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 cf@ 20/40 20/20 cf@ 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 cf@ 20/40 20/40 cf@ 20/20 20/20 20/60 20/30 20/40 cf @ 20/40 20/40 cf@ 20/40 20/10 cf@ 20/40 20/40 20/40 cf@ 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. 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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. 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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
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