Original Paper


Received: July 15, 2014 Accepted after revision: November 27, 2014 Published online: February 7, 2015

Ophthalmologica DOI: 10.1159/000371584

Prevalence of Age-Related Macular Degeneration in Portugal: The Coimbra Eye Study – Report 1 Maria da Luz Cachulo a, b Conceição Lobo a–c João Figueira a, b Luisa Ribeiro b Inês Laíns a António Vieira f Sandrina Nunes b Miguel Costa b Sílvia Simão b Victor Rodrigues d Nelson Vilhena e José Cunha-Vaz b Rufino Silva a–c   













a Department of Ophthalmology, Centro Hospitalar e Universitário de Coimbra, b Association for Innovation and Biomedical Research on Light and Image (AIBILI), c Ophthalmology Department, Faculty of Medicine, and d Instituto de Higiene e Medicina Social, Faculty of Medicine, University of Coimbra, and e Critical Health, Coimbra, and f Primary Health-Care Center, Mira, Portugal  






Abstract Purpose: To evaluate the age- and gender-specific prevalence of early and late age-related macular degeneration (AMD) in a Portuguese population-based sample. Methods: All patients aged ≥55 years of a Portuguese primary healthcare unit were recruited for a cross-sectional populationbased study. Responders underwent complete ophthalmological examination and digital fundus imaging. Early and late AMD was defined according to the International AgeRelated Macular Epidemiological Study Group Classification, and the adopted staging for AMD was the same as that used in the Rotterdam study. The age- and gender-adjusted prevalence of early and late forms of AMD was calculated. Results: Of the 4,370 eligible subjects, 3,000 underwent study procedures (68.6% response rate) and 2,975 were included in the analysis; they had a mean age of 68.9 ± 8.6 years. The overall prevalence of early and late AMD was 15.53% (95% CI

© 2015 S. Karger AG, Basel 0030–3755/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/oph

14.25–16.88) and 0.67% (95% CI 0.41–1.04), respectively. Neovascular AMD (NV-AMD) and geographic atrophy (GA) accounted for 0.44% (95% CI 0.23–0.75) and 0.27% (95% CI 0.12–0.53) of individuals, respectively. The highest prevalence of advanced AMD was among those aged ≥75 years (1.13% for NV-AMD; 0.63% for GA). Conclusions: To our knowledge, this is the first AMD epidemiological study in a Portuguese population. The early forms of the disease had a similar prevalence to that of other large-scale populationbased cohorts, but late AMD was less frequent than previously reported. © 2015 S. Karger AG, Basel


Age-related macular degeneration (AMD) is the leading cause of irreversible, severe loss of vision in developed countries among people aged ≥55 years [1]. Currently, there is no universally accepted accurate definition of the AMD phenotype for either clinical or research purposes. Early stages of AMD have been characterized by the presMaria da Luz Cachulo AIBILI, Azinhaga de Santa Comba, Celas PT–3000-548 Coimbra (Portugal) E-Mail 4c @ aibili.pt

Downloaded by: Selçuk Universitesi - 2/9/2015 10:11:38 AM

Key Words Age-related macular degeneration · Neovascular age-related macular degeneration · Geographic atrophy


Ophthalmologica DOI: 10.1159/000371584

provide standards to assist clinicians and researchers in the diagnosis and management of this disorder. Most of these have been based on standardized grading color fundus photographs and relied on experienced graders to manually grade fundus images [2, 3, 29–32].

Methods Study Design This cross-sectional single-center population-based study adhered to the tenets of the Declaration of Helsinki (2008) and was approved by the Ethics Committee. All patients provided written, informed consent. Subjects Inclusion Between August 2009 and April 2011, subjects aged ≥55 years were recruited from the primary health-care center of Mira. To ensure a good response rate, two initial contacts were made by telephone: the first one to explain the aims of the study and to invite individuals to participate and the second one, 1 or 2 weeks later, to confirm the date and time for the appointment at the primary health-care center. All subjects who had agreed to participate but did not attend their scheduled visit were offered another for them more convenient date, in an effort to increase participation. At the appointment, the nature of the study was explained again in detail and a signed informed consent was obtained. Sociodemographic and clinical data of interest were then collected. Ophthalmic Examination All participants underwent complete bilateral ophthalmological examination. Best-corrected visual acuity (BCVA) was tested in each eye separately using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. If the BCVA of either eye was less than logMAR 0.6, refraction was performed with an autorefractor, and the amended BCVA was recorded. Evaluation also included anterior segment biomicroscopy, tonometry, and color fundus photographs after pharmacological mydriasis. Two 35° nonsimultaneous stereoscopic color fundus photographs were taken from fields 1M (centered on the optic disc), 2M (centered on the macula), and 3M (temporal to the macula), using a digital mydriatic Topocon® fundus camera (TRC-50EX; Topcon Corp., Tokyo, Japan). Fundus reflex photographs were similarly obtained to document media opacities. Fundus Photographic Grading Images were exported in the TIFF format and analyzed in a step-wise manner by a centralized reading center (Coimbra Ophthalmology Reading Center, CORC – AIBILI). We performed two analyses: a general analysis, independently performed by 4 certified ophthalmologists, aiming to identify major retinal pathology and a differential analysis for AMD lesions. The latter was done by 2 senior ophthalmologists that manually marked AMD lesions on the study digital photographs. The International Classification and Grading System (ICGS) for age-related maculopathy (ARM) and AMD was the chosen classification [2]. All graders underwent training sections, and only after certification by the reading center, did they start to grade the study images.

Cachulo  et al.  

Downloaded by: Selçuk Universitesi - 2/9/2015 10:11:38 AM

ence of drusen and pigmentary abnormalities within 2 disc diameters of the fovea [2, 3]. These lesions have also been identified as risk factors for the development of advanced AMD, but the proportion of subjects who progress to the late forms of the disease has been shown to be relatively small [4]. Two main forms of late AMD have been identified: geographic atrophy (GA), associated with an extensive loss of the choriocapillaris and overlying retinal pigment epithelium, and neovascular AMD (NV-AMD), which is characterized by blood and serum leakage from newly formed blood vessels in the macular region, causing irreversible damage and progressive vision loss. AMD is a multifactorial disease. Genetic and environmental risk factors have been implied in its pathology [5, 6]. Among them, smoking is the main modifiable risk factor and age and family history the main nonmodifiables [7]. Several studies have described other factors which might be linked, but the results were inconsistent [7–9]. Considering the clinical relevance of this age-related disease, several epidemiological studies have been performed all over the world. In the United States, the prevalence of late AMD seems to range from 0.2 to 1.6% [10– 15] and similar rates have been observed in Caucasians from Australia [16, 17] and Europe [18–22], taking into account the different age distribution between studies. In European cohorts, the prevalence of late AMD ranged from 1.65 to 3.5% [18–23]. Recently, the meta-analysis of Friedman et al. [24] provided a good estimate of prevalence rates for early and late AMD in Caucasian populations, gathering data from >25,000 individuals. Conversely to what was originally thought, late AMD is also not rare in the Asian population. Prevalence rates in the Chinese from the United States and Taiwan are similar to those in Caucasians but the prevalence rates in the Chinese from Mainland China were lower [15, 25, 26]. Despite all these data, in Europe all reports refer almost exclusively to the northern countries (e.g. the Rotterdam Study [18], the EUREYE Study [19], the Reykjavik Eye Study [21] and the Tromso Eye Study [27]). In view of the paucity of population-based epidemiological data on AMD in southern Europe (e.g. the Thessaloniki Eye Study [20] and the PAMDI Study [28]) and its environmental specificities, we undertook the present study, the Coimbra Eye Study. Our aim was to provide precise estimates of the prevalence of AMD in Portugal. This first report presents the results obtained in a coastal village in the center of this country, Mira. Several AMD classification schemes, grading systems, and severity scales have been developed in an effort to

Fig. 1. Standard grid used in the International Classification and

Grading System (ICGS) for ARM and AMD, superimposed on a color fundus image, showing the standard and freeform shapes used to grade drusen, pigmentary abnormalities, exudative maculopathy, and GA (Retmarker AMD Research software).

Table 1. Definition of the stage of ARM




No ARM features or only drusen 125 μm and decreasing density from the center outwards and fuzzy edges were considered as soft indistinct drusen. Pigmentary irregularities were classified into either hypopigmentation (without visualization of choroidal vessels) or hyperpigmentation. Late AMD was defined by the presence of NV-AMD or GA within the grid (3,000 μm from the center of the fovea). NV-AMD included serous or hemorrhagic detachment of the retinal pigment epithelium or sensory retinal or subretinal pigment epithelium hemorrhages and fibrous scar. GA was defined as an area of retinal depigmentation, with a diameter of 175 μm or larger, characterized by a sharp border and visualization of choroidal vessels. When GA and NV-AMD coexisted in the same eye, it was categorized as NVAMD and when eyes had different ARM grades, the worst grade of severity was recorded. The signs of ARM were stratified into 5 exclusive stages (ARM, stage 0–4) using the Rotterdam staging system (table 1). These definitions are in line with those previously used in other large epidemiological studies, such as the Rotterdam Study and the EUREYE Study, in order to facilitate the analysis and to make comparisons with other European studies it possible [18, 19].

Color version available online

This AMD grading was supported by a software to visualize digital color fundus photographs and to grade retinal lesions – Retmarker AMD Research (Critical Health, SA, Portugal). It was specifically developed to assist manual grading of AMD lesions according to the International ARM Epidemiological Study Group Classification and automatically contabilizes the number of lesions, their size, area, and location (fig. 1). Therefore, it was used in our study to visualize the color photographs and to grade AMD lesions. Briefly, the grading process always began by calibration, using the optic disc as a reference, with an adopted diameter of 1.5 mm. Afterwards, it was performed as previously described [33]. The stages of ARM disease were graded based on the features observed. The severity of maculopathy was classified based on the criteria of the International ARM Epidemiological Study Group [2] into 5 stages as defined elsewhere (table 1) [18, 19]. The AMD type was classified as atrophic or neovascular using the standard definition of the international classification.

Total Mira population (n = 4,370)

Subjects not included (n = 1,370): • Did not attend (n = 926) • Unreachable (n = 29) • Did not want to participate (n = 258) • Health problems (n = 157)

Sujects included (n = 3,000)

Subjects excluded from the grading analysis (n = 25): • Eyes did not dilate (n = 2) • Refused to have their eyes dilated (n = 20) • Images not recorded (n = 2) • Blind in both eyes (n = 1)

Fig. 2. CONSORT chart of the study par-

Table 2. Demographic characteristics of the study population (n = 2,975) in the Coimbra Eye Study, Portugal


n (%)

Gender Male Female Age 55 – 64 65 – 74 75 – 84 ≥85 Smoking Smoker Ex-smoker Nonsmoker Familiar history of ARM Yes No Does not know Diabetes Hypertension


1,291 (43.4) 1,684 (56.6) 1,051 (35.3) 1,125 (37.8) 659 (22.2) 140 (4.7) 63 (2.1) 142 (4.8) 2,770 (93.1) 339 (11.4) 2,516 (84.6) 120 (4.0) 538 (18.1) 1,413 (47.5)

Ophthalmologica DOI: 10.1159/000371584

sample comprised 2,975 participants. Figure 2 presents the CONSORT chart for the study participants. Most of the participants were recruited during a 20-month period from August 2009 to April 2011. Participating rates were calculated considering all subjects who were interviewed and underwent the ophthalmological examination. Nonresponders included those who were initially selected but with whom it was impossible to establish contact due to repeated absence (n = 29; 0.66%), those who were successfully contacted but who declined to participate either by refusing outright (n = 258; 5.9%) or because they were unable to attend the center as a result of health problems (n = 157; 3.6%), and those who agreed to participate but did not attend the scheduled examination on two occasions (n = 926; 21.1%). Twenty-five subjects were excluded from the analysis because the images were impossible to grade in at least one eye or because they refused to have their eyes dilated (fig. 2). Ninety-five percent (99.2%) of the fundus photographs obtained were gradable. The demographic characteristics of the 2,975 subjects included are shown in table 2. The mean (±SD) age of the study participants was 68.9 ± 8.6 years and 56.6% were females. Most participants (93.1%) were nonsmokers, Cachulo  et al.  

Downloaded by: Selçuk Universitesi - 2/9/2015 10:11:38 AM

Sujects analyzed (n = 2,975)

ticipants selected and inclued in the analysis.

Classification Frequency n

95% CI %

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

2,493 254 191 17 20

83.80 8.54 6.42 0.57 0.67






82.42 7.56 5.57 0.33 0.41

85.11 9.60 7.36 0.91 1.04

only 2.1% were current smokers, and just 4.8% of the population had been smokers in the past. Considering data from the Portuguese National Institute of Statistics about Mira’s population in 2009, our sample was found to be representative of the original population in the categories of age and sex, except in the older age categories. In fact, in the group aged ≥85 years, as regards both men and women, our sample had fewer subjects than the main population (p < 0.001 for both). We also included fewer women between 65 and 74 years of age than present in the original population (p = 0.041); 99.7% of the population was Caucasian. Prevalence of AMD The crude prevalence of the different stages of AMD is shown in table 3. Most participants (83.8%, n = 2,493) had no or minimal morphological changes in either eye (grade 0), 15.53% (n = 462) had some sign of early AMD (grade 1–3), and 0.67% (n = 20) had some sign of late AMD (grade 4). The demographic characteristics of the study population according to the presence or absence of early or late AMD are shown in table 4. Patients with early or late AMD were significantly older than those without AMD (p < 0.001). There was a higher percentage of women with early or late AMD than men, but this difference was not statistically significant (p = 0.241). Considering smoking, there were no significant differences between the prevalence of early or late AMD among nonsmokers and current or ex-smokers; moreover, all the participants with late AMD were nonsmokers (p = 0.466).

generally increased with age, but it was more frequent in the group of patients aged 75–84 years than in that of those aged ≥85 years, both in men and women. Concerning late AMD, prevalence increased always with age and was higher in the group of patients aged ≥85 years. Regarding gender, the global prevalence of early AMD was 14.25% in men and 16.51% in women. Indeed, this higher prevalence in women was observed in almost all age categories except for the oldest group. The same was not true for late disease; higher prevalence depending on gender was variable according to the age categories. Soft drusen were common in both genders and across all age groups (10.49–21.96%) and were present in 15.6% of the cases. Large soft drusen (≥125 μm) were found to increase with age, both in men and women, from 3.48% in women and 6.03% in men in those aged 55–64 years to 11.38 and 12.10%, respectively, in those aged 75–84 years. Hyperpigmentation and hypopigmentation were found in 1.2 and 0.4% of the cases, respectively. Men had a significantly higher prevalence of pigmentary changes than women (2.17 vs. 0.95%; p = 0.006). Except for hypopigmentation abnormalities, the prevalence of distinct and indistinct soft drusen, hyperpigmentation, or early AMD was strongly age related in both women and men (p < 0.05). The total prevalence of NV-AMD in this population, across all age groups, was 0.44%. This prevalence increased with age in both women and men. However, the highest prevalence in men was observed in subjects aged ≥85 years (1.75%) and in women in the 75- to 84-year age group (1.59%). Overall, there was a higher prevalence of NV-AMD in women than in men, but this difference was not statistically significant (p = 0.357). In the ≥85-year age group, a slightly higher proportion of participants with NV-AMD were men (1.75% compared with 1.20% of women). GA was uncommon in this population overall, affecting only 0.27% of the study participants. The age group analysis suggests that GA was more frequent in men than in women; this difference did not reach statistical significance (p = 0.071).

Analysis by Age and Gender Considering the presented results, a stratified analysis by age and gender was performed (table 5). There were only 20 late disease cases (0.67%) and 11 of them were female. The prevalence of all kinds of early AMD lesions

Multivariate Analysis Early AMD. Controlling for age, gender, and smoking (table 6), age was significantly associated with the prevalence of early AMD (p < 0.001). Per each year of age increase, there was an increase of 1.028 in the odds of having early AMD (95% CI 1.026–1.039). Considering gender, we did not find any association between this factor and the prevalence of early AMD (p = 0.053). No significant association between current or previous smoking and the prevalence of early AMD was found. This was also the case

Prevalence of AMD in a Portuguese Population

Ophthalmologica DOI: 10.1159/000371584


Downloaded by: Selçuk Universitesi - 2/9/2015 10:11:38 AM

Table 3. Prevalence of the different stages of AMD

Table 4. Demographic characteristics of the study population according to the stage of AMD

Mean age ± SD, years Gender, n (%) Female Male Smoking, n (%) Nonsmokers Current or ex-smokers




Early AMD

Late AMD

68.57 ± 8.66

70.61 ± 8.19

75.40 ± 9.29

Prevalence of Age-Related Macular Degeneration in Portugal: The Coimbra Eye Study - Report 1.

To evaluate the age- and gender-specific prevalence of early and late age-related macular degeneration (AMD) in a Portuguese population-based sample...
160KB Sizes 0 Downloads 9 Views