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Quantitative Electroretinogram Measures of Phototransduction in Cone and Rod Photoreceptors
Normal Aging, Progression With Disease, and Test-Retest Variability
David G. Birch, PhD;
Donald C. Hood, PhD;
Kirsten G. Locke, RN, CRA;
Dennis R. Hoffman, PhD;
Radoul T. Tzekov, MD, PhD
Arch Ophthalmol. 2002;120:1045-1051.
ABSTRACT
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Objectives To determine (1) reference values for cone and rod phototransduction
variables derived from the a-wave of the electroretinogram, (2) their dependence
on age, (3) the progression in cone and rod variables in patients with X-linked
retinitis pigmentosa (XLRP), and (4) the test-retest variability in these
a-wave measures compared with the variability in cone and rod b-wave measures.
Participants One hundred control subjects aged 5 to 75 years and 24 patients with
XLRP aged 5 to 38 years.
Methods High-intensity stimuli were used to elicit electroretinograms in the
dark and in the presence of a rod-saturating background. Computer averaging
and computer subtraction of cone components from mixed rod-cone responses
were used to derive rod-only and cone a-waves. Rod and cone phototransduction
variables were derived by computer fitting physiologically based computational
models to the leading edges of a-wave ensembles.
Results Phototransduction efficiency, as indexed by the sensitivity variable
(S), decreased with age for cone and rod-only responses,
whereas maximum cone and rod photoresponses (RmP3) remained constant. In patients with XLRP tested annually for 4 years, RmP3 for rods and, to a lesser extent, cones
declined with disease progression, whereas S remained
stable. The test-retest variability in the a-wave RmP3 is lower than previously reported measures of the variability in
b-wave peak-to-peak amplitude.
Conclusion The leading edge of the a-wave of the electroretinogram can be related
to rod and cone phototransduction variables through quantitative models. RmP3, rather than S,
should be the outcome measure of choice when using the a-wave to follow photoreceptor
function in prospective studies and treatment trials.
INTRODUCTION
THE ELECTRORETINOGRAM (ERG) is widely used to help diagnose and follow
patients with genetic eye disease.1-2
The International Society for Clinical Electrophysiology of Vision (ISCEV)
established standards for the full-field ERG.3
The ERG has also become an important outcome measure in clinical trials.4 Historically, the focus has been on the amplitude
and implicit time of the b-wave, and much is known about the decline of b-wave
amplitude with age in control subjects,5-6
its inherent test-retest variability,7-9
and the natural history of b-wave decline in retinitis pigmentosa (RP).7-8 To our knowledge, this kind of information
is not available for the a-wave of the ERG.
The a-wave of the ERG has long been known to reflect primarily photoreceptor
activity.10-13
More specifically, the leading edge of the rod-only response has been shown
to behave similarly to isolated rod photoreceptor recordings in response to
changes in intensity, wavelength, and adaptation state.14-16
After the elaboration of a computational model that relates the response to
events in the phototransduction cascade,17
we showed that an equivalent model could be fit to the leading edge of the
rod-only,18 and subsequently cone,19-20 a-wave.
More recently, we21 presented a rapid
protocol for the clinical assessment of photoreceptor activity. During the
past few years, we used this protocol in 100 control subjects. We also attempted
to use this protocol in several hundred patients with RP (R.T.T., K.G.L.,
D.C.H., et al, unpublished data, 2002). The purpose of the present study is
to analyze reference cone and rod phototransduction variables and their variation
with age; to evaluate progression in cone and rod variables over time in a
subset of patients with XLRP; and to compare the test-retest variability of
these a-wave variables with the variability in cone and rod b-wave measures.
PARTICIPANTS AND METHODS
PARTICIPANTS
ERG A-Wave
Cone and rod a-waves to high-intensity stimuli were obtained from 100
controls aged 5 to 75 years (mean ± SD age, 41 ± 19 years) with
no findings on eye examinations. The sample included 55 males and 45 females.
To obtain test-retest measures, a-waves were obtained from a subset of 20
controls aged 9 to 73 years (mean ± SD age, 48 ± 18 years) in
whom one eye was tested twice within 1 year.
To evaluate the feasibility of monitoring progression in phototransduction
variables, high-intensity a-wave recordings were obtained yearly for 4 years
(5 visits) from 24 patients with X-linked RP (XLRP) aged 5 to 38 years (mean
± SD age, 16 ± 8 years). All 24 patients were participating
in a masked, placebo-controlled clinical trial to determine possible benefits
of nutritional supplementation on the rate of disease progression. All patients
were genotyped and represented supplemented and placebo groups. They were
selected for analysis simply because they retained sufficient cone and rod
photoreceptor function for computational analysis (all had cone maximum amplitude
[RmP3] >6 µV; 20 of 24 had rod RmP3 >9 µV). The purpose was to explore
the feasibility and utility of repeated measures of photoreceptor function
rather than to provide novel data on progression in what is admittedly a heterogeneous
group of patients.
ERG B-Wave
To compare test-retest variability in a-wave variables to that in b-wave
variables, ISCEV standard responses3 were obtained
twice in 2 months from 46 young patients (mean age, 16 years) with XLRP and
17 older patients (mean age, 26 years) with isolated RP. To obtain test-retest
measures for controls representative of those participating in drug safety
trials, ISCEV test-retest variability was assessed in a subset of 20 controls
aged 50 to 65 years. Each was tested twice in 1 year.
All patients were recruited from the data files of the Retina Foundation
of the Southwest. The tenets of the Declaration of Helsinki were followed,
and written consent was obtained after all procedures were fully explained.
METHODS
Electroretinographic testing was conducted after pupil dilation (using
1% tropicamide and 2.5% phenylephrine hydrochloride) and 45 minutes of dark
adaptation. Pupil size was measured immediately after testing. Bipolar contact
lens electrodes were used in all tests. All lenses were tested at least monthly
for integrity, but no attempt was made to use the same lens for repeated measures.
Dark-adapted ISCEV standard responses were followed by a-waves to high-intensity
achromatic stimuli. As described previously,21
responses to several achromatic flashes for each of 4 increasing intensities
were obtained in the dark. The intensities ranged from approximately 3.2 to
4.4 log scotopic troland-seconds (log sc td-s), with precise values depending
on the measured pupil size for each patient. For each intensity, 3 replications
were selected for averaging by computer. The time between flashes was at least
30 seconds and was long enough for complete recovery before a subsequent flash.
Light-adapted ISCEV responses and the same 4 high intensities (5 replications
with 5 seconds between flashes) were later presented against a rod-saturating
background (3.2 log td). The resulting cone a-waves were subtracted from the
dark-adapted responses to produce rod-only a-waves. The rod-only a-wave ensemble
was fit with a computational model describing the response (R) as a function
of time (t) and intensity (i):
where RmP3 is the maximum amplitude, S is a sensitivity variable, and td is a brief
delay before the response onset.18 The cone
model contained an additional time constant to reflect the capacitance of
the cone outer segment.20 The delay (td) was held constant at 1.7 milliseconds for cones and 3.2 milliseconds
for rods.
STATISTICAL ANALYSIS
All computer fits satisfied a least-squares goodness-of-fit criterion
that was used to exclude "noisy" data. Electroretinographic variables were
transformed to log values, and the normality of the data was verified using
the Shapiro-Wilk test. The Bland-Altman analysis was used to determine repeated
(test-retest) variability, with the repeatability coefficient defined as 2
SDs of the test-retest difference distribution.22
Threshold criteria were determined for change to be significant at the 95%
confidence limit.
RESULTS
A representative set of data from an elderly control subject is shown
in Figure 1. Figure 1A shows computer-averaged responses recorded in the dark
to 4 intensities of achromatic flash (3.2, 3.7, 4.0, and 4.4 log sc td-s).
These same intensities are presented again in the presence of a background
of 3.2 log td (Figure 1B). This
background is sufficient to completely eliminate any rod contribution to the
response, but it does not measurably light adapt the cones.20
To isolate the rod photoresponses, the light-adapted responses are subtracted
from the dark-adapted responses (Figure 1C). Dashed lines in C show the fit of the equation shown in the
"Methods" subsection to the leading edge. Finally, the intensities presented
in the presence of the background range from 2.9 to 4.0 log photopic troland-seconds
(log ph td-s) (Figure 1D) and are
ideal for modeling the cone a-wave (dashed lines).
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Figure 1. Representative a-wave responses
from a 65-year-old control subject. A, Responses in dark to intensities ranging
from 3.2 to 4.4 log scotopic troland-seconds (log sc td-s). B, Same 4 intensities
presented against a 3.2–log td background. C, Rod-isolated responses.
Dashed lines show fit of the equation shown in the "Methods" subsection to
the leading edge, where log sensitivity is 0.89 s-2[td-s]-1 and log maximum amplitude is 2.37 log µV. D, Cone responses
and model fits (dashed lines) with log sensitivity of 1.48 s-2[td-s]-1 and log maximum amplitude of 1.7 log µV.
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A comparable analysis is shown in Figure
2 for a patient with XLRP. The dark-adapted responses (Figure 2A) are approximately 15% of the reference
range, whereas the light-adapted responses (Figure 2B) are approximately 33% of the reference range. Thus, the
rod-only (Figure 2C) and cone-only
(Figure 2D) responses differ in
amplitude by a factor of 2 rather than the typical factor of 4 to 5 in controls.
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Figure 2. Representative a-wave responses
from a 23-year-old man with X-linked retinitis pigmentosa. A, Responses in
dark to intensities ranging from 3.2 to 4.4 log scotopic troland-seconds (log
sc td-s). B, Same 4 intensities presented against a 3.2–log td background.
C, Rod-isolated responses. Dashed lines show fit of the equation shown in
the "Methods" subsection to the leading edge, where log sensitivity is 0.59
s-2[td-s]-1 and log maximum amplitude is
1.5 log µV. D, Cone responses and model fits (dashed lines) with log
sensitivity of 0.78 s-2[td-s]-1 and log
maximum amplitude of 1.13 log µV.
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Cone and rod phototransduction variables from all 100 controls are summarized
in Table 1. The distribution of
log values for each variable was not significantly different from a normal
distribution. For cone and rod a-waves, the SD for RmP3 was lower than for S. For convenience, the
mean and lower limits (P<.05) have been converted
to linear units in the last 2 columns of Table 1.
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Table 1. Cone and Rod A-Wave Variables*
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Cone phototransduction variables from controls are shown as a function
of age in Figure 3. As shown in Figure 3A, there is virtually no relationship
between log cone RmP3 and age (r2 = 0.01; P = .85) There is, however,
a significant dependence of log S on age (r2 = 0.29; P<.001) such that
cone log S declines by approximately 0.04 log units
per decade (Figure 3B).
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Figure 3. Cone phototransduction variables
as a function of age. A, Cone log maximum amplitude (RmP3) is not significantly related to age. B, Cone log sensitivity
(S) shows a significant decline with age.
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Variation in normal rod phototransduction variables with age is shown
in Figure 4. Log RmP3 shows a slight but significant decline with age (r2 = 0.06; P = .01)
(Figure 4A). The slope of the best-fit
regression equation is 0.0013 log RmP3/y,
or approximately 0.01 log unit per decade. The relationship between log S and age is considerably stronger (Figure 4B). The correlation is highly significant (r2 = 0.58; P<.001), and the
slope is clinically meaningful in that log S declines
0.006 log unit/y, or 0.06 log units per decade. Thus, the rod log S value for a control at age 70 years is likely to be approximately
0.3 log units lower than that of a teenager. Because cone and rod phototransduction
variables are age dependent, values for controls younger and older than the
median age are also given separately in Table 1.
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Figure 4. Rod phototransduction variables
as a function of age. A, Rod log maximum amplitude (RmP3) is not significantly related to age. B, Rod log sensitivity (S) shows a significant decline with age.
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To evaluate progression in a-wave variables, responses to high intensities
were obtained yearly for 4 years from 24 patients with XLRP. As shown in Figure 5A, there was a modest decline in
cone log RmP3 (F = 2.18; P = .08) during the 4 years of follow-up and a more pronounced decline
in rod log RmP3 (F = 5.08; P<.001). The maximum amplitude of the rod photoresponse declined
by 0.25 log unit (45%) in 4 years. Yearly average values of cone and rod log S are shown in Figure 5B. Although the average values of cone and rod log S were significantly below the mean reference values of 1.67 and 1.10,
respectively, for the younger age group (Table 1), there was no systematic variation in log S during 4 years of follow-up (F = 1.4; P
= .25).
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Figure 5. Cone and rod a-wave variables
in patients with X-linked retinitis pigmentosa. A, Decline in cone and rod
log maximum amplitude (RmP3) during 4
years of follow-up. B, Cone and rod log sensitivity (S)
variables show no significant variation during 4 years of follow-up. Error
bars represent SD.
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Repeatability coefficients for test-retest measures of RmP3 in 20 controls were determined for cone and rod-only
a-waves. The repeatability coefficients for cone and rod-only responses were
0.243 and 0.137, respectively. Criteria for a change to be significant at
the 95% confidence level are given in Table
2. For cone RmP3, the maximum
amplitude had to decrease by 37% before the change could be considered significant.
A decrease in rod RmP3 of 23% should be
considered significant. Cone and rod-only repeatability coefficients for the
a-wave are also compared with previously reported values for the b-wave in Table 2.
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Table 2. Criteria for a Decrease to Be Significant at the 95% Confidence
Level (P>.95)*
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These measures of repeatability in "single-flash" a- and b-waves can
also be compared with repeated variability measures for cone amplitude to
31-Hz flicker stimulation. Figure 6
shows repeatability measures based on 3 groups of patients: (1) young males
with XLRP (mean age, 16 years; n = 46) tested twice in 2 months, (2) older
patients with RP (mean age, 26 years; n = 17) tested twice in 2 months, and
(3) older controls (mean age, 54 years; n = 20) tested twice in 1 year. As
shown by the dashed lines indicating 2 SDs, the repeatability coefficient
for cone amplitude to 31-Hz flicker is 0.24 log unit. This coefficient does
not seem to vary with the age of the patient (Figure 6A) or the mean amplitude of the response (Figure 6B). Cone flicker b-wave amplitude must decline by 37% for
progression to be considered significant at the 95% confidence level.
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Figure 6. Test-retest repeatability measures
based on 3 groups of patients: young males with X-linked retinitis pigmentosa
tested twice in 2 months, older patients with retinitis pigmentosa tested
twice in 2 months, and older controls tested twice in 1 year. Dashed lines
indicate 2 SDs. A, Test-retest differences do not vary with the age of the
patient. B, Test-retest differences do not vary with the amplitude of the
response.
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COMMENT
The protocol described recently21 for
isolating cone and rod-only a-waves from the ERG is highly efficient. Sufficient
data for rigorous derivation of cone and rod phototransduction variables can
be obtained from 8 light intensities. The first 4 intensities (3.2-4.4 log
sc td-s) are obtained after dark adaptation. Even with averaging and after
allowing for complete recovery after each flash, these dark-adapted responses
can be obtained in 6 to 8 minutes. The same 4 intensities are then presented
on a 3.2–log td background, which is sufficient to completely eliminate
any rod contribution without measurably light adapting the cones.20 Because less time is needed between the flashes under
light-adapted conditions, these cone responses can be obtained in approximately
3 minutes. Thus, the entire high-intensity protocol adds approximately 10
minutes to the ISCEV protocol. Although sophisticated software is presently
required for modeling the photoresponse and deriving sensitivity and amplitude
variables, it should be possible to simplify data analysis for routinely deriving
the true maximum photoresponse amplitude. Whereas the present ISCEV responses
were developed to detect abnormal retinal function, the maximum photoresponses
may provide better longitudinal measures for natural history and treatment
trials.
Because it requires a fairly short time, the high-intensity protocol
can be attempted in patients with RP. Of 589 consecutive patients with RP,
we obtained cone a-wave variables on 174 (30%) (R.T.T., K.G.L., D.C.H., et
al, unpublished data, 2002). Only 11 (6%) of these 174 patients had a cone
response to 31-Hz flicker of less than 2 µV. Rod variables in addition
to cone variables were analyzable in 144 (24%) of 589 consecutive patients.
Of these 144 patients, rod b-waves to the ISCEV standard rod stimulus measured
less than 2 µV in 19 (13%). Thus, cone and rod transduction variables
can be followed in the approximately one quarter of patients with RP in our
population who retain cone or rod responses of greater than 2 µV to
ISCEV standard stimuli.
We found virtually no decline in the maximum cone a-wave amplitude (log RmP3) with age. This finding is consistent with
histologic studies24-26
reporting minor age-related decline in numbers of cone photoreceptors outside
the macula. There was, however, a significant decrease in cone log S with age. The decrease is such that the difference in cone log S between controls at age 20 years and at age 70 years
is approximately 0.2 log units. This decrease in cone photoreceptor transduction
efficiency is consistent with the decline in cone b-wave amplitude with age.5-6
We also found little decline in rod RmP3 with age. This too is consistent with available histologic findings,
which suggests that some rods die with age but that the remaining rods swell
to fill the vacant areas.27 Presumably, this
results in a fairly constant number of cyclic G-gated channels with age. The
significant decrease in rod log S with age was such
that sensitivity decreased 0.3 log units between the ages of 20 and 70 years.
This decrease in log S completely accounts for the
50% reduction in rod b-wave amplitude by age 69 years in controls.6 The decrease has been noted previously and is much
greater than expected from preretinal absorption.28-29
Cideciyan and Jacobson29 suggested that one
possible cause could be a buildup of cholesterol in outer segments, with age
leading to decreased membrane fluidity and a subsequent slowing of activation
stages.30-31
Prospective measures of a-wave function have not previously been reported
in RP. In a cross-sectional analysis,32-33
it was reported that patients of all ages with autosomal dominant RP associated
with the pro-23-his rhodopsin mutation show low values of log S. Patients with RP associated with other mutations have normal values
of log S.34-36
In this study, we followed a-wave variables in 20 patients with XLRP for 4
years. There was no significant variation in log S
over time. Log RmP3, the maximal photoreceptor
response amplitude, clearly depends on the stage of the disease. Both cone
and rod RmP3 values showed progression
in XLRP during the 4 years, with rod amplitudes declining faster than cone
amplitudes. The RmP3 is proportional to
the total number of cyclic guanosine monophosphate gated channels37 and decreases as a result of either outer segment
shortening/disarray or the death of entire photoreceptors.33
Test-retest variability for rod and cone a-wave measures has not been
reported previously, to our knowledge. Published data for computer-averaged
rod and cone b-wave amplitudes, however, are in line with the values reported
herein,8, 23 and the values tend
to be higher than those for a-wave RmP3values,
perhaps because of the choice of intensities for ISCEV rod and cone responses.
Because they are derived from regions where amplitude is linearly related
to intensity, ISCEV responses are sensitive to disease but are also affected
by variations in pupil size, flash variations, and so on. In a prospective
natural history study of patients with RP or cone-rod dystrophy, Birch et
al8 reported that the cone and rod b-waves
had to decrease by 35% and 46%, respectively, to reach the threshold for significant
decrease at P<.05. Similarly, values for elderly
patients participating in a drug treatment trial were 55% and 46% for cone
and rod b-waves, respectively (S. Grover, MD, G. A. Fishman, MD, D. G. Birch,
PhD, K. G. Locke, RN, and B. Rosner, PhD, unpublished data, 2002). Published
values for 31-Hz flicker amplitude tend to be lower than for single-flash
cone b-waves, ranging from 35% to 55%.7-9
One conclusion to be drawn from the present results is that RmP3, rather than log S, should
be the outcome measure of choice when using the a-wave to follow photoreceptor
function in prospective studies. Log S, which reflects
the efficiency of the transduction steps between light absorption and channel
closure, usually declines with age, which complicates its interpretation in
any long-term study. The RmP3, on the
other hand, is remarkably stable with age for cones and rods. Thus, any decline
observed in a prospective study should reflect progression of the disease
process.
AUTHOR INFORMATION
Submitted for publication October 11, 2001; final revision received
April 8; accepted April 24, 2002.
This study was supported in part by grants EY-05235 and EY-09076 from
the National Eye Institute, Bethesda, Md; the Foundation Fighting Blindness,
Owings Mills, Md; grant FD-R-001232 from the US Food and Drug Administration,
Rockville, Md; and generous gifts from Steve and Nancy Rogers and Richard
F. McCarthy.
Corresponding author and reprints: David G. Birch, PhD, Retina Foundation
of the Southwest, 9900 North Central Expressway, Suite 400, Dallas, TX 75231
(e-mail: dbirch{at}retinafoundation.org).
From the Retina Foundation of the Southwest, Dallas, Tex (Drs Birch
and Hoffman and Ms Locke); the Department of Ophthalmology, The University
of Texas Southwestern Medical School, Dallas (Dr Birch); Department of Psychology,
Columbia University, New York, NY (Dr Hood); and Department of Ophthalmology,
University of California, Davis (Dr Tzekov).
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