Reports
IOVS, October 1998, Vol. 39, No. 11
Refractive Error and Age-Related
Maculopathy: The Blue
Mountains Eye Study
Jiejin Wang,1 Paul Mitchell,1 Wayne Smith2
2167
ratios (ORs) were provided. Because large population-based
studies have not previously reported a detailed examination of
the association, our study aimed to assess the relationship
between refractive error and ARM in a representative older
population.
assess associations between refractive error
(hyperopia, myopia, and spherical equivalent [SEq]) and
age-related maculopathy (ARM) in an older population.
METHODS
A population-based survey examined 3654 people aged 49 years or older, 82% of whom were permanent
residents in an area west of Sydney, Australia. Participants
had a detailed eye examination, including standardized
refraction and stereo macular photographs. ARM was diagnosed from blinded photographic grading. Autorefractor measurements and subjective refraction were used to
assess SEq refractive error for each eye in diopters. Mean
SEq of the two eyes was used to define emmetropia,
myopia, and hyperopia in each person.
The Blue Mountains Eye Study is a population-based survey of
vision and common eye diseases in an urban population aged
49 years or older, who were residents of two postal codes in
the Blue Mountains region, west of Sydney, Australia. The
survey methods and procedures have been described previously.7 Of 4433 eligible residents, 3654 (82.4%) were examined
from 1992 through 1993- The Study was approved by the
Western Sydney Area Health Service Human Ethics Committee
and signed informed consent was obtained from all participants. This research was conducted according to the recommendation comprising the Declaration of Helsinki. A questionnaire that included question about smoking and family history
of eye disease was administered, and participants underwent a
detailed eye examination, including 30° stereo retinal photographs (Zeiss FF3; Carl Zeiss, Oberkochen, Germany) of the
macula and other fields of both eyes in 97% of participants and
in at least one eye in 98% of participants.
Visual acuity of each eye was measured with current
eyeglasses on, if worn, and a pinhole, using a logMAR chart.7
An autorefractor (model 530; Humphrey Instruments, San Leandro, CA) was used to obtain an objective refraction. A subjective refraction test was then performed if initial visual acuity
was less than 54 letters read correctly (Snellen equivalent
20/20), using the Beaver Dam Eye Study modification of the
Early Treatment Diabetic Retinopathy Study protocol.7 Spherical equivalent (SEq), measured in diopters, was calculated
using the spherical dioptric power plus half the cylindrical
dioptric power. Mean SEq of the two eyes was used to define
refractive status for each participant. Participants with aphakia
or pseudoaphakia in one or both eyes (n = 226) were excluded. Emmetropia was defined as a mean SEq between
^1.00 and ^ — 1.00 diopters. Three levels of myopia and hyperopia were defined from the mean SEq (Table 1). Moderate
and high levels of myopia and hyperopia were combined for
the statistical analyses.
The presence of ARM lesions was assessed by blind grading of the retinal photographs by one of two observers and was
found reliable with good interobserver and intraobserver
agreement.8 The Wisconsin Age-Related Maculopathy Grading
System was closely followed with minor modifications, and a
grid was used, courtesy of Dr. Ronald Klein, University of
Wisconsin-Madison, to define the macular area. All diagnoses
of ARM and lesions were confirmed by a second detailed
grading session. Late-stage ARM (late ARM), also termed agerelated macular degeneration, was defined as the presence of
two end-stage lesions, neovascular maculopathy, or geographic
atrophy involving the foveal center, which was in agreement
with descriptions from the International ARM classification.8'9
For classification purposes, ARM status for each subject was
the grading for the worse eye. A retina specialist (PM) differ-
PURPOSE. TO
METHODS.
After known ARM risk factors (age, sex, ARM family
history, current smoking) had been adjusted for, no association was found between mean SEq (two eyes) and late ARM
(odds ratio [OR], 1.0; 95% confidence interval [CI], 0.9-1.1).
However, a statistically significant increased risk of early
ARM was found for each diopter of increase in mean SEq
(OR, 1.1; CI, 1.0-1.2). In logistic regression models, moderate to high hyperopia was significantly associated with increased early ARM risk (OR, 2.0; CI, 1.2-3.4). When a generalized estimating equation model (GEE), which assessed
the relationship at eye level while accounting for the correlation between the two eyes, was used, this association was
marginally insignificant (OR, 1.3; CI, 0.9-1.9). No significant
associations were found between myopia and any ARM stage
with either model.
RESULTS.
These population-based data suggest a weak
association between hyperopia and early ARM. (Invest
Ophthalmol Vis Sci. 1998;39:2l67-2171)
CONCLUSIONS.
efractive error, particularly hyperopia, has been associated
R
with age-related maculopathy (ARM) in a number of casecontrol studies'" and a case series report, most strongly for
4
5
34
neovascular ARM. ' However, in most of these studies,1'2'4
selection bias may have influenced the findings. In the report
of a small population-based prevalence study (560 subjects) in
Oulu County, Northern Finland,6 it was noted that no association was found between ARM and myopia, although no odds
From the 'Department of Ophthalmology, the University of Sydney, Australia; and the 2National Centre for Epidemiology and Population Health, Australian National University, Canberra.
Supported by the Australian Department of Health and Family
Services and the Save Sight Institute, University of Sydney.
Submitted for publication October 30, 1997; revised January 23,
1998, and April 14, 1998; accepted April 28, 1998.
Proprietary interest category: N.
Reprint requests: Paul Mitchell, Department of Ophthalmology,
University of Sydney, Hawkesbury Road, Westmead, NSW, Australia
2145.
Study Population and Procedures
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2168
Reports
IOVS, October 1998, Vol. 39, No. 11
1. Three Levels of Myopia and Hyperopia Defined on the Basis of the Mean
Spherical Equivalent
TABLE
Myopia
Hyperopia
Mild
Moderate
High
<-1.00 to >-3.00
>1.00 to <300
<-3.00 to >-6.00
>3.00 to <6.00
<-6.00
>6.00
entiated neovascular maculopathy in which associated signs of
myopic retinopathy were present. Two subjects with neovascular maculopathy and myopic retinopathy were thus excluded from the case group. Early stage age-related maculopathy (early ARM) was denned as the absence of AMD and either
large (>125 /am in diameter) indistinct soft or reticular drusen
or both large distinct soft drusen and retinal pigmentary abnormalities, within the area of the grid.8 For this study, the prevalence of early ARM was slightly lower than in our previous
report8 because we did not classify subjects with maximum
drusen size smaller than 125 jam as having early ARM.
Statistical Analysis System (SAS Institute, Cary, NC) was
used for analyses, including both a logistic regression model
(which uses each subject as a unit), and the more conservative
Generalized Estimating Equation (GEE) model, which uses
each eye as a unit and allows for correlations between the two
eyes.10 Late ARM and early ARM were dependent variables;
when early ARM was considered, late ARM cases were excluded from analyses. In both models, age and SEq were used
as continuous variables, whereas sex, family history of ARM,
and smoking were used as dichotomous variables. Comparisons were made between either myopia and emmetropia or
hyperopia and emmetropia, while excluding other cases. Multivariate models included variables found to be significantly
associated with ARM. ORs and 95% confidence intervals (CIs)
are given.
RESULTS
There were 71 participants with no gradable photographs of
both eyes and 226 with aphakia or pseudophakia in one or
both eyes. After these two groups and subjects with missing
data on refractive error had been excluded, a total of 3351
participants were included. The distribution of refraction categories by age and sex in the population is shown in Table 2.
Similar prevalence rates were found for the three different
refraction categories in men and women. Figure 1 shows prevalence rates for late and early ARM by age and sex. Higher
age-specific rates for both early and late ARMs were found in
women than in men for all age groups.
SEq and ARM
After we adjusted for known ARM risk factors (age, sex, family
history of ARM, and current smoking), late ARM was not
significantly associated with mean SEq of the two eyes by
logistic regression, or the SEq of each eye with the GEE model,
shown in Table 3- However, a modest statistically significant
association was found between early ARM and increasing SEq
when both statistical models were used. For each diopter
increase in SEq, the ORs for early ARM were 1.14 (95% CI,
1.04-1.25) with logistic regression and 1.08 (95% CI, 1.011.15) with the GEE model. This association was also studied in
right or left eyes separately for each subject, and the findings
TABLE 2. Distribution of Refractive Error by Age Groups and Sex in the Population
Refractive Error Status
Hyperopia
Myopia
Age Group (y)
Mild
Moderate
High
Emmetropia
Mild
Moderate
High
Total
90(9.1)
59 (4.7)
67 (7.9)
24 (9.2)
240 (7.2)
40 (4.0)
40 (3.2)
17 (2.0)
8(3.1)
105 (3.1)
21 (2.1)
9 (0.7)
8 (0.9)
2 (0.8)
40(1.2)
599 (60.3)
551 (44.1)
294 (34.7)
74 (28.4)
1518(45.3)
215(21.7)
517(41.4)
118(45.2)
1226 (36.6)
26 (2.6)
68 (5.4)
82 (9.7)
33 (12.6)
209 (6.2)
2 (0.2)
6(0.5)
3 (0.4)
2 (0.8)
13 (0.4)
993 (29.6)
1250 (37.3)
847 (25.3)
261 (7.8)
3351 (100.0)
44 (10.2)
29 (5.2)
32 (9.2)
9 (8.5)
114(7.9)
18 (4.2)
13(2.3)
10 (2.9)
4 (3.8)
45(3.1)
4 (0.9)
1 (0.2)
2 (0.6)
1 (0.9)
8 (0.6)
272 (63.0)
277 (49.4)
136(39.0)
36 (34.0)
721 (49-8)
85 (19.7)
214 (38.2)
146(41.8)
46 (43.4)
491 (33.9)
8(1.9)
24 (4.3)
23 (6.6)
9(8.5)
64 (4.4)
1 (0.2)
3 (0.5)
0 (0.0)
1 (0.9)
5 (0.4)
432 (29.8)
561 (38.7)
349(24.1)
106 (7.3)
1448 (100.0)
46 (8.2)
30 (4.4)
35 (7.0)
15 (9.7)
126(6.6)
22 (3.9)
27 (3.9)
7(1.4)
4 (2.6)
60 (3.2)
17 (3.0)
8(1.2)
6(1.2)
1 (0.7)
32(1.7)
327 (58.3)
274 (39.8)
158(31.7)
38 (24.5)
797(41.9)
130 (23.2)
303 (44.0)
230 (46.2)
72 (46.5)
735 (38.6)
18 (3.2)
44 (6.4)
59(11.9)
24(15.5)
145 (7.6)
1 (0.2)
3 (0.4)
3 (0.6)
1 (0.7)
8 (0.4)
561 (29.5)
689 (36.2)
498 (26.2)
155(8.2)
1903 (100.0)
Men and Women
<60
60-69
70-79
80+
Total
Men only
<60
60-69
70-79
80+
Total
Women only
<60
60-69
70-79
80+
Total
376 (.44.4)
Subjects with aphakia or pseudophakia in one or both eyes and subjects with missing data for refractive error were excluded.
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Reports
IOVS, October 1998, Vol. 39, No. 11
18
16
14
12
10
0/0
/c 8
6
4
2
0
2169
-e- women late ARM
-a- men late ARM
-*- women early ARM
men early ARM
<60
60-69
70-79
80+
age group (years)
FIGURE 1.
Frequency distribution (%) of early and late age-related maculopathy (ARM) by age
and sex in the population.
were unchanged (results not shown). When early and late
ARMs were combined (any ARM), the significant association
remained (Table 3).
Refractive Error and ARM
The relationship between different refractive error categories
and late, early, or any ARM, is shown in Table 4. No significant
association or trend was found between late ARM and refractive error category. However, the prevalence and ORs for early
(or any) ARM progressively increased as the refractive error
category changed from moderate to high myopia and moved
toward moderate to high hyperopia.
3. Association between Age-Related
Maculopathy and Spherical Equivalent
TABLE
Multivariate Adjusted* Odds Ratio for
Each Diopter Increase in SEq (95% CI)
Late ARM
Early ARM
Any ARMf
Logistic
Regression
Models
Generalized
Estimating
Equation Models
0.99(0.86-1.13)
1.14(1.04-1.25)
1.09(101-1.19)
0.99(0.88-1.13)
1.08(1.01-1.15)
1.05(1.00-1.11)
SEq, spherical equivalent; CI, confidence interval; ARM, age-related maculopathy.
* Adjusted for age, sex, family history of age-related macular degeneration, and current smoking.
t Combined early and late ARM.
Hyperopia
After multivariate adjustment, no statistically significant association was found between moderate to high hyperopia and late
ARM in either the logistic regression or GEE model. However,
mild hyperopia was significantly associated with reduced odds
for late ARM (OR, 0.5; 95% CI, 0.3-0.9) with the GEE model
(Table 4).
Compared with emmetropia, no significant association
was found between mild hyperopia and early ARM with either
model. For moderate to high hyperopia and early ARM, a
statistically significant association was found in the multivariate-adjusted logistic regression model (OR, 2.0; 95% CI, 1.23.4), but a nonsignificant association was found when the GEE
model was used (OR, 1.3; 95% CI, 0.9 -1.9). When early and
late ARM cases were combined, the association with moderate
to high hyperopia remained marginally nonsignificant in both
models (logistic model: OR, 1.5; 95% CI, 0.9-2.4; GEE model:
OR, 1.3, 95% CI, 0.9-1.7) (Table 4).
Myopia
After multivariate adjustment, no significant association was
found between late or early ARM and mild or moderate to high
myopia in either statistical model (Table 4).
DISCUSSION
Although a possible association between hyperopia and ARM
has been suggested in a number of reports,1"5 there is no
generally accepted underlying hypothesis to explain this association. Therefore the possibility that selection bias could have
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IOVS, October 1998, Vol. 39, No. 11
TABLE 4. Associations between Stages of Age-Related Maculopathy and Increasing Hyperopic Refractive Error,
Analyzed by Logistic Regression and Generalized Estimating Equation Models
Myopia
Hyperopia
Stage of ARM
Moderate/High
Mild
Emmetropia
Mild
Moderate/High
Late ARM*
Logistic regression model
GEE model
Early ARMf
Logistic regression model
GEE model
Any ARM*
Logistic regression model
GEE model
1/145 (0.7)
0.5 (0.006-3.5)
0.8 (0.2-2.7)
2/144(1.4)
0.3(0.08-1.3)
0.6(0.3-1.3)
3/145 (2.1)
0.3(0.1-1.1)
0.7(0.4-1.3)
6/240 (2.5)
1.3(0.5-3.2)
0.8(0.4-1.6)
11/234(4.7)
0.9(0.5-1.7)
0.9(0.5-1.4)
17/240(7.1)
1.0(0.6-1.7)
0.9(0.6-1.3)
20/1518(1.3)
1.0 (reference)
1.0
50/1498 (3.3)
1.0 (reference)
1.0
70/1518(4.6)
1.0 (reference)
1.0
20/1226(1.6)
0.6(0.4-1.2)
0.5 (0.3-0.9)
65/1206(5.4)
1.2(0.8-1.7)
1.1 (0.8-1.4)
85/1226 (6.9)
1.0(0.7-1.4)
1.0(0.8-1.2)
5/222 (2.3)
0.5(0.2-1.5)
0.9 (0.4-2.0)
25/217(11.5)
2.0(1.2-3.4)
1.3(0.9-1.9)
30/222 (13.5)
1.5(0.9-2.4)
1.3(0.9-1.7)
ARM, age-related maculopathy; GEE, generalized estimating equation.
Values are odds ratios with 95% confidence intervals in parentheses, adjusted for age, sex, ARM family history, and current smoking, for
variables myopia and hyperopia with both models.
Values are number of subjects, with percentage in parentheses.
t Excluding late ARM cases.
influenced observations from previous studies and led to spurious findings needs to be considered.l'
The Blue Mountains Eye Study is a population-based survey conducted in a defined geographic area with a high response rate. These features would tend to minimize the possibility of selection bias because cases and noncases were from
the same population sample. All ARM cases were diagnosed
from blinded retinal photographic gradings and confirmed by a
detailed second grading. The use of standardized Early Treatment Diabetic Retinopathy Study subjective refraction with
best corrected visual acuity is also likely to have minimized
measurement error in the assessment of refraction. The Blue
Mountains Eye Study thus provides a good opportunity to
assess the relationship between ARM and refractive error.
Findings from previous studies have been confined primarily to a postulated association between neovascular ARM
and hyperopia.3"5 Reported associations have been either
crude, without adjustment for other factors such as age,4'5 or
were nonsignificant after multivariate adjustment.3 To date, the
evidence supporting this association is weak at best and is
possibly spurious. Our study could not confirm a significant
association between late ARM and hyperopia. This may be
caused by limited power in the study. However, a consistently
weak association was found between increasing SEq and early
ARM. Compared with emmetropia, our data indicated a possible association between moderate to high hyperopia and early
ARM. A risk gradient was also found for the relationship between early ARM and increasing levels of hyperopia. This risk
gradient was more obvious when three levels of hyperopia
(mild, moderate, and high) were used, although there were
only 13 cases of high hyperopia in the population. Given the
recent evidence that lesions comprising our definition of early
ARM (indistinct soft drusen or distinct soft drusen with pigmentary changes) strongly predict progression to late ARM,12
the findings from our study suggest a possible true but weak
association between moderate to high hyperopia and ARM.
A hyperopic shift in refractive error occurs with increasing age. Age is also a strong predictor of ARM.8 Whether we
have been able to control adequately for age in the multivariate
logistic regression and GEE models is difficult to assess. However, if age had confounded this association, it would be more
likely to have affected the relationship between late ARM and
hyperopia, because people with late ARM are older. In contrast, the association found in our study was more prominent
for early ARM than for late ARM.
In this population there were no cases with high myopia
graded as having early or late ARM. A cautious interpretation of
thisfindingis needed, because signs of typical myopic retinopathy were differentiated and excluded from the cases groups of
both early and late ARM. There were two such subjects with
neovascular scars and some other subjects with retinal pigmentary changes, who were classified as having typical myopic
retinopathy and not included as ARM cases.
A biologically plausible explanation for an association
between moderate to high hyperopia and ARM is not evident. However, finding a statistically significant association
does not necessarily imply a causal relationship. An increased coefficient of scleral rigidity was found to be associated with ARM in one case- control study.13 Although axial
length was not found to be associated with scleral rigidity in
this small study, it is possible that refractive error may have
an association with scleral rigidity. A more likely possibility
is that the link between the two conditions could be genetic, because refractive error and ARM are both known to
have strong familial influences. Both conditions might share
a common gene.
The limitations of our study need to be emphasized. It was
a cross-sectional study and cannot therefore be used to answer
temporal questions. Its statistical power is also limited by the
small number of cases, particularly subjects with late ARM. The
finding of an association between moderate to high hyperopia
and ARM could have occurred by chance alone. More crosssectional studies with sufficient power or long-term cohort
studies that examine the incidence of ARM in relation to
refractive error may be valuable.
In summary, these population-based data provide limited
support for previous case- control study findings of an association between hyperopia and ARM. The weak association
found was confined to the relationship between early ARM and
moderate to high hyperopia but displayed a risk gradient for
early ARM with increasing hyperopia.
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IOVS, October 1998, Vol. 39, No. 11
Reports
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4. Sandberg MA, Tolentino MJ, Miller S, Berson EL, Gaudio AR. Hyperopia and neovascularization in age-related macular degeneration. Ophthalmology. 1993;1OO:1OO9-1O13.
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age-related maculopathy in a population 70 years of age or older.
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visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology. 1996;103:357-364.
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maculopathy in Australia: the Blue Mountains Eye Study. Ophthalmology. 1995:102:1450-1460.
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grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol. 1995:39:367-374.
Katz J, Zeger S, Liang KY. Appropriate statistical methods to
account for similarities in binary outcomes between fellow eyes.
Invest Ophthalmol Vis Sd. 1994;35:246l-2465.
Vingerling JR, Klaver CC, Hofman A, de Jong PT. Epidemiology of
age-related maculopathy. Epidemiol Rev. 1995;17:347-360.
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.
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Effect of Glutamate Analogues
and Inhibitory
Neurotransmitters on the
Electroretinograms Elicited by
Random Sequence Stimuli in
Rabbits
photopic short-flash ERG. Glycine and GABA minimized the oscillatory potentials (OPs) of the photopic
ERGs, and also reduced the amplitude of the positive
wave of the first-order kernel slightly but caused a
large reduction in the amplitude of the second-order
kernel.
CONCLUSIONS. The data suggest that the ON and OFF bipolar cells contribute significantly to the photopic short-flash
ERG, as previously shown, and to the first-order kernel of
the responses elicited by the pseudorandom binary sequence stimuli. The second-order kernel and the OPs
receive a strong contribution from the cells of the inner
retinal layers. (Invest Ophthalmol Vis Set. 1998;39:
2171-2176)
Masayuki Horiguchi, Satoshi Suzuki,
Mineo Kondo, Atsuhiro Tanikawa, and
Yozo Miyake
study the origin of the different components of the electroretinogram (ERG) elicited by a random
binary m-sequence stimulus.
OBJECTIVE. TO
Electroretinograms were recorded from pigmented rabbits before and after the injection of glutamate
analogues (2-amino-4-phosphono-butyric acid [APB; DL
form] and cw-2,3-piperidine-dicarboxylic acid [PDA]) and
inhibitory neurotransmitters (glycine and y-aminobutyric
acid [GABA]) to abolish the contribution of different cell
types to the ERG. Two types of stimuli were used: conventional full-field stimulation with short- and long-duration flashes and a random binary m-sequence of flashes
designed to mimic the pseudorandom binary m-sequence
stimulation used in the multifocal ERG technique.
METHODS.
The effects of APB and PDA on the first-order
kernel of the random ERGs were similar to those on the
RESULTS.
From the Department of Ophthalmology, Nagoya University
School of Medicine, Japan.
Submitted for publication January 12, 1998; revised May 1, 1998;
accepted June 4, 1998.
Proprietary interest category: N.
Reprint requests: Masayuki Horiguchi, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho,
Showa-ku, Nagoya, 466 Japan.
2171
T
he multifocal electroretinographic (ERG) technique has
been developed to test retinal function in localized areas
of the retina1'2 and may be useful for detecting acute zonal
occult macular dystrophy3 and occult macular dystrophy.4
This technique can also be used to differentiate optic nerve
and macular diseases.5 However, the origin of these focal
responses,1 which are elicited by binary m-sequence (pseudorandom) stimuli, has not been fully determined. Hood et
al.6 compared the waveform of the first-order kernel of the
multifocal response to the full-field, photopic ERGs elicited
by short flashes and concluded that they originate from the
same retinal neurons.
The origin of the photopic a-, b-, d-waves and oscillatory
potentials (OPs) of photopic ERGs has been extensively
studied. The studies using glutamate analogues (2-amino
4-phosphonobutyric acid [APB; DL form] and czs-2,3-piperidine-dicarboxylic acid [PDA]) showed that the photopic
b-wave arises from depolarizing and hyperpolarizing bipolar
cells, and the photopic a-wave originates from hyperpolarizing bipolar cells and/or cones.7'8 The experiments in
which inhibitory neurotransmitters (glycine and y-aminobutyric acid [GABA]) were used indicated that the OPs arise
from the inner retinal layers.9"11 We approached the ques-
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