14-Year Incidence, Progression, and Visual Morbidity of Age-Related Maculopathy

14-Year Incidence, Progression, and Visual Morbidity of Age-Related Maculopathy The Copenhagen City Eye Study Helena Buch, MD,1 Niels V. Nielsen, MD, DMSc,1 Troels Vinding, MD, DMSc,1 Gorm B. Jensen, MD, DMSc,3,4 Jan U. Prause, MD, DMSc,1 Morten la Cour, MD, DMSc2 Purpose: To describe the 14-year incidence of age-related maculopathy (ARM) lesions and the related visual loss. Design: Population-based cohort study. Participants: Nine hundred forty-six residents (age range, 60 – 80 years) of Copenhagen participated in the study from 1986 through 1988. Excluding participants who had died since baseline, 359 persons (97.3% of survivors) were reexamined from 2000 through 2002. Methods: Participants underwent extensive ophthalmologic examinations. Age-related maculopathy lesions were determined by grading color fundus photographs from the examinations using a modified Wisconsin Age-Related Maculopathy Grading System. Main Outcome Measures: Incidence of drusen type and size, pigmentary abnormalities, pure geographic atrophy, exudative ARM, visual impairment, and blindness. Results: The 14-year incidences of early and late ARM were 31.5% and 14.8%, respectively. Individuals 75 to 80 years of age at baseline had significantly (Pⱕ0.05) higher 14-year incidences of the following lesions than those aged 60 to 64 years: medium or large drusen (ⱖ125 ␮m; 34.2% vs. 12.8%, respectively), soft drusen (45.2% vs. 21.4%), pigmentary abnormalities (31.4% vs. 17.0%), pure geographic atrophy (17.4% vs. 1.0%), and exudative ARM (23.3% vs. 5.7%). Severe drusen type, large drusen, and retinal pigmentary abnormalities at baseline were important predictors of incident late ARM. The 14-year incidences of visual impairment (⬍20/40 but ⬎20/200) or legal blindness from late ARM were 6.0% and 3.4%, respectively. Late ARM caused 35.7% of all visual impairment and 66.7% of all blindness. Conclusions: There is a high incidence of ARM lesions in this elderly white population. Severe drusen type and size or a combination of drusen and pigmentary abnormalities significantly increases the risk of developing late ARM, the most frequent cause of legal blindness in this population. Ophthalmology 2005;112:787–798 © 2005 by the American Academy of Ophthalmology.

In the industrialized world, it is well recognized that the leading cause of blindness in elderly white persons is age-related maculopathy (ARM).1–5 Globally, the number of elderly individuals is increasing, and consequently, low vision resulting from ARM is expected to develop more frequently and to contribute to loss of independence in old age. Despite this, information on the natural history and consequences of this disease is sparse. Most studies derive their information from Originally received: June 14, 2004. Accepted: November 17, 2004.

Manuscript no. 240452.

1

Department of Ophthalmology, National University Hospital (Rigshospitalet), Copenhagen, Denmark.

2

Department of Ophthalmology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 3 The Copenhagen City Heart Study, Epidemiological Research Unit, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark. 4 Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. © 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.

case series of patients with ARM,6 –16 clinical trials,6,7,17 or clinicopathologic studies.18 –23 The incidence of ARM has been reported previously in 6 population-based studies from 3 continents that used similar highly standardized procedures. In Europe, the 2-year,24 6.5-year,25 and 7-year26 incidences of age-related macular disease have been described. Two Australian populationbased studies have reported on the 5-year27,28 incidence, Poster presented at: Association for Research in Vision and Ophthalmology Congress, April 27, 2004; Fort Lauderdale, Florida. Supported by the Carl and Nicoline Larsens Foundation, Copenhagen, Denmark; The Danish Eye Research Foundation, Copenhagen, Denmark; and the Danish Velux Foundation of 1981, Copenhagen, Denmark. The authors have no financial or commercial interests in the subject matter or materials mentioned herein. Correspondence and reprint requests to Helena Buch, MD, Department of Ophthalmology, National University Hospital (Rigshospitalet), Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: [email protected]. ISSN 0161-6420/05/$–see front matter doi:10.1016/j.ophtha.2004.11.040

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Ophthalmology Volume 112, Number 5, May 2005 and information from United States populations has emerged from 5-year29,30 and 10-year31 follow-up studies. Some of these studies provided data on the association between early ARM lesions and the incidence of more severe ARM lesions29 –31 or reported on the related visual loss.26,32 Nevertheless, because the reported incidence rates vary considerably among studies, and because data on persons older than 85 years of age are scant, the long-term incidence among the eldest northern Europeans is unknown. As the population ages, acquiring accurate long-term incidence data is important for planning future eye care services and intervention trials for treating and preventing ARM. Thus, the aim of this study was to investigate the 14-year incidence and natural course of the typical lesions of early and late ARM and to quantitate the long-term visual morbidity caused by these lesions in an elderly northern European population. This study is the first Scandinavian study to assess the incidence of ARM using standardized grading of fundus photographs, and it has the longest followup period and highest response rate of any ARM epidemiologic study.

Patients and Methods Population The study was approved by the Ethical Committee of Copenhagen, and informed consent was obtained from all participants. The Copenhagen City Eye Study is a population-based survey of vision and common eye diseases in a representative urban elderly population residing in the Copenhagen metropolitan area. The study population is an age-stratified and gender-stratified, random subsample of 1000 persons aged 60 to 80 years from the Copenhagen City Heart Study population that comprised a random sample of 20 000 of 90 000 citizens from a district in Copenhagen, Denmark.33,34 Of the 976 eligible subjects, 946 (96.9%) were examined during a baseline eye examination from 1986 through 1988.34 The present follow-up study population was recruited from the surviving cohort of persons who participated in the baseline examination. During the recruitment period for the follow-up study, 369 persons of the original 946 subjects were alive. At recruitment, the surviving cohort was older than the general Danish population. Of the 369 survivors, 359 persons (229 women, 130 men) participated in the 14-year follow-up examination between May 1, 2000, and May 1, 2002. After excluding deceased individuals, we achieved a response rate of 97.3% (359/369). Of the participants, 300 were examined in the eye clinic; 43 in sheltered homes, that is, private homes with medical assistance; and 16 were examined at nursing homes. The mean age of the study population at follow-up was 82.35 years (standard deviation [SD], ⫾4.63 years; median, 81 years; range, 75–95 years). There was a significant difference in age between men (mean age, 81.58 years; SD, ⫾4.10 years; median, 80 years; range, 75–92 years) and women (mean age, 82.80 years; SD, ⫾4.87 years; median, 82 years; range, 75–95 years; P ⫽ 0.012). Comparisons between the 359 participants and the 641 nonparticipants (including alive and dead persons) in the 14-year Copenhagen City Eye Study follow-up examination (data not shown) revealed that persons who did not participate in the 14-year follow-up were older and more often men than those who participated. Controlling for age and gender, nonparticipants were significantly different from the 359 persons examined at follow-up in that they were more likely at baseline to have early ARM, to have fewer

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years of education, to have a lower income, to have a history of smoking, to have higher alcohol consumption, and to have a poorer cardiovascular risk profile than persons who participated.

Procedures Letters from the principal investigator were sent to eligible individuals followed by a phone call until contact was made. People not interested in participating in the examination were asked to respond by telephone to a questionnaire, and file data were sought for those who permitted access to case notes. Similar eye examination procedures were used at baseline34 and follow-up. Subjective refraction and pinhole tests were performed. Best-corrected distance visual acuity (BCVA) was measured using the Snellen E-chart.34,35 A slit-lamp examination was performed including tension measurement, and ophthalmoscopy using a Goldmann 3-mirror lens for assessment of pathologic features present in the eye. If the examination revealed any need for further investigation or treatment or an examination at the visual rehabilitation clinic, a referral was made. Additionally, color fundus photographs centered on the macular were obtained. At baseline, a TRC-WT fundus camera (Topcon Europe B.V., The Netherlands) and Kodachrome 64 (Kodak, Denmark) film were used to obtain 30° and 45° photos. In the follow-up study, 30° color fundus photographs were obtained by an FF 450 IR fundus camera (Carl Zeiss Meditec AG, Jena, Germany) and Fujichrome Velvia 135 film (FujiFilm, Valhalla, NY). When participants were uncooperative or were examined at home, a portable hand-held Kowa Genesis fundus camera (Kowa Europe GmbH, Germany) and Ektachrome E100 films (Kodak) were used.

Grading Definitions The ARM lesions were defined solely on the appearance on the color fundus transparencies from the baseline and follow-up examinations, according to a modification of the Wisconsin AgeRelated Maculopathy Grading System (WARMGS) protocol.36,37 This version mimics the detailed ARM grading protocol used in the Los Angeles Latino Eye Study previously described.38 The approach of the present study to the definitions of the WARMGS protocol represents a major departure from the baseline study, in which grading was based on the clinical examination and was performed according to the classification used in the Framingham Eye Study.34 Modifications to the WARMGS protocol were necessary because of a lack of a stereo effect in many baseline photographs, different camera magnifications, and the fact that only 1 person graded the photographs. The modifications included: a nonstereoscopic grading that was followed by a stereoscopic evaluation for the presence of retinal elevation when ever possible, adaptation of the WARMGS grid and measuring tools to the magnifications of the 3 cameras used in this study, and finally, determination of each lesion for the grid as a whole and not for separate subfields.

Definitions of Incidence, Bilaterality, and Changes The 14-year cumulative incidence of a lesion, henceforth referred to as incidence, was defined by the number of eyes with a lesion not present in any subfield at baseline but present in at least 1 subfield at follow-up divided by the number of eyes at risk. Eyes at risk were eyes without a lesion at baseline. The definitions of the incidence of the different ARM lesions closely followed the definitions previously reported.30,31 The incidence was calculated as person-specific incidence rates (i.e., in either eye) and for the right and left eyes. The incidence of ARM bilaterality was defined by the number of individuals without ARM in 1 or both eyes in which ARM

Buch et al 䡠 Incidence, Progression, and Visual Morbidity of ARM developed in the better eye at follow-up divided by the number of individuals at risk.

Visual Acuity and Definitions of Vision Changes To study the incidence of visual impairment and blindness and the proportion caused by ARM visual acuity (VA) measures of the 359 participants at both examinations were used; 3 persons lacked VA data because of dementia. Visual acuity data were available for 310 of the 313 persons with gradable photographs of at least 1 eye at both examinations that were included in the ARM analyses. Visual acuity data were reliable in 77.2% of the survivors (275/356) with visual acuity data at follow-up, because 84 persons could cooperate only minimally with VA testing. The incidence of visual impairment was defined as the development of BCVA of worse than 20/40 but better than 20/200 in the better eye at follow-up in an individual who had a BCVA of 20/40 or better in the better eye at baseline. The incidence of blindness was defined as the development of BCVA of 20/200 or worse in the better eye in an individual who had BCVA better than 20/200 in the better eye at baseline.39

Definition of Age-Related Maculopathy Lesions as the Cause of Visual Loss Late ARM was considered the main cause of visual loss if the patients had pure geographic atrophy or exudative ARM in the fovea with or without cataract. Subjects with late ARM lesions as the cause of visual disability in both eyes were assigned the specific late-stage diagnosis (i.e., pure geographic atrophy or exudative ARM) of the least affected eye. Early ARM was considered a contributing cause of visual impairment in eyes with coexistent cataract.

Quality Control Procedures Photographs from the baseline and follow-up examinations were graded in a masked and randomized fashion by one grader (HB). The mean period of time between gradings of photos of each participant was 20.3 days (SD, ⫾30.9). All questionable and late-stage lesions were assessed in a blinded fashion by one of the authors (NVN). Furthermore, series of longitudinal and crosssectional edits and reviews were performed as side-by-side grading of the photographs for eyes that were identified as having a significant difference in ARM lesions between visits for the same eye and between eyes for the same visit. As a result of this, changes were made for at least 1 ARM lesion in 252 of the 1202 graded eyes (21.0%) included in the main analysis. Intergrader and Intragrader Variability. To check for systematic bias and drift in concordance over time, an interobserver agreement session and incorporated masked intraobserver agreement gradings were carried out. The interobserver agreement session was performed by one of the authors (HB) and a senior grader (MS) from the Beaver Dam Eye Study (BDES) group. This reliability test of the gradings was assessed on a random representative subsample of 60 eyes. On a 3-level scale, exact agreement between the graders occurred 98.33% of the time, and agreement within 1 step occurred in 99.58% of eyes with early ARM and late ARM. The weighted and unweighted ␬ scores were 0.98 and 0.97, respectively. Thus, the interobserver agreement was almost perfect. To estimate the intragrader variability and internal consistency maintained throughout, one third of the Danish standards were copied 3 times each and masked and randomly intermingled among the study photos to obtain a 3-time recycling during the

grading period. On the 3-level scale, the exact intraobserver agreement levels between the first and second gradings and between the first and third gradings were both 95%; the agreement levels within 1 step were 98.8% and 98.7%, respectively. The unweighted and weighted ␬ scores were almost perfect.

Statistical Analysis The Statistical Analysis System40 was used for tabulations and most statistical analyses. Additionally, Stata software41 was used to calculate 1-step agreement (%), weighted ␬ estimates, and related standard errors. The interobserver and intraobserver estimates were obtained by a 3-level comparison of ARM. The percentages of agreement, exact and within 1 step, were calculated, and unweighted and weighted ␬ scores were computed.42 Weights assigned were 1.0 for full agreement, 0.75 for disagreement by 1 step, and 0 for greater disagreement. ␬ levels of agreement were interpreted according to the guidelines of Landis and Koch as previously described.37,42 Categorical variables were represented by frequency distribution. Differences between categorized data were analyzed using logistic regression analyses. When testing for trend in age, we used a logistic regression model that controlled for gender; when testing for differences between gender, we used a logistic regression model that controlled for age; when testing for trend in lesion progression, we used a logistic regression model that controlled for age and gender. The Fisher exact test was used to test differences between categorical variables when the number of cases was few. The continuous normalized data variables are presented as means and standard deviations, median, and range. Differences between continuous variables were tested using t tests. Comparisons between age-specific annual rates reported were calculated from the incidence rates with the formula: CIt ⫽ 1 ⫺ e(⫺IR*t), where CI is the cumulative incidence over a period of t years and IR is the incidence rate. Age was defined as the age at baseline.

Inclusion and Exclusion of Participants Based on Fundus Photograph Gradability To evaluate changes in lesions between visits, retinal photographs were necessary from corresponding eyes at both visits. Of the 359 subjects who participated in the baseline and follow-up studies, 330 had gradable photographs of 1 or both eyes at baseline (319 for both eyes, 11 for 1 eye). Of these, 327 subjects had gradable photographs at the follow-up visit (313 for both eyes, 14 for 1 eye). Photographs of 82 eyes of 50 persons were unavailable. Of these, 66 eyes of 39 subjects lacked baseline photographs. Confounding ocular lesions, such as media opacity, were responsible for the ungradability of 13 photos in 9 persons and additionally prevented grading of any drusen characteristics and retinal pigment abnormalities in 22 eyes. Of the 327 people with gradable photographs in at least 1 eye at both examinations, 14 persons (14 bilateral at both examinations, 8 unilateral at baseline, and 10 unilateral at follow-up) were excluded from analysis because of the presence of confounding lesions unrelated to ARM.43 Another 4 subjects had then 1 eye excluded from the analyses because the photographs were ungradable or missing from one of the examinations. Thus, for purposes of this report, the 327 subjects with gradable photographs at both visits were included in the analyses concerning bilaterality. The 313 subjects with at least 1 eye evaluable and without confounding lesions at both examinations were included in the remaining analyses (288 bilateral, 25 unilateral; 13 right eyes,

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Ophthalmology Volume 112, Number 5, May 2005 Table 1. 14-Year Incidence of Drusen by Size and Type, Increased Retinal Pigment, Retinal Pigment Epithelial Depigmentation, Pure Geographic Atrophy, and Exudative Age-Related Maculopathy in the Right Eye Lesions Drusen size ⬍63 ␮m in diameter (small) ⱖ63 ␮m to ⬍125 ␮m in diameter (moderate) ⬎125 ␮m to ⬍250 ␮m in diameter (medium) ⱖ250 ␮m in diameter (large) Drusen type Hard distinct Soft distinct Soft indistinct Pigmentary abnormalities Increased retinal pigment RPE depigmentation Pure geographic atrophy Exudative ARM

No. Missing*

No. with Lesion Present at Baseline

No. at Risk

Incidence, (Cases) %

62 62 62 62

201 101 47 19

96 196 250 278

(21) 21.9 (47) 24.0 (46) 18.4 (43) 15.5

62 62 62 69 59 64 62† 58

188 82 35 25 20 18 0 4

109 215 262 265 280 277 297 297

(23) 21.1 (55) 25.6 (72) 27.5 (68) 25.7 (67) 23.9 (51) 18.4 (15) 5.1 (29) 9.8

ARM ⫽ age-related maculopathy; RPE ⫽ retinal pigment epithelium. *Number missing because photo was missing, or the lesion was ungradable or confounding at baseline or follow-up. † Eyes with exudative ARM at baseline were excluded (placed in the missing group).

12 left eyes). Of these eyes, 45 had 45° photographs taken, 102 were photographed using the Kowa camera, and 1055 had 30° color fundus photographs. A total of 16.6% (100/601) had stereoscopic fundus photographs at baseline, whereas 87.0% (523/601) had these from the follow-up examination. Additionally, of the included photographs, 85.4% had good quality images, 12.0% had borderline quality images, and 2.6% had poor quality images at baseline, whereas 58.9% had good quality images, 36.5% had borderline quality images, and 4.7% had poor quality images at follow-up.

Results Participants The mean and median times between the baseline and the 14-year follow-up examinations were 14.5 years and 14.7 years, respectively. Of the 946 participants in the baseline examination, 577 died before the follow-up examination. Of the surviving 369 persons, 359 participated in the follow-up examination and 10 persons declined to participate. Of those examined at both visits, 87.2% (313/359) were included in the analyses with at least 1 eye gradable at both examinations (288 bilateral, 25 unilateral; 13 right eyes, 12 left eyes). Because the correlations are high between eyes, the following analyses for lesions associated with ARM are presented for the right eye only.

There were no statistically significant differences in the 14-year incidence of drusen of different maximum sizes between right and left eyes. The incidence of moderate drusen (63 to ⬍125 ␮m) in either eye was 27.4%, the incidence of medium drusen was 25.3%, and the incidence of large drusen was 22.0%. Drusen Type. Table 1 and Figure 2 show the incidences of the most severe drusen type observed in right eyes. The incidence of soft drusen increased significantly with age from 21.4% among persons 60 to 64 years of age to 45.2% among persons 75 to 80 years of age (P ⫽ 0.007). This was the result of the age-related increase in the incidence of soft indistinct drusen (P ⫽ 0.002). In those 75 to 80 years of age, soft indistinct drusen were 2.4 times (50.0/21.1) as likely to develop as in those 60 to 64 years of age at baseline. There were no statistically significant differences in the 14-year change in different types of drusen between right and left eyes. The incidence of soft distinct drusen in either eye was 30.6% and the incidence of soft indistinct drusen was 34.7%. Retinal Pigmentary Abnormalities. The incidence of pigmentary abnormalities was 25.7% (Table 1). This incidence increased 1.9 times with age (from 20.0% to 38.0%; P ⫽ 0.08, test

Incidence Components of Early Age-Related Maculopathy. Drusen Size. The 14-year changes in maximum drusen size in the right eyes are shown in Table 1 and Figure 1. The incidence of small and moderate drusen (⬍125 ␮m in diameter) decreased with age (P ⫽ 0.01, test for trend), whereas the incidence of medium drusen (125–249 ␮m) and large drusen (ⱖ250 ␮m) increased with age (P ⫽ 0.003). Over the 14-year study, in those 75 to 80 years of age at baseline, medium drusen were 1.8 times as likely to develop and large drusen were 3.5 times as likely to develop, respectively, compared with persons 60 to 64 years of age (P⬍0.05, test for trend).

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Figure 1. Relation of age to the 14-year incidence rates of various-sized drusen in the right eye.

Buch et al 䡠 Incidence, Progression, and Visual Morbidity of ARM

Figure 3. Relation of age to the 14-year incidence of early and late age-related maculopathy (ARM) in the right eye.

Figure 2. Relation of age to the 14-year incidence of soft drusen and pigmentary abnormalities in the right eye. RPE ⫽ retinal pigment epithelium.

for trend). Increased retinal pigment developed more frequently than retinal pigment epithelium depigmentation. The incidence of increased retinal pigment increased 1.8 times with increasing age from 20.0% among persons 60 to 64 years of age to 36.0% among persons 75 to 80 years of age (P ⫽ 0.08), whereas the age-related increase in the incidence of retinal pigment epithelium depigmentation was 1.6 times (from 14.0% to 23.1%; P⬎0.1). There were no statistically significant differences in the 14-year change in retinal pigmentary abnormalities between right and left eyes. The incidence of pigmentary abnormalities in either eye was 32.6% (84/258): for increased retinal pigment it was 30.0%, and for retinal pigment epithelium depigmentation it was 23.8%. Early Age-Related Maculopathy. The overall incidence of early ARM in right eyes was 31.5% (Table 2), and it increased with age (P ⫽ 0.025, test for trend; Fig 3). Over the 14-year period, those aged 75 to 80 years at baseline were twice as likely to experience early ARM as those 60 to 64 years of age. There was no difference in the 14-year incidence of early ARM between eyes. The overall incidence of early ARM in either eye was 37.8%, which increased from 34% in persons 60 to 64 years of age to 47.4% in persons 75 to 80 years of age. Late Age-Related Maculopathy. The overall incidence of late ARM in right eyes was 14.8% (Table 2), and it increased with age

(P⬍0.001, test for trend; Fig 3). Over the 14-year period, persons 75 to 80 years of age at baseline were 5.5 times as likely to experience late ARM as persons 60 to 64 years of age. There were no differences in the 14-year incidence between right and left eyes. The overall incidence of late ARM in either eye was 16.9% (52/308), which increased from 9.8% (20/205) in persons 60 to 69 years of age to 31.1% (32/103) in persons 70 to 80 years of age. Of the 52 participants with incident late ARM in either eye, 75.0% (39/52) of cases were bilateral. The incidence of bilaterality of late ARM was 12.8% (42/327) and rose with age from 6.8% (8/118) among persons 60 to 64 years of age to 26.2% (11/42) among persons 75 to 80 years of age (P⬍0.05, test for trend). Of the incident bilateral cases, 16.7% (7/42) were mixed, that is, pure geographic atrophy in 1 eye and exudative ARM in the other eye. The 14-year incidence of pure geographic atrophy in right eyes was 5.1% (Table 1) and increased with age (P ⫽ 0.004). Geographic atrophy developed at a higher age than did exudative ARM (Fig 4). Individuals 75 years of age or older were 14 times (13.3/0.95) as likely to experience pure geographic atrophy as those 60 to 64 years of age at baseline. The incidence in either eye was 4.9% (15/308), increasing from 0.9% (1/108) in those 60 to 65 years of age to 12.5% (4/32) in those 75 to 80 years of age (P ⫽ 0.01). The incidence of bilateral pure geographic atrophy was 3.1% (10/327) and rose with age. The 14-year incidence of exudative ARM in right eyes was 9.8% (Table 1). This incidence increased with age from 5.7% in

Table 2. Relation of Age and Gender to the 14-Year Incidence of Early and Late Age-Related Maculopathy in the Right Eye Age (yrs) Men 60–69 70–80 Total Women 60–69 70–80 Total Men and women 60–69 70–80 Total

No. at Risk at Baseline*

Incidence of Early Age-Related Maculopathy, (Cases) %

No. at Risk at Baseline*

Incidence of Late Age-Related Maculopathy, (Cases) %

73 19 92

(22) 30.1 (7) 36.8 (29) 31.5

78 29 107

(4) 5.1 (8) 27.6 (12) 11.2

112 50 162

(31) 27.7 (20) 40.0 (51) 31.5

121 69 190

(11) 9.1 (21) 30.4 (32) 16.8

185 69 254

(53) 28.6 (27) 39.1 (80) 31.5

199 98 297

(15) 7.5 (28) 28.6 (44) 14.8

*The number at risk at baseline was those seen at follow-up. Number of missing (right eye) was 64 because of missing or ungradable photo, or confounding lesion at baseline or follow-up

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Figure 4. Relation of age to the 14-year incidence of pure geographic atrophy and exudative maculopathy (exudative age-related maculopathy [ARM]) in the right eye.

those younger than 65 years of age to 23.3% in those 75 years or older at baseline (P⬍0.01; Fig 4). The incidence of exudative ARM in either eye was 12.0% (37/308), increasing from 6.5% in those 60 to 65 years of age to 28.1% in those 75 to 80 years of age (P⬍0.01). The incidence of bilateral exudative ARM was 7.6% (25/327) and rose with age. Of the participants in whom late ARM had developed by follow-up, 38.5% (20/52) were examined in their homes. Incidence and Gender. The incidences of early and late ARM and most of the individual ARM lesions were slightly higher in women than in men (Table 2). However, only the incidence of large drusen was significantly higher among women than among men when controlling for age (19.6% vs. 8.1%; P ⫽ 0.03).

Morphologic Risk Factors for Age-Related Maculopathy Progression and Visual Loss For eyes with drusen at baseline, the risk of developing more severe ARM lesions increased with increasing drusen size observed at baseline. Right eyes with medium drusen size (⬎125 to ⬍250 ␮m in diameter) at baseline were more likely than right eyes with smaller drusen at baseline to develop any pigmentary abnormalities (59.1% vs. 20.8%; P⬍0.001), pure geographic atrophy (17.9% vs. 1.6%; P ⫽ 0.001), or exudative ARM (28.6% vs. 5.1%; P⬍0.001). Similarly, right eyes with large drusen size (⬎250 ␮m in diameter) were more likely to develop any pigmentary abnormalities (75.0% vs. 24.0%; P ⫽ 0.004) and late ARM lesions (86.7% [3/15] vs. 11.2% (31/278); P⬍0.001) than right eyes with only smaller drusen at baseline. The severity of drusen type observed at baseline was correlated with the presence of more severe ARM lesions at follow-up (Table 3).

Right eyes with soft distinct drusen at baseline were more likely to develop soft indistinct drusen (60.4% vs. 27.6%), pigmentary abnormalities (31.7 vs. 24.3), or signs of late ARM (26.7% vs. 2.9%) than eyes with only hard drusen present at baseline (P⬍0.001, test for trend; Table 3). Similarly, right eyes with soft indistinct drusen were more likely to develop pigmentary abnormalities (72.2% vs. 26.4%; P⬍0.001), pure geographic atrophy (34.4% vs. 2.6%; P⬍0.001), or exudative ARM (53.1% vs. 7.9%; P⬍0.001) than right eyes that had only soft distinct or hard distinct drusen at baseline (Table 3). The relation of drusen size, type, and area at baseline and the presence of late ARM at follow-up was analyzed using a multiple logistic regression model. This showed that the risk of development of late ARM is strongly associated with the presence of soft drusen, especially soft indistinct drusen (soft distinct: odds ratio [OR], 12.2; 95% confidence interval [CI], 3.2– 47.0; P⬍0.001; soft indistinct: OR, 225.9; 95% CI, 30.9 –1651.2; P⬍0.001). It also showed that increased drusen size is a significant risk factor (63–124 ␮m: OR, 5.0; 95% CI, 1.7–14.4; P ⫽ 0.003; ⬎125 ␮m: OR, 7.6; 95% CI, 1.9 –29.2; P ⫽ 0.003). Drusen area was a significant risk factor in the univariate analysis, but was not after adjustment for drusen type in the multivariate analysis. The presence of pigmentary abnormalities in association with soft drusen at baseline was a strong predictor of late ARM (Table 4). The risk of developing late ARM rose with the severity of accompanying drusen, with soft indistinct drusen associated with pigmentary abnormalities being the strongest predictor.

Subject-Specific Morphologic Risk Factors for Late Age-Related Maculopathy Twenty-three subjects with unilateral early ARM at baseline were examined during follow-up. Of these, late ARM developed in 10 (43.5%; 4 bilateral, 6 unilateral). Bilateral early ARM was present in 28 subjects at baseline and in 23 of them (82.1%), late ARM had developed at follow-up. In all cases, the late ARM was bilateral. Exudative ARM was found in 28 eyes, and pure geographic atrophy was found in 18 eyes. Two subjects with unilateral late ARM at baseline were examined at follow-up. Of these, late ARM had developed in both (100%) in the other eye over the 14-year period.

Incidence of Visual Impairment and Blindness Caused by Late Age-Related Maculopathy Table 5 shows the 14-year incidence of visual impairment and blindness by ARM status in the study population stratified by age. The table also shows the causal bilateral late ARM status specified as the ARM lesion in the better eye as evaluated at follow-up.

Table 3. Relation of Drusen Type at Baseline to the 14-Year Incidence of Retinal Pigment Epithelium Depigmentation, Increased Retinal Pigment, Pure Geographic Atrophy, and Exudative Age-Related Maculopathy in the Right Eye Soft Indistinct Drusen

Retinal Pigment Epithelium Depigmentation

Increased Retinal Pigment

Any Pigmentary Abnormality

Early Age-Related Maculopathy

Pure Geographic Atrophy

Exudative Age-Related Maculopathy

Late Age-Related Maculopathy

Drusen Type

(N)

%

(N)

%

(N)

%

(N)

%

(N)

%

(N)

%

(N)

%

(N)

%

None or hard indistinct Hard distinct Soft distinct Soft indistinct

(109)

12.8

(107)

11.2

(109)

14.7

(104)

16.4

(109)

24.8

(109)

0

(109)

0

(109)

0

(105) 27.6 (48) 60.4 —

(104) (46) (22)

15.4 19.6 63.6

(104) (44) (20)

21.2 34.1 65.0

(103) (41) (18)

24.3 31.7 72.2

(104) 34.6 (41) 41.5 —

(105) (47) (32)

0 8.3 34.4

(105) (47) (32)

2.9 19.2 53.1

(105) (47) (32)

2.9 27.7 87.5

N ⫽ number at risk at baseline.

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Buch et al 䡠 Incidence, Progression, and Visual Morbidity of ARM Table 4. Relation of Pigmentary Abnormalities and Early Age-Related Maculopathy at Baseline to the 14-Year Incidence of Drusen Type, Pure Geographic Atrophy, Exudative Maculopathy, and Late Age-Related Maculopathy in the Right Eye

Pigmentary Abnormalities and Early Age-Related Maculopathy at Baseline Increased retinal pigmentation Absent Present RPE depigmentation Absent Present Any pigmentary abnormalities Absent Present Early ARM Absent Present

Soft Distinct Drusen

Soft Indistinct Drusen

Pure Geographic Atrophy

Exudative Age-Related Maculopathy

Late Age-Related Maculopathy

(N)

%

(N)

%

(N)

%

(N)

%

(N)

%

(213) (1)

24.9 100

(257) (5)

26.4 80.0

(277) (16)

2.9 43.8

(277) (16)

8.7 31.2

(277) (16)

11.6 75.0

(211) (3)

24.6 66.7

(257) (5)

27.2 40.0

(277) (16)

3.6 31.3

(277) (16)

8.3 37.5

(277) (16)

11.9 68.8

(211) (3)

24.6 66.7

(254) (8)

26.4 62.5

(272) (21)

2.2 42.9

(272) (21)

8.5 28.6

(272) (21)

10.7 71.4

— —

— —

— —

— —

(254) (37)

0.8 32.4

(254) (37)

4.3 48.6

(254) (37)

5.1 81.1

ARM ⫽ age-related maculopathy; N ⫽ number at risk at baseline; RPE ⫽ retinal pigment epithelium.

The cumulative 14-year incidences of visual impairment and blindness were 16.7% (56/335) and 5.1% (18/353), respectively. The 14-year incidence of visual impairment caused by late ARM in the better eye was 6.0% (20/335), and that of blindness caused by late ARM was 3.4% (12/353). The incidence of visual impairment or blindness in the better eye, caused by late ARM, rose significantly with age. Subjects aged 70 to 80 years at baseline were 8.4 times as likely to have incident visual impairment caused by late ARM and 3.1 times as likely to have incident blindness caused by late ARM than subjects 60 to 64 years of age at baseline (visual impairment: 15.2% [17/112] vs. 1.8% [4/223]; P⬍0.001; blindness: 5.6% [7/126] vs. 1.8% [4/227]; P ⫽ 0.06). Late ARM in the better eye was responsible for 35.7% (20/56) of all incident visual impairment and for 66.7% (12/18) of all incident blindness. Of the individuals with incident blindness resulting from late ARM, pure geographic atrophy accounted for 33.3% (4/12) of severe visual losses in the better eye. Early ARM was not a cause of blindness but contributed, in association with cataract, to an incidence of visual impairment of 3.6% (12/335; Table 5). Although VA was measured using the pinhole test, the magnitude of the effect of early ARM lesions on vision could not be determined completely. Of the 18 subjects with incident blindness, 10 (55.6%) were found to be blind during home examinations. Similarly, 7 of the 12 cases of blindness (58.3%) resulting from late ARM were discovered during home examinations.

Visual Loss on an Eye Level Despite late ARM being the most frequent cause of incident blindness, only 74.2% (66/89) of the 89 eyes with incident ARM and available VA data had a BCVA of 20/40 or worse, and only 39.3% (35/89) had developed visual loss to 20/200 or worse. The frequency of a BCVA of 20/200 or worse was similar in eyes with incident exudative ARM (38.9%; 23/59) and in eyes with incident pure geographic atrophy (40.0%; 12/30).

Morphologic Risk Factors for Visual Loss Caused by Late Age-Related Maculopathy The severity of ARM lesions at baseline was associated with the risk of visual loss resulting from late ARM. In right eyes, incident

visual loss to 20/200 or less developed in 14% of right eyes with soft distinct drusen at baseline, in 35% of right eyes with soft indistinct drusen at baseline, and in 55% of right eyes with soft indistinct drusen and pigmentary abnormalities at baseline. All 4 subjects with late ARM and VA better than 20/200 in the right eye at baseline progressed to blindness (BCVA, ⱕ20/400) during the study. Thus, late ARM predisposed to blindness in 100% of the persons affected at baseline.

Discussion No previous study has reported on a population this old with as long a follow-up period and low rates of declined participation. We used a standardized objective system for grading color fundus photographs for ARM.37,38 Photos from the baseline and the follow-up examination were graded in a masked and randomized fashion by a single grader (HB). The mean period of time between gradings of photos of each participant was 20.3 days (SD, ⫾30.9 days). This makes bias an unlikely result of the same grader grading photographs of the same participant. Additionally, systematic difference in the evaluation of lesions between baseline and follow-up is highly unlikely. Another strength of this study is that it was carried out before the antioxidant prevention therapy in persons with ARM was released in Denmark, and the proportion of subjects with incident late ARM who had received laser or photodynamic therapy treatment was less than 5% (3.4%; 2/52). This provided a unique opportunity to study the natural course of ARM. It also means that our study is not indicative of the current practice or of modern therapy that may well alter the course of ARM. In our northern European urban study population aged 60 to 80 years at baseline, we found a cumulative 14-year incidence of 37.8% for early ARM and of 16.9% for late ARM. The incidence of ARM lesions was strongly correlated with age. We also found that larger drusen size and more severe drusen type at baseline were associated with a higher risk of more severe ARM lesions at follow-up.

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Ophthalmology Volume 112, Number 5, May 2005 Table 5. Relation of 14-Year Incidence of Binocular Changes in 14-Year Incidence of Visual Impairment and Visual Impairment ⬍20/40 to ⬎20/200 Cataract and Early Age-Related Maculopathy

Pure Geographic Atrophy

Exudative Age-Related Maculopathy

No Age-Related Maculopathy

Ungradable

Total

Age (yrs)

n (N)

%

n (N)

%

n (N)

%

n (N)

%

n (N)

%

n (N)

%

60–69 70–80 Total

7 (223) 5 (112) 12 (335)

3.1 4.5 3.6

0 (223) 11 (112) 11 (335)

0 9.8 3.3

4 (223) 5 (112) 9 (335)

1.8 4.5 2.7

10 (223) 12 (112) 22 (335)

4.5 10.7 6.6

1 (223) 1 (112) 2 (335)

0.4 0.9 0.6

22 (223) 34 (112) 56 (335)

9.9 30.4 16.7

ARM ⫽ Age-related maculopathy; n ⫽ number of cases; N⫽ number at risk at baseline; % ⫽ the incidence of visual impairment and blindness for the *Incidence of visual impairment and blindness defined by the better eye. Late ARM category was defined by the better eye.

†

Further, especially soft indistinct drusen and pigmentary abnormalities at baseline were associated with a high risk of late ARM and visual loss (ⱕ20/200) at follow-up. To our knowledge, there are only 8 other populationbased reports on the incidence of ARM in white populations that were based on almost similar ARM protocols.29 The BDES was the only population-based study with as long a follow-up period as 10 years.24 –28,30,31 The estimated annual incidence of early ARM in our population was 3.4% and that of late ARM was 1.3%. Because only 39% of the individuals examined at baseline survived, these estimates of the incidence rates must be regarded as lower bounds. The 10-year incidences of early ARM and late ARM for BDES subjects older than 65 years of age at baseline can be calculated as 3.7% per year and 0.6% per year, respectively.31 The calculated incidence rate for early ARM is remarkably similar to that in the present study. For late ARM, we found an incident rate more than twice that found in the BDES. Comparing age-standardized rates, the difference between studies was still present. This difference may be the result of a number of factors. First, differences in participation rates may be important. We obtained an almost complete follow-up rate (97.3%). The high rate of follow-up was achieved through home examinations of participants too disabled to be examined in an eye clinic; 38.5% of our incident late ARM cases were found through home examinations. The high incidence of late ARM observed among individuals examined in homes, nursing homes, or sheltered homes underscores the need for almost complete follow-up if reliable estimates of the occurrence of ARM lesions are to be obtained among the oldest patients. Second, the older age of the Copenhagen cohort than the Beaver Dam cohort is likely to cause the higher incidence of late ARM in our study. The calculation of the incidence rate from the cumulative 14-year incidence assumes that the incidence remains constant over time. Because this is far from the truth, especially for late ARM, comparisons of calculated incidence rates are meaningful only among studies with similar lengths of follow-up. Additionally, differences in study design, sample variability, geographic location, and methodology may be sources of disparity among studies. Notably different definitions of early ARM have been

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used in the recent population-based epidemiologic studies of ARM.10,25,27,30 In the present study, the definition of early ARM included hard distinct drusen when associated with pigmentary abnormalities. This was the same definition used in the BDES,30,31 and accordingly similar incidence rates of early ARM were found in the 2 studies. Other studies required soft drusen to be present before a diagnosis of early ARM could be made.25,27 However, a comparison between definitions of early ARM with and without inclusion of hard distinct drusen in association with pigmentary abnormalities showed that the incidence rates in our study did not differ (31.5% vs. 32.9%). This was because pigmentary abnormalities in association with hard distinct drusen were not present in our population, and therefore it was redundant to include them in the definition. In addition, because the incidence of small hard distinct drusen was not positively associated with increasing age and the occurrence of late ARM, our findings suggest that small drusen may not be related to ARM and probably should not be considered to be an early ARM lesion. We found that women had more than twice the incidence of large drusen and 1.8 times the incidence of exudative maculopathy as men, which agreed with some previous studies.30,31,44 However, these differences may result from survival bias, because we found that deceased nonparticipants were more likely to be men and to have early ARM at baseline. This is consistent with previous studies in which no significant gender differences were found in the incidence of ARM lesions.24,25,27 Soft drusen and pigmentary changes are precursor lesions that increase the risk of geographic atrophy and exudative maculopathy.29 –31 In agreement with the literature, we found that large drusen size, severe drusen type, that is, soft indistinct drusen, and pigmentary abnormalities were strongly predictive of late ARM. The presence of both soft indistinct drusen and pigmentary abnormalities at baseline was associated with a risk of 55% for development of late age-related macular degeneration and visual loss to 20/200 or worse. The type of incident late ARM (exudative or pure geographic atrophy) could not be deducted from the baseline lesions, which agrees with a previous study.25 However, our

Buch et al 䡠 Incidence, Progression, and Visual Morbidity of ARM Vision by Age to Age-Related Maculopathy Status in the Better Eye Blindness* in Relation to Age-Related Maculopathy Status† Blindness ⱕ20/200 Cataract and Early Age-Related Maculopathy n (N)

%

0 0 0

Pure Geographic Atrophy

Exudative Age-Related Maculopathy

No Age-Related Maculopathy

Ungradable

n (N)

%

n (N)

%

n (N)

%

n (N)

2 (227) 2 (126) 4 (353)

0.9 1.6 1.1

2 (227) 6 (126) 8 (353)

0.9 4.8 2.3

3 (227) 2 (126) 5 (353)

1.3 1.6 1.4

0 1 (126) 1 (353)

Total %

n (N)

%

0.8 0.3

7 (227) 11 (126) 18 (353)

3.0 8.7 5.1

specified category.

number of incident late ARM cases was relatively small (44 in right eyes), and therefore, the power to detect a difference in baseline early ARM lesions may have been insufficient. The bilaterality of late ARM was pronounced: 75% of subjects with incident late ARM had bilateral disease. Bilaterality in this study was higher than rates previously reported of between 42% and 59%.44 This may be because of the older study population in the present study and the higher likelihood of development of bilateral disease with age. Moreover, the concordance of lesion type in incident bilateral late ARM cases is higher than what can be explained by chance45,46 and may reflect that exudative ARM and pure geographic atrophy are different diseases. The presence of unilateral late ARM at baseline signified a very high risk of bilateral late ARM at follow-up (100%). In those with early ARM in both eyes at baseline, bilateral late ARM had developed in 82% at follow-up. These rates are higher than previously reported.31 However, the number of incident cases was small. Nevertheless, our findings support evidence of a high risk of late ARM in the second eye of those with late ARM in their first eye and patients with bilateral early ARM, as previously documented.6,8 The overall 14-year incidence of legal blindness in our study population was 5.1%, corresponding to a calculated incidence rate of 0.37% per year. When using the same criteria, our rate is somewhat higher than in the 10-year incidence study of the Beaver Dam population,32 where the cumulative 10-year incidence of legal blindness was 2.5% among participants more than 65 years of age at baseline, corresponding to a calculated incidence rate of only 0.25% per year. However, a 7-year cumulative incidence of legal blindness of 11.4% was found among persons 77 years or older at baseline in the 7-year incidence study of the aged Melton Mowbray, Leicestershire, UK population.26 This corresponds to an incidence rate of 1.7% per year, which is higher than the calculated annual incidence rate of 0.60% found in the present study among participants older than 70 years at baseline. Our study revealed that late ARM was responsible for 66.66% of all incident blindness, in accordance with previous findings,2,32,47,48 and caused a 14-year cumulated incidence of legal blindness of 3.39% and a calcu-

lated incidence rate of 0.22% per year. Only 2 previous population-based studies provided incidence data regarding ARM and visual loss.32,49 In both studies, ARM was reported as the most frequent primary cause of severe incident visual loss. Additionally, studies drawing on data from registries of blindness provide such information.48,50 Only the study of Rosenberg and Klie48 used the same definition of blindness as that in the present study. In the former study, which draws on data from the Danish registry for the blind (population, 5.3 million), the incidence rate of registered blindness was 0.11% per year among individuals older than 60 years of age; 71.4% of registered blindness was caused by late ARM.48 Although the proportion of blindness caused by late ARM was similar, the incidence of blindness was more than 3 times lower than in the present study. This difference is probably the result of significant underregistration of blindness, especially among the elderly.48 The fact that 55% of the blind individuals were found through home examinations underscores the importance of aggressive searches if reliable estimates of blindness are to be obtained. This is emphasized further by the fact that only 44% of the blind individuals in this study were registered in the Danish Registry of the Blind. In our population, the frequency of VA of 20/200 or worse was not significantly higher in eyes with incident exudative ARM (38.9%) than in eyes with incident pure geographic atrophy (40.0%). These frequencies correspond to the cross-sectional frequencies reported in the literature of 48% and 41.9%, respectively.2 These data show that both exudative ARM and pure geographic atrophy have an important impact on vision. Data from earlier populationbased studies have combined pure geographic atrophy with early age-related retinal lesions,4,51,52 resulting in the conclusion that pure geographic atrophy is less likely to be associated with decreased VA. However, in accordance with the BDES,2 our data demonstrated that although pure geographic atrophy occurs less frequently than exudative ARM, it seems to be associated with almost the same frequency of blindness as the exudative form of the disease. Previous studies have shown significant variation in the occurrence of exudative ARM and pure geographic atrophy

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Ophthalmology Volume 112, Number 5, May 2005 in different parts of the world and among different ethnic groups. The ratio of incident exudative ARM compared with that of pure geographic atrophy found in this study is consistent with the 3-continent pooled prevalence and incidence data, respectively, on a very large sample of white persons from North America, Australia, and the Netherlands.53,54 However, pure geographic atrophy is more frequent in whites in Iceland55 and Norway (Invest Ophthalmol Vis Sci 44:eabstract 3082, 2003) and among Inuits in Greenland.56,57 We speculate that the reasons for these differences may be differences in genetic and environmental factors. Although not all eyes with incident late ARM had visual loss to 20/200 or worse, development of late ARM was the cause of 66.7% of incident blindness in the study population, which is higher than the 57.9% reported by Klein et al32 in the BDES 10-year follow-up study and may reflect the ARM progression with age. Comparing the BCVA in the better eye at the initial and the subsequent examination, we found that the VA among many of those who progressed to visual impairment and blindness resulting from the development of late ARM had unaffected VA at baseline. However, eyes with late ARM at baseline and preserved VA better than 20/200, all had visual decreases to 20/200 or less at follow-up. This indicates that VA is not a functional risk parameter for progression of ARM and underscores the importance of evaluating retinal lesions when estimating the risk for progression of ARM.14,16,27,30 The most important information gleaned from the subjects with ARM lesions in 1 or both eyes was the prognosis for visual loss caused by late ARM. The present study showed that because of progression in severity of ARM lesions, the risk of decreasing VA among those with ARM lesions was considerable. The early ARM lesions most strongly associated with progression and vision loss are soft indistinct drusen and pigmentary abnormalities responsible for an estimated risk of 16% to 25%, respectively, for legal blindness resulting from late ARM development. Even worse was the prognosis for those with late ARM in 1 eye at baseline, of whom 100% were blind at follow-up. The frequent coexistence of cataract and early ARM lesions may have introduced misclassification bias in the evaluation of early ARM as the possible cause of visual loss. Because early ARM and cataract were associated, the magnitude of the effect of both could not be determined completely. Nevertheless, we may conclude that development of early ARM at follow-up did not contribute to the age-related increase in the incidence of blindness but contributed in a limited way to the incidence of visual impairment. However, our findings suggest that these lesions later may progress to late ARM, become bilateral, and cause incident visual loss. Based on our data, it can be calculated that in a typical Northern European population of 1 million, new late ARM will develop in 6100 eyes annually. There will be 3477 new patients with late ARM, and 605 new cases of legal blindness resulting from late ARM. These estimates are higher than those previously reported.3 As the population in industrialized countries ages, our incidence data

796

indicate a major public health problem, because there are few successful medical interventions to prevent late ARM.58 This study therefore emphasizes that, because of the current demographic shift toward an increasing elderly population, the number of individuals with visual impairment or blindness caused by late ARM is likely to increase considerably.

Limitations There are some obvious limitations in the current study that may have contributed to underestimation of the true incidence of age-related maculopathy lesions and associated impaired vision. First, the main limitation of our study is its small baseline and follow-up sample sizes. Of the 946 persons who participated in the baseline study, only 359 persons participated in the follow-up examination because 60.9% of the original cohort had died. This small study population may cause important effects to be undetected because it limits the ability to detect statistical significance as witnessed by large confidence intervals. Additionally, it makes the population vulnerable to the sampling technique used. This may have resulted in a distortion of the follow-up study population in relation to the general population and thus a distortion of our results. However, examination of almost the entire surviving cohort that initially was based on a representative random sample may provide our small sample some degree of representation. Second, changes in procedures between the baseline and follow-up examination (e.g., different film, cameras, and photography techniques) may have introduced bias. Change in cameras may have caused images where drusen edges and density could be determined by lower level of accuracy in one of the studies. The Fuji Velvia films used at follow-up may have produced a more reddish color, making the judgment of pigmentary abnormalities less accurate. The lack of stereo in many baseline photographs made it likely that retinal elevation at baseline had been overlooked. However, in the nonstereo cases, clinical data from the examination were evaluated. This revealed that no cases of retinal elevation had been overlooked. Nevertheless, the above-mentioned factors seem of minor importance as long as high-quality fundus photographs were obtained. However, the distributions of photograph quality at baseline and follow-up were not similar as a result of the ageing of the study population. These factors may have resulted in bias toward an underestimation of the incidence of subtle early ARM lesions. Third, survival bias may have caused an underestimation of the true incidence of late ARM if those who died before the follow-up had experienced advanced ARM lesions after the first examination. Because these persons who died were more likely to have had early ARM at baseline, this supposition is plausible. Accordingly and finally, the lack of intervening examinations also may have contributed to underestimation of early ARM incidence rates, because cases among individuals examined at baseline but who died before follow-up were not counted. Therefore, loss to follow-up because of death was a major concern, which made our 14-year risk of ARM and associated visual loss conditional on staying alive. Thus, because the surviving population represents

Buch et al 䡠 Incidence, Progression, and Visual Morbidity of ARM only approximately one third (39%) of the small original study population, caution should be exercised when interpreting these rates. In conclusion, our population-based data provide further insight into the natural history of ARM and add evidence of the progressive nature of the disease and its consequences. This study underscores the necessity for nearly complete follow-up, including home examinations, if reliable estimates of the incidence of ARM lesions, in particular late ARM, are to be obtained. We found twice the incidence of late ARM than previously reported from North American and Australian studies and more than 4 times the incidence reported earlier in a Northern European study.24,25,27,31 Earlier hopes that the incidence of late ARM may be lower in Northern Europe than in North America and Australia therefore seem moot. The study also confirms the importance of pigmentary abnormalities as an important risk factor for the development of late ARM. Patients with both soft indistinct drusen and pigmentary abnormalities therefore are interesting targets for preventive strategies. These data may be clinically useful and valuable when considering prevention therapy and when planning the future need for eye examination, treatment, counseling, and rehabilitative services. Acknowledgments. The authors thank senior grader Maria Swift for her assistance in WARMGS manual training and reproducibility grading, and Dr Ronald Klein and Stacy Meuer for providing valuable advice, all individuals affiliated with the Ocular Epidemiology Reading Center as part of the Department of Ophthalmology and Visual Sciences at the University of Wisconsin. The authors also thank Henrik Scharling for providing extensive data handling and statistical assistance and The Copenhagen City Heart Study Group for providing data and facilities without which this study could not have been completed.

8.

9.

10.

11. 12. 13. 14. 15. 16. 17. 18. 19.

References 20. 1. Buch H, Vinding T, la Cour M, Nielsen NV. The prevalence and causes of bilateral and unilateral blindness in an elderly urban Danish population. The Copenhagen City Eye Study. Acta Ophthalmol Scand 2001;79:441–9. 2. Klein R, Wang Q, Klein BE, et al. The relationship of agerelated maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182–91. 3. la Cour M, Kiilgaard JF, Nissen MH. Age-related macular degeneration: epidemiology and optimal treatment. Drugs Aging 2002;19:101–33. 4. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24(suppl):335– 610. 5. Tielsch JM. Vision Problems in the U.S. A Report on Blindness and Vision Impairment in Adults Age 40 and Older. Schaumburg, IL: Prevent Blindness America; 1994:1–2. 6. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol 1993;111:1189 –99. 7. Macular Photocoagulation Study Group. Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization second-

21. 22. 23. 24. 25. 26. 27. 28.

ary to age-related macular degeneration. Arch Ophthalmol 1997;115:741–7. Baun O, Vinding T, Krogh E. Natural course in fellow eyes of patients with unilateral age-related exudative maculopathy. A fluorescein angiographic 4-year follow-up of 45 patients. Acta Ophthalmol (Copenh) 1993;71:398 – 401. Bressler SB, Maguire MG, Bressler NM, Fine SL, The Macular Photocoagulation Study Group. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. Arch Ophthalmol 1990; 108:1442–7. Chang B, Yannuzzi LA, Ladas ID, et al. Choroidal neovascularization in second eyes of patients with unilateral exudative age-related macular degeneration. Ophthalmology 1995;102: 1380 – 6. Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973;90:206 –17. Gregor Z, Bird AC, Chisholm IH. Senile disciform macular degeneration in the second eye. Br J Ophthalmol 1977;61: 141–7. Holz FG, Wolfensberger TJ, Piguet B, et al. Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology 1994;101:1522– 8. Roy M, Kaiser-Kupfer M. Second eye involvement in agerelated macular degeneration: a four-year prospective study. Eye 1990;4:813– 8. Smiddy WE, Fine SL. Prognosis of patients with bilateral macular drusen. Ophthalmology 1984;91:271–7. Strahlman ER, Fine SL, Hillis A. The second eye of patients with senile macular degeneration. Arch Ophthalmol 1983;101: 1191–3. Barondes MJ, Pagliarini S, Chisholm IH, et al. Controlled trial of laser photocoagulation of pigment epithelial detachments in the elderly: 4 year review. Br J Ophthalmol 1992;76:5–7. Feeney-Burns L, Ellersieck MR. Age-related changes in the ultrastructure of Bruch’s membrane. Am J Ophthalmol 1985; 100:686 –97. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519 –35. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988; 2:552–77. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 1976;60:324 – 41. Sarks SH, Van Driel D, Maxwell L, Killingsworth M. Softening of drusen and subretinal neovascularization. Trans Ophthalmol Soc U K 1980;100:414 –22. van der Schaft TL, Mooy CM, de Bruijn WC, et al. Histologic features of the early stages of age-related macular degeneration. A statistical analysis. Ophthalmology 1992;99:278 – 86. Klaver CC, Assink JJ, van Leeuwen R, et al. Incidence and progression rates of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2001;42:2237– 41. van Leeuwen R, Klaver CC, Vingerling JR, et al. The risk and natural course of age-related maculopathy: follow-up at 61/2 years in the Rotterdam Study. Arch Ophthalmol 2003;121:519–26. Sparrow JM, Dickinson AJ, Duke AM, et al. Seven year follow-up of age-related maculopathy in an elderly British population. Eye 1997;11:315–24. Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 2002;109:1092–7. Mukesh BN, Dimitrov PN, Leikin S, et al. Five-year incidence of age-related maculopathy: the Visual Impairment Project. Ophthalmology 2004;111:1176 – 82.

797

Ophthalmology Volume 112, Number 5, May 2005 29. Bressler NM, Munoz B, Maguire MG, et al. Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities. Waterman study. Arch Ophthalmol 1995;113:301– 8. 30. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997;104:7–21. 31. Klein R, Klein BE, Tomany SC, et al. Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology 2002;109:1767–79. 32. Klein R, Klein BE, Lee KE, et al. Changes in visual acuity in a population over a 10-year period: the Beaver Dam Eye Study. Ophthalmology 2001;108:1757– 66. 33. Schnohr P, Jensen G, Nyboe J, Hansen AT. The Copenhagen City Heart Study. A prospective cardiovascular population study of 20,000 men and women [in Danish]. Ugeskr Laeger 1977;139:1921–3. 34. Vinding T. Age-related macular degeneration. An epidemiological study of 1000 elderly individuals. With reference to prevalence, funduscopic findings, visual impairment and risk factors. Acta Ophthalmol Scand Suppl 1995;217:1–32. 35. Dreyer V. On the exactness of visual acuity determination charts with decimal, Snellen, and logarithmic notation. Acta Ophthalmol (Copenh) 1964;42:295–306. 36. Klein R, Klein BE. Beaver Dam Eye Study. Manual of Operations (Revised). Rept. for 16 Jun 87–31 May 92. Springfield, VA: National Technical Information Service; 1991. NTIS Publication PB91-149823. 37. Klein R, Davis MD, Magli YL, et al. The Wisconsin AgeRelated Maculopathy Grading System. Ophthalmology 1991; 98:1128 –34. 38. Varma R, Fraser-Bell S, Tan S, et al, Los Angeles Latino Eye Study Group. Prevalence of age-related macular degeneration in Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2004;111:1288 –97. 39. Klein R, Klein BE, Lee KE. Changes in visual acuity in a population: the Beaver Dam Eye Study. Ophthalmology 1996; 103:1169 –78. 40. SAS for Windows [computer program]. Release 8.02. Cary, NC: SAS Institute; 1999. 41. Stata [computer program]. Release 6.0. College Station, TX: Stata Corp.; 1999. 42. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159 –74. 43. AREDS summary maculopathy grading protocol. Fundus photograph reading area. Appendix 15B. Wisconsin Age-Related Maculopathy Grading System. Confounding lesions. Available at: http://www.eyephoto.ophth.wisc.edu/ResearchAreas/AREDS/

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44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.

Chapter15B.html#ConfoundingLesions. Accessed August 23, 2000. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933– 43. VanNewkirk MR, Nanjan MB, Wang JJ, et al. The prevalence of age-related maculopathy: the Visual Impairment Project. Ophthalmology 2000;107:1593– 600. Wang JJ, Mitchell P, Smith W, Cumming RG. Bilateral involvement by age related maculopathy lesions in a population. Br J Ophthalmol 1998;82:743–7. Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:357– 64. Rosenberg T, Klie F. The incidence of registered blindness caused by age-related macular degeneration. Acta Ophthalmol Scand 1996;74:399 – 402. Foran S, Mitchell P, Wang JJ. Five-year change in visual acuity and incidence of visual impairment. The Blue Mountains Eye Study. Ophthalmology 2003;110:41–50. Krumpaszky HG, Ludtke R, Mickler A, et al. Blindness incidence in Germany. A population-based study from WurttembergHohenzollern. Ophthalmologica 1999;213:176 – 82. Ferris FL III, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984;102:1640 –2. Vinding T. Visual impairment of age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmol (Copenh) 1990;68:162–7. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001;108:697–704. Tomany SC, Wang JJ, van Leeuwen R, et al. Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents. Ophthalmology 2004;111:1280 –7. Jonasson F, Arnarsson A, Sasaki H, et al. The prevalence of age-related maculopathy in Iceland: Reykjavik Eye Study. Arch Ophthalmol 2003;121:379 – 85. Rosenberg T. Prevalence of blindness caused by senile macular degeneration in Greenland. Arctic Med Res 1987;46:64 –70. Rosenberg T. Prevalences and causes of blindness in Greenland. Arctic Med Res 1987;46:13–7. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS report no. 8. Arch Ophthalmol 2001;119:1417–36.