(Investigative Ophthalmology and Visual Science. 2000;41:513-517.)
© 2000
by The Association for Research in Vision and Ophthalmology, Inc.
Multifocal Electroretinogram in Occult Macular Dystrophy
Chang-Hua Piao,
Mineo Kondo,
Atsuhiro Tanikawa,
Hiroko Terasaki and
Yozo Miyake
From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.
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Abstract
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PURPOSE. Occult macular dystrophy (OMD) is an unusual macular dystrophy
presenting with an essentially normal fundus and fluorescein
angiography but with progressive central visual loss. The authors
studied the function of local retinal areas in the posterior pole of
patients with OMD using multifocal electroretinograms (ERGs).
METHODS. Multifocal ERGs were recorded using the Visual Evoked Response Imaging
System with 61 hexagonal elements within a visual field of 30° radius
from 8 OMD patients and 20 age-matched, normal subjects. The amplitudes
and implicit times of the patients and normal control subjects were
compared at the various retinal eccentricities.
RESULTS. The amplitudes of the multifocal ERGs in the OMD patients were markedly
reduced in the central 7° of the fovea. The difference of the ERG
amplitudes between OMD and normal subjects became smaller toward the
peripheral retina. Most OMD patients had slight but significantly
delayed implicit times across the whole testing field, and the
differences between the OMD and the normal subjects did not change with
retinal eccentricity.
CONCLUSIONS. Our results for multifocal ERG amplitudes support the idea that OMD
patients have localized retinal dysfunction distal to the ganglion
cells in the central retina. The delayed implicit times across the
whole test field suggest that the retinal dysfunction has a broader
boundary than expected by ERG amplitudes and psychophysical perimetric
results.
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Introduction
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Occult macular dystrophy (OMD) is an unusual, inherited macular
dystrophy characterized by an essentially normal fundus and fluorescein
angiography but progressive decline of visual acuity in both
eyes.1
2
These patients have normal full-field
electroretinograms (ERGs) but severely reduced focal macular ERGs,
which were recorded by conventional techniques using small stimuli
under the background illumination.1
2
Thus, it has
generally been presumed that patients with OMD have a local retinal
dysfunction distal to the ganglion cells in the central retina. It has
been emphasized that the main key to differentiate OMD from other
diseases, such as optic neuritis, dominant optic atrophy, amblyopia or
psychological disorders, was the recording of focal ERGs from the
central retina.1
2
3
The multifocal ERG allows a rapid, simultaneous recording of focal ERGs
from multiple retinal locations from the posterior pole of the
eye4
5
and thus can evaluate local retinal
function.6
7
8
9
10
11
12
We previously have demonstrated in a
preliminary study2
that the multifocal ERG technique can
be a valuable tool to diagnose OMD patients. One might expect that it
would allow us to explore retinal function topographically in OMD
patients. There is some evidence that the implicit times, as well as
amplitudes, of the multifocal ERGs can be a potentially useful
parameter to determine the locus of the retinal dysfunction in retinal
diseases.10
11
In the present study, we therefore examined
the multifocal ERGs of OMD patients to assess the amplitudes and
implicit times of local retinal cone function in patients with OMD.
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METHODS
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Subjects
We recruited eight patients diagnosed with OMD from our clinic
(Department of Ophthalmology, Nagoya University School of Medicine).
The diagnosis of OMD was made by the following findings: bilateral
involvement, normal ophthalmoscopic findings, normal fluorescein
angiography, decreased visual acuity, normal full-field ERG for both
rod and cone components, and decreased focal macular cone ERGs. Some of
these characteristics are summarized in Table 1
. The eight patients, five men and three women, ranged in age from 43 to
66 years (mean, 52.9 years). Five of eight patients (patients 2, 4, 5,
6, and 8) have been reported previously,2
and these
patients correspond to patients 4, 6, 11, 10, and 1, respectively, of
the previous paper.2
Three patients (3, 6, and 7) were
considered to be autosomal dominant, and the other five patients were
classified as sporadic, because none knew of other family members with
a similar visual problem. The corrected visual acuities ranged from 0.1
(20/200) to 0.4 (20/50). Light-adapted perimetry, originally designed
by Jacobson et al.,13
showed abnormally elevated cone
thresholds within the central 10° in all patients. One randomly
selected eye of the patients was tested with multifocal ERG. Twenty
age-matched normal subjects, age range from 38 to 69 years (mean, 53.3
years), were selected out of a pool of our normal data. This selection
was made only by factor of age, and they were selected before analysis
of patients’ data. All normal subjects had normal visual acuity,
normal color vision, and normal full-field ERGs.
Informed consent was obtained after a full explanation of the
procedures. All studies were conducted in accordance with the
principles embodied in the Declaration of Helsinki.
Multifocal ERGs
Multifocal ERGs were recorded with the Visual Evoked Response
Imaging System (EDI, San Mateo, CA), developed by Sutter et
al.4
5
The stimulus matrix consisted of 61 hexagonal
elements that were displayed on a CRT color monitor (GDM 2038; Sony,
Tokyo, Japan) and driven at a 75-Hz frame rate. The size of the
hexagons were scaled with eccentricity to elicit approximately equal
amplitude responses at all locations (Fig. 1)
. At a viewing distance of 27 cm, the radius of the stimulus array
subtended approximately 30°. The luminance of each hexagon was
independently alternated between black and white according to a
pseudorandom binary m-sequence at 75 Hz. The maximum luminance was
138.0 cd/m2, and the minimum luminance was 3.5
cd/m2, resulting in a mean luminance of
approximately 70.8 cd/m2. A small red fixation
spot was placed at the center of the stimulus matrix.
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Figure 1. A diagram of the stimulus array used to elicit the multifocal ERGs.
Stimulus consisted of 61 hexagonal elements that were scaled to elicit
approximately equal response amplitudes at all locations. Responses
were grouped into five retinal eccentricities.
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ERGs were recorded with a Burian–Allen bipolar contact lens electrode
(Hansen Ophthalmic Laboratories, Iowa City, IA), and a ground electrode
was attached to the earlobe. The subjects’ pupils were fully dilated
with a combination of 0.5% tropicamide and 0.5% phenylephrine
hydrochloride. The opposite eye was occluded. After the subjects were
optically corrected to their best visual acuity for the viewing
distance, they were asked to maintain fixation on the red spot. The
signal was amplified by 100K, and the bandpass was set at 10 to 300 Hz
(Grass, Quincy, MA). An artifact elimination technique was
used.4
The total recording took 4 minutes and was divided
into eight equal segments. The first-order component and a
three-dimensional plot were obtained with VERIS 2.05 software (EDI, San
Mateo, CA).
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Results
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Amplitude of the Multifocal ERGs
Figure 2
shows representative local ERGs from 61 loci (top) and a 3D plot of the
amplitudes of the multifocal ERGs (bottom) recorded from the left eye
of a normal subject (left) and a patient with OMD (patient 2). The
multifocal ERG consists of a negative wave followed by a positive wave,
and these negative and positive deflections have been shown to
correspond to conventional a- and b-waves, respectively, of the flash
cone ERG.14
15
As was expected from our previous
study,1
2
the OMD patients had severely depressed
responses from the central retina but relatively well-preserved
responses in the peripheral retina. The three-dimensional plot did not
show the central peak, as was observed in the normal control subject.
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Figure 2. Multifocal ERGs and three-dimensional plots for a normal subject
(left) and a patient with OMD (right).
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To quantify these changes, the responses were grouped by retinal
eccentricity as shown in Figure 1
, and the amplitude of the positive
component was measured (the first trough to the positive peak). The
response density (nV/deg · deg) was calculated by dividing the
response amplitude (nV) by the retinal area (deg · deg). Figure 3 a shows the response densities at five eccentric rings for the eight
patients. The gray region represents the calculated 2.5 and 97.5
percentile range for the 20 normal control subjects. It is clear that
all eight patients had severely reduced response densities, especially
in the central areas (rings 1 and 2). The response of two of the
patients fell within the gray region for rings 3 and four of the
patients for ring 4. At the most peripheral area (ring 5), six of eight
patients had response densities that fell within the gray zone.
However, two patients had abnormally decreased response densities even
at the most peripheral ring (20–30°).
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Figure 3. Response densities (amplitude/retinal area) at five eccentric rings in
eight patients with OMD. (a) Individual response densities
at five eccentric rings. The gray region represents the
2.5 and 97.5 percentile range for 20 normal control subjects.
(b) Means ± SD of response densities at five eccentric
rings for 8 patients and 20 normal subjects. *Significant differences
at P < 0.05; Mann–Whitney U
test.
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Figure 3b
shows the means ± SD of the response densities for the
five eccentric rings for the OMD patients and normal subjects. The mean
response densities of the OMD group were significantly decreased up to
the fourth ring (P < 0.05, Mann–Whitney
U test; see also Table 2
). The difference of the response density between OMD and normal control
subjects decreased with increasing eccentricity.
Implicit Times of the Multifocal ERGs
The responses were grouped by retinal eccentricity as described
above, and the implicit times of the initial positive component at the
five eccentric rings were measured. Figure 4
a shows the individual implicit times at the five eccentric rings for
the eight patients with OMD. The gray region represents the range for
the normal control subjects (the 2.5 and 97.5 percentile). Most of the
patients had delayed or slightly delayed implicit times at all
eccentricities. It should be noted that five of eight patients had
abnormally delayed times even at the most peripheral ring, and four
patients had implicit times within the normal range for the central
ring, where all patients had severely depressed amplitudes.
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Figure 4. Implicit times at five eccentric rings in the eight patients with OMD.
(a) Individual implicit times at five eccentric rings. The
gray region represents the 2.5 and 97.5 percentile range
for the 20 normal control subjects. (b) Means ± SD of
implicit times at five eccentric rings for the 8 patients and 20 normal
subjects. *Significant differences at P < 0.05;
Mann–Whitney U test.
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Figure 4b
shows the means ± SDs of the implicit times at the five
eccentric rings for the 8 patients and 20 normal subjects. Implicit
times of the OMD group were significantly delayed at all concentric
rings (P < 0.05, Mann–Whitney U
test; see also Table 2
). The difference between OMD and normal subjects
was maintained with eccentricity.
Figure 5
shows averaged waveforms of multifocal ERGs from the five eccentric
rings. Responses for the 8 OMD patients and 20 normal subjects are
superimposed. The vertical dotted line indicates an implicit time of
29.4 msec. These findings not only show the depression of the amplitude
but also the significant delay of the implicit times at all five rings.
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Figure 5. Averaged waveforms of multifocal ERGs for the five eccentric rings.
Responses for the 8 OMD patients and 20 normal subjects are
superimposed. The vertical dotted line indicates an
implicit time of 29.4 msec.
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No correlation was found between the amplitude decrease and implicit
time delay for the OMD patients. For instance, patients 4 and 6 had
normal amplitude at both rings 4 and 5, but had delayed implicit times.
On the other hand, the implicit times of patients 1, 3, 5, and 7 were
within normal limits at ring 1, but their amplitudes were significantly
reduced. We plotted the amplitude decrease relative to the mean of the
control subjects against the implicit time delay relative to the mean
of the control subjects for the eight patients at each five eccentric
rings. There was no significant correlation (r =
-0.17, P = 0.26, Spearman’s rank correlation
test).
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Discussion
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The present study demonstrated that the amplitudes of the
multifocal ERGs in OMD patients were markedly depressed in the central
retina: all patients had reduced amplitude for rings 1 and 2 (within
7° of the fovea). The differences in the amplitudes for the patients
with OMD and the normal control subjects became smaller toward the
periphery. These findings are consistent with the proposed
interpretation that the disease has localized dysfunction of the retina
in the central field. We have previously shown that focal macular ERGs
were abnormally decreased, whereas full-field ERGs were within normal
range for all OMD patients.1
2
In addition, we also have
reported that the cone psychophysical perimetric thresholds were
abnormally elevated within 10° of the macula but were within the
normal range outside the 10° in all OMD patients.2
A large variation in the amplitude was observed among the patients. For
instance, patients 1 and 4 had reduced amplitude only within 7°
(rings 1 and 2) but normal amplitude outside the 7°. On the other
hand, patients 2 and 5 had abnormally reduced amplitude across the
whole field of study, although the amplitude tended to be closer to
normal in the periphery. This large variation in the amplitudes among
the OMD patients may be explained by the stage or severity of the
disease, because it is known that OMD is a progressive
disorder.1
2
We also have previously shown that younger
patients tended to have only the macular cone system involved, but some
of the older patients had both the macular cone and rod system
involved.2
Another explanation for the large variation is that our OMD patients
may have included different clinical entities with similar appearance
but of different genetic basis. To clarify this point, recent genetic
techniques should be useful to determine whether patients have same
genetic disorder or different genetic changes as in retinitis
pigmentosa.16
Our finding that most patients had slight but statistically significant
delayed implicit times over 60° of the posterior pole is interesting.
Five of eight patients had delayed implicit times even at most
peripheral ring (20–30°), whereas five patients had normal ERG
amplitude, and all patients had normal cone thresholds by
psychophysical perimetry (see Table 1 ). Moreover, timing difference
between the OMD patients and the normal subjects did not change with
eccentricity, as did the amplitudes. Odel et al.17
have
reported similar results in their two patients with OMD. Although the
exact reason for the timing delay at peripheral eccentricities is
unknown, there are several possibilities. One plausible hypothesis is
that some of the OMD patients may have a subtle but broad dysfunction
in the posterior pole than might be expected by the results of
psychophysical perimetry and ERG amplitudes. Hood et al.11
reported that some patients with retinitis pigmentosa had delayed
responses in regions, even with near normal sensitivity measured by
psychophysical perimetry. They concluded that the implicit time delay
in the multifocal ERG can be an early indication of local retinal
damage in retinal disease. Thus, the delayed implicit times in the OMD
patients in the presence of normal amplitudes may indicate an early
sign of retinal dysfunction.
The question then arises is to why conventional full-field ERGs did not
detect such implicit time delays in the OMD patients. We suggest that
this arises from the same differences in the amplitude, viz., the
delayed responses in the multifocal ERGs arise from the cells within a
limited area (only the central 60° of the retina, which contains less
than one quarter of the total cones),14
whereas in the
full-field ERGs, the implicit time is determined by neurons over the
entire retina.
Another factor is the recording conditions in the OMD patients. OMD is
a macular disease that predominantly affects the central retina and can
lead to some fixation problems. It also is not known how this fixation
problem affects the response of the multifocal ERG. Unstable fixation
during recording may result in abnormal implicit times in the entire
visual field. To clarify this point, it is necessary to study the
effect of fixation on the response of multifocal ERGs. The new
multifocal ERG system with fundus monitoring may help answer this
question.18
In conclusion, our results demonstrated that the amplitude of the
multifocal ERGs revealed localized retinal dysfunction, predominantly
in the central retina. Although the exact reason for the delayed
implicit times across large regions of the retina still remains
uncertain, our results provide useful topographical information about
the pathophysiology of OMD. We also believe that our results can be
valuable when one uses this technique for the diagnosis of OMD.
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Footnotes
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Supported by Grant 08457462 from the Ministry of Education, Science, Sports, and Culture, Japan.
Submitted for publication May 20, 1999; revised September 1, 1999; accepted September 13, 1999.
Commercial relationships policy: N.
Corresponding author: Chang–Hua Piao, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466, Japan. piao{at}med.nagoya-u.ac.jp
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Top
Abstract
Introduction
