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1 From the Departments of Epidemiology and Biostatistics and 2 Ophthalmology, Erasmus University Medical School, Rotterdam, The Netherlands; 3 The Netherlands Ophthalmic Research Institute-KNAW, Amsterdam; and the 4 Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands.
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Abstract |
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METHODS. A group of 4953 subjects aged 55 years and older living in Rotterdam, The Netherlands, was studied at baseline and at 2-year follow-up to determine the incidence of neovascular and atrophic AMD. A subgroup of 1244 subjects was studied for progression of early stages of ARM. Fundus transparencies were graded for features of ARM using the International Classification System. ARM was stratified in four exclusive stages, according to type of drusen and presence of pigmentary irregularities.
RESULTS. The overall 2-year cumulative incidence of AMD was 0.2%, increasing to 1.8% in subjects of 85 years and older. Of those in the early stages, one fourth showed progression to a more severe stage. The most important predictors for progression were more than 10% of macular area covered by drusen (odds ratio [OR] 5.7, 95% confidence interval [CI] 2.9–11.3), presence of depigmentation (OR 4.0, 95% CI 2.5–6.4), and hyperpigmentation (OR 3.4, 95% CI 2.1–5.4).
CONCLUSIONS. The incidence of AMD appears to be lower in The Netherlands than in the United States. Progression of early ARM stages occurs in a distinct pattern at a stable rate, with a large area of drusen and presence of pigmentary changes as the most important predictors.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The purpose of this study was to describe the incidence and progression rates of ARM in the population-based Rotterdam Study in The Netherlands. We studied the incidence of AMD in the entire cohort and investigated progression of early ARM features in specific subgroups. Furthermore, we sought to assess the prognostic value of the various fundus features that are associated with ARM.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of 10,275 subjects aged 55 years and older living in Ommoord (a suburb of Rotterdam), 7,983 (78%) agreed to participate in the baseline phase of the entire study. The eye examination became part of the Rotterdam Study after the initial phase, therefore a smaller portion (n = 6872) was eligible for ophthalmic study. Gradable fundus transparencies were available on 6418 (93%) subjects, in 105 (1.6%) of whom atrophic or neovascular AMD was diagnosed. This resulted in a cohort of 6313 subjects potentially at risk for incident AMD.
Procedures and Definitions
The screening for presence of ARM followed the same protocol at
baseline and at follow-up. The procedures have been described in detail
elsewhere.2
9
During the screening eye examination, 35°
color transparencies were taken of the macular area (model TRV-50VT
fundus camera; Topcon Optical Co., Tokyo, Japan). The diagnosis of ARM
features was based on grading of fundus transparencies according to the
International Classification System,10
in which all
features of maculopathy related to age are named ARM and its late
stages (i.e., atrophic or neovascular macular degeneration) are named
AMD. At baseline, fundus transparencies of the entire cohort were
graded in a detailed manner to identify all features of ARM in the
macular grid area (radius, 3000 µm). At follow-up, all fundus
transparencies of the entire cohort were graded for presence of AMD
using side-by-side grading with the transparencies of the baseline
phase. Inter- and intragrader agreement on each fundus feature was
regularly assessed, and consensus training was initiated when 
values were below 0.6. All photographs showing AMD and all uncertain
diagnoses were adjudicated by senior investigators (PTVMdeJ, CCWK,
JRV).
To assess the incidence and progression rates of early ARM features, ARM at baseline was stratified in four exclusive stages of disease (Table 1) . On the basis of previous findings,7 8 11 12 we assumed more macular disease and a higher risk of development of AMD with each successive stage of early ARM. Stratification was based on the eye with the most severe stage. ARM stages 1a and 1b were considered one stage of clinical severity, as were stages 2a and 2b. For reasons of feasibility and efficiency, only a randomly selected subset of subjects with no ARM or ARM stage 1a at baseline underwent detailed grading of early ARM features at follow-up. For the remaining stages, the entire group of subjects with gradable fundus transparencies underwent detailed grading at follow-up. All detailed grading at follow-up was performed using side-by-side grading with the transparencies from baseline.
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Statistical Methods
Subjects with AMD at baseline were excluded from the incidence
and progression analyses. The age-specific incidence rates of AMD were
obtained per 10-year age categories by dividing the number of incident
cases by the number of person-years per age category. The latter was
calculated by summing each participant’s contribution of follow-up
time per age category. Confidence intervals of incidence rates were
calculated with the exact method. Age at onset of incident AMD
was set at the midpoint between age at baseline and age at follow-up.
Cumulative incidences were calculated from the incidence rates with the
formula
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Progression of early ARM stages was studied by logistic regression analysis with age, gender, baseline stage of ARM and duration of the follow-up period fixed in the model. In an initial analysis with these fixed factors, the predictive powers of drusen size and location, proportion of macular grid area covered by drusen, most frequent drusen size, largest drusen size, drusen confluence, presence and area of hyperpigmentation, and presence and area of depigmentation were assessed. Statistical interaction between macular area of drusen and hyper- or depigmentation, between hyper- and depigmentation, as well as between area of drusen and drusen confluence, was studied by entering the product term of these factors in the model. Determinants or product terms with a significant odds ratio (OR) were entered in a subsequent multivariate analysis to determine the independence and magnitude of prognostic factors.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Incident AMD was strongly associated with stage of ARM at baseline. Neither ARM stage 0 nor stage 1 progressed to incident AMD. ARM stage 2 progressed in two subjects to incident atrophic AMD and in five to incident neovascular AMD. For this stage, the overall incidence rate of AMD was 14.0 per 1000 person-years (2-year cumulative incidence 3%), ranging from 0 per 1000 person years in subjects under 65 years to 25.7 per 1000 person-years (2-year incidence 5.0%) in subjects aged 85 years and older. Stage 3 at baseline progressed in two subjects to incident atrophic AMD and in three to incident neovascular AMD. For stage 3, the total incidence rate of AMD was 48.2 per 1000 person-years (2-year incidence 9%), and the age category in which this occurred was less than 85 years.
Of the 31 subjects with AMD in only one eye at baseline, incident AMD had developed in the second eye in three subjects with atrophic AMD and in three subjects with neovascular AMD, by the 2-year follow-up. This resulted in an incidence rate of 170.6 per 1000 person-years (2-year cumulative incidence 28.9%) for involvement of the second eye. In the three subjects with unilateral atrophic AMD at baseline, the same type of AMD developed in the second eye. Neovascular AMD developed in the second eye of two of the three subjects with neovascular AMD, and atrophic AMD developed in the fellow eye of the remaining subject. The baseline ARM stages of the second eye were stages 2 (three subjects) and 3 (three subjects).
Progression of Early Stages
Of the 1244 subjects who were included in the early ARM
progression analyses, disease in 316 progressed to a more severe stage
of ARM. For the total cohort, this implied a 2-year cumulative
progression rate of 21.5%. Table 4
shows the incidence rates of the various stages of ARM at follow-up.
Age was associated with progression: Adjusted for gender, follow-up
time, and baseline stage of ARM, the OR of progression for age per year
was 1.04 (95% [CI] 1.01–1.06). Gender was not associated with
progression: The OR for women versus men was 0.90 (95% CI 0.62–1.31;
adjusted for age, follow-up time and baseline stage of ARM).
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175 µm versus area <175 µm, 2.3; 95%
CI 1.5–3.5). Areas of hyperpigmentation larger than 125 µm did not
have higher ORs than areas of 125 µm or smaller, indicating that
larger areas of hyperpigmentation were not significantly of additional
prognostic value. We found no evidence for statistical interaction
between area of drusen and pigmentary irregularities, between hyper-
and depigmentation, or between area and confluence of drusen (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A good estimate of the incidence of AMD requires the follow-up of many subjects over a long period, because the occurrence of this clinical end stage is relatively infrequent. A large study population with a significant number of elderly is one of the strengths of the Rotterdam Study. However, the length of the follow-up period was not long, and the number of subjects in whom incident AMD developed was low. This resulted in wide confidence intervals around the estimated incidence rates. The short follow-up period was a benefit, however, for the study of the progression of early ARM stages. This enabled us to register small changes and to determine a pattern of progression, which may add to the understanding of the natural course of this disease.
Loss to follow-up was a concern in this study as it is in all cohort studies. Nonparticipation in the second round was mainly due to death and nonresponse to the entire study, not to the eye examination itself. Comparison of participating and nonparticipating subjects showed that the latter group was older and had more vascular disease; however, the groups did not significantly differ in stage of ARM at baseline. Thus, selection bias regarding ARM disease status due to loss to follow-up appears to be limited in our study.
The age-specific incidences of AMD appeared to be lower in the Rotterdam Study than in the Waterman Study7 and Beaver Dam Eye Study8 (Fig. 1) . The US studies took place in different parts of the US, but showed incidences within the same range. Although a longer follow-up period is needed to confirm the incidences, the difference appears to be considerable, is consistent over the age-groups, and is in agreement with earlier reports indicating global differences in the occurrence of AMD. Comparison of prevalence data from the Beaver Dam Eye Study, the Blue Mountain Eye Study, and the Rotterdam Study show that the prevalence of AMD is highest in the US and lowest in The Netherlands.1 2 3 The three studies used very similar methods of diagnosis based on fundus photography, which makes it less likely that the differences were a result of observation bias. Known risk factors such as smoking and cardiovascular disease did not explain the differences,13 and it remains a key point of interest to identify the environmental and genetic factors that are accountable.
The 2-year cumulative incidence of AMD in the fellow eye in subjects with unilateral AMD was 29% in the entire study, and the type of AMD was not necessarily concordant with the first eye. The Beaver Dam Eye Study found a 5-year incidence of 22% for the second eye,8 considerably lower than the Rotterdam Study. The lower maximum age at baseline in the Beaver Dam study may account for this difference. Our data are in line with clinic-based studies reporting the rate of fellow eye involvement. The majority of these studies focused on patients with neovascular AMD, and estimates for annual second eye incidence mostly ranged from 4% to 15%.11 14 15 16 17 18 19 All prevalence figures in these studies were crude prevalences, because numbers were mostly too small for any stratification. Therefore, comparison of these prevalences is hampered by differences in age, duration of disease, and diagnosis. Long-time follow-up of large, well-defined study groups is needed to provide valid and precise estimates and to enable more profound comparisons.
An important objective of this study was to describe the progression of early features of ARM. It has long been known that soft drusen and pigmentary changes are precursor lesions that increase the risk of geographic atrophy and neovascular macular degeneration.7 8 11 12 13 14 15 16 17 18 19 20 21 After appearing, drusen and pigmentary changes may regress and disappear, but this may be a result of appearance of more severe lesions.7 8 In the Rotterdam Study, we did not focus on individual fundus lesions. To enhance clinical relevance, we preferred to study progression of ARM in exclusive stages of disease. We stratified early features of ARM in three stages based on type of drusen and presence of pigmentary changes, the factors that have been shown to be strong predictors for the development of AMD.7 8 11 12 The ranking of the stages proved to be in accordance with clinical severity: the risk of AMD increased from virtually no risk for stages 0 and 1, to a 2-year risk of 3% and 9% for stages 2 and 3, respectively. An interesting finding was that progression was predominantly to only one more advanced stage at a rate of approximately one-fourth of the cohort per 2 years for the earliest stages (Table 4) . Progression from stage 3 to 4 was slower and occurred at a rate of 9% in 2 years. In some subjects, maculopathy progressed fast and skipped a stage, but no subjects skipped more than one stage in the 2 years of follow-up. Although future studies are awaited to confirm these data, our findings add to the view that development of ARM is not a random chain of events, but rather seems to follow a well-defined pattern at a stable rate.
In accordance with Klein et al.,8
we found that a large
area of the macula covered by drusen and pigmentary irregularities were
important predictors of ARM progression, independent of stage of
disease. Other predictors were number of small drusen and drusen
confluence. The number of intermediate (64–124 µm) and large (125
µm) drusen did not have additional predictive power, neither did
location of drusen. Although small drusen (
63 µm) are not
considered an ARM feature in the International Classification System,
our data indicate that more than 10 small drusen are predictive of ARM
progression, independent of other features. This is consistent with
findings from the Waterman Study7
and the Beaver Dam Eye
Study,8
both of which reported that presence of many small
drusen increases the risk of large and soft indistinct drusen, but not
of AMD.
From our results and those of others we conclude that progression of early ARM appears to follow a distinct pattern. A large number of small, hard drusen or isolated pigmentary changes may indicate the very early start of ARM. Then soft drusen emerge. Subsequently, at a stable rate, multiple drusen of various sizes appear and become confluent, the total area increases, and some of the drusen become soft and indistinct. The appearance of pigmentary changes at this stage, especially large areas of depigmentation, then further increases the risk of AMD. Subretinal neovascularization or development of geographic atrophy denote the end stage of ARM.
In conclusion, the incidence of AMD in the Rotterdam Study was 1.2 per 1000 subjects per year. Our data provide further evidence that ARM is a progressive disease with a distinct temporal sequence of events ultimately resulting in AMD.
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Acknowledgements |
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Footnotes |
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Submitted for publication September 26, 2000; revised February 9, 2001; accepted March 5, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Paulus T. V. M. de Jong, The Netherlands Ophthalmic Research Institute-KNAW, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. p.dejong{at}ioi.knaw.nl
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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