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The Rod Photoreceptors in Retinopathy of Prematurity
An Electroretinographic Study
Anne B. Fulton, MD;
Ronald M. Hansen, PhD;
Robert A. Petersen, MD;
Deborah K. Vanderveen, MD
Arch Ophthalmol. 2001;119:499-505.
ABSTRACT
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Objective To test the hypothesis that the more severe the acute phase retinopathy
of prematurity (ROP) was in the preterm weeks, the more severely compromised
is rod photoreceptor function after the ROP has resolved.
Methods Electroretinographic (ERG) responses were recorded from 25 dark-adapted
children (ages 2.5 months' postterm to 14 years) categorized by maximum, acute
phase ROP (None to Very Severe). From the ERG a-wave "S," a sensitivity parameter
for the rod photoreceptor response, and Rmp3, the saturated amplitude
of the rod photoreceptor response were calculated using a model of the activation
of rod phototransduction. The patients' results were compared with those of
healthy controls (n = 71).
Results Among those in the None, Mild, Moderate, and Severe categories, both
S and Rmp3 varied significantly with severity of acute phase ROP.
In the Very Severe category, ERG responses were too attenuated to calculate
S and Rmp3.
Conclusions The rod photoreceptors must be involved in ROP. The more severe the
acute phase ROP, the more severe is the compromise of the processes involved
in the activation of phototransduction in the rods.
INTRODUCTION
THE CLINICAL hallmark of retinopathy of prematurity (ROP) is abnormal
retinal vasculature.1 On the other side of
the retina, the photoreceptors have no role in ROP according to conventional
wisdom. Nevertheless, in 5 patients with a history of mild (stage 1 or stage
2) ROP that had resolved completely without any intervention, and in an additional
4 patients included in a report about refractive errors in ROP, there was
electroretinographic (ERG) evidence of abnormal rod photoreceptor function.2-3 Additionally, elevations of scotopic
visual thresholds indicate photoreceptor involvement in children with a history
of resolved, mild ROP.4-5 In a
rat model of ROP, structural and biochemical alterations in the rod outer
segments have been documented.6 The rats had
the same type of ERG abnormalities7 as the
patients with ROP.2-3 These studies
have led to the suggestion that photoreceptors are involved in the ROP disease
process.6 After all, ROP has its onset at preterm
ages,8 during which the rod photoreceptor outer
segments elongate rapidly.9-10
As the outer segments grow, the needs for oxygen escalate to meet the demands
for energy used in phototransduction processes, outer segment turnover, and
the sodium pumps for the photoreceptors' circulating current.11-16
Therefore, it is reasoned that as the preterm infants' photoreceptors demand
more oxygen, the remainder of the retina becomes relatively hypoxic.2-3,6, 17 Even
in normal circumstances, the photoreceptors have just enough oxygen to maintain
normal structure and function.15, 18
Thus, if the oxygen needs are not met, the preterm infant's photoreceptors
become damaged. According to this perspective, the more severe the photoreceptor
involvement and retinal hypoxia, the more severe the ROP.
A small series of former preterm infants, categorized according to severity
of acute phase ROP, is presented. Their rod photoreceptor function has been
studied using contemporary ERG procedures and analyses. We tested the hypothesis
that the more severe the acute phase ROP, the more severely compromised is
rod photoreceptor function.
PATIENTS AND METHODS
PATIENTS
The former preterm infants, who had been examined in the nursery for
ROP, were recruited by mail. Excluded were those receiving ventilation at
the time of the ROP examinations or on supplemental oxygen at the time of
the ERG test. The patients (Table 1)
are categorized (None, Mild, Moderate, Severe, and Very Severe) by maximum,
acute phase ROP. The International Classification of ROP system was used to
specify the severity and extent of acute ROP.1, 19
Sixteen patients (Table 1) had
standardized examinations1, 19
in the newborn nursery by two of us (D.K.V. or R.A.P.), who were certified
for the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity
study.20 Nine infants (Table 1, patients 4, 5, 7, 13, 15, 16, 19-21) have been included
in previous reports.2-3 Gestational
age (Table 1) varied significantly
in the ROP group (F4,20 = 7.4, P<.01).
Although many of the patients had mild neuromotor handicaps, all patients
have been in good general health, and their cases have been followed at our
institution since infancy.
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Table 1. Clinical Characteristics*
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The ROP categories are defined as follows: The definitions of the Mild
and Moderate categories are similar to those used by others.21
"None" indicates that there were no signs of ROP. "Mild" ROP designates ROP
in zone II, in stage 2 or less, with no plus disease, or with all ROP first
appearing in zone 3. "Moderate" ROP includes zone I or zone II with stage
2+ or stage 3 with less than threshold severity. The retinal vessels of one
infant (patient 17) in the Moderate group reached zone III before progressing
to 5 clock hours of stage 3 disease in temporal retina; this patient received
diode laser treatment to the avascular temporal retina. Also remarkable is
another infant (patient 18) in the Moderate group who was small for gestational
age. Patients in the "Severe" group had threshold ROP ( 5 contiguous clock
hours or 8 cumulative clock hours of stage 3 ROP in the presence of plus
disease). "Very Severe" ROP indicates those patients with stage 4 disease
that has caused retinal folds and partial or total retinal detachments. All
patients in the Severe and Very Severe groups received peripheral diode laser
photocoagulation to the avascular retina, with the exception of patients 21
and 23 who were treated with cryotherapy, and patient 25 who had detachments
discovered without antecedent threshold disease having been identified. The
detachments of patients 22 through 25 had been treated with drainage and buckling.
No patient had active ROP or a retinal detachment at the time of the ERG test.
The study was approved by the Children's Hospital Committee on Clinical Investigation.
ERG PROCEDURES
The pupil was dilated with 1% cyclopentolate hydrochloride and the child
dark adapted for 30 minutes. After dark adaptation, in dim red light, 0.5%
proparacaine hydrochloride was instilled and a bipolar Burian-Allen electrode
was placed on the left cornea, except in patient 25, who had a long-standing,
funnel detachment of the left retina; the healthier right eye was then tested.
Blue (Wratten 47B,  <510 nm; Eastman Kodak Co, Rochester,
NY) strobe stimuli (Novatron, Dallas, Tex) were delivered through a 41-cm
integrating sphere, controlled in intensity by calibrated neutral-density
filters, and ranged from those evoking a small b-wave (<15 µV) to
those that saturated the a-wave amplitude. The unattenuated flash, measured
with a detector (S350; United Detector Technology, Orlando, Fla) placed at
the position of the subject's cornea, was 3.82 log µW/cm2
per flash. The scotopic troland value of the stimulus was calculated22-24 by taking each child's
pupillary diameter, the average axial length for age,25
and media density26-27 into account.
All responses were differentially amplified (bandpass, 1-1000 Hz; gain,
1000), displayed on an oscilloscope, digitized, and stored on disk for analysis
later using a Nicolet Compact 4 (Nicolet Biomedical Instruments, Madison,
Wis). An adjustable voltage window was used to reject records contaminated
by artifacts. Two to 16 responses were averaged in each stimulus condition.
The interstimulus interval ranged from 2 to 60 seconds and was selected so
that subsequent b-wave amplitudes were not attenuated.
The rod photoresponse characteristics were calculated from the a-wave
responses using the Hood and Birch28 formulation
of the Lamb and Pugh model12, 29
of the biochemical processes involved in the activation of phototransduction.
The main parameters of this model are S and Rmp3. "S" is a sensitivity
parameter, and "Rmp3" is the amplitude of the saturated rod response.12, 29 A curve-fitting routine (MATLAB,
fmins) to determine the best fitting values of S, Rmp3, and "td," a brief time delay, was used in the equation:
where "I" is the flash in isomerizations per rod per flash. Approximately
8.5 isomerizations per rod per flash are produced by 1 scotopic troland second.30 Fitting of the model was restricted to the leading
edge of the a-wave response, or to a maximum of 20 milliseconds after stimulus
onset. All 3 parameters were free to vary.
For the rod-driven b-wave, which represents mainly the activity of the
bipolar cells,31-32 the stimulus/response
function
was fit to the b-wave amplitudes of each subject using an iterative
procedure that minimized the mean square deviation of the data from the equation.
In equation 2, "V" is the b-wave amplitude, "Vmax" is the saturated
amplitude, "I" is the stimulus in scotopic troland seconds, and " "
is the stimulus that evoked a half-maximum b-wave amplitude. Thus, 1/
is a measure of sensitivity. The stimulus/response function was fit up to
those higher flash intensities at which a-wave intrusion occurs.33
STATISTICAL ANALYSES
The photoreceptor response parameters S and Rmp3 of an individual
patient with ROP were compared with the normal values for age.34
The patient's value was expressed as a percent of normal for age.34 Analysis of variance was used to test the hypothesis
that the photoreceptor response parameters varied significantly with category
of ROP. Deficits in photoreceptor sensitivity S were examined for significant
correlation with deficits in bipolar cell sensitivity. Deficits in saturated
amplitude of the photoreceptor response Rmp3 were examined for
significant correlation with deficits in the saturated b-wave amplitude Vmax. These parameters will be correlated if deficits in photoreceptor
function determine the deficits in bipolar cell response parameters.35
RESULTS
Sample records (Figure 1)
and a-wave and b-wave model fits (Figure 2) for patient 6 (Table 1)
and a normal, term born control infant show that a-wave and b-wave responses
of the ROP patient are attenuated. In Figure
2, the upper panels show the first 40 milliseconds of the responses
on an expanded time scale, and the fit of equation 1 (dashed lines) to the
leading edge of the a-wave. In the lower panels of Figure 2, b-wave amplitude is plotted as a function of stimulus
intensity; the fit of equation 2 to the data is shown by the dashed curve.
The b-wave responses to higher flash intensities, at which a-wave intrusion
occurs,33 are not included in the fits. The
patients' values of S, Rmp3, log , and Vmax
are presented in Table 2 along
with the normal values. Patients 22 through 25, whose response amplitudes
were not sufficient for these analyses, are not included in Table 2.
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Figure 1. A, Sample electroretinographic
record at 2.5 months' postterm in patient 6 with Mild retinopathy of prematurity
(ROP). B, Electroretinographic record of a healthy, term born infant. The
numbers to the left of each trace indicate the stimulus in log scotopic troland
seconds.
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Figure 2. For records of patient 6, the
dashed lines show the fits of the equation R(i,t) = Rmp3(1-exp[-0.5
S I {t-td}2]) to the a-wave (A) and of the equation
V/Vmax = I/(I + ) to the b-wave data (B). ROP indicates
retinopathy of prematurity; R,mp3, the amplitude of the saturated
rod response; V, b-wave amplitude; Vmax, the saturated b-wave amplitude;
S, sensitivity parameter for the rod photoreceptor response; I, stimulus in
scotopic troland seconds; td, a brief time delay; and ,
the half-maximum b-wave amplitude evoked stimulus.
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Table 2. Electroretinographic Parameters*
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In Figure 3, S is expressed
as a percentage of normal for age34 and grouped
according to ROP category. For the None, Mild, Moderate, and Severe groups,
S varies significantly with ROP category for analysis of variance (F3,17 = 9.28, P<.01). The deficits in Rmp3 also vary significantly with ROP category using the analysis of
variance (F3,17 = 9.68, P<.01). The
brief delay, td, in patients was within the range found in healthy
subjects.
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Figure 3. Rod photoreceptor sensitivity,
S, is grouped according to retinopathy of prematurity (ROP) category. Each
plotted point represents an individual patient; patient numbers are also shown.
S varies significantly with ROP category.
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For the 3 in the None category, both S and Rmp3 are within
the 95% prediction limit36 for normal.34 In the Mild group, 4 infants (Table 1, patients 4, 9-11), including 1 tested at age 2.5 months'
postterm, were normal for age,34 and 6 (Table 1, patients 5-8, 12, 13) are only
approximately 50% (range, 32%-55%) of normal for age. Of these, the 2 (Table 1, patients 5 and 13) who were tested
after infancy had become high myopes before age 2 years4;
the 4 who were tested at 2.5 months postterm were not myopic (Table 1) although only 1 (patient 4) had values for S and Rmp3 that were normal for age (Table
2). In the Moderate and Severe groups, both S and Rmp3
were approximately 50% (range 36%-66%) of the normal for age. For patients
in the Very Severe category, whose markedly attenuated ERG responses precluded
fits of the a-wave and b-wave models, responses to a blue flash producing
retinal illumination of approximately 103 log scotopic troland
seconds were detectable, but less than a third (11-207 µV) of the normal
mean amplitude (627 µV; SD = 144 µV; n = 25).
If departures of b-wave parameters from normal are accounted for completely
by abnormal photoreceptor inputs to the rod-driven bipolar cells,35 the points in Figure
4, which show the relation of a-wave to b-wave parameters, would
lie on the diagonal lines. The deficits in the b-wave sensitivity parameter, ,
are correlated (r = 0.44; P<.05)
with deficits in S (Figure 4, A).
In Figure 4B, the correlation (r = 0.84; P< .01) of the saturated
b-wave amplitude, Vmax, and Rmp3 is shown. Thus, in
these patients, departures of the b-wave response parameters from normal can
be accounted for by rod photoreceptor dysfunction.35
None of the a-wave or b-wave parameters vary significantly with gestational
age at birth.
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Figure 4. A, Deficits in the rod sensitivity
parameter, S, are correlated with deficits in the b-wave sensitivity parameter, .
B, Deficits in the amplitude of the saturated rod response, Rmp3,
are correlated with the saturated amplitude of the b-wave response, Vmax.
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COMMENT
These data demonstrate a significant association of rod photoreceptor
dysfunction and ROP. The compromise in photoreceptor function varies significantly
with the severity of acute phase ROP (Figure
3). The deficits in the responses of the photoreceptors are sufficient
to account for the b-wave response parameters (Figure 4). The rod cell dysfunction represented by deficits in S
and Rmp3 are neither explained by prematurity alone nor by photocoagulation
alone. The response parameters S and Rmp3 (Table 2) are normal for age34 in
the former preterm infants who had no ROP. Photocoagulation alone does not
explain the results. Six infants (patients 5-8, 12, 13) in the Mild group
and 4 infants (patients 14-16, 18) in the Moderate group who received no ROP
treatment whatsoever have response parameters (Table 2) below normal for age.34
The rod response parameters summarize the molecular processes involved
in the activation of rod phototransduction.12, 29
The sensitivity parameter, S, reflects the cascade of events from photon capture
up to, and including, closure of the cyclic guanosine monophosphate–regulated
channels in the outer segment plasma membrane. The amplitude of the saturated
response from the photoreceptors, Rmp3, reflects the number of
channels in the outer segment membrane that are available for closure by light.
Short outer segments, a low amount of rhodopsin and consequent diminished
quantum catch, impaired mobilities of the transduction cascade proteins (rhodopsin,
transducin, and phosphodiesterase) in the disc membranes, and abnormal disc-to-channel
relations are nonmutually exclusive explanations for low values of S and Rmp3. In a rat model of ROP, rhodopsin content was not low, but disorganization
of the outer segments explained the low values of S and Rmp3. The
outer segment abnormalities rendered the stimuli less effective at evoking
photoreceptor responses.6, 17
The significant association of rod photoreceptor dysfunction and severity
of ROP do not distinguish cause and effect. However, we note that in animal
models of ROP, structural abnormalities of the outer segments,6
photoreceptor dysfunction,17 and expression
of a gene that causes photoreceptor disease37
all antedate the appearance of the retinal vascular changes that define clinical
ROP.1, 19 Thus, the photoreceptors'
high demands for oxygen and energy may contribute to the retinal hypoxia that
leads to ROP.
Although outer segment abnormalities can account for the ERG results,
the primary insult to the rods is unlikely to strike the outer segments directly.
Mammalian outer segments are turned over and completely renewed approximately
every 10 days.16 Therefore, in the children,
and even in the infants (Table 1),
outer segments have turned over many times between the age at which ROP was
active and the age at which the ERG was recorded. To produce the long-term
effects on the outer segments indicated by these ERG results, we suspect that
the events that lead to ROP alter synthesis of the outer segment discs and
the cytoskeleton of the rod photoreceptors. Indeed, in a mouse model of ROP,
Pierce et al37 have found that the gene for
dominant retinitis pigmentosa, Rp1, which is rapidly
regulated by retinal oxygen status, is expressed in the photoreceptor inner
segments and cell bodies. Additionally, it is noted that Rp1 is upstream of several photoreceptor-specific genes, including
those for opsin and arrestin, and the Rp1 protein
has a region of homology with the Drosophila protein
BIF that is required for normal photoreceptor morphogenesis.37
It remains to be determined what, if any, role Rp1
or other genes expressed in the photoreceptors have in human ROP.
No matter what the molecular cause of the alterations in the rod photoreceptors
of the patients with ROP, the low rod sensitivity in some of the patients
(Figure 2) has implications for
rod-mediated vision. In ROP subjects, elevation of dark-adapted thresholds
and altered adaptation to steady background lights are attributable to rod
dysfunction.4-5 There are regional
variations in rod-mediated visual sensitivity, which have significant associations
with early high myopia in mild ROP.4-5
Because the retina, including the photoreceptors, is involved in the control
of eye growth,38-41
the alterations in the retinal function that can be analyzed in ERG studies
may be involved in the deregulation of eye growth and development of refractive
errors that are so common in these (Table
1) and other patients with ROP.3, 21, 42
AUTHOR INFORMATION
Accepted for publication August 9, 2000.
This study was supported in part by grant EY 10597 from the National
Eye Institute, Bethesda, Md (Dr Fulton).
Corresponding author: Anne B. Fulton, MD, Department of Ophthalmology,
Children's Hospital, 300 Longwood Ave, Boston, MA 02115 (e-mail: fulton_a{at}a1.harvard.edu).
From the Department of Ophthalmology, Children's Hospital at Harvard
Medical School, Boston, Mass. None of the authors has a commercial or proprietary
interest in any of the products mentioned in this article.
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