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(Investigative Ophthalmology and Visual Science. 2000;41:320-324.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Background Adaptation in Children with a History of Mild Retinopathy of Prematurity

Ronald M. Hansen and Anne B. Fulton

From the Department of Ophthalmology, Children’s Hospital and Harvard Medical School, Boston, Massachusetts.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. In children with a history of mild retinopathy of prematurity (ROP), test the hypothesis that elevation of the parafoveal over peripheral dark-adapted threshold is due to photoreceptor rather than postreceptor dysfunction.

METHODS. A forced choice procedure was used to measure thresholds for detection of 2o diameter, 50 msec, blue stimuli presented 10o (parafoveal) or 30o (peripheral) eccentric in the dark and in the presence of steady red backgrounds (-4 to +2 log scot td). Four ROP and four control subjects were tested at both eccentricities. A model of the increment threshold function was fit to the data to calculate the eigengrau and dark-adapted threshold.

RESULTS. Both ROP subjects with elevated parafoveal thresholds also have elevated parafoveal eigengraus. On the other hand, parafoveal and peripheral eigengraus are equal in ROP subjects without parafoveal threshold elevation. Nevertheless, the dark-adapted thresholds of all ROP subjects are higher than those of any control subject at both sites.

CONCLUSIONS. The parafoveal threshold elevation is due to rod dysfunction. There is also evidence of peripheral rod photoreceptor involvement in the subjects with ROP.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Retinopathy of prematurity (ROP) onset occurs during preterm ages when the rod outer segments are rapidly developing.1 2 Studies of electroretinogram (ERG) rod phototransduction processes in infants and children with a history of ROP show that significant alterations of rod function persist long after active ROP has resolved.3 4 In a rat model of ROP, ERG abnormalities5 of the same type as in the children and also alterations of the structure and molecular properties of the rod outer segments6 have been demonstrated.

In addition, rod-mediated vision is affected in some children with a history of mild ROP.7 Specifically, the dark-adapted psychophysical threshold in the parafoveal retina is elevated relative to the threshold in the peripheral retina.7 In control subjects, the parafoveal and peripheral thresholds are equal. Because the course of development of primate parafoveal rod outer segments is delayed compared with that of peripheral rod outer segments,1 8 9 parafoveal rods are less mature than peripheral rod outer segments during the time of active ROP, and possibly7 more susceptible to the outer segment abnormalities that occur in ROP. Short disorganized outer segments were found in a rat model that had ERG abnormalities.6 Assuming similar outer segment changes in ROP subjects, reduced quantum catch and consequent threshold elevation may occur. However, threshold is determined not only by receptoral but also by postreceptoral processes.10 11 12 13

Psychophysical studies of scotopic background adaptation in patients with retinal disorders can distinguish between receptoral and postreceptoral sites of the action of the disease.12 14 15 16 For example, a disease acting on the photoreceptors to reduce quantum catch by reducing pigment content, shortening outer segments, or misaligning the receptors, a disease that causes differential loss of receptors at different locations, or a disease that reduces response amplitude will decrease detection of both the test and background stimuli.12 In this situation, the dark-adapted threshold and the background at which threshold rises significantly above the dark-adapted level are both elevated. Thus, if the relative elevations of the dark-adapted parafoveal threshold in ROP subjects7 are due to rod dysfunction, the parafoveal increment threshold function, displayed on log-log coordinates, will be shifted up and over from the peripheral increment threshold function.12 Changes limited to postreceptoral sites shift the increment threshold function vertically without any horizontal shift.12 We obtained parafoveal and peripheral increment threshold functions from ROP and control subjects to test the hypothesis that relative elevation of the parafoveal dark-adapted threshold in ROP is due to rod photoreceptor dysfunction.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Rod-mediated thresholds for detection of 50 msec, 2o diameter, blue (Wratten 47B, {lambda} < 440 nm) spots were obtained using a two alternative forced-choice procedure. Stimuli were presented on a rear projection screen 10o (parafoveal) or 30o (peripheral) from the center. A red light-emitting diode (LED) fixation target that subtended 30-minute arc and flickered at 1 Hz was at the center of the screen. The steady red (Wratten 29, {lambda} > 610 nm) background field was circular (109o diameter) and concentric with the fixation target. Calibrated neutral density filters controlled the intensity of the test and background lights.

Calculation of the retinal illuminance produced by the test and background lights was based on luminance measurements made with a calibrated photodiode (UDT S-350) placed in the position of the subject’s eyes. The scotopic troland value of the stimuli17 was calculated taking each subject’s measured pupillary diameter and media density17 into account. The subject’s pupillary diameter was estimated by direct observation with an infrared viewer and comparison to the diameter of the cornea (which is 11 mm).18

After 30 minutes of dark adaptation, the subject sat 50 cm in front of the rear projection screen. As in previous studies of dark-adapted thresholds,7 19 20 subjects viewed stimuli with both eyes. The subject was instructed to fixate on a flickering, red, LED fixation target. Then, a stimulus was presented, and the subject reported stimulus position (right or left). On every trial, the subject received feedback. Threshold was determined with a transformed up-down staircase that estimated the 70.7% correct point of the psychometric function.21 At least five alternations were recorded.

Subjects were tested first in the dark-adapted (no background) condition and then while adapted to backgrounds that produced retinal illuminances of approximately -4 to approximately +2 log scot td. Half of the subjects were tested first at the parafoveal site and half at the peripheral site. Each subject completed testing in one session.

A model of the increment threshold function11 12 13 was fit to the threshold data to calculate the values of dark-adapted threshold (TD) and eigengrau (AO) that minimized the sum of squared deviations from the following equation:

(1)
where T is the threshold at background intensity I. Disease limited to the receptors elevates both TD and AO. Disease limited to a postreceptoral site elevates TD only.12

From a sample of ROP subjects previously studied in the dark-adapted condition,7 two with, and two without, relative elevation of the parafoveal over peripheral threshold were recruited for this study of background adaptation. Control subjects were recruited by word of mouth. The characteristics of the subjects are summarized in Table 1 . The study conformed to the tenets of the Declaration of Helsinki and was approved by the Children’s Hospital Committee on Clinical Investigation. Written informed consent was obtained.


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  		Table 1. Characteristics of Subjects

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The model11 12 provides a good description of the increment threshold functions in ROP (Fig. 1) and control (Fig. 2) subjects. The values of TD and AO for each subject are summarized in Table 2 .



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  		Figure 1. The increment threshold functions of ROP subjects. Thresholds at the peripheral site are represented by filled circles, and at the parafoveal site by open circles. The smooth curves plot Equation 1 fit to the data (parafoveal, solid line; peripheral, dashed line). If, in a given adaptation condition, only a filled circle is shown, the parafoveal threshold (open circle) was the same.

 


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  		Figure 2. Increment threshold functions of control subjects. All features of these graphs are as in Figure 1 .

 

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  		Table 2. Parameters of Increment Threshold Functions

 
In the ROP subjects (Nos. 1 and 2) known to have relative elevation of the dark-adapted parafoveal threshold,7 the parafoveal increment threshold function is shifted from the peripheral function (Fig. 2 , left panels). The eigengrau values, AO, for the parafoveal increment threshold function are shifted toward brighter backgrounds, by 0.86 and 0.35 log units higher than those for the peripheral increment threshold function (Table 2) . The dark-adapted thresholds, TD, of these two ROP subjects were 0.43 and 0.52 log units higher in the parafoveal than peripheral retinas (Table 2) and agree well with their thresholds (Table 1) measured 2 years earlier.7 Furthermore, their dark-adapted peripheral thresholds at -3.20 and -3.22 log scot td sec are approximately 0.2 log unit above the median dark-adapted threshold of controls (Table 2) . Of interest, their rod photoreceptor sensitivities,4 derived from ERG responses to full-field stimuli, were 0.33 and 0.38 log units below the normal mean (Table 1) .

In both ROP subjects (Nos. 3 and 4) without elevation of the dark-adapted parafoveal threshold, the parafoveal and peripheral increment threshold functions are superimposed (Fig. 1 , right panels). The values of TD and AO are the same at the parafoveal and peripheral sites (Table 2) . The calculated values of TD are similar (Table 1) to those measured 2 years earlier.7 Even though TDs in parafoveal and peripheral retinas are equal, they are higher, by 0.23 and 0.25 log units, than the median TD in control subjects. Their values of AO (-2.56 to -2.74 log scot td) were significantly lower (Mann–Whitney U = 31; P = 0.004), that is, shifted toward dimmer backgrounds, than those of controls (-2.28 to -2.61 log scot td). Thus, their increment threshold functions differ from those of controls by equal changes in TD and AO. In other words, compared with controls, their increment threshold functions are shifted up and over along a diagonal, indicating that receptoral function also determines the threshold differences between these two ROP subjects without relative parafoveal threshold elevation and the control subjects.

Dark-adapted parafoveal and peripheral thresholds are equal (within 0.04 log unit) in every control subject. The parafoveal and peripheral increment threshold functions of the control subjects, even if myopic, are superimposed (Fig. 2) . Their eigengrau values in the parafoveal (-2.28 to -2.61 log scot td) and peripheral (-2.31 to -2.55 log scot td) retinas do not differ significantly.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The shift in the parafoveal increment threshold functions of ROP subjects 1 and 2 is evidence that rod dysfunction accounts for the relative elevation of the dark-adapted parafoveal threshold. The calculated values of the parafoveal eigengrau, AO, for these two ROP subjects are higher than their peripheral values. Furthermore, their peripheral eigengrau values are higher than those of any of the control subjects. This suggests that their rods, both peripheral and parafoveal, have higher intrinsic noise than normal and that the parafoveal rods are noisier than peripheral rods. Possibly these ROP subjects have some disorganization of the rod outer segments, such as that demonstrated in a rat model of ROP.6

ROP subjects, Nos. 3 and 4, who do not have a shift of their increment threshold functions, have, nevertheless, significant elevations of their dark-adapted thresholds. Their eigengrau values also differ, by a small but significant amount, from those of the controls, being shifted to dimmer backgrounds by approximately 0.2 log unit, an amount equal to the threshold elevation. In these subjects, reduced quantum catch (elevated TD) and lower intrinsic noise may be explained by short outer segments, as was found in the rat model,6 and as is also consistent with the low amplitudes of the saturated rod response obtained in ROP subjects.3 4 A difference between the dark-adapted peripheral thresholds of ROP and control subjects was not recognized in the Reisner et al. study.7 The controls in that study were older (range, 10–48 years) than those in the present study, and a correction for media density was not applied. Assuming that media density increases with age, on average, 0.12 log unit per decade,22 23 the median peripheral threshold for controls in the Reisner et al. study7 is -3.43 log scot td sec, or 0.24 log unit more sensitive than the median peripheral threshold of the ROP subjects in the Reisner et al. study.7 In any case, it is well to keep in mind that these are small differences, similar to the intersubject variability reported with this type of testing.7 19

Even though all ROP subjects have nearly identical peripheral dark-adapted thresholds that are higher than those of the controls (Table 2) , only the two (subjects 1 and 2) who were high myopes from early childhood have further elevation of the parafoveal threshold. As the results from subjects 5 and 6 attest, myopia alone does not cause parafoveal threshold elevation.7 Subjects 1 and 2 are also known to have mild acuity deficits (20/30 or 20/40 rather than 20/20).7 Thus, both the late-developing parafoveal rods and the foveal cones, which have an even more protracted course of development,24 may have been disturbed in these ROP subjects. The mechanisms that lead to the association of myopia in mild ROP and parafoveal rod dysfunction remain to be defined. In view of the previous studies of ROP subjects3 4 7 and the rat model,5 6 the present psychophysical results lead us to suspect that those factors that cause persistent disorganization of the photoreceptor outer segments are also involved in the regulation of eye growth in ROP.


   Footnotes
 
Supported by National Institutes of Health Grant EY10597.

Submitted for publication May 20, 1999; revised July 26, 1999; accepted August 27, 1999.

Commercial relationships policy: N.

Corresponding author: Ronald M. Hansen, Department of Ophthalmology, Children’s Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. hansen_r{at}a1.tch.harvard.edu


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Hendrickson, AE, Drucker, D. (1992) The development of parafoveal and midperipheral retina Behav Brain Res 19,21-32
  2. Hendrickson, AE (1994) The morphologic development of human and monkey retina Albert, DM Jakobiec, FA eds. Principles and Practice of Ophthalmology: Basic Sciences ,561-577 WB Saunders Philadelphia.
  3. Fulton, AB, Hansen, RM (1996) Electroretinogram responses and refractive errors in patients with a history of retinopathy of prematurity Doc Ophthalmol 91,87-100
  4. Fulton, AB, Hansen, RM (1996) Photoreceptor function in infants and children with a history of mild retinopathy of prematurity J Opt Soc Am (A) 13,566-571
  5. Reynaud, X, Hansen, RM, Fulton, AB (1995) Effect of prior oxygen exposure on the electroretinographic responses of infant rats Invest Ophthalmol Vis Sci 36,2071-2079[Abstract/Free Full Text]
  6. Fulton, AB, Reynaud, X, Hansen, RM, et al (1999) Rod photoreceptors in infant rats with a history of oxygen exposure Invest Ophthalmol Vis Sci 40,168-174[Abstract/Free Full Text]
  7. Reisner, DS, Hansen, RM, Findl, O, Petersen, RA, Fulton, AB (1997) Dark adapted thresholds in children with histories of mild retinopathy of prematurity Invest Ophthalmol Vis Sci 38,1175-1183[Abstract/Free Full Text]
  8. Dorn, EM, Hendrickson, L, Hendrickson, AE (1995) The appearance of rod opsin during monkey retinal development Invest Ophthalmol Vis. Sci. 36,2634-2651[Abstract/Free Full Text]
  9. Timmers, AM, Fox, D, He, L, Hansen, RM, Fulton, AB (1999) The pattern of rod photoreceptor cell maturation in mammalian retina Curr Eye Res 18,393-402[Medline][Order article via Infotrieve]
  10. Brown, AM (1986) Scotopic sensitivity of the two-month-old human infant Vision Res 26,707-711[Medline][Order article via Infotrieve]
  11. Hood, DC (1988) Testing hypotheses about development with electroretinographic and increment threshold data J Opt Soc Am (A) 5,2159-2165
  12. Hood, DC, Greenstein, V. (1990) Models of the normal and abnormal rod system Vision Res 30,51-68[Medline][Order article via Infotrieve]
  13. Walraven, J, Enroth–Cugell, C, Hood, DC, MacCleod, DIA, Schnapf, JL (1990) The control of visual sensitivity Spillman, L Werner, JS eds. Visual Perception: The Neurophysiological Foundations ,53-101 Academic Press New York.
  14. Alexander, KR, Derlacki, DJ, Fishman, GA, Peachey, NS (1991) Acuity-luminance and foveal increment threshold functions in retinitis pigmentosa Invest Ophthalmol Vis Sci 32,1446-1454[Abstract/Free Full Text]
  15. Yates, DW, Derlacki, DJ, Pepperberg, DR, Alexander, KR, Fishman, GA (1989) Rod increment thresholds in cone-rod dystrophy Appl Optics 28,1115-1121
  16. Young, RSL, Price, J, Harrison, J. (1986) Psychophysical study of rod adaptation in patients with congenital stationary night blindness Clin Vis Sci 1,137-143
  17. Wyszecki, G, Stiles, WS. (1982) Color science: concepts and methods, quantitative data and formulae ,102-103 Wiley New York.
  18. Robb, RM (1982) Increase in retinal surface area during infancy and childhood J Pediatr Ophthalmol Strabismus 19,16-20[Medline][Order article via Infotrieve]
  19. Hansen, RM, Fulton, AB (1995) Dark adapted thresholds at 10 deg and 30 deg eccentricities in 10-week old infants Vis Neurosci 12,509-512[Medline][Order article via Infotrieve]
  20. Hansen, RM, Fulton, A. (1999) The course of maturation of rod mediated visual thresholds in infants Invest Ophthalmol Vis Sci 40,1883-1885[Abstract/Free Full Text]
  21. Wetherill, GB, Levitt, H. (1965) Sequential estimation of points on a psychometric function Brit J Math Stat Psychol 18,1-10
  22. Pokorny, J, Smith, VC, Lutze, M. (1987) Aging of the human lens Appl Optics 26,1437-1440
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  24. Yuodelis, C, Hendrickson, AE (1986) A qualitative and quantitative analysis of the human fovea during development Vision Res 26,847-855[Medline][Order article via Infotrieve]
  25. . Committee for the Classification of Retinopathy of Prematurity (1984) An international classification of retinopathy of prematurity Arch Ophthalmol 102,1130-1134[Abstract]



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