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1 From the Schepens Eye Research Institute, and 2 Harvard Medical School, Boston, Massachusetts.
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Abstract |
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METHODS. A new autofluorescence imaging device was used to study lipofuscin distribution associated with individual drusen in 20 patients with ARM/AMD. Paired monochromatic and autofluorescence fundus images were used for detailed analysis of the topography of autofluorescence at specific sites containing drusen. In four eyes, image analysis was used to compare the spatial distribution of the autofluorescence with the location of drusen and to quantify the autofluorescence distribution over individual drusen (54 drusen).
RESULTS. A specific pattern of autofluorescence was frequently found to be spatially associated with hard drusen and soft drusen between 60 and 175 µm in size. The pattern is characterized by a central area of decreased autofluorescence surrounded, in most cases, by an annulus of increased autofluorescence. The location of this pattern was highly correlated with the position of individual distinct drusen. The central low autofluorescence focus was on average 16% below the surrounding background, and the annulus, when present, was on average 6% more fluorescent than the background. Soft drusen larger than 175 µm and confluent soft drusen show either multifocal areas of low autofluorescence or a more heterogeneous distribution.
CONCLUSIONS. Autofluorescence imaging permits measurement of RPE lipofuscin at specific sites. RPE overlying drusen have altered autofluorescence, suggesting changes in RPE health.
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Introduction |
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The aging RPE is characterized by massive accumulation of lipofuscin,7 8 9 which contains several fluorophores.10 The predominant, deep orange fluorophore was determined to be an adduct of two vitamin A molecules and ethanolamine (A2-E).11 When fed to cultured RPE cells, A2-E inhibits lysosomal degradation of proteins.12 Thus, incomplete digestion of photoreceptor membranes could account for their accumulation in Bruch’s membrane in the formation of drusen.
Lipofuscin fluorescence can be studied noninvasively by spectrophotometry13 14 15 16 17 and/or imaging.18 19 20 21 22 23 Spectral studies13 15 of fundus autofluorescence (AF) have demonstrated that it exhibits the spatial distribution, excitation (Ex) and emission (Em) spectra, age-related increases, and localization among retinal layers that are characteristic of RPE lipofuscin.7 9 10 Observations in patients with AMD suggest that elevated lipofuscin may precede or coexist with the earliest stages of pathology in age-related maculopathy (ARM) but that advanced stages of pathology are associated with decreased RPE lipofuscin.14 16 Spectral measurements in fundus regions containing many drusen have demonstrated a shift of the emission spectrum toward short wave lengths, suggesting a contribution from drusen fluorophores.14 17 Furthermore, because RPE over drusen in histologic sections can appear stretched and thin, it was reasonable to question whether drusen would be associated with alterations in the distribution of lipofuscin in the overlying RPE.
Imaging of fundus AF, using the scanning laser ophthalmoscope (SLO),18 has made it possible to correlate changes in AF distribution with pathologic features.18 19 20 21 22 23 In AMD patients, AF imaging has shown that AF is very low in areas of atrophy, high in the junctional zone around areas of atrophy,19 23 and increased in focal areas of hyperpigmentation.20 However, no consistent conclusions have been drawn about the AF levels over drusen,20 22 and there have been no reports on a specific spatial AF distribution over individual drusen. In fact, drusen are often not individually recognized in SLO autofluorescence images.
We investigated RPE lipofuscin distribution in ARM/AMD using a non-SLO imaging device. We found a variety of AF distributions in the RPE over and around drusen, related to the presence of drusen but not associated with specific drusen. However, we found that a distinct AF pattern was frequently associated with hard drusen and soft drusen. This pattern, which is spatially associated with individual drusen, consists of a center with low AF, surrounded, in some cases, by an annulus of high AF.24
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Methods |
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AF Imaging
AF images were obtained with a modified Topcon fundus camera
(TRC-FE; Topcon Corp., Tokyo, Japan) coupled to a scientific grade CCD
camera operated at -20°C (MicroMax; RS Princeton Instruments,
Trenton, NJ). An aperture, inserted in the illumination optics of the
camera, restricted the field of fundus excitation to a 13° diameter
circle (to minimize the loss in contrast caused of light scattering and
fluorescence from the crystalline lens). Two filter combination were
used for AF imaging: a 470-nm excitation filter [central wavelength,
467 nm; full width at half maximum or minimum (FWHM), 30 nm] with a
high-pass OG515 blocking filter (1% of maximum transmission at 499 nm;
half maximum at 513 nm); and a 550-nm excitation filter (central
wavelength, 548 nm; FWHM, 27 nm) with a high-pass OG590 blocking filter
(1% maximum at 576 nm; half maximum at 587 nm). Excitation filters
were of the interference type (Omega Optical, Brattleboro, VT), whereas
the blocking filters were 6-mm-thick glass absorbing filters (Schott
Glass Technologies, Duryea, PA). The rejection of each filter
combination was higher than 10,000 at all wavelengths. A lens located
between the fundus camera optics and the CCD array imaged the 13°
diameter retinal field into a 4.5-mm-diameter circle within the
rectangular array (6.9 x 4.6 mm, 768 x 512 pixels; 9 µm
square pixels). The overall retina CCD magnification was then 1.16
mm/mm (instead of 2.42 mm/mm for the standard camera, which represents
a light gain of 4.4). Images were recorded with 4 CCD pixels grouped
into one. The size of this combined pixel was then 2 x (9
µm)/1.16 = 15.6 µm at the retina (we will be refer to this
area as 1 pixel).
After alignment of the subject’s pupil to the camera, retinal focus was attained by observing the CCD monitor (200-msec exposures, every 0.6 seconds) under illumination with the 550-nm filter. A 550-nm monochromatic image26 was obtained with the 50 W/sec xenon flash setting. AF images (Ex = 470 nm, Em > 515 nm and Ex = 550 nm, Em > 590 nm) were obtained using the 300-W/sec setting. Retinal exposure for AF imaging was 3 to 5 mJ/cm2 (flash duration, 1–2 msec), which is more than 1000 times lower than maximum permissible light levels.27 Acquired images were transferred using 12 bit conversion (gray levels, 0–4095) into a computer, under control of IPLab Spectrum software (Scanalytics, Fairfax, VA). Gray levels were typically 300 to 1300 (above CCD black level) for monochromatic images, 30 to 180 for AF images with Ex = 470 nm, and 50 to 200 for AF images with Ex = 550 nm.
Image Analysis
Quantitative measurements of AF and reflectance over drusen were
made using IGOR image analysis software (WaveMetrics, Lake Oswego, OR).
After subtracting the CCD black level, monochromatic images were
aligned to AF images using translations and matching the position of
retinal landmarks in the superimposed images. Variations in the
background (low spatial frequencies) were eliminated by creating a
heavily smoothed copy of the original image using convolution with a
Gaussian filter (half-width, 50–60 pixels, approximately
of
the field diameter) and by dividing the original image by the smoothed
image. The resulting "flattened" image has minimal background
variation, with no significant change in the signal distribution at
small individual features. The mean level in the flattened images was
~1, and the SD was typically 0.08 to 0.15 (compared to 0.2–0.4 in
the original image).
Spatial correspondence of the foci of low AF with drusen was
investigated as follows. Thresholding in the flattened monochromatic
images was used to identify pixels clearly associated with drusen and
those associated with vessels. "Drusen" pixels had reflectance
greater than background by at least 1/2 SD.
"Vessel" pixels were identified as those with reflectance more than
20% below background. In the flattened AF images, "low AF" pixels
were defined as having an AF below background by at least
SD. All pixels associated with vessels were removed from both images.
The resulting binary images were superimposed, allowing to obtain
counts (a, b, c, d) of four types of pixels: (a) pixels with "low
AF" and associated with a "druse," (b) pixels with no "low
AF" but associated within a "druse," (c) pixels with "low AF"
but not corresponding with a "druse," and (d) pixels containing
neither "low AF" nor "drusen." The total number of pixels is
then N = a + b + c +
d. The probability of a low AF pixel to occur on a druse
a/N was compared to the predicted probability of
the same event occurring with randomly distributed drusen and low AF
pixels (a + b)(a +
c)/N2. The comparison was
assessed with Z-test statistics assuming binomial
distribution.
The autofluorescence and reflectance distributions at individual drusen
were determined by first locating crosshairs at the center of the druse
and at the center of the focus of low AF. Average signals
S(r) in concentric annuli (1 pixel wide) with
center radii r = 0, 1, 2, ... , and 12 pixels were
then computed (1 pixel: 15.6 µm at the retina). To avoid neighboring
features (such as vessels or other drusen), the operator could perform
this averaging in a segment (e.g., signals were averaged clockwise
between 3 and 9 o’clock to avoid a horizontal vessel located above the
druse). With the S(r) profiles displayed, the
operator selected—aided by plots of the differentials of each
profile—the annulus (radius =
rb), where both profiles
started to flatten outside the druse. The average backgrounds
S(rb) were computed in a
3-pixel-thick (46.8 µm) background annulus with
rb as inner radius. The profiles were
expressed as the relative deviation from the average backgrounds
S(rb) by
 | (1) |
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Results |
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The drusen-associated patterns of AF were also observed in patients 2 and 3 (Fig. 2) . In patient 2 (Figs. 2A 2B) , very distinct AF patterns associated with soft drusen are observed (see bottom of image, in rectangle), as well as an area with multiple large foci of decreased AF that are not spatially correlated with individual drusen in the monochromatic image (upper left corner of rectangle). We interpret this decreased AF as representing RPE thinning and early atrophy. In patient 3 (Figs. 2C 2D) , drusen larger than 175 µm were found to have less consistent patterns, whereas confluent drusen have multifocal areas of low AF. The latter appear to mark the sites of adjacent individual drusen that became confluent over time and lost their individual borders.
Small hard drusen (<60 µm), frequently observed in the aging eye, are not associated with a clear AF pattern. Although it was possible to see correspondence between localized low- or high-AF sites with the position of hard drusen, the majority of the individual foci were very small (containing 4 pixels or less, <30-µm diameter) and possibly below the resolution of the technique. However, AF patterns are seen overlying larger (>60 µm) hard drusen in AMD eyes (Figs. 1 2) . Numerous AF patterns also are observed in patient 4 (Fig. 3) , who has a large number hard and soft drusen (40–150 µm), but it is difficult to visually ascertain the concordance of the AF patterns and drusen.
Additional images of 15 patients with AMD/ARM were analyzed. Hard and soft drusen with sizes between 60 and 175 µm exhibited the pattern most clearly (types A and B patterns). In more advanced disease (confluent drusen, around geographic atrophy, near hyperpigmentation), the pattern became less distinct and foci of high and low AF not clearly associated with the loci of drusen were increasingly seen. The monochromatic image of patient 5 (Fig. 4A ) showed hard and soft drusen in a patient with AMD. The AF image (Fig. 4B) exhibited numerous foci of low and high AF, some corresponding to drusen but most exhibiting no correspondence to the drusen distribution.
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, then type A profiles
were found for 42 of 54 drusen (13/17, 12/16, 8/8, and 9/13 for
patients 1, 2,;T1> 3, and 4, respectively). Table 1
gives the ranges, means, and correlation with drusen size for the
center value P(0), the FWHM, and the dimension and
amplitude of the AF annulus.
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The center of the dark AF foci was 3% to 30% less fluorescent than the surrounding AF background (mean, 16%) and the annulus was 2% to 12% more fluorescent than the background (mean, 6%). For the reflectance profile, the drusen center was 9% to 96% more reflecting than the background (mean, 47%). The AF and reflectance center values P(0) were not significantly correlated with drusen size. The central spot of the type B profiles were slightly darker (P = 0.01) than for type A (-0.20 ± 0.08 and -0.14 ± 0.07, respectively).
Finally, we compared the center value P(0) of the AF pattern for images obtained with excitation at 470 nm (Fig. 1C) with that for excitation at 550 nm (n = 29 drusen, in the 3 patients). As expected from examination of Figures 1C and 1D , the center values were lower with 550-nm than with 470-nm excitation (means, -0.17 ± 0.08 versus -0.08 ± 0.06). The difference was statistically significant (paired t-test; P < 0.0001), indicating that AF dark foci from the 550-nm image were darker (more negative) and thus more contrasted than those from the 470-nm images.
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Discussion |
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The overall contrast of the AF patterns was found to be higher when using an excitation at 550 nm than at 470 nm. This increase in contrast with excitation wavelength may be explained by the relative increase in the fluorescence of lipofuscin compared to that of drusen. Indeed, lipofuscin and drusen fluorescence with 550-nm excitation are, respectively, higher and lower than with 470-nm excitation.14 17 The decrease in contrast could also result from a decreased contribution of lens fluorescence either scattered within the lens or reflected by the fundus. The relative contributions of these two components are not known at present but can be expected to show large individual variability; fluorescence reflected by the fundus is likely to be the smallest component.13 Moreover, with 550-nm excitation light, absorption by ocular media is reduced, and foveal detail is not obscured by macular pigment which absorbs at 470 nm, but not at 550 nm (Figs. 1C 1D) .
In this study, we report a pattern of AF distribution associated with drusen which has not been reported previously. The pattern consists of decreased AF in the center of the druse surrounded, in most cases, by an annulus of increased AF that is spatially correlated with drusen. Moreover, the size of the annulus matches the outer dimension of the druse in the monochromatic images. Although the majority of individual drusen were associated with a pattern, not all foci of low AF were associated with drusen (Fig. 5) . It is known that fundus images in AMD reveal only sites of local increases in the diffuse thickening of Bruch’s membrane.4 Infrared imaging of fundi with early AMD reveals drusen and other deposits that are not seen in color and monochromatic imaging.28
The dark central focus of the AF pattern is not black, as may be interpreted from examination of the high contrast AF images (Figs. 1 2 3) but on average is 16% (and as much as 30%) lower than the surrounding AF background (Table 1) . Several factors would tend to increase the signal at the center of the patterns and render them less dark: a contribution of drusen fluorescence would tend to be larger at the drusen center than at its periphery, reflectance of lens fluorescence would also be larger at the center where the drusen reflect most efficiently (Fig. 6) , and image degradation of the small dark foci would reduce their contrast. Thus, it is reasonable to expect that the actual distribution of RPE lipofuscin may be more accentuated.
The reduced AF was not due to melanin pigment in the overlying RPE, because the monochromatic images show no evidence of melanin absorption. There are several possible explanations for the observed pattern. (1) RPE stretched over a discrete druse3 4 may contain a much thinner layer of lipofuscin granules and thus exhibit reduced fluorescence. Cells draped over the sides of a discrete druse may be sampled along longer path lengths (eventually more than one cell), thus creating an annulus of increased fluorescence. This explanation may account for the pattern seen in hard drusen, but is less likely to account for annular patterns of RPE fluorescence over soft drusen, which tend to be flatter thickenings of Bruch’s membrane. (2) Another possible explanation for the annular pattern is that the druse causes the central overlying RPE to release lipofuscin granules, which are phagocytosed by RPE at the periphery of the druse, creating reduced central fluorescence surrounded by an annulus of elevated fluorescence. (3) A third possibility is that drusen are formed as a consequence of incipient RPE atrophy. In this model, loss of lysosomal function12 would lead first to reduced digestion of outer segments membranes and accumulation of lipids in Bruch’s membrane.4 With further erosion of lysosomal capacity, turnover of critical cellular proteins may be so impeded that atrophy follows.
If the annular pattern of AF over drusen represent peripheral
displacement of the RPE cells or their granules, with a corresponding
thinning from central RPE to peripheral regions, there should be net
conservation in the amount of lipofuscin. To test this hypothesis, we
calculated the total AF emanating from the entire AF pattern (central
dark focus and surrounding annulus) and compared it to the surrounding
background. Using the relative profile amplitude
P(r) defined in Equation (1) , we calculate the
total fluorescence AFTotal (expressed
in µm2) by integration of the profile:
 | (2) |
·rb2·SE
(SE is the SE associated with the AF background average; see above).
For the 54 drusen in 4 patients,
AFTotal over drusen varied between
-2280 and +2440 µm2 (mean, 250 ± 970
µm2). AFTotal
was not significantly different from zero for 41 drusen (35 type A and
6 type B), significantly increased for 7 drusen (all type A), and
significantly decreased for 6 drusen (obviously, all type B). Thus, for most drusen in this small sample, this finding is consistent with a peripheral displacement of the overlying RPE cytoplasm and/or lipofuscin granules without an actual loss of the RPE. However, several drusen had increased total fluorescence, suggesting reduced turnover of lipofuscin and a net increase in the amount of lipofuscin. Alternatively, the fluorescence from the drusen themselves may occasionally be large enough to raise the measured total AF. Finally, and perhaps most importantly, several type B profiles exhibited significant decrease in total AF, which may indicate incipient atrophy of the RPE. These dark AF foci without a distinct annulus were seen in advanced AMD and may mark areas were drusen have regressed. This would be consistent with histopathologic findings that the RPE is attenuated at the site of faded soft drusen.4
The AF patterns observed in this study have not been reported by investigators using SLO autofluorescence imaging.18 19 20 21 22 Although resolution of this apparent discrepancy awaits comparative imaging in the same patients with our technique and the SLO, several reasons for this difference may be identified. As discussed above, the shorter wavelength used in SLO imaging (488 nm) will contribute to a lower contrast for these patterns. The contrast of vessels in SLO images in clearly higher than with our technique, even using the 470-nm excitation. This results from the confocal nature of SLO imaging,28 where only light from the immediate vicinity of the illuminated image element is sampled, resulting in a reduction of laterally diffused autofluorescent light. Infrared SLO imaging in the indirect mode favors this laterally diffused light and produces images of drusen that have sharp edges, which are sometimes darker than the drusen center.28 29 These observations cannot be extrapolated to AF imaging because the light emitting layer, the RPE, overlies the drusen. Finally, one cannot rule out that the contrast of SLO imaging—with its low light levels requiring image summation—is inferior to that attainable with our technique.
Hard and soft drusen between 60 and 175 µm in size are characterized by foci of reduced autofluorescence that may or may not be surrounded by an annulus of increased autofluorescence. The formation of larger drusen by fusion of smaller hard or soft drusen is suggested by multiple foci and/or irregular areas of low AF on large drusen. The specific pattern are lost as drusen converge, resulting in the irregular autofluorescence distribution observed for patients with advanced AMD.
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Acknowledgements |
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Footnotes |
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Submitted for publication May 27, 1999; revised August 27, 1999; accepted September 13, 1999.
Commercial relationships policy: N.
Corresponding author: François C. Delori, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. delori{at}vision.eri.harvard.edu
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