Relations between fundus appearance and function. Eyes

Investigative Ophthalmology & Visual Science, Vol. 32, No. 1, January 1991
Copyright © Association for Research in Vision and Ophthalmology
Relations Between Fundus Appearance and Function
Eyes Whose Fellow Eye Hos Exudorive Age-Relared Mocu/or Degeneration
Alvin Eisner,*f Vasiliki D. Stoumbos,*^ Michael L. Klein,}: and Susan A. Fleming*-]Foveal visual function was compared with fundus appearance for 41 eyes that had good acuity but
whose fellow eye had exudative age-related macular degeneration (AMD). The visual functions tested
were among those reported to be compromised by AMD. They included: (1) dark adaptation, (2)
absolute sensitivity, (3) S cone-mediated sensitivity, and (4) color matching. The fundus features used
to evaluate the risk of developing exudative AMD included: (1) drusen confluence, (2) drusen size, and
(3) focal hyperpigmentation. For the group of eyes defined by the presence of one or more high-risk
fundus characteristics, all visual functions were compromised significantly. In particular, all 21 eyes
with abnormally slow rates of dark adaptation had high-risk fundi, and all 16 eyes with abnormal color
matching (ie, a small effect of test area on the color match or rejection of all potential color matches)
had high-risk fundi. Conversely, 30 of the 32 eyes with high-risk fundi had abnormally slow rates of
dark adaptation or abnormal color matching. In addition, reduced acuity in the fellow exudative eye
was associated significantly with a high-risk fundus in the nonexudative eye. Invest Ophthalmol Vis
Sci 32:8-20,1991
The eyes of people with unilateral exudative agerelated macular degeneration (AMD) in the fellow
eye have a wide range of functional capacities, even
when they retain good visual acuity.1 The fundus appearance of these eyes also varies greatly, from few
drusen and no pigment epithelial atrophy to marked
change, including the presence of known risk factors
for progression to exudative AMD.2 These eyes,
therefore, constitute a useful population for comparing visual function with fundus appearance. By comparing different visual functions with several aspects
of fundus appearance, relations between functional
loss and funduscopic change may be understood
more precisely.
The visual functions that we chose to measure were
among those likely to be especially vulnerable to the
effects of AMD. The functions that we measured included: (1) dark adaptation,3 (2) color matching,4 (3)
absolute sensitivity,5 and (4) S (or "blue") cone-mediated sensitivity.6'7 We have shown these functions
to be compromised or altered in a group of eyes
whose fellow eye has unilateral exudative AMD.'
The fundus features that we chose to analyze were
among those that are used to determine the risk of
developing exudative AMD. The fundus features that
we analyzed included: (1) focal hyperpigmentation,89
(2) drusen confluence,8"10 and (3) drusen size. 9 "
By relating visual function to fundus appearance
for a population of eyes with a high incidence rate of
exudative AMD, we hoped to identify visual functions that should be evaluated prospectively for their
ability to predict the development of exudative
AMD. Sunness et al5 already have reported that low
absolute sensitivity can predict the development of
advanced AMD with relatively good specificity. The
systematic relations between function and fundus appearance we describe suggest that other functions also
should be evaluated.
Materials and Methods
Eligibility Criteria
From the *Department of Ophthalmology, fR- S. Dow Neurological Sciences Institute, Good Samaritan Hospital and Medical
Center; ^Department of Ophthalmology, Oregon Health Sciences
University, Portland, Oregon.
Supported by National Institutes of Health grant EY05047 and
by the Oregon Lions Sight and Hearing Foundation.
Submitted for publication: March 30, 1989; accepted June 13,
1990.
Reprint requests: Alvin Eisner, PhD, R. S. Dow Neurological
Sciences Institute, 1120 N. W. 20 Avenue, Portland, OR 97209.
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Forty-one patients aged 60 years and older with
unilateral exudative AMD served as the test subjects.
Every subject had unilateral subretinal neovascularization. To be eligible for the study, all subjects had
corrected visual acuity of no worse than 20/25 in
their study eye, ie, the eye without exudative AMD.
They also met a number of other inclusion criteria,
such as (1) normal intraocular pressure, (2) no history
of eye disease other than AMD, and (3) no congenital
No. 1
FUNDU5 APPEARANCE AND VISUAL FUNCTION / Eisner er ol
color vision defects. The inclusion criteria are described in detail elsewhere, along with our procedures
for recruitment of the subjects.112 Twenty-six subjects were men, and 15 were women. All subjects gave
written informed consent before testing.
Visual Function Testing
The results of six visual function tests are reported:
absolute sensitivity, S cone-mediated sensitivity, rate
of dark adaptation after extinction of a bleach, anomaloscope color matching, the Farnsworth panel
D-l 5 test of color arrangement, and visual acuity (the
only function measured for the eye with exudative
AMD). Details of the testing procedure for all tests
but acuity are given elsewhere.1213 All measurements
were foveal or centered on the fovea.
Briefly, absolute sensitivity was measured with a
long-wavelength (660 nm), large (3° diameter), longduration (160 msec) test stimulus. S cone-mediated
sensitivity (1.5 Hz, 100% square-wave modulation of
a 440-nm test stimulus on a 1000-troland, 580-nm
background) was measured with both 1° and 3° diameter foveal test stimuli. Dark adaptation after extinction of a substantial partial bleach (3-min duration; 20,000 troland; 580 nm) was measured with the
same stimulus used to measure absolute sensitivity.
Red/green Rayleigh color matching was measured
using both small (1.1°)- and large (5.8°)-diameter foveally centered test stimuli. The time constant of dark
adaptation was computed and used to summarize the
rate of dark adaptation, and the difference between
large- and small-field Rayleigh color matches was
computed. This difference, termed the color-matcharea effect,414 is strongly related to the quantumcatching ability, or effective photopigment density, of
the foveal cones.414 We use the term "photosensitivity" synonymously with "effective photopigment
density."
The D-15 test was administered according to standard procedures15 under Macbeth illumination.13
The test was graded "pass" or "fail" using the criteria
described by Adams et al.16 That is, any major error
or more than one minor error constituted failure.
Acuity in the exudative eye was measured with a
Snellen projection system while the subjects viewed
letters through a pinhole and their existing corrective
lenses. For acuities worse than 20/400 a "counting
fingers" measure was calculated from the distance at
which subjects could correctly identify the orientation of a hand-held 10/200 "E."
Grading of Fundus Photographs
Stereoscopic color fundus photographs were taken
of both eyes of each subject. These were taken imme-
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
diately after functional testing for all but three subjects. For two of these three subjects, the photographs
were taken 2-3 weeks before functional testing. For
one subject, about 5 months elapsed after testing before the photography; this subject had a relatively
unaffected fundus.
The photographs were graded by the University of
Wisconsin Fundus Photograph Reading Center using
their AMD grading system.17'18 Exudative eye photographs were not graded; they were used only to verify
a history of exudative disease.
Unless specified otherwise, all analyses in this
paper used fundus-appearance grades that pertained
to the macula. The macular region,19 ie, a 6000-Atm
diameter region centered on the fovea, was subdivided into nine subregions; various aspects of fundus
appearance graded for each subregion were used to
derive scores for the entire macula. The central subregion was 1000 ixm in diameter. Because this subregion and the 3° test stimulus imaged in it (subtending
a retinal diameter of about 900 nm) each lie within
the anatomic fovea,19 each will be referred to as "foveal." Our use of the term "foveal" should not be
confused with the clinical use of the term that refers
to the anatomic foveola. Similarly, our use of the
term "macular" should not be confused with the
clinical use of the term that refers to the macula lutea.
For each subregion, categoric estimates were made
of largest drusen size, drusen area, and the proportion
of that drusen area occupied by confluent drusen.
Predominant drusen size was categorized only for the
entire macula, rather than by subregion. The upper
and lower bounds that defined the categoric estimates
and the borders that defined all nine subregions are
specified in the Appendix. Small, indistinct, or questionable drusen and stippling were not used to compute drusen area, in accordance with Reading Center
specifications. Similarly, reticular drusen, defined as
"yellowish material that looks like soft drusen arranged in ill-defined networks of broad interlacing
ribbons,"1718 were considered confluent.
The total macular area occupied by a particular
funduscopic feature, eg, confluent drusen, was calculated by using weighted sums of the affected areas
from each of the nine subregions. The weight ascribed
to each subregion corresponded to the proportion of
the macula occupied by that subregion. Categoric
scores were converted to numeric values for each subregion by computing arithmetic means of upper and
lower bounds.
Categorizations regarding focal hyperpigmentation
were derived from "increased pigment" grades as follows. Eyes were assigned a focal hyperpigmentation
score of "none" when and only when they had been
given an "increased pigment" grade of "none" for all
10
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / Jonuory 1991
nine macular subregions. Atrophic areas were defined by comparisons with standard photographs;
thus very mild hypopigmentation1 was not considered to be atrophy. Faded drusen with well-defined
borders were considered to be drusen, not atrophy.
Eyes with any grade of retinal pigment epithelial
(RPE) degeneration or geographic atrophy other than
"none" in any subregion were considered to have
atrophy, although questionable atrophy was not used
to compute atrophic area. (The three eyes with some
geographic atrophy are distinguished from eyes with
only RPE degeneration in Table 1.) Weighted sums
were used to compute total macular atrophic area as
they were to compute total macular drusen area.
Statistical Analyses
Because functional scores were not normally distributed, significance was evaluated using nonparametric tests unless stated otherwise. Statistical significance for differences of central tendency (eg, when
comparing functional scores between eyes with highrisk versus low-risk fundus appearance) was evaluated using Mann-Whitney U tests. Statistical significance for frequency differences (eg, for determining
whether abnormal function is specific for high-risk
fundus appearance) was evaluated using Fisher exact
tests. All correlations are Spearman rank-order correlations, except for a single comparison of two Pearson
correlation coefficients. All tests were one sided except when noted otherwise. The statistical package
SYSTAT (SYSTAT, Evanston, IL) was used to compute and evaluate the data, along with statistical
tables.20
Results
This section is divided into three parts. In the first
part, study eyes are classified operationally into two
groups: high risk and low risk, according to the presence or absence of certain funduscopic characteristics
known to be associated with a high risk of developing
exudative AMD. In the second part, eyes in the highrisk group are shown to have compromised function
compared with eyes in the low-risk group. Lastly, relationships between functional compromise and
fundus appearance are evaluated in more detail.
Funduscopic Classification of Risk
At present,9 three especially strong funduscopic
risk factors for developing exudative AMD appear to
be: (1) the presence of focal hyperpigmentation,8 (2)
more than minimal drusen confluence,810 and (3)
large drusen size.'' Accordingly, eyes were classified
operationally into two groups: high risk and low risk,
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Vol. 32
according to criteria established for each of these
three risk factors.
For focal hyperpigmentation, risk classification
was straightforward; eyes were classified as high risk
when they were assigned a grade other than "none."
Eyes were considered to have more than minimal
drusen confluence, and thus were classified as high
risk, when confluent drusen occupied 0.5% or more
of the macula. A cutoff of 0.5% is compatible with
Smiddy and Fine's8 corresponding operational definition (ie, more than 3 specific areas of confluent
drusen); 0.5% corresponds to a circular area of approximately 425 nm in diameter. Had we decreased
the cutoff for the operational definition to 0.2%, only
one additional eye would have been classified as high
risk.
For drusen size, two criteria were used to define
high risk. Eyes were classified as high risk when (1)
the predominant drusen diameter was greater than 63
^m or (2) the largest drusen diameter was greater than
250 ^m. The 63-jum cutoff was chosen because it was
the potential cutoff nearest to the diameter (50 iim)
identified by Bressler et al.2 as tending to separate
hard drusen from soft drusen. However, had we applied the same 63-^m cutoff to the largest drusen size
to define high risk operationally, then 37 of 41 eyes
would have been classified as high risk on the basis of
that criterion alone. Had we increased the cutoff to
125 iim, the next potential cutoff, then 35 eyes would
still have been classified as high risk on the basis of
that single criterion. By choosing the next higher potential cutoff, 250 ixm, the proportion of eyes, 19 of
41, classified as high risk on the basis of largest drusen
size became comparable to the proportion of eyes,
56%, reported to have large drusen by Bressler et al.9
for a similar population.
Of the 41 eyes that we evaluated, 32 were classified
as high risk on the basis of one or more of the four
possible criteria. The remaining nine eyes were classified as low risk, by definition. Of the 32 high-risk
eyes, 22 were so classified on the basis of drusen appearance (ie, confluence or size) alone. None of the
32 high-risk eyes were so classified on the basis of
focal hyperpigmentation alone.
Relationship of Function to Funduscopic
Classification of Risk
Dark adaptation: Figure 1 is a plot of the dark-adaptation time constant versus age. The solid symbols
represent data from high-risk eyes; the open symbols
represent data from low-risk eyes. The differently
shaped solid symbols represent eyes with different
combinations of high-risk features, as specified in the
legend.
dividual data: visual function and fundus appearance scores
Dark
adaptation
time
constant
67
101
107
110
114
116
122
123
139
139
144
147
152
156
158
159
162
169
172
187
205
225
232
237
250
251
260
272
276
299
324
346
349
359
362
369
370
376
397
401
483
Confluent
Largest
Drusen Predominant drusen
Focal
drusen
hyperpigmentation
area (%) area (%) drusen size
size
(mac/fov) (macula)
(macula)
(mac/fov)
(mac/fov)
2.5/7.0
0.2/0
5.7/0
0/0
0.4/14.1
0.7/0
7.5/56.3
1.4/1.8
0.5/7.0
0/0
0.4/0
0/0
0.4/14.1
0.6/0
0.9/0
0/0
5.6/3.5
0/0
0/0
0.1/3.5
5.2/28.1
22.6/7.0
7.7/1.8
27.4/3.5
7.5/14.1
7.9/7.0
4.1/0
0/0
2.7/0
56.5/28.1
2.0/0
7.5/7.0
22.2/7.0
4.7/1.6
0.8/0
0.6/1.8
5.5/0
1.4/0
5.5/0
20.4/1.0
1.4/0.2
3.3
0.5
4.5
0.1
0.9
1.6
11.0
2.2
0.8
0.0
0.6
0
1.0
1.5
2.6
0.1
7.2
0.0
0.2
0.8
9.8
30.3
1.8
36.7
2.2
3.2
7.2
1.7
5.7
3
2
5
2
2
5
5
2
2
2
5
1
5
4
5
0
5
1
2
2
5
6
5
4
3
3
3
5
5
48.7
6
3.4
2.4
5
29.6
10.1
3.3
3.2
5.2
4.2
4.5
5
6
5
27.2
5
5
6
2
6
6
3.7
5
.
4/3
4/1
4/3
2/2
5/5
5/2
5/5
6/3
4/4
2/0
5/0
1/0
5/4
4/2
4/3
3/3
5/3
2/0
4/2
3/3
5/4
6/3
4/3
5/4
5/5
4/4
5/3
4/2
5/3
6/4
5/4
4/4
6/3
5/3
5/4
5/3
6/2
4/3
6/2
6/4
4/3
5/3
0/0
0/0
0/0
0/0
0/0
2/2
0/0
0/0
0/0
0/0
0/0
2/0
0/0
2/0
0/0
0/0
0/0
0/0
0/0
0/0
7/1
2/2
0/0
0/0
0/0
0/0
0/0
0/0
0/0
7/0
0/0
0/0
0/0
0/0
7/1
0/0
0/0
2/2
0/0
2/2
nctional and funduscopic scores for all 41 study eyes ordered by dark adaptation time
separates macular (left) from foveal (right) fundus appearance scores when applicable.
s signify high-risk fundus appearance, ie, focal hyperpigmentation, more than minimal
ce or large drusen (see Methods for definitions). The scale for drusen size is: 0 = none, 1
uestionable < 63 ^m diameter or stippling, 2 = distinct < 63 nm, 3 = < 125 ^m, 4 = <250
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Atrophic
area (%)
(mac/fov)
26.4*/0
0/0
.
2.3/.
1.7/12.5
•
0/0
5.5/12.5
22.9*/0*
.
1.4*/0
2.4/37.5
o/.
Absolute
sensitivity
4.71
6.36
5.59
5.69
5.60
5.89
5.90
6.04
5.95
6.23
5.66
6.19
5.98
6.06
5.48
6.29
5.68
6.05
6.33
6.21
6.02
5.44
4.92
5.81
6.19
5.95
6.00
6.02
6.15
4.69
6.39
5.65
5.81
6.09
6.11
5.15
6.16
5.98
5.68
5.30
5.53
S cone
mediated
Color-match- sensitivity
area-effect
(3°)
_
0.060
0.000
0.060
0.007
0.005
0.016
0.099
0.040
0.073
0.015
0.050
0.000
0.078
—
0.024
—
0.067
0.076
0.060
—
0.015
0.000
0.000
—
0.051
0.070
0.070
0.126
—
0.057
0.050
0.050
—
0.058
0.040
0.020
0.080
0.050
0.048
0.024
3.06
5.16
4.34
4.84
4.85
4.67
4.86
4.90
4.74
4.93
4.95
5.58
4.84
4.95
5.03
4.56
5.09
5.14
4.82
4.90
4.18
4.30
4.42
4.71
4.59
5.19
4.72
4.44
4.11
3.78
3.92
4.26
4.89
4.67
4.73
4.32
4.83
5.29
4.64
3.87
4.40
Scone
sensitivity
sizefactor
D-15
test
0.35
0.53
1.00
0.29
0.84
0.34
0.71
0.32
0.59
0.48
0.27
0.33
0.21
0.80
0.69
0.53
0.33
0.42
0.15
0.30
0.45
0.34
1.03
0.38
0.40
0.40
0.55
0.52
0.53
0.87
0.21
-0.04
0.30
0.35
0.49
0.32
0.49
0.66
0.45
0.22
0.62
Fail
Pass
Pass
Pass
Pass
Fail
Pass
Fail
Pass
Pass
Fail
Pass
Fail
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Fail
Fail
Fail
Pass
Pass
Pass
Fail
Fail
Fail
Fail
Fail
Fail
Pass
Pass
Pass
Fail
Pass
Pass
Pass
Fail
Fail
Exuda
eye ac
cf @
20/30
[email protected]
20/40
20/20
[email protected]
20/20
20/40
20/60
20/50
20/50
20/30
20/50
20/30
20/10
20/60
20/40
20/40
20/20
20/40
[email protected]
20/40
20/40
[email protected]
20/20
20/20
20/60
20/30
20/40
cf @
20/40
20/40
[email protected]
20/40
20/10
[email protected]
20/40
20/40
20/40
[email protected]
20/70
nm, 5 = ^250 fitn, 6 = reticular. The scale for focal hyperpigmentation (in the most affected subfield)
= none, I = questionable, 2 = area less than that of a disc 250 /im in diameter, and 3 = area not less
that of a disc 250 pm in diameter. For atrophy, 0% = questionable, " •" = none; an asterisk signifies s
geographic atrophy. The S cone sensitivity size factor is defined to be the difference between log S c
mediated sensitivity to 3° and 1° diameter tests.
12
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
DARK ADAPTATION TIME CONSTANT
500
2I/)
O
o
60
AGE (years)
Fig. 1. Dark adaptation time constant versus age for 3°, 660 nm
160 msec test stimuli following a 3 min duration, 20,000 troland
580 nm bleach. Open symbols represent eyes with low-risk fundus
appearance. Closed symbols represent eyes with high-risk fundus
appearance; squares represent eyes with focal hyperpigmentation,
upward pointing triangles represent eyes with more than minimal
drusen confluence, downward pointing triangles represent eyes
with large drusen, and diamonds represent eyes with both more
than minimal confluence and large drusen (predominant size ^ 63
jim or largest size S; 250 Mm). Displacement of some data by xh year
is to eliminate overlap. The horizontal dashed line represents the
approximate upper limit of normal (203 sec).
By definition, larger time constants reflect slower
rates of recovery from a given level of desensitization
to a fully dark-adapted level of sensitivity. High-risk
eyes tended to have larger time constants and therefore slower rates of recovery than low-risk eyes (P
<0.01).
A time constant of slightly more than 200 sec corresponds to the upper limit of normal,12* and is represented by the dashed line. All 21 eyes with time constants greater than 200 sec were high risk. In other
words, an abnormally slow dark-adaptation rate was
very specific for high-risk fundus appearance (P
< 0.001).
Color matching: Of the eight high-risk eyes with
time constants less than 200 sec and with measurable
1.1° color matches, six had abnormally small colormatch-area effects (less than 0.0212).f
* (The 95th percentile of mideye time constants from 143 agematched normal subjects with 20/25 or better acuity in each eye
was 203 sec. This value was coincidentally exactly two standard
deviations greater than the mean time of 118 sec derived after
discarding outlying mideye times in our study, ie, greater than or
equal to 267 sec).
f The fifth percentile of mideye color-match-area effects from
normal subjects with 20/25 or better acuity in each eye was 0.015.
However, because the distribution was trimodal,1 the lower limit of
normal was slightly greater than 0.015. On the assumption that the
main unimodal distribution was normal, the fifth percentile for
that distribution was calculated to be 0.019 (given a mean of 0.054
and a standard deviation of 0.021).
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Vol. 32
Because a small color-match-area effect indicates
that effective photopigment density (ie, photosensitivity) at the fovea is low, 4 | the photosensitivity of
these six eyes probably was abnormally low. Therefore, these eyes may have regained sensitivity at apparently normal rates because the adapting light was
effectively too dim to cause the rate of recovery to be
abnormally slow.
In fact, of the 11 high-risk eyes with time constants
less than 250 sec and with measurable color matches,
the color-match-area effects of nine were abnormally
small; all 14 high-risk eyes with time constants greater
than 250 sec and with measurable color matches had
color-match-area effects that were normal.
The complementary relations between dark adaptation and color matching can be seen graphically in
Figure 2. Dark-adaptation time constant is plotted
versus color-match-area effect. The vertical and horizontal dashed lines represent the lower and upper
limits of normal, respectively, for the color-matcharea effect and for the dark-adaptation time constant.
Note that all nine eyes with abnormally small colormatch-area effects were high risk and that the eyes of
all seven subjects who did not accept any red/green
ratio for a color match were also high risk. Therefore,
all 16 eyes that did not have a normal color-matcharea effect were high risk. In other words, abnormal
color matching was specific for high-risk fundus appearance (P < 0.005).
Although high-risk eyes tended to have smaller
color-match-area effects than low-risk eyes (P
< 0.05), an abnormal color-match-area effect was not
by itself very sensitive for high risk. In particular, 16
high-risk eyes had color-match-area effects that were
normal. Similarly, an abnormal dark-adaptation
time constant was not by itself very sensitive for high
risk, since 11 high-risk eyes had dark-adaptation time
that were normal. However, the combination of an
abnormal color-match-area effect and an abnormal
dark-adaptation time constants was very sensitive for
high risk (P < 0.001). Only two of 32 high-risk eyes
had both a normal color-match-area effect and a normal dark-adaptation time constants.
Had high risk been defined using criteria more inclusive (eg, had we chosen a cutoff of 63 /xm for largest drusen size), then the combination would have
been less sensitive for high risk, although it would still
X More generally, a small color-match-area effect implies that the
effective photopigment density of the foveal and parafoveal cones
are similar,14'21 consistent with two possibilities: (1) the effective
photopigment density of the foveal cones is low or (2) the effective
photopigment density of the parafoveal cones is high. However, the
first of these two possibilities is a priori more likely and is consistent
with the systematic relationship between dark-adaptation rate and
color-match-area effect we describe.
No. 1
13
FUNDUS APPEARANCE AND VISUAL FUNCTION / Eisner er ol
DARK ADAPTATION TIME CONSTANT
vs
COLOR-MATCH-AREA-EFFECT
500
Fig. 2. Dark adaptation time constant versus
color-match-area-effect. Dashed lines represent
upper and lower limits of normal, respectively,
for the dark adaptation time constant and for the
color-match-area-effect. Eyes without any acceptable small-field Rayleigh match are represented
on the left. Note that two eyes are represented at
about each of the following two sets of coordinates: (0.00, 235) and (0.05, 347). Symbols as in
Figure 1.
V)
XJ
c
o
o
400
<D
CO
300-^
I—
o
200
o
100-<
0.10
0.05
0.00
0.15
(LOG R/G| a r g e - LOG R/G s m a M )
be significant. Using more inclusive criteria would,
by definition, not have decreased specificity.
Both the dark-adaptation time constant and the
color-match-area effect depended little on age. Figure
3 is a plot of color-match-area effect versus age. The
non-significant dependence on age was consistent
with corresponding data from normal eyes. (The
color-match-area effect did decrease significantly
with age for a large population of normal eyes, but the
linear regression accounted for only about 3% of the
variance.12 The dark-adaptation time constant did
not change significantly with age for normal eyes but
might tend to be smaller for people in their 80s than
for younger people,22 at least with our choice of stimulus parameters.)
Absolute sensitivity: For the two other quantitative
ratio measures of visual function, ie, absolute sensitivity and S cone-mediated sensitivity, the effect of
age can be expected to be substantial.l2-23-24 Figure 4 is
a plot of absolute sensitivity versus age. High-risk
eyes tended to have lower absolute sensitivity than
low-risk eyes (P < 0.001). Although the relations between risk and age was not significant (P = 0.12,
two-sided test), the correlation between high risk and
relatively low sensitivity may have depended to some
extent on age. In particular, 15 of the 16 oldest eyes
were high risk, and absolute sensitivity decreased significantly with age (Spearman r = -0.32, P < 0.025).
The decrease appeared to accelerate with age faster
than it did for normal eyes. Nevertheless, even in a
COLOR-MATCH-AREA-EFFECT
0.15
Fig. 3. Color-match-area-effect versus age, derived from 1.1° and 5.8° Rayleigh matches.
Dashed line represents lower limit of normal
(0.019). Eyes without any acceptable small-field
Rayleigh match are represented on the bottom.
Symbols as in Figure 1.
I
0.10-O
O
fijO m
0.05 <>
o
O.OO+
•
•
•
• •
CD
D
7T
••
a:
o
o
AGE (years)
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
I I—(—t-
ABSOLUTE SENSITIVITY
6.50
£{?
Vol. 32
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / January 1991
14
6.00 ••
B
A
*°
•••
4.50
60
65
70
75
80
85
90
AGE (years)
Fig. 4. Absolute sensitivity versus age, for 660 nm, 3° diameter,
160 msec, test stimuli. Symbols as in Figure 1.
limited age range, 66-74 years (chosen because of
gaps in the age distribution), high-risk eyes still
tended to have relatively low absolute sensitivity (P
< 0.05).
For reference, the lower limit of normal absolute
sensitivity for people in their 60s is roughly 6.0 log
(deg2//iW); the normal age-related decrease of sensitivity is about 0.1 log unit per decade. These estimates
are derived from previous work in this laboratory
using identical stimulus parameters.12
For the eyes tested in the current study, absolute
sensitivity and color-match-area effect were strongly
correlated (Spearman r = 0.58, P < 0.001). The
strong correlation suggests that losses of absolute sensitivity might result in part from decreased photosensitivity.
S cone-mediated sensitivity: Figure 5 is a plot of S
cone-mediated sensitivity (3° diameter stimuli)
versus age. High-risk eyes tended to have lower S
cone-mediated sensitivity than low-risk eyes (P
< 0.01) for both 1° and 3° diameter stimuli, the two
stimulus sizes used to measure S cone-mediated sensitivity. The comparisons were significant (P < 0.05)
in the limited age range: 66-74 years.
Because S cone-mediated sensitivity may change
with age at different rates for men and women in a
way that could depend either on lens density12-25 or
test area,26 these sensitivities were also analyzed separately by gender. High-risk eyes had significantly
lower S cone-mediated sensitivity than low-risk eyes
for men (P < 0.01). For women this comparison was
not significant, either for the entire age range or for
the limited age range; non-significance could be due
to the small number of women tested, especially in
the limited age range.
For normal subjects, the rate at which the S conemediated-sensitivity size factor (ie, the ratio of 3° to
1° sensitivity) changed with age did not appear to
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
depend on gender.12 However, for the eyes tested in
the current study, the rate at which the size factor
changed with age did appear to be gender relatea; for
women the correlation between size factor and age
was appreciable (Spearman r = 0.43, P = 0.12, twosided test) and probably different from that of men
(Spearman r = -0.28). The Pearson correlation coefficients (0.41 and —0.26) were significantly different (P
< 0.05 two-sided test Fisher r-to-z transformation).
The probable gender-dependent relations between
age and size factor is consistent with the finding of de
Monasterio et al.26 that the spatial density of S cones
decreased in the central fovea for old female but not
for old male macaques. Size factor was not significantly related to any aspect of fundus appearance, for
men, women, or both sexes together. The non-significant negative correlation for men is consistent with a
non-significant age-related decrease of macular pigment density.27)
Commercial tests: We administered the D-15 test
to all 41 subjects. Only nonexudative eyes were
tested. Seventeen of 41 eyes failed the D-15 test according to the pass-fail criteria specified by Adams et
al.16 All 17 eyes were high risk. Thus, for eyes that
met our eligibility standards, D-15 failure was specific
for high-risk fundus appearance (P < 0.005). All 17
eyes that failed the D-15 test had an abnormal darkadaptation time constant or abnormal color matching. Had we graded the D-15 test according to the
criteria described in its instruction manual, only 12 of
the 17 eyes would have failed. (The criteria specified
by the manual failed fewer patients because the D-15
test was designed to detect and categorize severe
color-vision loss resulting from congenital defects in
individual classes of photoreceptor, rather than from
more diffuse and/or less profound acquired defects.)
We also measured acuity in the exudative eyes of
all 41 subjects. Acuity was the only function that we
S CONE MEDIATED SENSITIVITY (3°)
6.00
>°
8*
3.00
60
65
70
75
80
85
AGE (years)
Fig. 5. S cone mediated sensitivity versus age for 440 nm, 3°
diameter, 1.5 Hz, tests on a 1000 troland 580 nm background.
Symbols as in Figure 1.
No. 1
15
FUNDUS APPEARANCE AND VISUAL FUNCTION / Eisner er ol
measured for the exudative eyes. Because macular
degeneration is considered to be a bilateral disease,28
the finding that "high risk" for the nonexudative eye
was associated significantly with relatively low acuity
in the exudative eye (P < 0.01, two-sided test) is a
plausible one. For subjects in the limited age range,
the corresponding significance level was P < 0.05.
The significant association between fundus appearance of the nonexudative eye and reduced acuity in
the fellow exudative eye could have resulted from a
duration-of-disease confounding factor. However,
the time elapsed since the diagnosis of exudative
AMD (typically months to years) did not appear to
differ systematically between the high- and low-risk
groups (P > 0.75, two-sided test). Furthermore, although acuity in the exudative eye correlated negatively with the time elapsed since the diagnosis of
exudative AMD (Spearman r = -0.17), the correlation was neither large nor significant. With the exception of the time elapsed since the diagnosis of exudative AMD, all individual data used for this section
are tabulated in Table 1.
Detailed Comparisons of Function and Fundus
Appearance
Comparisons with separate aspects of fundus appearance: Visual function was compared with fundus
appearance separately for the different aspects of
fundus appearance that were used for determining
the risk class. Specifically, visual function was compared across groups of eyes that were categorized according to scores based on grades for (1) focal hyperpigmentation, (2) drusen confluence, and (3) drusen
size. Visual function was compared also across
groups of eyes categorized according to the presence
or absence of atrophy.
The results of these comparisons are given in Table
2. The entries are significance values derived from
between-group comparisons; statistically significant
entries are italicized. The nonparenthetic entries are
significance values derived from comparisons of categories that together comprised all 41 eyes. The parenthetic entries are significance values derived from
comparisons of categories that together comprised
fewer than 41 eyes. For the parenthetic entries, eyes
had been eliminated for statistical computations to
minimize the effects of potential confounding factors.
All entries for comparisons regarding focal hyperpigmentation, drusen confluence, and drusen size in
Table 2 are significance values obtained using the
categorizations described for classifying eyes into
high- and low-risk groups. The parenthetic values for
(1) focal hyperpigmentation and (2-4) for the several
high-risk drusen characteristics were calculated from,
respectively, (1) only the 32 high-risk eyes and (2-4)
only the 31 eyes with a hyperpigmentation score of
"none." Since all eyes classified as high risk on the
basis of focal hyperpigmentation also had high-risk
drusen, effects of potential confounds were reduced
by eliminating (1) the nine eyes classified as low risk
and (2-4) the ten eyes that could be classified as high
risk on the basis of focal hyperpigmentation, respectively.
From Table 2, it is evident that eyes with focal
hyperpigmentation tended to have lower absolute
sensitivity than eyes without focal hyperpigmentation. Probably, eyes with focal hyperpigmentation
tended also to have relatively small color-match-area
effects and therefore reduced photosensitivities.
Drusen confluence, on the other hand, appeared to
be strongly associated with slow dark-adaptation
rates. In particular, eyes with more than minimal
drusen confluence tended to have slower dark-adaptation rates than eyes with no drusen confluence or
with only minimal drusen confluence. Similarly, eyes
with more than minimal drusen confluence tended to
have reduced absolute sensitivity and reduced S
Table 2. Significance levels for comparisons between fundus appearance and functional compromise
More than minimal drusen
Focal
hyperpigmentation
confluence
Dark adaptation time
constant
Absolute sensitivity
S cone mediated
sensitivity (3°)
Color-match-area-effect
Acuity, exudative eye
Age
Predominant drusen size
Atrophy
Largest drusen size
All
eyes
(High-risk
eyes only)
All
eyes
(Eyes w/o focal
hyperpigmentation)
All
eyes
(Eyes w/o focal
hyperpigmentation)
All
eyes
(Eyes w/o focal
hyperpigmentation)
All
eyes
(High-risk
eyes only)
0.293
0.006
(0.452)
(0.019)
0.002
0.009
(0.002)
(0.036)
0.005
0.003
(0.004)
(0.14)
0.038
0.244
(0.041)
(0.053)
0.386
0.008
(0.404)
(0.032)
0.033
0.013
0.328
0.044
(0.112)
(0.061)
(0.332)
(0.092)
0.007
0.291
0.000
0.074
(0.031)
(0.469)
(0.007)
(0.305)
0.001
0.015
0.013
0.042
(0.004)
(0.090)
(0.016)
(0.107)
0.048
0.054
0.060
0.244
(0.027)
(0.102)
(0.056)
(0.368)
0.030
0.006
0.403
0.078
(0.100)
(0.035)
(0.275)
(0.158)
Significance values (1-sided Mann-Whitney U tests) for between-group comparisons.
Statistically significant entries are italicized. From left toright,comparisons for (1) focal
hyperpigmentation—none versus questionable or present, (2) drusen confluence—none
or minimal versus more than minimal, (3) predominant drusen size—<63 fim versus ^63
inn or reticular, (4) largest drusen size, <2S0 /im versus s25O pm or reticular and (5)
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
atrophy—none versus questionable or present. Nonparenthetical entries are significance
levels computed using data from all 41 eyes; parenthetical entries use data from the 31 eyes
without focal hyperpigmentation for comparisons between groups separated by drusen
appearance, and from all 32 high-risk eyes for comparisons between groups separated by
hyperpigmentation or atrophy.
16
Vol. 32
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
cone-mediated sensitivity. The corresponding association regarding drusen confluence in the nonexudative eye and reduced acuity in the fellow exudative
eye may have been the strongest association of all.
Given the possible categorizations allowed by the
Reading Center's grading system, predominant drusen size appeared to be more closely associated with
function than was largest drusen size. With the possible exception of the color-match-area effect, all functions appeared to be more compromised when either
large or reticular drusen were present than when
mainly small drusen were present.
Eyes with atrophy also appeared to have compromised function. Specifically, eyes with atrophy
tended to have relatively low absolute sensitivity and
relatively small color-match-area effects. Probably,
eyes with atrophy tended also to have relatively low S
cone-mediated sensitivity. In Table 2, the parenthetic
values for atrophy are for high-risk eyes only, as they
were for focal hyperpigmentation. Of the ten eyes
with atrophy, nine had focal hyperpigmentation, and
of the ten eyes with focal hyperpigmentation, nine
had atrophy, implying an almost perfect correspondence between these two independent descriptors of
macular fundus appearance.
Correlations with several aspects of fundus appearance: In addition to the comparisons between groups
summarized in Table 2, correlations between fundus
appearance and function were also calculated, when
possible. Rank-order correlation coefficients are
given in Table 3. Parenthetic entries were computed
using data only from eyes without focal hyperpigmentation. Significant correlations are italicized.
Because only one eye had no measurable drusen
area and six eyes did not have any drusen confluence,
significance was simpler to evaluate for correlations
of function with total drusen area than with total
confluent drusen area, which was highly correlated
with total drusen area (Spearman r = 0.96). The correlations between total drusen area and reduced
function were significant for all functions but color
matching. When the corresponding correlations were
computed using the total affected area (drusen area
plus atrophic area) rather than the total drusen area
alone, the magnitude of all intraocular correlations
increased, except for that of the dark-adaptation
time, which decreased. All correlations of function
with total affected area were significant.
Associations with foveal fundus appearance: Lastly,
we evaluated relations of function with foveal fundus
appearance. Deriving conclusions specifically regarding foveal appearance is problematic, however, because foveal fundus appearance and extrafoveal
fundus appearance are not statistically independent
(eg, the rank-order correlation coefficient of foveal
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Table 3. Rank order correlation coefficients
of function with fundus appearance
Dark adaptation time
constant
Absolute sensitivity
S cone sensitivity (3°)
Color-match-area-effect
Acuity, exudative eye
Age
Drusen area
Total affected
(Eyes w/o
focal hyperAll eyes pigmentation)
area (drusen
area +
atrophic
area)
0.51
-0.40
-0.45
-0.21
-0.57
0.16
(0.63)
(-0.46)
(-0.49)
(-0.13)
(-0.65)
(0.14)
0.44
-0.49
-0.53
-0.33
-0.59
0.17
Spearman rank order correlation coefficients between functional scores
and quantitative indices of fundus appearance: (1) macular drusen area, and
(2) total affected area (macular drusen area + macular atrophic area). Nonparenthetical entries use data from all 41 eyes, parenthetical entries use data
only from the 32 high-risk eyes. Statistically significant entries are italicized.
drusen area with extrafoveal drusen area = 0.49).
Nevertheless, foveal drusen confluence was not significantly associated with slow dark-adaptation rates,
even though macular drusen confluence was strongly
associated with slow dark adaptation. The lack of significance held for all potentially relevant comparisons that we made, including those made after deletion of data from eyes without normal color matches.
There was some evidence, however, that eyes with
drusen confluence at the fovea might tend to have
relatively small color-match-area effects. That is,
even though the color-match-area effect appeared to
be unrelated to high-risk macular drusen confluence
(Table 2), eyes with some foveal drusen confluence
perhaps tended to have smaller color-match-area effects than eyes without any foveal drusen confluence
(P < 0.01 for all eyes and P = 0.11 for eyes without
focal hyperpigmentation).
Discussion
Relations between Functional Funduscopic
Compromise
We have found that macular features indicative of
high risk for exudative AMD are associated with
compromised foveal visual function. That is, focal
hyperpigmentation, more than minimal drusen confluence and/or large drusen, were all associated with
compromised visual function. The association held
for eyes whose fellow eye had unilateral exudative
AMD. How the associations generalize to a broader
population is not yet clear. Eyes with high-risk fundus
features tended to have relatively slow rates of dark
adaptation, reduced absolute sensitivity and S conemediated sensitivity, and abnormal color matching
(ie, refusal to accept a Rayleigh color match or rela-
No. 1
FUNDUS APPEARANCE AND VISUAL FUNCTION / Eisner er ol
tively small color-match-area effects, consistent with
reductions in photosensitivity).
Functional compromise was related differentially
to different aspects of funduscopic change. In particular, a reduced rate of dark adaptation was strongly
associated with high-risk drusen but not with focal
hyperpigmentation or atrophy, whereas a reduced
color-match-area effect appeared to be more strongly
associated with the presence of focal hyperpigmentation or atrophy than with the presence of high-risk
drusen. Absolute sensitivity losses, and probably S
cone-mediated sensitivity losses also, were associated
with all types of funduscopic change.
Interestingly, reduced acuity in the fellow eye with
exudative AMD was strongly related to the presence
of high-risk drusen (but not to the presence of focal
hyperpigmentation) in the nonexudative eye. The
strength of the relations suggests that drusen disease
has a high degree of bilateral symmetry, consistent
with evidence presented in a recent report by Pauleikhoffetal.29
Unfortunately, the distributions of functional
scores were too non-Gaussian (even after transformations to reduce skewness) and too few eyes were
tested to allow meaningful analysis of interaction effects between different aspects of funduscopic
change. In addition, determining whether functional
deficits were related to local funduscopic change at
the fovea rather than to more diffuse change was further complicated by correspondences between foveal
and extrafoveal fundus appearance. Nevertheless, the
weak or non-significant relations between dark adaptation and foveal drusen confluence suggest that the
physiologic consequences of drusen disease are diffuse, at least for dark adaptation. Sunness et al.30
found (scotopic) sensitivity directly over drusen not
to be reduced preferentially and concluded that sensitivity loss associated with drusen was due to diffuse
RPE disease.
Although advanced drusen disease is likely to
disrupt the RPE processes necessary for normal photopigment regeneration,31"33 we cannot conclude that
a slow rate of photopigment regeneration is the sole
cause for a slow rate of dark adaptation. That is,
disruption of neural processes responsible for normal
adaptation could also alter dark-adaptation rates.334
Studies that more directly measure photopigment regeneration kinetics would help separate the effects of
AMD on photopigment regeneration from the effects
on neural processing.
Although all eyes with very slow dark-adaptation
rates had high-risk drusen, not all eyes with high-risk
drusen had very slow dark adaptation rates. Many of
the high-risk eyes with more normal rates of recovery
had abnormally small color-match-area effects and
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
17
presumably abnormally low photosensitivities. Consequently, for these eyes, the bleaching fields may
have been too dim to induce a very slow rate of dark
adaptation. Reduced photosensitivity could have resulted from structural changes4'35 caused by RPE atrophy and perhaps by drusen confluence.
The complementary relations between dark adaptation and color matching may help explain why
Smiddy and Fine8 did not find any correlation between photostress recovery time and the severity of
drusen disease. It is more likely, however, that the
apparent discrepancy between our results and those
of Smiddy and Fine occurred because the time required to identify suprathreshold letters for the photostress test does not correspond to the exponential
time constant that summarizes the rate of sensitivity
change for detection of spots of light during dark adaptation. Edge detection appears to be only one component of the dark-adaptation process for detection
of spots of light.36 Furthermore, dark-adaptation
rates can depend greatly on the visual task and on the
precise choice of adaptation and test parameters.37
Interestingly, we found evidence that, compared
with 3° S cone-mediated sensitivity, 1° sensitivity
declined faster with age for women than for men.
Such a gender-dependent relationship would be consistent with the finding by de Monasterio et al.26 that
the spatial density of S cones decreased in the central
fovea for old female but not for old male primates.
Our failure to find a corresponding effect of test size
for a much larger population of normal eyes12 suggests that macular degeneration might be viewed as
accelerated aging.
Consistent with our results, Haegerstrom-Portnoy
et al.6 reported that S cone-mediated sensitivity to 2°
tests is less for women than for men with nonexudative AMD. However, Sunness et al.,38 who also used
2° tests, did not find evidence of any gender-dependent effect. Given the different results across studies
and the retrospective nature of our own results, the
gender-dependent effect of test size (or locus) needs to
be evaluated prospectively. Sunness et al. found that
S cone-mediated sensitivity losses were associated
with a high-risk fundus appearance. However, the association found by Sunness et al. may have been
weaker than that found in our study, perhaps because
the criteria used to define high risk were not identical
to the criteria we used and because the fellow eyes of
the eyes tested by Sunness et al. did not all have exudative AMD.
Implications for Clinical Visual Function Testing
The strong associations that we find between functional compromise and known funduscopic risk in-
18
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
dicators do not imply that tests of function can
themselves be adapted for prognostic use. Only prospective studies will determine the utility of functional tests. Sunness et al5 have already reported,
however, that low absolute sensitivity may be a risk
factor for development of advanced maculopathy.
The associations that we found between reduced absolute sensitivity and both focal hyperpigmentation
and high-risk drusen are consistent with their report.
However, Sunness et al used smaller diameter tests
(1.8°) than we did (3.0°), and the size difference
could be important.
Because the dark-adaptation time constant was
nearly independent of age for our choice of stimulus
parameters12 and because we found a slow rate of
dark adaptation to be very specific for high-risk
fundus appearance, the use of dark adaptation to help
establish high risk is especially promising. Furthermore, a slow dark-adaptation rate may be subjectively self-evident39 and thereby alert a person to seek
clinical attention at or prior to the time when treatment may be possible.40'41
Similarly, because the color-match-area effect
changes relatively little with age in the seventh and
eighth decades12 and because we found an abnormal
color-match-area effect to be very specific for highrisk fundus appearance, the use of color matching to
help establish high risk also is very promising.
Unlike color matching and dark adaptation separately, the combination of dark adaptation and color
matching was not only very specific for high-risk
fundus appearance, it was also very sensitive, at least
for our operational definition of high-risk. Of course,
a perfect correspondence between function and
fundus appearance would suggest that a risk categorization based on function could not be both a more
sensitive and a more specific predictor than a risk
categorization based on fundus appearance. However, because function can be more readily quantified
than fundus appearance, functional cutoffs could be
manipulated more easily than funduscopic cutoffs to
adjust sensitivity/specificity ratios in response to altered risk/benefit ratios resulting from new treatments or prophylactic therapies. Whatever the theoretic advantages or disadvantages, however, the relative utility of any test can only be evaluated
empirically.
Many individuals, about one in six whom we
tested, did not accept any red/green ratio for a Rayleigh color match. Rejection of all potential color
matches was associated with funduscopic high risk.
We found earlier that a small red/green color matching range appeared paradoxically to forecast acuity
loss in an 18-month period after measurement of the
color match.42 The reason(s) for small or nonexistent
color-matching ranges is unclear, but rejection of all
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
Vol. 32
potential color matches has been observed before for
people with nonexudative AMD4 and might be associated with rod intrusion into the color match.43 The
rod-intrusion possibility is testable. Rod intrusion
could result from any of several factors, including
reduced ocular transmittance, reduced photosensitivity, and reduced gain or summation in the outer
retina. Whatever the reason(s) for small or nonexistent color-matching ranges, a shrinking range should
be regarded as suspect, as should an expanding range.
The association between funduscopic risk in the
study eye and poor acuity in the fellow exudative eye
suggests that relatively severe exudative AMD in one
eye carries an unfavorable prognosis for progression
to exudative AMD in the other eye. However, because a long history of macular disease can be associated both with reduced acuity in the exudative eye
and with evolving disease in the nonexudative eye,
potentially confounding factors need to be evaluated
in more detail. Nevertheless, whether or not poor
acuity in the exudative eye is a true risk factor for the
other eye, those patients with severe central loss in
one eye will be disabled most from central loss of
vision in their other eye. For this reason alone they
should be especially vigilant about receiving prompt
clinical attention for suspicious changes in their unaffected eyes. Comparison of incidence rates of exudative AMD in studies using different eligibility criteria10'44 suggests that an exudative lesion involving the
foveal avascular zone in one eye may signify relatively great risk for development of exudative AMD
in the other eye.45
For the eyes that met our strict eligibility criteria,
failure of the D-15 test (graded using Adams et al.'s16
criteria) signified a high-risk fundus appearance with
100% specificity and more than 50% sensitivity. A
desaturated version of the D-15 test has less specificity.39 Because the D-15 test is readily available commercially, is easy to administer and score, and does
not have a high false-positive rate,16 its suitability as a
potential alternative to more time-consuming colorarrangement tests should be further evaluated.
Key words: drusen, retinal pigment epithelium, age-related
macular degeneration, dark adaptation, color matching
Acknowledgments
The authors thank the Fundus Photograph Reading
Center of the University of Wisconsin-Madison for grading
fundus photographs, for permission to describe grading categories, and for providing us with grading materials. They
also thank Dr. Richard Chenoweth for subject referral; Drs.
Fadi El Baba, Fawaz Kaba, and Manning Mauldin for subject screening; and Julie Arends, COMT, for her work as
study coordinator. Drs. Stephen Burns, Ann Eisner, Michael Kaplan, and Charlotte Shupert provided written criticism of an early version of this manuscript.
No. 1
FUNDU5 APPEARANCE AND VISUAL FUNCTION / Eisner er ol
References
1. Eisner A, Fleming SA, Klein ML, and Mauldin WM: Sensitivities in older eyes with good acuity: Eyes whose fellow eye has
exudative AMD. Invest Ophthalmol Vis Sci 28:1832, 1987.
2. Bressler NM, Bressler SB, Seddon JM, Gragoudas ES, and
Jacobson OP: Drusen characteristics in patients with non-exudative, age-related macular degeneration. Retina 8:109, 1988.
3. Collins M and Brown B: Glare recovery and age related maculopathy. Clin Vis Sci 4:145, 1989.
4. Smith VC, Pokorny J, and Diddie KR: Color matching and the
Stiles-Crawford effect in observers with early age-related macular changes. J Opt Soc Am [A] 5:2113, 1988.
5. Sunness JS, Massof RW, Johnson MA, Bressler NM, Bressler
SB, and Fine SL: Diminished foveal sensitivity may predict the
development of advanced age-related macular degeneration.
Ophthalmology 96:375, 1989.
6. Haegerstrom-Portnoy G and Brown B: Two-color increment
thresholds in early age-related maculopathy. Clin Vis Sci
4:165, 1989.
7. Applegate RA, Adams AJ, Cavender JC, and Zisman F: Early
color vision changes in age-related maculopathy. Applied
Optics 26:1458, 1987.
8. Smiddy WE and Fine SL: Prognosis of patients with bilateral
macular drusen. Ophthalmology 91:271, 1984.
9. Bressler SB, Bressler NM, Maguire MG, Burgess D, Hawkins
BS, Orth D, Smith-Brewer S, Wilkonson CP, and Jeffreys JL:
Drusen characteristics and risk of exudation in the fellow eye
of argon SMD patients in the Macular Photocoagulation
Study. ARVO Abstracts. Invest Ophthalmol Vis Sci
30(Suppl):154, 1989.
10. Strahlman ER, Fine SL, and Hillis A: The second eye of patients with senile macular degeneration. Arch Ophthalmol
101:1191, 1983.
11. Gregor Z, Bird AC, and Chisholm IH: Senile disciform macular degeneration in the second eye. Br J Ophthalmol 61:141,
1977.
12. Eisner A, Fleming SA, Klein ML, and Mauldin WM: Sensitivities in older eyes with good acuity: Cross-sectional norms. Invest Ophthalmol Vis Sci 28:1824, 1987.
13. Eisner A: D-15 test results in people aged sixty and older. In
Noninvasive Assessment of the Visual System: Technical Digest. Optical Society of America, WA3-1986.
14. Burns SA and Eisner AE: Color matching at high illuminances:
The color-match area effect and photopigment bleaching. J
Opt Soc Am [A] 2:698, 1985.
15. Committee on Vision, Assembly of Behavioral and Social
Sciences, National Research Council: Procedures for Testing
Color Vision: Report of Working Group 41. Washington,
D.C., National Academy Press, 1981, pp. 57-60.
16. Adams AJ, Rodic R, Husted R, and Stamper R: Spectral sensitivity and color discrimination changes in glaucoma and glaucoma-suspect patients. Invest Ophthalmol Vis Sci 23:516,
1982.
17. Beaver Dam Eye Study: Manual of Operations. Madison, WI,
University of Wisconsin, Department of Ophthalmology,
1987.
18. Framingham Eye Study Group: Manual of Operations. Madison, WI, University of Wisconsin, Department of Ophthalmology, 1986.
19. Bishop PO: Binocular vision. In Adler's Physiology of the Eye:
Clinical Applications, 8th ed, Moses RA and Hart WM, editors. St. Louis, CV Mosby, 1987, pp. 619-689.
20. Sachs L: Applied Statistics: A Handbook of Techniques, 2nd
ed. New York, Springer Verlag, 1984, pp. 398-399.
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
19
21. Pokorny J and Smith VC: Effect offieldsize on red-green color
mixture equations. J Opt Soc Amer 66:705, 1976.
22. Eisner A: Comparisons across age of selected visual functions.
Doc Ophthalmol Proc Ser 46:99, 1987.
23. Johnson CA, Adams AJ, Twelker JD, and Quigg JM: Age-related changes in the central visual field for short-wavelengthsensitive pathways. J Opt Soc Am [A] 5:2131, 1988.
24. Werner JS and Steele VG: Sensitivity of human foveal color
mechanisms throughout the life span. J Opt Soc Am [A]
5:2122, 1988.
25. Guggenmoos-Holzmann I, Engel B, Henke V, and Naumann
GOH: Cell density of human lens epithelium in women higher
than in men. Invest Ophthalmol Vis Sci 30:330, 1989.
26. de Monasterio FM, McCrane EP, Newlander JK, and Schein
SJ: Density profile of blue-sensitive cones along the horizontal
meridian of macaque retina. Invest Ophthalmol Vis Sci
26:289, 1985.
27. Werner JS, Donnelly SK, and Kliegl R: Aging and human
macular pigment density: Appended with translations from the
work of Max Schultze and Ewald Hering. Vision Res 27:257,
1987.
28. Gass JDM: Drusen and disciform macular detachment and
degeneration. Arch Ophthalmol 90:206, 1973.
29. PauleikhofTD, Barondes MJ, Minassian D, Chisholm IH, and
Bird AC: Drusen as risk factors in age-related macular disease.
Am J Ophthalmol 109:38, 1990.
30. Sunness JS, Massof RW, Johnson MA, and Marcus S: Retinal
sensitivity over drusen and nondrusen areas: A study using
fundus perimetry. Arch Ophthalmol 106:1081, 1988.
31. Alpern M and Krantz DH: Visual pigment kinetics in abnormalities of the urea-retinal epithelium interface in man. Invest
Ophthalmol Vis Sci 20:183,1981.
32. van Meel GJ, Smith VC, Pokorny J, and van Norren D: Foveal
densitometry in central serous choroidopathy. Am J Ophthalmol 98:359, 1984.
33. Burns SA, Eisner AE, and Lobes LA: Foveal cone photopigment bleaching in central serous retinopathy. Applied Optics
27:1045, 1988.
34. Pokorny J and Smith V: Color vision and night vision. In
Retina, Ryan S and Ogden TE, editors. St. Louis, CV Mosby,
1989, pp. 109-126.
35. Weleber RG and Eisner A: Retinal function and physiological
studies. In Retinal Dystrophies and Degenerations, Newsome
DA, editor. New York, Raven Press, 1988, pp. 21-69.
36. Eisner A: Multiple components in photopic dark adaptation. J
Opt Soc Am [A] 3:655, 1986.
37. Eisner A: Losses of foveal flicker sensitivity during dark adaptation following extended bleaches. Vision Res 29:1401, 1989.
38. Sunness JS, Massof RW, Bressler NM, and Bressler SB: S cone
pathway sensitivity in eyes with high risk and low risk drusen
characteristics. Applied Optics 28:1158, 1989.
39. Collins M and Brown B: Glare recovery and its relation to
other clinicalfindingsin age-related maculopathy. Clin Vis Sci
4:155, 1989.
40. Grey RHB, Bird AC, and Chisholm IH: Senile disciform macular degeneration: Features indicating suitability for photocoagulation. Br J Ophthalmol 63:85, 1979.
41. Macular Photocoagulation Study Group: Argon laser photocoagulation for senile macular degeneration: Results of a randomized clinical trial. Arch Ophthalmol 100:912, 1982.
42. Eisner A, Fleming SA, and Klein ML: An association between
red-green color discrimination and loss of visual acuity 18
months later in people with unilateral exudative AMD. In
Noninvasive Assessment of the Visual System, Technical Digest Series 3. Washington, DC, Optical Society of America, 22,
1988.
20
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
43. Pokorny J, Smith VC, and Went LN: Color matching in autosomal dominant tritan defect. J Opt Soc Am 71:1327, 1981.
44. Bressler SB, Bressler NM, Fine SL, Hillis A, Murphy RP, Oik
RJ, and Patz A: Natural course of choroidal neovascular
membranes within the foveal avascular zone in senile macular
degeneration. Am J Ophthalmol 93:157, 1982.
45. Bressler NM, Bressler SB, and Fine SL: Age-related macular
degeneration. Surv Ophthalmol 32:375, 1988.
Definition of Subregions
Foveal: within a 500-/xm radius of the foveal center
Macular: within a 3000-jum radius
Inner quadrants (superior, nasal, inferior, temporal): between 500-1500-/im radii
Outer quadrants (superior, nasal, inferior, temporal): between 15OO-3OOO-/im radii
Drusen Size
Reticular Drusen Area
< 63 ^m in diameter
z> 63 /an, < 125 nm
Downloaded From: http://iovs.arvojournals.org/ on 06/15/2017
< 1/64 of subregion, ^ lower bound dependent on subregion
^ 1/64, < 1/32 of subregion
;> 1/32, < 1/16 of subregion
si 1/16, < 1/8 of subregion
S: 1/8, < 1/4 of subregion
> 1/2 of subregion
Drusen Confluence
Appendix
Stippling, hard-indistinct, or questionable < 63
diameter
< 63 fim, hard-distinct
^ 63 nm, < 125 nm
2: 125 Mm, < 250/mi
^ 250 urn
Vol. 32
in
None
Questionable or < 10% of drusen area is confluent
^ 10%, < 25%
> 25%, < 50%
;> 50%
Increased Pigment
None
Questionable pigment deposits
Area of pigment < that of a disc 250 /im in diameter
Area of pigment ^ that of a disc 250 nm in diameter
Pigment Epithelial Atrophy (RPE degeneration and
geographic atrophy).
None
Questionable
< 25% of subregion
^ 25%, < 50% of subregion
> 50% of subregion