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Symmetry of Bilateral Lesions in Geographic Atrophy in Patients With Age-Related Macular Degeneration
Caren Bellmann, MD;
Jork Jorzik, MD;
Georg Spital, MD;
Kristina Unnebrink, PhD;
Daniel Pauleikhoff, MD;
Frank G. Holz, MD
Arch Ophthalmol. 2002;120:579-584.
ABSTRACT
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Background As a cause for severe visual loss, geographic atrophy of the retinal
pigment epithelium is about half as common as choroidal neovascularization
in patients with advanced age-related macular degeneration. To assess symmetry,
we determined intraindividual variations of various features of bilateral
geographic atrophy in patients with atrophic age-related macular degeneration
in a cross-sectional study.
Methods Patients were examined with the use of a confocal scanning laser ophthalmoscope
(Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany).
Digital infrared reflection images (excitation, 830 nm) and fundus autofluorescence
images (excitation, 488 nm) were recorded. The eyes of each patient were compared
regarding number, size, and convex hull of the atrophic areas with the use
of image analysis software and with respect to fundus autofluorescence changes
in the junctional zone.
Results Seventy-two patients (mean ± SD age, 76.3 ± 7.9 years)
were examined. The number of atrophic areas ranged from 1 to 23 (mean ±
SD, 4.9 ± 4.6); the size of geographic atrophy, from 0.18 to 30.20
(mean ± SD, 7.0 ± 6.6) mm2; and the size of the convex
hull, from 0.18 to 39.20 (mean ± SD, 11.7 ± 8.4) mm2.
No statistically significant difference was found when comparing these variables
between each left and right eye: number, P = .62;
size, P = .81; and convex hull, P = .78. Identical patterns of fundus autofluorescence were observed
in 43 (80%) of 54 patients.
Conclusions There is intraindividual symmetry in eyes with bilateral geographic
atrophy in the presence of a wide range of interindividual variability. The
findings are in accordance with the view that age-related macular degeneration
is not merely the result of a nonspecific aging process. Symmetric manifestations,
rather, reflect specific individual determinants in the pathogenesis and manifestation
of the disease.
INTRODUCTION
AGE-RELATED macular degeneration (ARMD) is the most common cause for
legal blindness in Western countries.1-6
Severe visual loss results from choroidal neovascularization (CNV), pigment
epithelial detachment, or geographic atrophy (GA) of the retinal pigment epithelium
(RPE).2-4,7-11
Geographic atrophy is less common than the neovascular form of ARMD. In about
12% to 21% of patients with advanced ARMD, severe loss of visual acuity results
from foveal involvement of GA.2-4,10-16
The severity of visual loss from GA may be just as great as from CNV, but
the process is much slower than with CNV. In contrast to CNV, GA tends to
spare the fovea until late in the course of the disease. While GA usually
develops in eyes with drusen and pigmentary alterations, it may also follow
flattening of RPE detachments.17-20
Histopathologic examinations have shown that the atrophy is not confined to
the RPE layer but also involves the corresponding choriocapillaris and outer
neurosensory retina.21-23
Evidence indicates that genetic factors play a role in the pathogenesis
of ARMD.24-34
Genetic influences are also thought to account for intraindividual symmetry
in the manifestation of the disease. Recently, symmetry has been evaluated
for drusen, CNV, disciform scars, and RPE tears.35-38
Geographic atrophy occurs bilaterally in 48% to 65% of the cases.9, 14, 21 Sunness and coworkers11 described a high correlation in the size and progression
of GA between both eyes. However, further characteristics of bilaterality
have not been assessed for advanced atrophic ARMD. With the advent of scanning
laser ophthalmoscopic imaging, topographic quantitative analysis and recording
of fundus autofluorescence (FA) are possible.39-44
We used a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph;
Heidelberg Engineering, Heidelberg, Germany) to evaluate the symmetric manifestation
of various characteristics of GA associated with ARMD in a cross-sectional
morphometric analysis, including autofluorescence pattern characterization.
PATIENTS AND METHODS
Patients with bilateral GA secondary to ARMD were recruited at 2 tertiary
ophthalmological referral centers in Germany (Department of Ophthalmology,
University of Heidelberg; and St Franziskus Hospital, Münster). An appropriate
institutional review board approved the project, and informed consent was
given by all participants before recruitment into the study.
Digital infrared reflection images (830 nm) produced by a confocal scanning
laser ophthalmoscope were recorded in both eyes of each patient. In addition,
in patients with clear media for sufficient image quality to allow a meaningful
analysis, FA images were obtained with the use of the confocal scanning laser
ophthalmoscope. For FA imaging, an argon blue laser (488 nm) was used for
excitation. The emitted light was detected above 500 nm (barrier filter).
For infrared reflection images and FA images, an image size of 30° x
30° was chosen. The optical and technical principles of the confocal scanning
laser ophthalmoscope have been described previously.39-42
To amplify the autofluorescence signal, a flash mode was introduced,
ie, the laser power was increased 2-fold for 32 milliseconds. Alternatively,
several images were aligned and a mean image was calculated from several images
after detection and correction of eye movements with the use of image analysis
software, as described previously.39-42
Before examination, the pupil was dilated with tropicamide and phenylephrine
hydrochloride eyedrops.
Planimetric measurements in the digital images obtained were performed
by encircling the area of interest with a mouse-driven arrow and by calculating
the area with the use of image analysis software (Heidelberg Eye Explorer
Software; Heidelberg Engineering).
Areas of atrophy are readily delineated on autofluorescence images because
they appear dark in the absence of RPE fluorophores (Figure 1 and Figure 2).41 Therefore, autofluorescence images were used for
quantitative analysis. In a few cases with poor autofluorescence image quality,
infrared reflection images were used for evaluation. Both eyes of each patient
were compared regarding number and size of the atrophic areas (Figure 1). Furthermore, the smallest convex areas, including all
patches of atrophy, were calculated (convex hull), and their sizes were compared
between both eyes of all patients (Figure
2).45 In some cases, it was difficult
to surround the GA. Therefore, we decided to use the convex hull as an additional
comparison of the severity of the GA.
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Figure 1. Fundus autofluorescence image
in an eye with multifocal patches of geographic atrophy. The patches are encircled
and the area quantitated by image analysis software.
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Figure 2. Fundus autofluorescence image
in the presence of multifocal patches of geographic atrophy.
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The characteristics (size of the GA, number of atrophic areas, and extent
of the convex hull) between both eyes were compared for statistically significant
differences using the Wilcoxon signed rank test, and confidence intervals
for the mean differences between right and left eyes were computed. For comparison
of the number of atrophic areas and for the pattern of autofluorescence in
both eyes, a  coefficient was calculated, after categorizing the data
into 5 groups for the number of atrophic areas and 4 groups for the pattern
of autofluorescence (Table 1 and Table 2, respectively).
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Table 1. Number of Atrophic Lesions in the Left and Right Eyes of 72
Patients*
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Table 2. Fundus Autofluorescence Pattern Comparing Left and Right Eyes
of 54 Patients*
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Areas of atrophic lesions and convex hulls were determined independently
by 2 readers (C.B. and J.J.) by encircling the areas with an arrow directed
by the personal computer's mouse. Areas were calculated with the use of image
analysis software, as previously described. Readers were not masked with regard
to right and left eyes of identical individuals. Interobserver variability
was assessed according to the method of Bland and Altman.46
For each observer, the differences in size of the atrophic lesions and in
the convex hulls between right and left eye were calculated. To determine
the degree of agreement between the 2 observers, we calculated the differences
between them for each patient. A difference of 0 represents perfect agreement.
We report the 95% confidence intervals of the mean difference between observers.
The differences against the mean of the 2 observers' readings were plotted
to detect changes in agreement with increasing sizes of atrophic lesions or
increasing sizes of convex hulls. Interobserver variability was small. The
mean deviation between the 2 independent observers was 0.2 mm2
for convex hulls (95% confidence interval, -0.91 to 0.98 mm2)
and 0.6 mm2 for size of atrophy (95% confidence interval, 0.38
to 1.44 mm2) (Figure 3).
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Figure 3. Mean differences between recordings
by 2 independent marked readers (C.B. and J.J.). A, Size of the atrophic areas.
Uppermost and bottommost lines indicate 95% limits of agreement (-7.0
to 8.1 mm2); central lines, 95% confidence interval (-0.38
to 1.44 mm2). B, Area of the convex hull. Uppermost and bottommost
lines indicate 95% limits of agreement (-8.0 to 8.0 mm2);
central lines, 95% confidence interval (-0.91 to 0.98 mm2).
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RESULTS
A total of 72 consecutive patients (48 women and 24 men; mean ±
SD age, 76.3 ± 7.9 years) with bilateral GA were recruited. The median
visual acuity in all patients was 20/80, ranging from perception of hand movements
to 20/20.
Of 144 eyes, 103 (71.5%) had multifocal patches of GA and 41 (28.5%)
had unifocal GA. Foveal involvement was present in 78 (54.2%) of the 144 eyes,
and 47 (32.6%) of the 144 eyes had 2 to 4 atrophic areas in 1 eye. In 3 eyes,
more than 16 atrophic lesions were observed (maximum of all eyes, 23 lesions;
mean ± SD, 4.9 ± 4.6 lesions; median, 3 lesions; and interquartile
range, 6 lesions) (Figure 4). The
size of atrophy ranged from 0.18 to 30.20 (mean ± SD, 7.0 ±
6.6; median, 6.4; and interquartile range, 7.8) mm2 (Figure 5). The extent of the convex hull ranged from 0.18 to 39.20
(mean ± SD, 11.7 ± 8.4; median, 12.5; and interquartile range,
11.4) mm2 (Figure 6).
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Figure 4. Number of atrophic areas in the
left and right eye of each patient.
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Figure 5. Areas of atrophy in the left and
right eye of each patient. There are obviously some patients with marked asymmetry
(P = .81).
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Figure 6. Areas of the convex hull of atrophic
areas in the left and right eye of each patient.
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We found a smaller area of atrophy in patients without foveal involvement:
for those with multifocal GA, the mean ± SD area was 4.3 ± 3.6
mm2 (median, 3.2 mm2); and for those with unifocal GA,
the mean ± SD area was 4.4 ± 5.3 mm2 (median, 2.4
mm2). In comparison, we measured the area of atrophy in patients
with foveal involvement: for those with multifocal GA, the mean ± SD
area was 10.3 ± 6.8 mm2 (median, 8.7 mm2); and
for those with unifocal GA, the mean ± SD area was 8.0 ± 8.2
mm2 (median, 6.1 mm2). Foveal involvement occurred more
often in eyes with unifocal GA (27 [65.9%] of 41 eyes) than in eyes with multifocal
GA (51 [49.5%] of 103 eyes).
No statistically significant difference was observed in measured characteristics
between each left and right eye: number of lesions, P
= .62; size of atrophy, P = .81; and convex hull
of atrophy, P = .78 (Wilcoxon signed rank test) (Figure 4, Figure 5, and Figure 6,
respectively). The 95% confidence intervals for the mean difference between
right and left eyes were as follows: number of lesions, -1.3 to 0.8;
size of atrophy, -1.6 to 1.4; and convex hull of atrophy, -1.3
to 1.6. The lengths of these confidence intervals give an impression of the
power this study had to detect differences between right and left eyes. For
the calculation of coefficients, we grouped the number of atrophic
lesions as follows: 1, 2, 3 to 5, 6 to 10, and more than 10 lesions. For the
number of lesions, the coefficient was 0.30 (95% confidence interval,
0.15-0.46) (Table 1). Correlation
coefficients between both eyes were as follows: r
= 0.58 for the area of atrophy, r = 0.67 for the
convex hull, and r = 0.56 for the number of atrophic
areas.
Fundus autofluorescence images with sufficient quality to allow a meaningful
analysis were available in 54 of the 72 patients (108 eyes). Three different
patterns of increased FA were observed, as previously described41:
a continuous band of increased autofluorescence in the junctional zone was
noted in 46 eyes (42.6%), a diffusely increased autofluorescence at the posterior
pole was observed in 18 eyes (16.7%), and a focal increased autofluorescence
in the junctional zone was present in 23 eyes (21.3%). Normal autofluorescence
outside to the atrophic area was noted in 21 eyes (19.4%). Identical patterns
of autofluorescence in both eyes of each patient were observed in 43 (80%)
of 54 patients. For calculating the coefficient, the areas of GA were
grouped in the 4 described autofluorescence patterns. The coefficient
was 0.74 (95% confidence interval, 0.59-0.88) between both eyes and shows
high concordance between both eyes (Table
2).
COMMENT
To evaluate symmetric bilateral manifestations of GA associated with
ARMD, we compared number and size of atrophic patches, area of convex hulls
in the presence of multifocal atrophic areas, and FA patterns between the
eyes of each patient with the use of scanning laser ophthalmoscopy. No significant
differences between both eyes of each patient were observed for area, number,
and convex hull of the atrophic patches. Furthermore, FA patterns also showed
a high degree of symmetry. Although the coefficient for the number
of atrophic areas between both eyes indicates only moderate values for symmetry,
the results from the Wilcoxon signed rank test show a tendency for intraindividual
symmetry for GA associated with ARMD in the presence of a wide spectrum of
interindividual manifestations.
High rates of symmetric manifestations of ARMD have recently been shown
in patients with bilateral drusen, disciform scars, and RPE tears.35-38,47
From these observations and the results described herein, it seems that individual
determinants play a role in the pathogenesis of the disease. This is not only
the case for the specific type of manifestation (eg, atrophic vs neovascular
ARMD) but also for a distinct topographic pattern of each particular manifestation.
The evolution of GA at the posterior pole seems to be predetermined for each
affected individual.
Environmental factors and nonspecific age processes have been implicated
in the pathogenesis of ARMD. Also, a familial effect on the presence of ARMD
has been shown in case-control series and in comparisons between spouses,
siblings, and twins.24-34
Age-related macular degeneration is considered to represent a complex multifactorial
disease, the pathogenesis of which is incompletely understood. Likewise, it
is unclear by what mechanisms a distinct topographic individual evolution
of lesions such as areas of atrophy might be genetically determined.
Several previous studies11-12,15
have described the progression of GA over time. In a retrospective study,
Schatz and McDonald15 found a rate of spread
of GA growth of 15 to 375 µm/y (average, 139 µm/y), whereby smaller
areas tended to grow slower than larger atrophic areas. A prospective study
on the natural history of the progression of GA by Sunness and coworkers11 recently demonstrated a mean enlargement of the total
area of GA of 2.2 disc areas by 2 years. They reported that the amount of
enlargement increased with increasing baseline total atrophy up to 5 disc
areas of baseline atrophy and, interestingly, leveled off above 5 disc areas.
From the results of our cross-sectional study, it may be speculated that the
rate of spread observed during a longer period would also show symmetric features
when examined in a longitudinal fashion. In addition, relative asymmetry in
both eyes with early GA at a certain point may evolve into symmetric manifestation
later during the natural course.
The confocal scanning laser ophthalmoscope used in this study, with
an excitation wavelength of 488 nm and a barrier filter above 500 nm, allows
for topographic detection of FA in vivo. Several findings of in vitro fluorescence
microscopic examinations and in vivo fundus spectrophotometric studies suggest
that the increased autofluorescence signal originates from lipofuscin accumulation
in the lysosomal compartment of postmitotic RPE cells.48-51
In eyes with GA, various patterns of increased autofluorescence in the junctional
zone, which phenotypically cannot be distinguished by conventional ophthalmoscopy,
were recently described.41 A high degree of
symmetry has been detected in these autofluorescence patterns. Therefore,
symmetry seems not to be confined to visible lesions at the posterior pole
but also involves metabolic changes in the surrounding RPE in the presence
of GA. The accumulation of autofluorescent material may affect normal cellular
function and may, therefore, be of pathophysiologic relevance.41, 49, 52-53
Further studies are needed regardless of whether different patterns of increased
autofluorescence have an impact on the progression of the atrophy and the
spread of corresponding scotoma and, therefore, whether they are of prognostic
value.
Limitations of the present study include its retrospective design and
the lack of longitudinal observations. Based on this cross-sectional study,
we initiated an expanded natural history study for further evaluation of the
progression over time, the functional impact, and the role of baseline autofluorescence
patterns for the subsequent course.
Our results indicate intraindividual symmetry between both eyes in patients
with GA associated with ARMD for number of lesions, size of atrophic areas,
and convex hulls in the presence of a wide spectrum of interindividual manifestations.
The findings support the view that genetics may play an important role in
the phenotypic appearance of ARMD and, therefore, that ARMD is not solely
a result of a nonspecific aging process. Intraindividual symmetric manifestations,
rather, reflect specific individual determinants, including genetic factors,
in the pathogenesis of the disease. However, it is difficult to exclude the
possibility that the similar phenotypic appearance in late stages of ARMD
could be the result of a similar long-term exposure.
AUTHOR INFORMATION
Submitted for publication March 2, 2001; final revision received January
9, 2002; accepted January 24, 2002.
This study was supported by grant Ho1926/1-1 from the Deutsche Forschungsgemeinschaft,
Bonn, Germany; the Deutsche Forschungsgemeinschaft Research Priority Program
Age-Related Macular Degeneration (SPP 1088); and research grant 500/2000 from
the state of Baden-Württemberg, Germany. Dr Bellmann is a Marie Curie
Fellow at the Institute of Ophthalmology, University College London, London,
England (European commission grant QLK6-CT2000-51262).
This study was presented at the Association for Research in Vision and
Ophthalmology Meeting, Fort Lauderdale, Fla, May 10, 1999.
Corresponding author and reprints: Frank G. Holz, MD, Department
of Ophthalmology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120
Heidelberg, Germany (e-mail: frank_holz{at}med.uni-heidelberg.de).
From the Department of Ophthalmology (Drs Bellmann, Jorzik, and Holz)
and the Coordination Centre for Clinical Trials (Dr Unnebrink), University
of Heidelberg, Heidelberg; and the Department of Ophthalmology, St Franziskus
Hospital, Münster (Drs Spital and Pauleikhoff), Germany.
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