition
The UK Royal National Institute of Blind People has information on age-related macular degeneration, including a video of a person describing their experiences of the condition
AMD Alliance International provides written and audio information in several languages about age-related macular degeneration, including a large selection of personal stories; the Macular Degeneration Partnership also provides information about age-related macular degeneration, including a simulation of the condition
MedlinePlus has links to additional resources about age-related macular degeneration (in English and Spanish)
doi:10.1371/journal.pmed.1001393
PMCID: PMC3576379  PMID: 23431274
2.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Purpose.
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Methods.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Results.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Conclusions.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
doi:10.1167/iovs.12-10073
PMCID: PMC3490538  PMID: 23060141
3.  FOUR-YEAR INCIDENCE AND PROGRESSION OF AGE-RELATED MACULAR DEGENERATION: THE LOS ANGELES LATINO EYE STUDY 
American journal of ophthalmology  2010;149(5):741-751.
Purpose
To estimate 4-year incidence and progression of early and advanced age-related macular degeneration (AMD).
Design
Population-based cohort study.
Methods
A comprehensive ophthalmologic examination including stereoscopic fundus photography was performed on adult Latinos at baseline and follow-up. Photographs were graded using a modified Wisconsin Age-Related Maculopathy Grading System. For estimations of incidence and progression of AMD, the Age Related Eye Disease Study Scale was used. Main outcome measures are incidence and progression of early AMD (drusen type, drusen size, and retinal pigmentary abnormalities) and advanced AMD (exudative AMD and geographic atrophy).
Results
4,658/6100 (76%) completed the follow-up examination. The 4-year incidence of early AMD was 7.5% (95%CI:6.6,8.4) and advanced AMD was 0.2% (95%CI:0.1,0.4). Progression of any AMD occurred in 9.3% (95%CI:8.4,10.3) of at-risk participants. Incidence and progression increased with age. Incidence of early AMD in the second eye (10.8%) was higher than incidence in the first eye (6.9%). Baseline presence of soft indistinct large drusen≥250μm in diameter was more likely to predict the 4-year incidence of pigmentary abnormalities, geographic atrophy, and exudative AMD than smaller or hard or soft distinct drusen.
Conclusions
Age-specific incidence and progression of AMD in Latinos are lower than in non-Hispanic whites. While incident early AMD is more often unilateral, the risk of its development in the second is higher than in the first eye. Older persons and those with soft indistinct large drusen had a higher risk of developing advanced AMD compared to those who were younger and did not have soft indistinct large drusen.
doi:10.1016/j.ajo.2010.01.009
PMCID: PMC3138505  PMID: 20399926
4.  Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study 
PLoS ONE  2014;9(3):e90973.
Background
Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.
Methods
The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.
Results
After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.
Conclusions
This study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis.
doi:10.1371/journal.pone.0090973
PMCID: PMC3946623  PMID: 24608419
5.  Bilateral involvement by age related maculopathy lesions in a population 
AIMS—To describe the influences of age and sex on the frequency of bilateral age related macular degeneration (AMD) and age related maculopathy (ARM) lesions.
METHODS—The Blue Mountains Eye Study examined 3654 older Australians, 82% of permanent residents living in an area west of Sydney. Stereo macular photographs were graded for AMD (neovascular maculopathy and geographic atrophy) and early ARM lesions (soft drusen, reticular drusen, hyperpigmentation, and hypopigmentation).
RESULTS—Among 230 gradable cases of AMD or early ARM, 183 (80%) were bilateral. For AMD, 39/69 cases (57%) were bilateral, while for early ARM, 123/161 cases (77%) had signs in both eyes. Of the individual lesions, reticular drusen (91%) and indistinct soft drusen (79%) were most frequently present in both eyes. Geographic atrophy was bilateral in 56%, neovascular AMD in 40%, and distinct soft drusen in 47%, while hyperpigmentation was bilateral in 38% and hypopigmentation in only 28% of cases. A consistent age related increase in bilateral distribution was observed for most lesions. After adjusting for effects of age, current smoking, and AMD family history AMD and ARM component lesions, except for soft drusen, were more frequently bilateral in women. This sex difference was significant only for neovascular AMD, odds ratio 7.7 (95% confidence intervals 1.3-46.7). An AMD family history was more frequently reported in cases with bilateral involvement.
CONCLUSIONS—This study has documented differences in the age related bilaterality of individual ARM components with higher bilateral rates for reticular or indistinct soft drusen compared with other lesions. The increased bilaterality of most ARM lesions among women is likely to contribute to the increased age adjusted risk of AMD blindness found in women. 

 Keywords: age related maculopathy; age related macular degeneration; drusen
PMCID: PMC1722690  PMID: 9924363
6.  Risk Factors for Four-Year Incidence and Progression of Age-Related Macular Degeneration: The Los Angeles Latino Eye Study 
American journal of ophthalmology  2011;152(3):385-395.
PURPOSE
To identify risk factors for 4-year incidence and progression of age-related macular degeneration (AMD) in adult Latinos.
DESIGN
Population-based prospective cohort study.
METHODS
Participants, aged 40 or older, from The Los Angeles Latino Eye Study (LALES) underwent standardized comprehensive ophthalmologic examinations at baseline and at 4 years of follow-up. Age-related macular degeneration was detected by grading 30-degree stereoscopic fundus photographs using the modified Wisconsin Age-Related Maculopathy Grading System. Multivariate stepwise logistic regression was used to examine the independent association of incidence and progression of AMD and baseline sociodemographic, behavioral, clinical, and ocular characteristics.
RESULTS
Multivariate analyses revealed that older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR per 10 mm Hg: 2.54; 95% CI: 1.36, 4.76) were independently associated with the incidence of any AMD. The same factors were associated with early AMD, soft indistinct drusen, and retinal pigmentary abnormalities. Additionally, presence of clinically diagnosed diabetes mellitus was independently associated with increased retinal pigment (OR: 1.66; 95% CI: 1.01, 2.85), and male gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI: 1.48, 4.23). Older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current smoking (OR: 2.85; 95% CI: 1.66, 4.90) were independently associated with progression of AMD.
CONCLUSIONS
Several modifiable risk factors were associated with 4-year incidence and progression of AMD in Latinos. The results suggest that interventions aimed at reducing pulse pressure and promoting smoking cessation may reduce incidence and progression of AMD, respectively.
doi:10.1016/j.ajo.2011.02.025
PMCID: PMC3159714  PMID: 21679916
7.  The Prevalence of Age-Related Macular Degeneration and Associated Risk Factors: The Beaver Dam Offspring Study 
Archives of ophthalmology  2010;128(6):750-758.
Objective
To determine the prevalence of age-related macular degeneration (AMD) and examine relationships of retinal drusen, retinal pigmentary abnormalities and early AMD to age, sex and other risk factors in 2810 people 21-84 years of age, participating in the Beaver Dam Offspring Study (BOSS).
Methods
The presence and severity of various characteristics of drusen and other lesions typical of AMD were determined by grading digital color fundus images using the Wisconsin Age-Related Maculopathy Grading System.
Results
Early AMD was present in 3.4% of the cohort and varied from 2.4% in those 21-34 years of age to 9.8% in those 65 years of age or older. In a multivariable model (expressed as Odds Ratio [OR]; 95% Confidence Interval [CI]), age (1.22 per 5 years of age; 1.09, 1.36), being male (1.65; 1.01, 2.69), more pack years smoked (1 to 10 vs 0, 1.31; 0.75, 2.29; 11+ vs 0, 1.67; 1.03, 2.73), higher serum HDL cholesterol (per 5 mg/dL 0.91; 0.83, 0.998), and hearing impairment (2.28; 1.41, 3.71) were associated with early AMD. There were no associations of blood pressure level, body mass index, physical activity, history of heavy drinking, white blood cell count, hematocrit, platelet count, serum total cholesterol, or carotid intimal-medial thickness with early AMD.
Conclusion
These data indicate that early AMD is infrequent before age 55 years but increases with age thereafter. Early AMD is related to modifiable risk factors, e.g., smoking and serum HDL cholesterol.
doi:10.1001/archophthalmol.2010.92
PMCID: PMC2896217  PMID: 20547953
age-related macular degeneration; prevalence; risk factors
8.  Inflammation, Complement Factor H, and Age-Related Macular Degeneration: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2008;115(10):1742-1749.
Objective
To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T→C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese.
Design
Population-based, cross-sectional study.
Participants
We included 5887 persons aged 45 to 84 years with gradable AMD.
Methods
Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained.
Main Outcome Measure
Prevalence of AMD.
Results
While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33–4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21–3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14–2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06–1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14–3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00–3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10–2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09–3.10), and large drusen area (OR, 1.66; 95% CI, 1.02–2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks.
Conclusions
This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.
doi:10.1016/j.ophtha.2008.03.021
PMCID: PMC2936447  PMID: 18538409
9.  The Epidemiology of Retinal Reticular Drusen 
American journal of ophthalmology  2007;145(2):317-326.
Purpose
To describe the prevalence and 15-year cumulative incidence of and risk factors for reticular drusen.
Design
Population-based prospective study.
Methods
Setting
Beaver Dam, Wisconsin
Study population
4,926 persons, 43-86 years of age in 1988-1990, of whom 3,684, 2,764, and 2,119 participated in 5-, 10-, and 15-year follow-up examinations, respectively.
Main outcome measures
Prevalence and 15-year incidence of reticular drusen determined by grading stereoscopic color fundus photographs.
Results
The prevalence at baseline and the15-year cumulative incidence in either eye of reticular drusen was 0.7% and 3.0%, respectively. The 15-year incidence of reticular drusen varied with age from 0.4% in those 43-54 years of age to 6.6% in those 75 years or older at baseline (P<0.001). In a multivariable model, while controlling for age, risk factors statistically significantly associated with increased risk of incident reticular drusen included (Odds ratio): being female (2.8), current smoking (vs never 1.9), less education (per category 1.7), B-vitamin complex use (vs none 2.5, single vitamin B (vs none 2.9), history of steroid eye drops use (5.9), glaucoma (2.8), and more severe drusen type (e.g., soft indistinct drusen) (1.4) while diabetes (0.1) at baseline was associated with decreased risk. Right eyes with reticular drusen at baseline had higher cumulative incidence of geographic atrophy (21% vs 9%) and exudative AMD (20% vs 10%) compared to eyes with soft indistinct drusen.
Conclusions
This population-based study documents the long-term cumulative incidence of reticular drusen, its risk factors, and shows its association with a high risk of incident late AMD.
doi:10.1016/j.ajo.2007.09.008
PMCID: PMC2258433  PMID: 18045568
Reticular drusen; epidemiology; incidence; age-related macular degeneration
10.  Prevalence of Age-related Macular Degeneration in Old Persons. Age, Gene/Environment Susceptibility Reykjavik Study 
Ophthalmology  2010;118(5):825-830.
Purpose
To describe the prevalence and signs of early and late age-related macular degeneration (AMD) in an old cohort.
Design
Population based cohort study
Participants
We included 5,272 persons 66 years and older, randomly sampled from the Reykjavik area.
Methods
Fundus images were taken through dilated pupils using a 45°digital camera and were graded for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System.
Main outcome measure
Age-related macular degenerationin an old cohort.
Results
Mean age of participants was 76 years. The prevalence of early AMD was 12.4% (95% confidence interval [CI] 11.0–13.9) for those 66–74 year old and 36% (95% CI 30.9–41.1) for those 85 years and older. The prevalence of exudative AMD was 3.3% (95% CI 2.8–3.8) and for pure geographic atrophy 2.4% (95% CI 2.0–2.8). The highest prevalence for late AMD was among those 85 years and older 11.4% (95% CI 8.2–14.5) for exudative AMD and 7.6% (95% CI 4.8–10.4) for pure geographic atrophy.
Conclusion
Persons 85 years and older have 10-fold higher prevalence of late AMD than those 70–74 years old. The high prevalence of late AMD in the oldest age-group and expected increase of old people in the western world in coming years call for improved preventive measures and novel treatments.
doi:10.1016/j.ophtha.2010.08.044
PMCID: PMC3087833  PMID: 21126770
Age-related macular degeneration; exudative AMD; geographic atrophy
11.  Age related macular degeneration 
Clinical Evidence  2007;2007:0701.
Introduction
Sight-threatening (late) age-related macular degeneration (AMD) occurs in 2% of people aged over 50 years in industrialised countries, with prevalence increasing with age. Early-stage disease is marked by normal vision, but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is preserved.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent progression of early- or late-stage age-related macular degeneration; and exudative age-related macular degeneration? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiangiogenesis (using pegaptanib, ranibizumab, interferon alfa-2a, or anecortave acetate), antioxidant vitamins plus zinc, external beam radiation, laser treatment to drusen, photodynamic therapy with verteporfin, submacular surgery, thermal laser photocoagulation, transpupillary thermotherapy.
Key Points
Sight-threatening (late) age related macular degeneration (AMD) occurs in 2% of people aged over 50 years in industrialised countries, with prevalence increasing with age. Early stage disease is marked by normal vision, but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is preserved.85% of cases are atrophic (dry) AMD, but exudative (wet) AMD, marked by choroidal neovascularisation, leads to a more rapid loss of sight.The main risk factor is age. Hypertension, smoking, and a family history of AMD are also risk factors.
High dose antioxidant vitamin and zinc supplementation may reduce progression of moderate AMD, but there is no evidence of benefit in people with no, or mild AMD, or those with established late AMD in both eyes.
CAUTION: Beta-carotene, an antioxidant vitamin used in AMD, has been linked to an increased risk of lung cancer in people at high risk of this disease.
Photodynamic treatment with verteporfin reduces the risk of developing moderate or severe loss of visual acuity and legal blindness in people with vision initially better than 20/100 or 20/200, compared with placebo. Photodynamic treatment is associated with an initial loss of vision and photosensitive reactions in a small proportion of people.
Thermal laser photocoagulation can reduce severe visual loss in people with exudative AMD. It is frequently associated with an immediate and permanent reduction in visual acuity if the lesion involves the central macula, but it remains a proven effective treatment for extrafoveal choroidal neovascularisation. About half of people treated with thermal lasers show recurrent choroidal neovascularisation within 3 years.We don't know whether laser treatment of drusen prevents progression of disease, and it may increase short term rates of choroidal neovascularisation.
Antiangiogenesis treatment using vascular endothelial growth factor (VEGF) inhibitors such as ranibizumab or pegaptanib reduces the risk of moderate vision loss, and may improve vision at 12 and 24 months. Antiangiogenesis treatment using anecortave acetate may be as effective as photodynamic therapy in reducing vision loss.
Studies investigating external beam radiotherapy have given contradictory results, and have failed to show an overall benefit in AMD.
Subcutaneous interferon alfa-2a and submacular surgery have not been shown to improve vision, and are associated with potentially severe adverse effects.
We found no RCT evidence on the effects of transpupillary thermotherapy.
PMCID: PMC2943806  PMID: 19454069
12.  Physical activity and the 15‐year cumulative incidence of age‐related macular degeneration: the Beaver Dam Eye Study 
The British Journal of Ophthalmology  2006;90(12):1461-1463.
Background
Cardiovascular disease and age‐related macular degeneration (AMD) may share common risk factors. Physical activity improves the cardiovascular risk profile; however, there have been few studies investigating a relationship between physical activity and the long‐term incidence of AMD.
Methods
The 15‐year cumulative incidence of AMD was determined through four examination phases at 5‐year intervals of a population‐based study conducted in Beaver Dam, Wisconsin, USA, initiated in 1988–90 (n = 3874 men and women between ages 43 and 86 years). Early AMD (pigment abnormalities or soft indistinct drusen), exudative AMD and geographic atrophy were determined by grading stereoscopic colour fundus photographs. Measures of physical activity were obtained through a questionnaire administered at the baseline examination.
Results
After controlling for age, sex, history of arthritis, systolic blood pressure, body mass index, smoking and education, people with an active lifestyle (defined as regular activity ⩾3 times/week) at baseline were less likely to develop exudative AMD (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1 to 0.7) compared with people without an active lifestyle. After multivariate adjustment, increased categories of number of blocks walked per day decreased the risk of exudative AMD (OR 0.7, 95% CI 0.6 to 0.97). Physical activity was not related to the incidence of early AMD or pure geographic atrophy.
Conclusions
These data show a protective effect of physical activity for incident exudative AMD, independent of body mass index and other confounders. They also suggest a possible modifiable behaviour that might be protective against developing AMD.
doi:10.1136/bjo.2006.103796
PMCID: PMC1857544  PMID: 17077116
13.  Drusen Ultrastructure Imaging with Spectral Domain Optical Coherence Tomography in Age-related Macular Degeneration 
Ophthalmology  2008;115(11):1883-1890.
Purpose
To categorize drusen ultrastructure in age-related macular degeneration (AMD) using spectral domain optical coherence tomography (SDOCT) and correlate the tomographic and photographic drusen appearances.
Design
Prospective case series.
Participants
Thirty-one eyes of 31 patients with non-neovascular AMD.
Methods
Subjects with drusen and a clinical diagnosis of AMD were enrolled in an SDOCT imaging study from August of 2005 to May of 2007. Foveal linear scans were acquired, and the image data were processed for analysis. Drusen were scored by 4 morphologic categories: shape, predominant internal reflectivity, homogeneity, and presence of overlying hyper-reflective foci. The prevalences of each morphologic pattern and combinations of morphologic patterns observed were calculated. The photographic appearance of each druse was compared with the tomographic classification. Interobserver and intraobserver agreement analysis was performed.
Main Outcome Measures
Prevalence of morphologic parameters using SDOCT.
Results
Twenty-one eyes of 21 patients had SDOCT B-scans of adequate quality for analysis. On the basis of the above morphologic categories, 17 different drusen patterns were found in 120 total drusen. The most common was convex, homogeneous, with medium internal reflectivity, and without overlying hyper-reflective foci, present in 17 of 21 eyes (81%). Of the 16 eyes (76%) with nonhomogeneous drusen, 5 had a distinct hyper-reflective core. Hyper-reflective foci overlying drusen were in 7 eyes (33%). Although half of the photographically soft-indistinct drusen were convex with medium internal reflectivity and homogeneous without overlying hyper-reflective foci, the other half had significant variability in their tomographic appearance. Both interobserver and intraobserver agreement in drusen grading were high. Readers agreed the most when grading drusen shape and reflectivity, whereas the least agreement was for drusen homogeneity.
Conclusions
Drusen ultrastructure can be imaged with SDOCT and characterized with a simple grading system. Photographic appearance may predict some but not all tomographic appearances. Trained observers have a high level of agreement with this grading system. These in vivo morphologic characteristics imaged with SDOCT may be distinct subclasses of drusen types, may relate closely to ultrastructural drusen elements identified in cadaveric eyes, and may be useful imaging biomarkers for disease severity or risk of progression. This will require validation from further studies.
doi:10.1016/j.ophtha.2008.04.041
PMCID: PMC3510676  PMID: 18722666
14.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
Objective
The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was:
What is the sensitivity and specificity of spectral domain OCT relative to the gold standard?
Clinical Need: Target Population and Condition
The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process.
There are two main types of AMD, ‘dry’ and ‘wet’. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called “drusen” that build up in Bruch’s membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It’s characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple.
DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year.
Optical Coherence Tomography
Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It’s a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It’s also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes.
There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) ‘real-time registration,’ which was not previously available with TD.
The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit.
Methods
Literature Search
A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review.
English-language articles and health technology assessments.
RCTs and observational studies of OCT and AMD or DME.
Studies focusing on either diagnosis or monitoring of disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies of pediatric populations.
Studies on OCT as a screening tool.
Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in “Comparisons of Interest”.
Outcomes of Interest
Studies of sensitivity, specificity.
Comparisons of Interest
Evidence exists for the following comparisons of interest:
OCT compared with the reference “fluorescein angiography” for AMD.
OCT compared with the reference “biomicroscopy” or “stereo or fundus photography” for DME.
Summary of Existing Evidence
No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review.
Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus – photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible.
Summary of Findings
The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows:
OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.
OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.
OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.
OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.
In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. For DME the treatment of choice is laser photocoagulation, which may be replaced with Lucentis® injections (Expert consultation). The evidence, as presented in systematic reviews and other health technology assessments, indicates that there are effective treatments available for both AMD and DME.
Considerations for the Ontario Health System
OCT testing is presently an uninsured service in Ontario with patients paying approximately $150 out-of-pocket per test. Several provinces do provide funding for this procedure, including British Columbia, Alberta, Saskatchewan, Newfoundland, Nova Scotia, Prince Edward Island, and the Yukon Territory. Provinces that do not provide such funding are Quebec, Manitoba and New Brunswick.
The demand for OCT is expected to increase with aging of the population.
PMCID: PMC3377511  PMID: 23074517
15.  Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration 
American journal of ophthalmology  2013;156(3):532-542.e1.
Purpose
To investigate the association of spontaneous drusen regression in intermediate age-related macular degeneration (AMD) with changes on fundus photography and fundus autofluorescence (FAF) imaging.
Design
Prospective observational case series.
Methods
Fundus images from 58 eyes (in 58 patients) with intermediate AMD and large drusen were assessed over 2 years for areas of drusen regression which exceeded the area of circle C1 (diameter 125μm; Age-Related Eye Disease Study grading protocol). Manual segmentation and computer-based image analysis were used to detect and delineate areas of drusen regression. Delineated regions were graded as to their appearance on fundus photographs and FAF images, and changes in FAF signals were graded manually and quantitated using automated image analysis.
Results
Drusen regression was detected in approximately half of study eyes using manual (48%) and computer-assisted (50%) techniques. At year 2, the clinical appearance of areas of drusen regression on fundus photography was mostly unremarkable, with a majority of eyes (71%) demonstrating no detectable clinical abnormalities, and the remainder (29%) showing minor pigmentary changes. However, drusen regression areas were associated with local changes in FAF that were significantly more prominent than changes on fundus photography. A majority of eyes (64–66%) demonstrated a predominant decrease in overall FAF signal, while 14–21% of eyes demonstrated a predominant increase in overall FAF signal.
Conclusions
FAF imaging demonstrated that drusen regression in intermediate AMD was often accompanied with changes in local autofluorescence signal. Drusen regression may be associated with concurrent structural and physiological changes in the outer retina.
doi:10.1016/j.ajo.2013.04.031
PMCID: PMC3748172  PMID: 23830564
16.  The Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration 
Archives of ophthalmology  2005;123(11):1484-1498.
Objective
To develop a fundus photographic severity scale for age-related macular degeneration (AMD).
Methods
In the Age-Related Eye Disease Study, stereoscopic color fundus photographs were taken at baseline, at the 2-year follow-up visit, and annually thereafter. Photographs were graded for drusen characteristics (size, type, area), pigmentary abnormalities (increased pigment, depigmentation, geographic atrophy), and presence of abnormalities characteristic of neovascular AMD (retinal pigment epithelial detachment, serous or hemorrhagic sensory retinal detachment, subretinal or sub-retinal pigment epithelial hemorrhage, subretinal fibrous tissue). Advanced AMD was defined as presence of 1 or more neovascular AMD abnormalities, photocoagulation for AMD, or geographic atrophy involving the center of the macula. We explored associations among right eyes of 3212 participants between severity of drusen characteristics and pigmentary abnormalities at baseline and development of advanced AMD within 5 years of follow-up.
Results
A 9-step severity scale that combines a 6-step drusen area scale with a 5-step pigmentary abnormality scale was developed, on which the 5-year risk of advanced AMD increased progressively from less than 1% in step 1 to about 50% in step 9. Among the 334 eyes that had at least a 3-step progression on the scale between the baseline and 5-year visits, almost half showed stepwise progression through intervening severity levels at intervening visits. Replicate gradings showed agreement within 1 step on the scale in 87% of eyes.
Conclusions
The scale provides convenient risk categories and has acceptable reproducibility. Progression along it may prove to be useful as a surrogate for progression to advanced AMD.
doi:10.1001/archopht.123.11.1484
PMCID: PMC1472813  PMID: 16286610
17.  Kidney function, albuminuria and age-related macular degeneration in NHANES III 
Nephrology Dialysis Transplantation  2011;26(10):3159-3165.
Background. Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
Methods. A cross-sectional nested case–control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
Results. There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51–6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11–1.29 and 1.57, 95% CI: 0.61–3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
Conclusions. Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation.
doi:10.1093/ndt/gfr022
PMCID: PMC3247860  PMID: 21339308
age-related macular degeneration; albuminuria; chronic kidney disease; dense deposit disease; glomerular filtration rate
18.  Prediction of Age-related Macular Degeneration in the General Population 
Ophthalmology  2013;120(12):2644-2655.
Purpose
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.
Design
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
Participants
People (n = 10106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Methods
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis.
Main Outcome Measures
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Results
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Conclusions
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
doi:10.1016/j.ophtha.2013.07.053
PMCID: PMC3986722  PMID: 24120328
19.  Routine Eye Examinations for Persons 20-64 Years of Age 
Executive Summary
Objective
The objective of this analysis was to determine the strength of association between age, gender, ethnicity, family history of disease and refractive error and the risk of developing glaucoma or ARM?
Clinical Need
A routine eye exam serves a primary, secondary, and tertiary care role. In a primary care role, it allows contact with a doctor who can provide advice about eye care, which may reduce the incidence of eye disease and injury. In a secondary care role, it can via a case finding approach, diagnose persons with degenerative eye diseases such as glaucoma and or AMD, and lead to earlier treatment to slow the progression of the disease. Finally in a tertiary care role, it provides ongoing monitoring and treatment to those with diseases associated with vision loss.
Glaucoma is a progressive degenerative disease of the optic nerve, which causes gradual loss of peripheral (side) vision, and in advanced disease states loss of central vision. Blindness may results if glaucoma is not diagnosed and managed. The prevalence of primary open angle glaucoma (POAG) ranges from 1.1% to 3.0% in Western populations, and from 4.2% to 8.8% in populations of African descent. It is estimated up to 50% of people with glaucoma are aware that they have the disease. In Canada, glaucoma disease is the second leading cause of blindness in people aged 50 years and older. Tonometry, inspection of the optic disc and perimetry are used concurrently by physicians and optometrists to make the diagnosis of glaucoma. In general, the evidence shows that treating people with increased IOP only, increased IOP and clinical signs of early glaucoma or with normal-tension glaucoma can reduce the progression of disease.
Age-related maculopathy (ARM) is a degenerative disease of the macula, which is a part of the retina. Damage to the macula causes loss of central vision affecting the ability to read, recognize faces and to move about freely. ARM can be divided into an early- stage (early ARM) and a late-stage (AMD). AMD is the leading cause of blindness in developed countries. The prevalence of AMD increases with increasing age. It is estimated that 1% of people 55 years of age, 5% aged 75 to 84 years and 15% 80 years of age and older have AMD. ARM can be diagnosed during fundoscopy (ophthalmoscopy) which is a visual inspection of the retina by a physician or optometrist, or from a photograph of the retina. There is no cure or prevention for ARM. Likewise, there is currently no treatment to restore vision lost due to AMD. However, there are treatments to delay the progression of the disease and further loss of vision.
The Technology
A periodic oculo-visual assessment is defined “as an examination of the eye and vision system rendered primarily to determine if a patient has a simple refractive error (visual acuity assessment) including myopia, hypermetropia, presbyopia, anisometropia or astigmatism.” This service includes a history of the presenting complaint, past medical history, visual acuity examination, ocular mobility examination, slit lamp examination of the anterior segment, ophthalmoscopy, and tonometry (measurement of IOP) and is completed by either a physician or an optometrist.
Review Strategy
The Medical Advisory Secretariat conducted a computerized search of the literature in the following databases: OVID MEDLINE, MEDLINE, In-Process & Other Non-Indexed Citations, EMBASE, INAHTA and the Cochrane Library. The search was limited to English-language articles with human subjects, published from January 2000 to March 2006. In addition, a search was conducted for published guidelines, health technology assessments, and policy decisions. Bibliographies of references of relevant papers were searched for additional references that may have been missed in the computerized database search. Studies including participants 20 years and older, population-based prospective cohort studies, population-based cross-sectional studies when prospective cohort studies were unavailable or insufficient and studies determining and reporting the strength of association or risk- specific prevalence or incidence rates of either age, gender, ethnicity, refractive error or family history of disease and the risk of developing glaucoma or AMD were included in the review. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to summarize the overall quality of the body of evidence.
Summary of Findings
A total of 498 citations for the period January 2000 through February 2006 were retrieved and an additional 313 were identified when the search was expanded to include articles published between 1990 and 1999. An additional 6 articles were obtained from bibliographies of relevant articles. Of these, 36 articles were retrieved for further evaluation. Upon review, 1 meta-analysis and 15 population-based epidemiological studies were accepted for this review
Primary Open Angle Glaucoma
Age
Six cross-sectional studies and 1 prospective cohort study contributed data on the association between age and PAOG. From the data it can be concluded that the prevalence and 4-year incidence of POAG increases with increasing age. The odds of having POAG are statistically significantly greater for people 50 years of age and older relative to those 40 to 49 years of age. There is an estimated 7% per year incremental odds of having POAG in persons 40 years of age and older, and 10% per year in persons 49 years of age and older. POAG is undiagnosed in up to 50% of the population. The quality of the evidence is moderate.
Gender
Five cross-sectional studies evaluated the association between gender and POAG. Consistency in estimates is lacking among studies and because of this the association between gender and prevalent POAG is inconclusive. The quality of the evidence is very low.
Ethnicity
Only 1 cross-sectional study compared the prevalence rates of POAG between black and white participants. These data suggest that prevalent glaucoma is statistically significantly greater in a black population 50 years of age and older compared with a white population of similar age. There is an overall 4-fold increase in prevalent POAG in a black population compared with a white population. This increase may be due to a confounding variable not accounted for in the analysis. The quality of the evidence is low.
Refractive Error
Four cross-sectional studies assessed the association of myopia and POAG. These data suggest an association between myopia defined as a spherical equivalent of -1.00D or worse and prevalent POAG. However, there is inconsistency in results regarding the statistical significance of the association between myopia when defined as a spherical equivalent of -0.5D. The quality of the evidence is very low.
Family History of POAG
Three cross-sectional studies investigated the association between family history of glaucoma and prevalent POAG. These data suggest a 2.5 to 3.0 fold increase in the odds having POAG in persons with a family history (any first-degree relative) of POAG. The quality of the evidence is moderate.
Age-Related Maculopathy
Age
Four cohort studies evaluated the association between age and early ARM and AMD. After 55 years of age, the incidence of both early ARM and AMD increases with increasing age. Progression to AMD occurs in up to 12% of persons with early ARM. The quality of the evidence is low
Gender
Four cohort studies evaluated the association between gender and early ARM and AMD. Gender differences in incident early ARM and incident AMD are not supported from these data. The quality of the evidence is lows.
Ethnicity
One meta-analysis and 2 cross-sectional studies reported the ethnic-specific prevalence rates of ARM. The data suggests that the prevalence of early ARM is higher in a white population compared with a black population. The data suggest that the ethnic-specific differences in the prevalence of AMD remain inconclusive.
Refractive Error
Two cohort studies investigated the association between refractive error and the development of incident early ARM and AMD. The quality of the evidence is very low.
Family History
Two cross-sectional studies evaluated the association of family history and early ARM and AMD. Data from one study supports an association between a positive family history of AMD and having AMD. The results of the study indicate an almost 4-fold increase in the odds of any AMD in a person with a family history of AMD. The quality of the evidence, as based on the GRADE criteria is moderate.
Economic Analysis
The prevalence of glaucoma is estimated at 1 to 3% for a Caucasian population and 4.2 to 8.8% for a black population. The incidence of glaucoma is estimated at 0.5 to 2.5% per year in the literature. The percentage of people who go blind per year as a result of glaucoma is approximately 0.55%.
The total population of Ontarians aged 50 to 64 years is estimated at 2.6 million based on the April 2006 Ontario Ministry of Finance population estimates. The range of utilization for a major eye examination in 2006/07 for this age group is estimated at 567,690 to 669,125, were coverage for major eye exams extended to this age group. This would represent a net increase in utilization of approximately 440,116 to 541,551.
The percentage of Ontario population categorized as black and/or those with a family history of glaucoma was approximately 20%. Therefore, the estimated range of utilization for a major eye examination in 2006/07 for this sub-population is estimated at 113,538 - 138,727 (20% of the estimated range of utilization in total population of 50-64 year olds in Ontario), were coverage for major eye exams extended to this sub-group. This would represent a net increase in utilization of approximately 88,023 to 108,310 within this sub-group.
Costs
The total cost of a major eye examination by a physician is $42.15, as per the 2006 Schedule of Benefits for Physician Services.(1) The total difference between the treatments of early-stage versus late-stage glaucoma was estimated at $167. The total cost per recipient was estimated at $891/person.
Current Ontario Policy
As of November 1, 2004 persons between 20 years and 64 years of age are eligible for an insured eye examination once every year if they have any of the following medical conditions: diabetes mellitus type 1 or 2, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus. Persons between 20 to 64 years of age who do not have diabetes mellitus, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus may be eligible for an annual eye examination if they have a valid “request for major eye examination” form completed by a physician (other than that who completed the eye exam) or a nurse practitioner working in a collaborative practice. Persons 20-64 years of age who are in receipt of social assistance and who do not have one of the 8 medical conditions listed above are eligible to receive an eye exam once every 2 years as a non-OHIP government funded service. Persons 19 years of age or younger and 65 years of age or older may receive an insured eye exam once every year.
Considerations for Policy Development
As of July 17, 2006 there were 1,402 practicing optometrists in Ontario. As of December 31, 2005 there were 404 practicing ophthalmologists in Ontario. It is unknown how many third party payers now cover routine eye exams for person between the ages of 20 and 64 years of age in Ontario.
PMCID: PMC3379534  PMID: 23074485
20.  Smoking, Dietary Betaine, Methionine, and Vitamin D in Monozygotic Twins with Discordant Macular Degeneration: Epigenetic Implications 
Ophthalmology  2011;118(7):1386-1394.
Objective
We evaluated monozygotic twin pairs with discordant age-related macular degeneration (AMD) phenotypes to assess differences in behavioral and nutritional factors.
Design
Case series.
Participants
Caucasian male twin pairs from the United States Twin Study of Macular Degeneration.
Methods
Twin pairs were genotyped to confirm monozygosity. Ocular characteristics were evaluated based on fundus photographs using the Wisconsin Grading System and a 5-grade Clinical Age-Related Maculopathy Staging System. We selected twin pairs discordant in each of the following phenotypic categories: Stage of AMD (n = 28), drusen area (n = 60), drusen size (n = 40), and increased pigment area (n = 56). The Wilcoxon signed-rank test and linear regression were used to assess associations between behavioral and nutritional characteristics and each phenotype within discordant twin pairs.
Main Outcome Measures
Differences in smoking and dietary factors within twin pairs discordant for stage of AMD, drusen area, drusen size, and pigment area.
Results
Representative fundus photographs depict the discordant phenotypes. Pack-years of smoking were higher for the twin with the more advanced stage of AMD (P = 0.05). Higher dietary intake of vitamin D was present in the twins with less severe AMD (P = 0.01) and smaller drusen size (P = 0.05) compared with co-twins, adjusted for smoking and age. Dietary intakes of betaine and methionine were significantly higher in the twin with lower stage of AMD (P = 0.009) and smaller drusen area (P = 0.03), respectively.
Conclusions
The twin with the more advanced stage of AMD, larger drusen area, drusen size, and pigment area tended to be the heavier smoker. The twin with the earlier stage of AMD, smaller drusen size and area, and less pigment tended to have higher dietary vitamin D, betaine, or methionine intake. Results suggest that behavioral and nutritional factors associated with epigenetic mechanisms are involved in the etiology of AMD, in addition to genetic susceptibility.
doi:10.1016/j.ophtha.2010.12.020
PMCID: PMC3711586  PMID: 21620475
21.  Spectral-Domain Optical Coherence Tomography Characteristics of Intermediate Age-Related Macular Degeneration 
Ophthalmology  2012;120(1):140-150.
Purpose
Describe qualitative spectral-domain optical coherence tomography (SD-OCT) characteristics of eyes classified as intermediate age-related macular degeneration (nonadvanced AMD) from Age-Related Eye Disease Study 2 (AREDS2) color fundus photography (CFP) grading.
Design
Prospective cross-sectional study.
Participants
We included 345 AREDS2 participants from 4 study centers and 122 control participants who lack CFP features of intermediate AMD.
Methods
Both eyes were imaged with SD-OCT and CFP. The SD-OCT macular volume scans were graded for the presence of 5 retinal, 5 subretinal, and 4 drusen characteristics. In all, 314 AREDS2 participants with ≥1 category-3 AMD eye and all controls each had 1 eye entered into SD-OCT analysis, with 63 eyes regraded to test reproducibility.
Main Outcome Measures
We assessed SD-OCT characteristics at baseline.
Results
In 98% of AMD eyes, SD-OCT grading of all characteristics was successful, detecting drusen in 99.7%, retinal pigment epithelium (RPE) atrophy/absence in 22.9%, subfoveal geographic atrophy in 2.5%, and fluid in or under the retina in 25.5%. Twenty-eight percent of AMD eyes had characteristics of possible advanced AMD on SD-OCT. Two percent of control eyes had drusen on SD-OCT. Vision loss was not correlated with foveal drusen alone, but with foveal drusen that were associated with other foveal pathology and with overlying focal hyperreflectivity. Focal hyperreflectivity over drusen, drusen cores, and hyper- or hyporeflectivity of drusen were also associated with RPE atrophy.
Conclusions
Macular pathologies in AMD can be qualitatively and reproducibly evaluated with SD-OCT, identifying pathologic features that are associated with vision loss, RPE atrophy, and even possibly the presence of advanced AMD not apparent on CFP. Qualitative and detailed SD-OCT analysis can contribute to the anatomic characterization of AMD in clinical studies of vision loss and disease progression.
doi:10.1016/j.ophtha.2012.07.004
PMCID: PMC3536919  PMID: 22968145
22.  CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD 
PLoS Medicine  2005;3(1):e5.
Background
Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear.
Methods and Findings
We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).
Conclusion
Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.
A common missense variant, Y402H, in the Complement Factor H gene is associated strongly with soft drusen, a precursor of advanced age-related macular degeneration
doi:10.1371/journal.pmed.0030005
PMCID: PMC1288033  PMID: 16300415
23.  Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis 
PLoS ONE  2013;8(1):e53830.
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10−31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10−24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10−6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10−6) and upstream of GLI2 (rs6721654; P = 6.5×10−6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10−6), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
doi:10.1371/journal.pone.0053830
PMCID: PMC3543264  PMID: 23326517
24.  Projected changes in age-related macular degeneration and driving license holders in Finland 
Purpose
The aim of the study was to approximate the occurrence of all forms of age-related macular degeneration (AMD) of the retina among the driving license holders aged 80 or more, and to project the changes to 2030 in Finland. AMD, destroying the visual cells in the central part of the retina, is a common disease of older age: one out of three individuals aged 70 or older shows early signs of AMD progressing later to relentless loss of vision. This eye disease can be detected only by an ophthalmologist. In general, little is known about the prevalence of AMD among driving license holders aged 80 or older.
Methods
At first the prevalence of individuals with either drusen or AMD in Finland among those 80 or older was approximated. Then the number of license holders in this age group was extracted from the statistics of the Finnish Transport Safety Agency and Eurostat provided us with the demographical data. The changes were projected to 2030.
Results
In Finland, with a population of 5.35 million, the number of those aged 80 or over will increase by 175,000 by 2030. The total number of individuals with either drusen or AMD will increase from 118,000 to 193,000 by the year 2030 and an increasing proportion of them will have a driving license. The proportion of women in 2012 having a driving license in the groups 60 or younger is about 45%, while in those aged 80 or older it is only 20%.
Conclusion
The number of people aged 80 years or older will increase in Finland by 2030. The number of those in this age group having a driving license will increase more rapidly as the population ages because the proportion of women with a driving license will increase in this age group. As the prevalence of drusen and AMD among women aged 80 or over is higher than among men at comparable age, this means that AMD will increase even more rapidly among drivers in this age group.
doi:10.2147/OPTH.S69246
PMCID: PMC4181625  PMID: 25284977
age-related macular degeneration; AMD; retina; driving license holders; Finland
25.  Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking 
PLoS Medicine  2007;4(12):e355.
Background
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
Methods and Findings
We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.
Conclusions
An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.
Anne Hughes and colleagues show that an individual's risk of developing age-related macular degeneration in old age can be predicted by combining haplotype data with smoking status.
Editors' Summary
Background.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The macula is the central region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. In the commonest form of AMD—“dry” AMD—the light-sensitive cells in the macula gradually die. In “wet” or “neovascular” AMD (one in 10 cases of AMD, but responsible for 90% of severe AMD-related blindness), abnormal blood vessels grow below the macula. Fluid leaking out of these vessels dislodges and damages the macula, after which loss of vision occurs rapidly. Both forms of AMD destroy the sharp central vision that is needed for reading and driving, leaving only dim, blurred images or a black hole at the center of vision. Neither form can be cured but with wet AMD the loss of vision can sometimes be slowed or halted if caught early by destroying the new blood vessels with laser surgery or a technique called photodynamic therapy or by blocking their formation by injecting special drugs into the eye.
Why Was This Study Done?
No-one knows what causes AMD but factors that increase a person's risk of developing the disease include increasing age, smoking, being white, and a family history of AMD. Recently, researchers have identified several “polymorphisms” (inherited DNA sequence variations that are common within populations) that are associated with AMD. These polymorphisms are in the complement factor H gene (the scientific symbol for this gene is CFH) and in a gene region called LOC387715/HTRA1. It would be useful to be able to use these risk factors to identify those people at the highest risk of developing neovascular AMD before the disease damages their vision. In this study, the researchers have investigated the association between AMD and polymorphisms in CFH and LOC387715/HTRA1 in more depth. They have then used this new information to build a model of AMD risk that should allow physicians to identify individuals at high risk of developing neovascular AMD.
What Did the Researchers Do and Find?
The researchers catalogued polymorphisms in CFH and LOC387715/HTRA1 in several hundred people with and without neovascular AMD. From these data, they identified three haplotypes (sets of polymorphisms that are inherited as a unit; everyone inherits two copies of each haplotype, one from each parent) in CFH that were more common in people with AMD than in those without and two that were associated with a decreased risk of developing AMD. In LOC387715/HTRA1 they identified one particularly detrimental haplotype. Compared to people without this haplotype, people with one copy of the deleterious haplotype were three times as likely to develop neovascular AMD; people with two copies were thirty times as likely to develop AMD. Smoking history also had a large effect on susceptibility to AMD. The researchers then developed a simple AMD risk scoring system based on CFH and LOC387715/HTRA1haplotypes and smoking status. From this, they calculated that people with the lowest risk scores have a minimal risk of developing AMD whereas about 15% of people with the highest risk scores are likely to develop AMD.
What Do These Findings Mean?
These findings indicate that it is possible to predict an individual's risk of developing AMD in old age by examining a small number of haplotypes and asking about their smoking status. The model developed by the researchers needs to be validated in other groups of people and may have to be modified if other gene variants that affect the risk of AMD are identified. For now, the results of this research provide physicians with a way to identify those individuals at the highest genetic risk of developing AMD so that they can step up their efforts to persuade these people to avoid smoking. In the future, when effective long-term treatments for AMD become available, the scoring system could also help doctors decide which of their elderly patients should be monitored most intensively for the early signs of AMD so that they can be treated before their vision is irreversibly damaged.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040355.
MedlinePlus provides links to information on macular degeneration and an encyclopedia page on macular degeneration (in English and Spanish)
Pages on the US National Institutes of Health NIH SeniorHealth site provides text and speech information about AMD
The US National Eye Institute and the UK Royal National Institute of Blind People also provide information about AMD
doi:10.1371/journal.pmed.0040355
PMCID: PMC2222948  PMID: 18162041

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