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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.

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.

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 + 𝛔) 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 𝛔, the half-maximum b-wave amplitude evoked stimulus.

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 + 𝛔) 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 𝛔, the half-maximum b-wave amplitude evoked stimulus.

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.

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.

Figure 4.
A, Deficits in the rod sensitivity parameter, S, are correlated with deficits in the b-wave sensitivity parameter, 𝛔. B, Deficits in the amplitude of the saturated rod response, Rmp3, are correlated with the saturated amplitude of the b-wave response, Vmax.

A, Deficits in the rod sensitivity parameter, S, are correlated with deficits in the b-wave sensitivity parameter, 𝛔. B, Deficits in the amplitude of the saturated rod response, Rmp3, are correlated with the saturated amplitude of the b-wave response, Vmax.

Table 1. 
Clinical Characteristics*
Clinical Characteristics*
Table 2. 
Electroretinographic Parameters*
Electroretinographic Parameters*
1.
Committee for the Classification of Retinopathy of Prematurity, An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;1021130- 1134Article
2.
Fulton  ABHansen  RM Photoreceptor function in infants and children with a history of mild retinopathy of prematurity. J Opt Soc Am A Opt Image Sci Vis. 1996;13566- 571Article
3.
Fulton  ABHansen  RM Electroretinogram responses and refractive errors in patients with a history of retinopathy of prematurity. Doc Ophthalmol. 1996;9187- 100Article
4.
Reisner  DSHansen  RMFindl  OPetersen  RAFulton  AB Dark adapted thresholds in children with histories of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1997;381175- 1183
5.
Hansen  RMFulton  AB Background adaptation in children with a history of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2000;41320- 324
6.
Fulton  ABReynaud  XHansen  RM  et al.  Rod photoreceptors in infant rats with a history of oxygen exposure. Invest Ophthalmol Vis Sci. 1999;40168- 174
7.
Reynaud  XHansen  RMFulton  AB Effect of prior oxygen exposure on the electroretinographic responses of infant rats. Invest Ophthalmol Vis Sci. 1995;362071- 2079
8.
Palmer  EAFlynn  JTHardy  RJ  et al.  Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;981628- 1640Article
9.
Grun  G The development of the vertebrate retina: a comparative survey. Adv Anat Embryol Cell Biol. 1982;781- 83
10.
Hendrickson  AE The morphologic development of human and monkey retina. Albert  DMJakobiec  FAeds. Principles and Practice of Ophthalmology: Basic Sciences Philadelphia, Pa WB SaundersCo1994;561- 577
11.
Ames  ALi  Y-YHeher  ECKimble  CR Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. J Neurosci. 1992;12840- 853
12.
Pugh  EN  JrLamb  TD Amplification and kinetics of the activation steps in phototransduction. Biochim Biophys Acta. 1993;1141111- 149Article
13.
Rando  R Membrane phospholipids as an energy source in the operation of the visual cycle. Biochemistry. 1991;30595- 602Article
14.
Winkler  BArnold  MBrassell  MSliter  D Glucose dependence of glycolysis, hexose monophosphate shunt activity, energy status, and the polyol pathway in retinas isolated from normal (nondiabetic) rats. Invest Ophthalmol Vis Sci. 1997;3862- 71
15.
Winkler  BDang  LMalinoski  CEaster  SJ An assessment of rat photoreceptor sensitivity to mitochondrial blockade. Invest Ophthalmol Vis Sci. 1997;381569- 1577
16.
Young  RW Visual cells and the concept of renewal. Invest Ophthalmol Vis Sci. 1976;15700- 725
17.
Reynaud  XHansen  RMFulton  AB The effect of prior oxygen exposure on the electroretinographic responses of infant rats. Invest Ophthalmol Vis Sci. 1995;362071- 2079
18.
Steinberg  R Monitoring communications between photoreceptors and pigment epithelial cells: effects of "mild" systemic hypoxia. Invest Ophthalmol Vis Sci. 1987;281888- 1903
19.
Committee for the classification of the late stages of retinopathy of prematurity, An international classification of retinopathy of prematurity, II: the classification of retinal detachment. Arch Ophthalmol. 1987;105906- 912Article
20.
Multicenter Trial of Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP ROP), Monitoring adherence to protocol certification procedures. Manual of Procedures: Multicenter Trial of Supplemental Theraputic Oxygen for Prethreshold Retinopathy of Prematurity(STOP ROP) 1993;10- 12
21.
Quinn  GEDobson  VKivlin  J  et al.  Prevalence of myopia between 3 months and 5½ years in preterm infants with and without retinopathy or prematurity: cryotherapy for retinopathy of prematurity cooperative group. Ophthalmology. 1998;1051292- 1300Article
22.
Wyszecki  GStiles  WS Color Science.  New York, NY John Wiley & Sons1982;102- 103
23.
Hansen  RMFulton  ABHarris  SJ Background adaptation in human infants. Vision Res. 1986;26771- 779Article
24.
Hansen  RMFulton  AB Development of scotopic retinal sensitivity. Simons  Ked. Early Visual Development: Normal and Abnormal New York, NY Oxford University Press1993;130- 142
25.
Larsen  J The saggital growth of the eye, I: ultrasonic measurement of the depth of the anterior chamber from birth to puberty. Acta Ophthalmol (Copenh). 1971;49239- 262Article
26.
Werner  JS Development of scotopic sensitivity and the absorption spectrum of the human ocular media. J Opt Soc Am. 1982;72247- 258Article
27.
Hansen  RMFulton  AB Psychophysical estimates of ocular media density of human infants. Vision Res. 1989;29687- 690Article
28.
Hood  DCBirch  DG Rod phototransduction in retinitis pigmentosa: estimation and interpretation of parameters derived from the rod a-wave. Invest Ophthalmol Vis Sci. 1994;352948- 2961
29.
Lamb  TDPugh  EN  Jr A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors. J Physiol (Lond). 1992;449719- 758
30.
Kraft  TWSchneeweis  DMSchnapf  JL Visual transduction in human rod photoreceptors. J Physiol (Lond). 1993;464747- 765
31.
Robson  JFrishman  L Response linearity and kinetics of the cat retina: the bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci. 1995;12837- 850Article
32.
Robson  JGFrishman  LJ Dissecting the dark adapted electroretinogram. Doc Ophthalmol. 1998-99;95187- 215Article
33.
Peachey  NSAlexander  KRFishman  GA The luminance-response function of the dark-adapted human electroretinogram. Vision Res. 1989;29263- 270Article
34.
Fulton  ABHansen  RM The development of scotopic sensitivity. Invest Ophthalmol Vis Sci. 2000;411588- 1596
35.
Shady  SHood  DCBirch  DG Rod phototransductrion in retinitis pigmentosa: distinguishing alternative mechanisms of degeneration. Invest Ophthalmol Vis Sci. 1995;361027- 1037
36.
Whitmore  GA Prediction limits for a univariate normal observation. Am Stat. 1986;40141- 143
37.
Pierce  EQuinn  TMeehan  T  et al.  Mutations in a gene encoding a new oxygen regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet. 1999;22248- 254Article
38.
Troilo  DWallman  J The regulation of eye growth and refractive state: an experimental study of emmetropization. Vision Res. 1991;311237- 1250Article
39.
Westbrook  AMCrewther  DPCrewther  SG Cone receptor sensitivity is altered in form deprivation myopia in the chicken. Optom Vis Sci. 1999;76326- 338Article
40.
Crewther  DPCrewther  SGBarila  AM A role for photoreceptor outer segments in the induction of deprivation myopia. Vision Res. 1995;351217- 1225Article
41.
Ehrlich  DSattayasai  JZappia  JBarrington  M Effects of selective neurotoxins on eye growth in the young chick. Block  GWiddows  Keds. Myopia and the Control of Eye Growth Chichester, NY John Wiley & Sons1990;63- 88
42.
Lue  C-LHansen  RMReisner  DS  et al.  The course of myopia in children with mild retinopathy of prematurity. Vision Res. 1995;351329- 1335Article
Clinical Sciences
April 2001

The Rod Photoreceptors in Retinopathy of PrematurityAn Electroretinographic Study

Author Affiliations

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.

Arch Ophthalmol. 2001;119(4):499-505. doi:10.1001/archopht.119.4.499
Abstract

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.

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.1116 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.

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, λ<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/cm2per flash. The scotopic troland value of the stimulus was calculated2224 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 "𝛔" is the stimulus that evoked a half-maximum b-wave amplitude. Thus, 1/𝛔 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 𝛔, and Vmaxare 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.

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.

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 Rmp3were 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, 𝛔, 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.

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,3841 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

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Article 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@a1.harvard.edu)

References
1.
Committee for the Classification of Retinopathy of Prematurity, An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;1021130- 1134Article
2.
Fulton  ABHansen  RM Photoreceptor function in infants and children with a history of mild retinopathy of prematurity. J Opt Soc Am A Opt Image Sci Vis. 1996;13566- 571Article
3.
Fulton  ABHansen  RM Electroretinogram responses and refractive errors in patients with a history of retinopathy of prematurity. Doc Ophthalmol. 1996;9187- 100Article
4.
Reisner  DSHansen  RMFindl  OPetersen  RAFulton  AB Dark adapted thresholds in children with histories of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1997;381175- 1183
5.
Hansen  RMFulton  AB Background adaptation in children with a history of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2000;41320- 324
6.
Fulton  ABReynaud  XHansen  RM  et al.  Rod photoreceptors in infant rats with a history of oxygen exposure. Invest Ophthalmol Vis Sci. 1999;40168- 174
7.
Reynaud  XHansen  RMFulton  AB Effect of prior oxygen exposure on the electroretinographic responses of infant rats. Invest Ophthalmol Vis Sci. 1995;362071- 2079
8.
Palmer  EAFlynn  JTHardy  RJ  et al.  Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;981628- 1640Article
9.
Grun  G The development of the vertebrate retina: a comparative survey. Adv Anat Embryol Cell Biol. 1982;781- 83
10.
Hendrickson  AE The morphologic development of human and monkey retina. Albert  DMJakobiec  FAeds. Principles and Practice of Ophthalmology: Basic Sciences Philadelphia, Pa WB SaundersCo1994;561- 577
11.
Ames  ALi  Y-YHeher  ECKimble  CR Energy metabolism of rabbit retina as related to function: high cost of Na+ transport. J Neurosci. 1992;12840- 853
12.
Pugh  EN  JrLamb  TD Amplification and kinetics of the activation steps in phototransduction. Biochim Biophys Acta. 1993;1141111- 149Article
13.
Rando  R Membrane phospholipids as an energy source in the operation of the visual cycle. Biochemistry. 1991;30595- 602Article
14.
Winkler  BArnold  MBrassell  MSliter  D Glucose dependence of glycolysis, hexose monophosphate shunt activity, energy status, and the polyol pathway in retinas isolated from normal (nondiabetic) rats. Invest Ophthalmol Vis Sci. 1997;3862- 71
15.
Winkler  BDang  LMalinoski  CEaster  SJ An assessment of rat photoreceptor sensitivity to mitochondrial blockade. Invest Ophthalmol Vis Sci. 1997;381569- 1577
16.
Young  RW Visual cells and the concept of renewal. Invest Ophthalmol Vis Sci. 1976;15700- 725
17.
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