Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration

Abstract

Purpose: To investigate the association of spontaneous drusen regression in intermediate age-related macular degeneration (AMD) with changes on fundus photography and fundus autofluorescence (FAF) imaging.

Design: Prospective observational case series.

Methods: Fundus images from 58 eyes (in 58 patients) with intermediate AMD and large drusen were assessed over 2 years for areas of drusen regression that exceeded the area of circle C1 (diameter 125 μm; Age-Related Eye Disease Study grading protocol). Manual segmentation and computer-based image analysis were used to detect and delineate areas of drusen regression. Delineated regions were graded as to their appearance on fundus photographs and FAF images, and changes in FAF signal were graded manually and quantitated using automated image analysis.

Results: Drusen regression was detected in approximately half of study eyes using manual (48%) and computer-assisted (50%) techniques. At year-2, the clinical appearance of areas of drusen regression on fundus photography was mostly unremarkable, with a majority of eyes (71%) demonstrating no detectable clinical abnormalities, and the remainder (29%) showing minor pigmentary changes. However, drusen regression areas were associated with local changes in FAF that were significantly more prominent than changes on fundus photography. A majority of eyes (64%-66%) demonstrated a predominant decrease in overall FAF signal, while 14%-21% of eyes demonstrated a predominant increase in overall FAF signal.

Conclusions: FAF imaging demonstrated that drusen regression in intermediate AMD was often accompanied by changes in local autofluorescence signal. Drusen regression may be associated with concurrent structural and physiologic changes in the outer retina.

Trial registration: ClinicalTrials.gov NCT00345176.

Published by Elsevier Inc.

Figures

Figure 1. Computer-assisted delineation of areas of drusen regression over two years in eyes with intermediate age-related macular degeneration

(top left, top middle) Normalized red-free monochromatic images of a study eye with intermediate age-related macular degeneration and large drusen captured at baseline (top left) and at year 2 (top middle). Multiple large drusen at the center of the macula (arrowhead) visible at baseline have undergone regression and cannot be visualized at year 2. (top right) Subtraction image between baseline and year 2 that generates an image of the regressing drusen. (bottom left) Inversion and binarization of the image shown in (top right). The areas of relevant drusen regression were highlighted manually for further processing (red outline). (bottom middle) Expanded image of the inset shown in (bottom left) demonstrating automated delineation of individual regions-of-interest (ROIs) of drusen regression (blue outline). ROIs of areas smaller than the area of circle C1 were excluded. (bottom right) Drusen regression ROIs (blue outlines) were superimposed on co-registered autofluorescence images captured at baseline and year 2 for further grading and analysis.

Figure 2. Computer-assisted measurement of autofluorescence changes in areas of drusen regression over two years in eyes with intermediate age-related macular degeneration

(top left, top middle) Areas containing background levels of autofluorescence and not involving areas of drusen or pigmentary changes were manually delineated following the inspection of red-free and fundus autofluorescence (FAF) images captured at baseline and year 2 (green outlines). These were referred to as “background” regions-of-interest (ROIs). (top right) The distribution of grayscale levels of all pixels located within “background” ROIs was plotted as a frequency histogram, and the mean±standard deviation (SD) for this distribution was calculated. (bottom left, bottom middle) Drusen regression ROIs defined from red-free fundus photographs were then superimposed on corresponding FAF images. (bottom right) The distribution of grayscale levels of all pixels located within all drusen regression ROIs was plotted as a frequency histogram. Pixels with a grayscale level that was greater than (Mean background grayscale level + 3 SD background grayscale level) were considered to have increased FAF levels (upper shoulder in distribution histogram), while pixels with a grayscale level that was less than (Mean background grayscale level - 3 SD background grayscale level) were considered to have decreased FAF levels (lower shoulder).

Figure 3. Example of drusen regression in intermediate age-related macular degeneration in Study Participant 1

Color (top left, bottom left), red-free monochromatic (top middle, bottom middle) fundus photographs, and fundus autofluorescence (FAF) (top right, bottom right) images at baseline (top row) and year 2 (bottom row) demonstrate areas of drusen regression in the macula (highlighted by arrowheads and box). These areas of drusen regression were not associated with pigmentary change or atrophy on either color fundus (bottom left) or red-free (bottom middle) photographs, and these areas had a normal appearance and were not significantly different from neighboring areas that were unaffected by drusen at baseline and year 2. However, these areas of drusen regression contained regions of abnormal (increased and decreased) FAF signal that were significantly different in appearance and pattern from “background” FAF signal. The change in FAF patterns in drusen regression areas in this study eye was judged as demonstrating an overall decrease in FAF signal (insets from top right and bottom right), in which areas of predominantly increased FAF signal were replaced by areas of predominantly decreased FAF signal.

Figure 4. Example of drusen regression over two years in intermediate age-related macular degeneration in Study Participant 2

Color (top left, bottom left), red-free monochromatic (top middle, bottom middle) fundus photographs, and fundus autofluorescence (FAF) (top right, bottom right) images at baseline (top row) and year 2 (bottom row) demonstrate two adjacent areas of drusen regression in the macula (highlighted by arrowhead and box). While the areas of drusen regression are of normal appearance on red-free photography (bottom middle), subtle trace pigmentary changes were observed on color photography (bottom left). However, on autofluorescence imaging, distinct areas of decreased FAF signal were localized to areas of drusen regression (bottom right and inset) that were not present at the baseline visit (top right and inset).

Figure 5. Example of drusen regression over two years in intermediate age-related macular degeneration in Study Participant 3

Red-free monochromatic (top left, bottom left) fundus photographs and fundus autofluorescence (FAF) (top right, bottom right) images at baseline (top row) and year 2 (bottom row) demonstrate two adjacent areas of drusen regression in the macula (highlighted by arrowhead and box). While the area of drusen regression appeared clinicallly unremarkable and devoid of pigmentary change or atrophy, FAF imaging demonstrated a predominant decrease in FAF in the corresponding areas of drusen regression.

Figure 6. Manual grading of clinical and fundus autofluorescence changes in areas of drusen regression over two years in intermediate age-related macular degeneration

Study eyes that met criteria for drusen regression (n = 28) were manually graded for (top) the clinical appearance within the areas of drusen regression at year 2 and (bottom) the overall change in fundus autofluorescence signal within the same areas between baseline and year 2.

Figure 7. Computer-assisted grading of fundus autofluorescence changes in areas of drusen regression over two years in intermediate age-related macular degeneration

Study eyes that met image-processing criteria for drusen regression (n = 29) were evaluated for changes in fundus autofluorescence (FAF) signals in drusen-regression regions of interest (ROIs). The areas of decreased FAF and increased FAF within drusen-regression ROIs in each eye were determined at baseline and at year 2, and the changes from baseline to year 2 calculated and plotted on a common graph. (top) Graph showing the percentage change in the area of increased FAF (y-axis) plotted against the percentage change in the area of decreased FAF (x-axis) with each eye represented as an individual point (n = 29). Eyes that demonstrated changes in area that were well-matched between increased FAF and decreased FAF (±5%) are represented by points that lie within the y=x (±5%) zone (unshaded region) which indicates “no overall changes” in general FAF. Eyes in which the change in the area of increased FAF exceeded the change in the area of decreased FAF change are represented by points lying above the unshaded zone (green region) and were considered to have “predominantly increased FAF.” Eyes in which the change in the area of decreased FAF exceeded the change in the area of increased FAF change are represented by points lying below the unshaded zone (red region) and were considered to have “predominantly decreased FAF.” (bottom) The distribution of eyes demonstrating different overall changes in FAF as defined in (top) shows that a majority of eyes (66%) exhibited significant decreases in overall FAF in the regions where drusen have regressed.