Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study.

Abstract

The aim of the study was to describe the 10-year incidence and progression of retinal drusen, retinal pigmentary abnormalities, and signs of late age-related maculopathy.
Population-based cohort study.
The study included 4926 persons, 43 to 86 years of age at the time of a baseline examination from 1988 through 1990, living in Beaver Dam, Wisconsin, of whom 3684 participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up.
Characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System.
Incidence of drusen type and size, pigmentary abnormalities, geographic atrophy, and exudative degeneration.
The 10-year incidence of early age-related maculopathy was 12.1% and of late age-related maculopathy it was 2.1%. There was a statistically significant increased incidence of age-related maculopathy lesions with age (P < 0.05). Individuals 75 years of age or older at baseline had significantly (P < 0.01) higher 10-year incidences of the following characteristics than people 43 to 54 years of age: larger sized drusen (125 micro m-249 micro m, 26.3% vs. 3.3%; > or =250 micro m, 16.2% vs. 1.0%), soft indistinct drusen (22.2% vs. 2.2%), retinal pigment abnormalities (19.5% vs. 0.8%), exudative macular degeneration (4.1% vs. 0%), and pure geographic atrophy (3.1% vs. 0%). Compared with those with small numbers of only small, hard drusen (1-2), those with large numbers of only hard drusen (8 or more) had an increased 10-year incidence of both soft drusen (12.3% vs. 6.7%) and pigmentary abnormalities (4.9% vs. 1.7%). Eyes with soft indistinct drusen or retinal pigmentary abnormalities at baseline, were more likely to develop late age-related macular degeneration at follow-up than eyes without these lesions (15.1% vs. 0.4% and 20.0% vs. 0.8%, respectively).
These population-based estimates document the high incidence of signs of age-related maculopathy in people 75 years of age or older. Our findings demonstrate that large numbers of hard drusen predict the incidence of soft drusen and pigmentary abnormalities and that the presence of the latter lesions significantly increases the risk for the development of geographic atrophy and exudative macular degeneration.

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Ten-Year Incidence and Progression of
Age-related Maculopathy
The Beaver Dam Eye Study
Ronald Klein, MD,1Barbara E. K. Klein, MD,1Sandra C. Tomany, MS,1Stacy M. Meuer, BS,1
Guan-Hua Huang, PhD2
Purpose:
retinal pigmentary abnormalities, and signs of late age-related maculopathy.
Design:
Population-based cohort study.
Participants:
The study included 4926 persons, 43 to 86 years of age at the time of a baseline examination
from 1988 through 1990, living in Beaver Dam, Wisconsin, of whom 3684 participated in a 5-year follow-up
examination and 2764 participated in a 10-year follow-up.
Methods:
Characteristics of drusen and other lesions typical of age-related maculopathy were determined
by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading
System.
Main Outcomes Measures:
Incidence of drusen type and size, pigmentary abnormalities, geographic
atrophy, and exudative degeneration.
Results:
The 10-year incidence of early age-related maculopathy was 12.1% and of late age-related
maculopathy it was 2.1%. There was a statistically significant increased incidence of age-related maculopathy
lesions with age (P ? 0.05). Individuals 75 years of age or older at baseline had significantly (P ? 0.01) higher
10-year incidences of the following characteristics than people 43 to 54 years of age: larger sized drusen (125
?m–249 ?m, 26.3% vs. 3.3%; ?250 ?m, 16.2% vs. 1.0%), soft indistinct drusen (22.2% vs. 2.2%), retinal
pigment abnormalities (19.5% vs. 0.8%), exudative macular degeneration (4.1% vs. 0%), and pure geographic
atrophy (3.1% vs. 0%). Compared with those with small numbers of only small, hard drusen (1–2), those with
large numbers of only hard drusen (8 or more) had an increased 10-year incidence of both soft drusen (12.3%
vs. 6.7%) and pigmentary abnormalities (4.9% vs. 1.7%). Eyes with soft indistinct drusen or retinal pigmentary
abnormalities at baseline, were more likely to develop late age-related macular degeneration at follow-up than
eyes without these lesions (15.1% vs. 0.4% and 20.0% vs. 0.8%, respectively).
Conclusions:
These population-based estimates document the high incidence of signs of age-related
maculopathy in people 75 years of age or older. Our findings demonstrate that large numbers of hard drusen
predict the incidence of soft drusen and pigmentary abnormalities and that the presence of the latter lesions
significantly increases the risk for the development of geographic atrophy and exudative macular degeneration.
Ophthalmology 2002;109:1767–1779 © 2002 by the American Academy of Ophthalmology.
The aim of the study was to describe the 10-year incidence and progression of retinal drusen,
Age-related macular degeneration is a leading cause of loss
of vision in persons 65 years of age or older in the United
States.1–4Most information regarding its natural history has
come from case series of patients attending ophthalmology
clinics,5–13clinical trials of the late stages of the dis-
ease,14–16or clinicopathologic studies.17–22Estimates of
progression to late stages of age-related maculopathy
(ARM) have usually been based on the study of the unin-
volved fellow eye of people with uniocular late age-related
macular degeneration.5–7,10–12,15,16Only a few studies have
examined the incidence of late age-related macular degen-
erationin peoplefree of
eyes.6,9,10,23–26In addition, there are few population-based
data regarding the association of small hard drusen to the
incidence of large soft drusen, pigmentary abnormalities,
and other more severe lesions of ARM.23,24The purpose of
this report was to describe the 10-year incidence, progres-
sion, regression, and interrelationships of lesions associated
with early and late ARM in a large population-based cohort.
thiscondition in both
Originally received: July 25, 2001.
Accepted: December 6, 2002.
1Department of Ophthalmology and Visual Sciences, University of Wis-
consin Medical School, Madison, Wisconsin.
2Department of Population Health Sciences, University of Wisconsin
Medical School, Madison, Wisconsin.
Supported by the National Institutes of Health, Bethesda, Maryland (grant
no.: EYO6594 [RK, BEKK]); and by Research to Prevent Blindness, New
York, New York (Senior Scientific Investigator Award [RK]).
The authors have no proprietary interest in the products or devices men-
tioned herein.
Correspondence to Ronald Klein, MD, MPH, Department of Ophthalmol-
ogy and Visual Sciences, University of Wisconsin-Madison, 610 North
Walnut Street, 460 WARF, Madison, WI 53726-2397.
Manuscript no. 210671.
1767
© 2002 by the American Academy of Ophthalmology
Published by Elsevier Science Inc.
ISSN 0161-6420/02/$–see front matter
PII S0161-6420(02)01146-6

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Materials and Methods
Population
Methods used to identify the population and descriptions of the
population have appeared in previous reports.27,28A private cen-
sus of the population of Beaver Dam, Wisconsin (99% white) was
performed from fall 1987 to spring 1988 in people 43 to 84 years
of age. Of the 5924 eligible individuals, 4926 participated in the
baseline examination from 1988 through 1990.28Of these, 3684
(81.1%) participated in the 5-year follow-up examination from
1993 through 1995. Comparisons between participants and non-
participants at baseline and the 5-year follow-up examinations
have appeared elsewhere.28,29
Table 1. Definitions of Changes in Lesions Associated with Age-related Maculopathy
Incidence
Progression
Disappearance
Regression
Maximum at
Baseline*
Maximum at Follow-
up*
Maximum at
Baseline*
Maximum at
Follow-up*
Drusen size0†
0 to ?63 ?m
0 to ?125 ?m
0 to ?250 ?m
?250 ?m
None, HI
None, HI, HD
None, HI, HD, SD
SI
?63 ?m
63 to ?125 ?m
125 ?m to ?250 ?m
?250 ?m
Same maximum size
as baseline but ?2
additional involved
subfields
0
?63 ?m
63 to ?125 ?m
125 to ?250 ?m
? 250 ?m
None, HI
HD
SD
SI
—
0
0 to ?63 ?m
0 to ?125 ?m
0 to ?250 ?m
—
None, HI
None, HI, HD
None, HI,
HD, SD
Same maximum size as
baseline but ?2
fewer involved
subfields
Drusen typeHD
SD
SI
—
Same maximum type
as baseline but ?2
additional involved
subfields
Same maximum as
baseline but ?2
fewer involved
subfields
Retinal pigment
epithelial
depigmentation (RPE
depigmentation)
The advent of definite RPE
depigmentation in any subfield when
none was present in any subfield at
baseline
Same maximum score
as baseline but ?2
additional involved
subfields
OR
An increase in the
maximum score
from baseline
(same as RPE
depigmentation)
An increase of ?2
additional involved
subfields from
baseline
OR
The extension from
the outer/inner
subfields into the
central circle when
the central circle
was not involved at
baseline
An increase of ?2
additional involved
subfields from
baseline
OR
The extension from
the outer/inner
subfields into the
central circle when
the central circle
was not involved at
baseline
OR
The appearance of
more severe
exudative ARM
lesions
The absence of RPE depigmentation
in all subfields when RPE
depigmentation was definitely
present in at least one subfield at
baseline
Same maximum score
as baseline but ?2
fewer involved
subfields
OR
A decrease in the
maximum score
from baseline
(same as RPE
depigmentation)
A decrease of ?2
involved subfields
from baseline
OR
The center circle
becoming
uninvolved
Increased retinal pigment (same as RPE depigmentation)(same as RPE depigmentation)
Pure geographic atrophy The advent of definite geographic
atrophy in any subfield when no
geographic atrophy was present in any
subfield at baseline
The absence of geographic atrophy
in all subfields when geographic
atrophy was definitely present in
at least one subfield at baseline
Exudative ARM
Retinal pigment
epithelial detachment
and/or
Subretinal hemorrhage
and/or
Subretinal fibrous scar
The advent of any exudative ARM in
any subfield when no exudative ARM
was present in any subfield at baseline
The absence of any exudative lesion
in all subfields when an exudative
lesion was definitely present in at
least one subfield at baseline
A decrease of ?2
involved subfields
from baseline
OR
The center circle
becoming
uninvolved
ARM ? age-related maculopathy; HD ? hard distinct; HI ? hard indistinct; SD ? soft distinct; SI ? soft indistinct.
* Baseline and follow-up conditions must be true.
†Whenever 0, none, or absent appear in the table, questionable is included.
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Of those surviving, 3684 (81%) took part in the baseline and
second examinations, 2764 (82.9%) participated in the 10-year
follow-up examination between March 1, 1998 and June 9, 2000.
The mean and median times between the baseline and 10-year
follow-up examinations were 10.1 years and 10 years, respec-
tively.
Comparisons between participants and nonparticipants at the
10-year follow-up have been presented elsewhere.30In general,
persons who did not participate in the 10-year follow-up were
older at baseline than those who did. After adjusting for age,
persons who did not participate were more likely to be retired, to
have completed fewer years of education, and to have lower
income, poorer visual acuity, a history of never drinking alcohol,
a higher number of packs-years smoked, and a poorer cardiovas-
cular risk profile than persons who participated. After adjusting for
age and gender, participants with early ARM at baseline were as
likely to participate as those in whom ARM was absent (data not
shown).
Procedures
Similar procedures were used at baseline and follow-up examina-
tions.27–35Informed consent was obtained at the beginning of each
examination. Pertinent parts of the examination at both baseline
and follow-up consisted of taking stereoscopic 30° color fundus
photographs centered on the disc (Diabetic Retinopathy Study
standard field 1) and macula (Diabetic Retinopathy Study standard
field 2) and a nonstereoscopic color fundus photograph temporal to
but including the fovea of each eye.
Of the 2698 people with gradable fundus photographs at the
baseline and 5-year follow-up examinations, 2685 (99.5%) had
gradable photographs at the 10-year visit (2617 in both eyes, 31 in
the right eye only, and 37 in the left eye only). Of the 2685 people
with gradable photographs in at least 1 eye at all examinations, 22
(0.8%) were excluded from the analyses because of the presence of
confounding lesions unrelated to ARM. For this reason, an addi-
tional 67 persons (2.5%) had 1 eye excluded from these analyses
Table 2. Ten-year Incidence of Drusen by Size and Type, Increased Retinal Pigment, Retinal Pigment Epithelial Depigmentation,
Geographic Atrophy, and Exudative Macular Degeneration in the Right Eye
Lesion
No.
Missing*
No. with Lesion
Present at Baseline
No. at
Risk
Incidence
(%)
Drusen size
?63 ?m
?63 ?m to ?125 ?m in diameter
? 125 ?m to ?250 ?m in diameter
?250 ?m in diameter
Drusen type
Soft distinct
Soft indistinct
Pigmentary abnormalities
Increased retinal pigment
RPE depigmentation
Geographic atrophy
Exudative macular degeneration
107
93
91
90
3006
847
327
87
362
2535
3057
3298
65.4
14.0
8.8
4.0
90
91
535
282
2850
3102
7.5
8.0
58
80
39
245
125
14
13
3172
3270
3422
3347
6.0
4.5
0.6
0.9 115
RPE ? retinal pigment epithelium.
* Number missing because lesion was ungradable at baseline or follow-up.
Table 3. Ten-Year Progression, Regression, and Disappearance of Drusen by Size and Type, Increased Retinal Pigment, Retinal
Pigment Epithelial Depigmentation, Geographic Atrophy, and Exudative Macular Degeneration in the Right Eye
Lesion
No. at
Risk
Progression*
(%)
No. at
Risk
Regression†
(%)
No. at
Risk
Disappearance‡
(%)
Drusen size
?63 ?m
?63 ?m to ?125 ?m in diameter
?125 ?m to ?250 ?m in diameter
?250 ?m in diameter
Drusen type
Soft distinct
Soft indistinct
Pigmentary abnormalities
Increased retinal pigment
RPE depigmentation
Geographic atrophy
Exudative macular degeneration
1951
519
239
28.6
15.0
18.4
12.8
1344
65
35
48.9
17.8
30.4
30.8
2159
520
246
87
14.8
16.6
32.1
58.2 8624
252
272
11.3
42.0
26
91
7.1
32.2
253
282
12.5
34.5
245
125
53.8
45.1
55.6
33.3
121
56
34.6
50.1
0
16.7
245
125
12
13
12.0
8.1
0
23.1
99
12 12
RPE ? retinal pigment epithelium.
* Progression is described here as including only those with condition at baseline and excludes eyes in which eight or nine subfields have lesions.
†Regression is described here as including only those with condition in three or more subfields at baseline.
‡Disappearance is described here as including only those with condition at baseline in the absence of a larger lesion.
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and 67 others had 1 eye excluded because it was ungradable at one
or more examination. For purposes of this report, the 2663 people
with at least 1 eye evaluable at all 3 examinations (right eye, n ?
2592; left eye, n ? 2600; both eyes, n ? 2529) are included in the
analyses. Additional data from 945 people seen only at the baseline
and 5-year follow-up examinations also contributes to the analysis.
Details of the grading procedure have been described previous-
ly.31–35In brief, a circular grid was placed on the photographic
slide, which divided the macular area into nine subfields, consist-
ing of a central (a single subfield), inner (comprising the four inner
subfields), and outer (comprising the four outer subfields) circle.
Some lesions were graded in each subfield, other lesions only in
Diabetic Retinopathy Study field 2 as a whole, and still others in
additional fields. For the purpose of this report, measurements
made only within the nine subfields defined by the grid are pre-
sented. Circles of defined size (63 ?m, 125 ?m, 175 ?m, 250 ?m,
322 ?m, 350 ?m, and 644 ?m in diameter) printed on clear plastic
were used to estimate size of drusen and areas involved by drusen,
increased retinal pigment, and retinal pigment epithelial (RPE)
depigmentation.
Two gradings were performed for each eye.24,30–35First, a
preliminary masked grading was carried out by one of two senior
graders (SMM). Next, detailed gradings were performed by one of
three other experienced graders. For detailed grading, each eye
was graded independently of the fellow eye. The assessment
consisted of a subfield-by-subfield, lesion-by-lesion evaluation of
each photograph set using the Wisconsin Age-Related Maculopa-
thy Grading System.33,34Next, a series of edits and reviews was
performed. The presence and severity of specific lesions at the
third examination (e.g., maximum drusen size, type, area, and
pigmentary abnormalities, as determined by detailed grading) were
compared with that of the preliminary grading. Standardized edit
rules were used to adjudicate disagreements.24,34As a result of this
edit, changes were made for at least 1 lesion in 1456 of the 5874
eyes (24.8%) graded at the 10-year follow-up.
Finally, the detailed graders were asked to make side-by-side
comparisons between baseline, 5-year, and 10-year follow-up pho-
tographs for eyes that showed change for ARM lesions between
baseline and follow-up. These edits were masked as to whether the
photographs were taken at baseline or follow-up. As a result of this
edit, changes were made for at least 1 ARM-related lesion in 2255
of the 11,748 eyes (19.2%) graded at baseline and follow-up.
Figure 1. Relation of age to 10-year (A) incidence and (B) progression rates of various sized drusen in the right eye in the Beaver Dam Eye Study.
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Definitions
Definitions of the incidence and progression of early and late ARM
and their component lesions are summarized in Table 1.24,33–35
To evaluate change in lesions between visits, it was necessary
to have data from corresponding gradable subfields at both visits.
For example, the inner superior subfields for the specific eye would
have to be gradable for a specific lesion at the first and second, the
first and third, or all visits to contribute to estimates of incidence
or progression of that lesion.
Incidence was determined for each maximum drusen size, each
drusen type, increased retinal pigment, RPE depigmentation, signs
of exudative macular degeneration, and pure geographic atrophy.
The incidence of a specific lesion was defined by its presence at
follow-up when it was not present at baseline in any of the
subfields that could be graded at both examinations. For example,
an eye was considered to have incident soft, indistinct drusen if
none of the subfields had this lesion at baseline and this lesion was
present in one or more subfields at follow-up.
The incidence of early ARM was defined by the presence of
either soft indistinct drusen or the presence of any type of drusen
associated with RPE depigmentation or increased retinal pigment
at follow-up when none of these lesions was present at baseline.
The incidence of late ARM was defined by the appearance of
either exudative macular degeneration or pure geographic atrophy
at follow-up when neither lesion was present at baseline.
Progression was also defined specifically for each lesion (Table
1). For example, progression of a specific size or type of drusen
was defined by the presence of that lesion in at least one subfield
at baseline and its appearance in two or more additional corre-
sponding gradable subfields at either the 5- or 10-year follow-up,
Figure 2. Relation of age to 10-year incidence, progression, regression, and disappearance rates of (A) soft distinct drusen and (B) soft indistinct drusen
in the right eye in the Beaver Dam Eye Study.
Figure 3. Relation of age to the 10-year development of increased drusen
area in the right eye in the Beaver Dam Eye Study.
Klein et al ? Incidence of Age-related Maculopathy
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