(Investigative Ophthalmology and Visual Science. 2000;41:274-281.)
© 2000
by The Association for Research in Vision and Ophthalmology, Inc.
Short-Wavelength Automated Perimetry and Capillary Density in Early Diabetic Maculopathy
Andreas Remky,
Oliver Arend and
Stefan Hendricks
From the Department of Ophthalmology, Medical School of the Technical University of Aachen, Germany.
 |
Abstract
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PURPOSE. To correlate short-wavelength cone-mediated sensitivity (SWS) assessed
by blue-on-yellow perimetry with alterations of the perifoveal vascular
bed in early diabetic maculopathy.
METHODS. Thirty-one patients (21 M, 10 F; mean age, 35 ± 12 years; no lens
opacities) with no clinically significant macular edema were included
in this study. All patients underwent short-wavelength automated
perimetry (SWAP) and conventional white-on-white perimetry (Humphrey,
10-2). In digitized video fluorescein angiograms (Scanning Laser
Ophthalmoscope), the size of the foveal avascular zone (FAZ) and the
mean perifoveal intercapillary area (PIA) as a measure of capillary
density were quantified interactively.
RESULTS. Mean thresholds of SWAP were significantly correlated with increasing
size of FAZ (r = -0.51, P =
0.003) and PIA (r = -0.47, P =
0.01), whereas visual acuity expressed by log MAR (FAZ:
r = 0.15, P = 0.41; PIA:
r = 0.06, P = 0.76) and mean
thresholds assessed with white-on-white perimetry (FAZ:
r = -0.25, P = 0.20; PIA:
r = -0.31, P = 0.14) were
unrelated to diabetic changes of the perifoveal capillary network.
CONCLUSIONS. The alterations of the perifoveal network are related to selective
disturbances of visual function as measured by
blue-on-yellow-perimetry. SWAP may act as an early detector of visual
function loss in early diabetic maculopathy and serve as a helpful
technique to predict early ischemic damage of the macula and to monitor
therapy.
 |
Introduction
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Visual field changes are commonly associated with diabetic
retinopathy.1
Most studies have focused on proliferative
and severe nonproliferative stages, when fundus alterations are clearly
visible by ophthalmoscopy or fluorescein angiography. Thus, deep and
large scotomas are associated with larger nonperfusion
areas2
3
and small scotomas with cotton-wool
spots.4
All these perimetric findings are confined to
losses in the midperiphery in advanced disease. The loss of macular
function, however, may be unrelated to the stage of retinopathy and
remains the most common sight-threatening complication of diabetic
retinopathy. New methods are required for understanding and defining
diabetic maculopathy. Furthermore, new clinical tools are needed for
screening in the early stages and managing further progression.
The diagnostic problem of diabetic maculopathy consists in
detecting very early morphologic and functional deficits related to
later visual outcome. The established assessment of visual acuity does
not have a high predictive value in the early stages, because acuity
remains stable until approximately 55% of all neuroretinal channels
are affected.5
Morphologic changes assessed by fluorescein
angiography, effective for detecting and quantifying capillary changes,
are not reflected in visual acuity loss until the disease is well
progressed.6
7
Diabetic patients may exhibit an abnormally
enlarged foveal avascular zone (FAZ) compared to healthy
subjects,8
without any measurable loss of visual acuity.
Further psychophysical work-up, however, may reveal functional losses,
particularly in color vision,9
in patients with diabetic
maculopathy and good visual acuity. A recent report on contrast
sensitivity in diabetic maculopathy showed that neuroretinal function
can be affected in the early stages and is related to alterations of
the macular microvasculature.10
In this investigation, sensitivity was assessed in the central 10°
visual field. In addition to the conventional white-on-white perimetry,
short-wavelength automated perimetry (SWAP) was performed. The
principle of this method is selective testing of the short-wavelength
sensitive (SWS) cone-mediated mechanisms. This method is established in
early detection of glaucoma,11
12
13
14
where its use is to
detect changes predominantly at the retinal ganglion cell level and
loss of retinal nerve fibers. SWS mechanisms also are reported to be
susceptible to damage in a variety of retinal
diseases,15
16
where changes are less specific for retinal
nerve fibers and more confined to alterations of the inner retina.
Animal experiments have shown a more selective loss of SWS cones to
phototoxic or ischemic stimuli.17
Several studies
underlined SWAP abnormalities in diabetic patients with advanced
retinopathy18
or macular edema.19
The purpose
of the present study is to determine the association, if any, between
retinal microcirculation and SWAP and conventional computerized
perimetry and visual acuity in diabetic patients with normal visual
acuity and without clinically significant macular edema.
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Materials and Methods
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Patients
Prospectively, 31 patients with diabetes mellitus, visual acuity
of 20/25 or better, and normal intraocular pressure (IOP) were
recruited. Patients with a history of other eye diseases, particularly
ocular hypertension and glaucoma, and eyes with a refractive error
greater than 3 diopters (D) were excluded. In one patient with a
physiologic large cupping, visual fields (Humphrey 24-2) and repeated
IOP measurements were in the normal range. The clinical and demographic
data are presented in Table 1
. The eye with the better visual acuity was selected; in case of equal
acuity the eye with the lower refractive error was chosen. Findings of
slit lamp examination of the anterior segment were normal in all eyes.
Patients with nuclear opacities were excluded, in the interest of
better quality of psychophysical and fluorescein studies.
The fundus photographs of all the patients were classified as having no
clinically significant macular edema according to Early Treatment
Diabetic Retinopathy Study (ETDRS) guidelines.20
Retinopathy level was estimated by fundus photography according to
ETDRS criteria.21
Nine patients (29%) had no retinopathy
(level 10), 5 (16%) microaneurysm formation only (level 20), 13 (42%)
mild retinopathy (level 35), 1 had moderate (level 45), and 2 severe
nonproliferative retinopathy (level 53), and 1 had proliferative (level
61) diabetic retinopathy.
Best corrected visual acuity was determined by an ophthalmologist
using objective refractometry (Rodenstock, Munich, Germany), lighting
conditions, and standardized charts as described by DIN
58220,22
followed by a complete ophthalmologic
examination. For statistical analysis all visual acuity scores were
converted into logarithmic equivalents (log MAR) for calculating acuity
values or computing correlation coefficients.
Informed consent was obtained from each subject, including detailed
explanations of all procedures before participation in this study. The
study protocol was reviewed and approved by the RWTH University
Institutional Review Board for the use of human subjects. The tenets of
the Declaration of Helsinki were followed.
Methods
A Humphrey visual field analyzer (model 750; Humphrey-Zeiss, San
Leandro, CA) was used for both blue-on-yellow (SWAP) and white-on-white
(achromatic) conditions. The method was the standard procedure
described in recent reports.13
Stimulus size was Goldmann
III (0.43° visual angle) for achromatic and Goldmann V (1.8° visual
angle) for blue-on-yellow perimetry. The background was a 10
cd/m2 broadband white for achromatic perimetry
and a 200 cd/m2 yellow. A full-threshold strategy
was applied for the central 10° field (program 10-2). Limited StatPac
(Humphrey-Zeiss) analysis (without probability data) was available only
for the white-on-white condition.
Quantification of the perifoveal capillary network was performed
in fluorescein angiograms, as described in detail
elsewhere.8
23
The fluorescein angiograms were performed
with a scanning laser ophthalmoscope (SLO; Rodenstock Institite,
Ottobrunn, Germany; at 20° field). Within 20 to 50 seconds after dye
injection, the capillary bed was well visualized, and sequences of
768 x 512 pixels images were digitized by a PC grabber card
(Matrox Millennium; Matrox Graphics, Quebec, Canada). In one digitized
image the perifoveal intercapillary area (PIA) and the foveal avascular
zone (FAZ) were measured using digital imaging processing (Matrox
Inspector, Matrox Graphics). PIA provides an estimate of capillary
density in the network around the FAZ (5°). The FAZ and the
perifoveal intercapillary areas were determined by an interactive image
program. The borders of these areas were marked interactively by
drawing around the surrounding capillaries with the cursor in the
digital image. The area described by the cursor was calculated from the
pixel size (5.6 x 5.6 µm) times the number of pixels within the
boundary drawn by the cursor. PIA was calculated as the mean area of
100 measured single areas, randomly chosen in a 5° measuring circle
around the center of the FAZ. Coefficients of variation of PIA
[cv(PIA)], calculated in one analysis characterize the homogeneity of
the capillary vasculature. All angiogram analyses were performed in a
masked fashion without prior knowledge of visual acuity, perimetry
results, or determined EDTRS level.
Reference values for comparison of the angiographic measures resulted
from previous studies8
and were derived from 31 healthy
subjects of similar age (35 ± 9 years) examined in the same
manner as the patients.
Statistical Analysis
Mean value and SD are given for all samples with normal
distributions (KolmogorovSmirnov test) and nonnormal distributions
median and percentiles (2.5% and 97%). The unpaired Students
t-test was used to assess the significance of the
differences between groups. Findings smaller than 0.05 were considered
statistically significant. Pearson correlation coefficients were
calculated to evaluate the relationship between the parameters.
P values were obtained after carrying out Fishers
r to z transformations.
 |
Results
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The study population consisted of patients with only mild macular
changes. At least 65% had an FAZ size greater than the mean and 1 SD
of the reference data. When compared to the age-matched normal
subjects, the diabetic patients displayed significantly enlarged FAZ,
whereas PIA did not differ significantly (Table 2)
. The cv(PIA) was significantly higher in the diabetic population,
indicating increased inhomogeneity of perifoveal vascularity. Figures 1
and 2 show examples of the perifoveal capillary network.

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Figure 1. Fluorescein angiogram (SLO 20° field, approximately 13° x 9°)
of the perifoveal network (OD) of Patient A, a 28-year-old male
diabetic patient (duration of diabetes: 20 years; mild nonproliferative
diabetic retinopathy) with normal visual acuity (20/20). The image
shows a relatively unaffected perifoveal capillary density with normal
PIA (1900 µm2) and normal FAZ size (0.134
mm2).
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Figure 2. Fluorescein angiogram (SLO 20° field, approximately 13° x 9°)
of the perifoveal network (OD) of Patient B, a 40-year-old male
diabetic patient (duration of diabetes: 15 years; mild nonproliferative
diabetic retinopathy) with best-corrected visual acuity of 20/20.
Moderate loss of capillary density around the FAZ resulting in an
increased PIA (4900 µm2, above the mean and 1 SD of
reference data) and FAZ (0.320 mm2, above the mean and 1 SD
of reference data) was detected.
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Conventional white-on-white perimetry (achromatic) revealed a
slightly reduced mean deviation and slightly increased pattern
deviation (Table 3)
. Because normative data are not available by the current software of
the field analyzer, further statistics cannot be given. SWAP mean
threshold (MT) had a higher range and differed more interindividually
from white-on-white data (cvSWAP: 17%; achromatic perimetry: 6%).
Achromatic perimetry MT (r = -0.30, P = 0.13) and SWAP MT (r = -0.27, P =
0.15) were not correlated to visual acuity expressed in log MAR. The SD
was significantly higher (P < 0.0004) for SWAP than
for achromatic perimetry. MT and SD for SWAP and achromatic perimetry
were correlated to each other (MT: r = 0.64,
P = 0.0002; SD: r = 0.42,
P = 0.03).
Figures 1
and 2
show the fluorescein angiograms of two patients, and
Figures 3
and 4
contain prints of perimetric results for both achromatic and SWAP. MT
and SD of SWAP were significantly correlated with the FAZ size and PIA,
whereas visual acuity expressed by log MAR and mean thresholds assessed
with achromatic perimetry were unrelated to changes of the perifoveal
capillary network. Table 4
shows the correlation coefficients and P values, and Figure 5
shows MTs for both conditions plotted against the FAZ.

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Figure 3. (A) Results of achromatic perimetry of Patient A (Figure 1)
with no defects (MT: 33.1 dB, MD: +0.01 dB, PSD: 1.16 dB).
(B) SWAP perimetry results from Patient A with no obvious
defects (MT: 29.2 dB, SD: 1.70 dB).
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Figure 4. (A) Results of achromatic perimetry from Patient B (Figure 2)
with no defects (MT: 31.2 dB, MD: -1.19 dB, PSD: 1.82 dB).
(B) SWAP perimetry results of Patient B with subtle defects
nasal to the center (MT: 24.1 dB, SD: 2.78 dB).
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Table 4. Correlation Coefficients of Perimetric Standard Parameters to
Morphologic Data on the Perifoveal Vasculature
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Figure 5. Mean threshold (MT) values as a function of foveal avascular zone:
significant correlation of SWAP MT ( ), no correlation of achromatic
MT ().
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SWAP MT may be influenced by transmission losses due to the aging lens.
In this cohort there was no significant correlation of MT to the
patient age (r = 0.07, P = 0.70).
Furthermore, because SWAP SD is also correlated to capillary
alterations, mean sensitivity losses do not seem to be strongly
attributed to absorption of ocular media.
 |
Discussion
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The angiographic measures performed in this study have proven to
be of particular value in detecting early diabetic capillary
nonperfusion even before microaneurysm formation occurs.7
In advanced diabetic disease, reduction of capillary density is coupled
with decreased visual acuity.8
In this study, as reported
previously,10
enlarged FAZ was found even in patients with
normal visual acuity and without clinically significant macular edema.
Capillary alterations may result in tissue ischemia with subsequent
macular edema, capillary dropout, development of microaneurysms, and
neovascular complications. Changes of the perifoveal vasculature may be
predictive of the visual outcome.
A controversial issue in recent reports on diabetic maculopathy
was whether a disturbance of neurosensory function or a change of the
bloodretinal barrier is the earliest sign of
pathology.24
Bek and LundAnderson25
reported that functional losses are relatively unrelated to localized
bloodretinal barrier defects; however, macular capillary density, was
not studied.
Visual acuity is not sufficiently sensitive to provide clinical
information about the impact of altered retinal function in early
stages of diabetic eye disease.26
Frisén5
found that visual acuity remains normal
until approximately 55% of the neuroretinal channels are affected.
Others have shown that contrast sensitivity is significantly reduced in
patients with normal visual acuity in diabetic
retinopathy.10
26
27
28
Clinical studies have shown early
color vision defects before diabetic retinopathy
occurs.29
30
Furthermore, a high spatial frequency loss of
contrast sensitivity10
26
27
points to an early
involvement of parvocellular cells or cone-specific alterations in the
diabetic disease course.
Our study showed both loss of function and vascular change in early
disease, when visual acuity is not affected. Alterations of SWS cone
mechanisms, as found in this study, seem to be a more sensitive
indicator of early visual impairment secondary to alterations in
retinal vasculature. Further longitudinal studies must define critical
thresholds for both methods and resolve whether functional losses
precede morphologic alterations in diabetic retinopathy. Our results,
particularly the increasing SD with increasing FAZ and PIA, are in
agreement with recent studies in diabetic patients. Although Lutze and
Bresnick18
found no overall sensitivity loss compared to
normals, significant sensitivity reduction and localized defects were
detected with more severe diabetic retinopathy. Hudson et
al.19
found more localized visual field loss using SWAP
compared to conventional perimetry in patients exhibiting a significant
macular edema.
The reason for the high susceptibility particularly of SWS cone
mechanisms to ischemic processes remains speculative.15
Early damage may be more readily detected in mechanisms with sparse
neural representation as in SWS cone mechanisms. These have only a very
small percentage of the total number of receptors and ganglion
cells,31
32
with receptive fields that do not
overlap,33
compared to the longer wavelength cone
mechanism. Also, differences in the response range32
and
the different nature of ganglion cells34
may account for
earlier measurable function loss. Animal experiments indicate a higher
vulnerability of SWS cones to phototoxic stimuli.17
Johnson et al.35
found that SWS conemediated sensitivity
(even after correction for ocular media) exhibit a loss with increasing
age much more than the other cone systems, and they concluded there was
a higher vulnerability of SWS cone mechanisms.
The alterations of the perifoveal network are related to
selective disturbances of visual function as measured by
blue-on-yellow-perimetry. SWAP may act as an early detector of visual
function loss in early diabetic maculopathy and as a helpful technique
to predict early ischemic damage of the macula and to monitor therapy.
For example, treatment of macular edema with focal photocoagulation is
less effective if the procedure is performed after macular ischemia
occurs.36
Particularly for understanding focal laser
treatment and defining more accurate indications, functional
alterations should be taken into account.
In summary, the presence of perifoveal ischemia is related to a subtle
deterioration of visual function as measured by SWAP. In patients
without clinically significant macular edema and with normal visual
acuity, SWAP could be a clinical adjunct for further identifying early
ischemic diabetic maculopathy.
 |
Footnotes
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Supported by START 4/964 (RWTH Aachen).
Submitted for publication May 14, 1999; revised August 9, 1999; accepted September 8, 1999.
Commercial relationships policy: N.
Corresponding author: Andreas Remky, Department of Ophthalmology, Pauwelsstraße 30, RWTH Aachen, 52057 Germany. andreas.remky{at}rwth-aachen.de
 |
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Short wavelength automated perimetry in age related maculopathy
Br. J. Ophthalmol.,
December 1, 2001;
85(12):
1432 - 1436.
[Abstract]
[Full Text]
[PDF]
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