Visual Acuity at 10 Years in Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study Eyes: Effect of Retinal Residua of Retinopathy of Prematurity

Objective  To describe recognition (letter) acuity at age 10 years in eyes with and without retinal residua of retinopathy of prematurity (ROP).

Design  Presence and severity of ROP residua were documented by a study ophthalmologist. Masked testers measured monocular recognition visual acuity (Early Treatment of Diabetic Retinopathy Study) when the children were 10 years old. Two hundred forty-seven of 255 surviving Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) randomized trial patients participated. A reference group of 102 of 104 Philadelphia-based CRYO-ROP study participants who did not develop ROP was also tested.

Results  More severe retinal residua were associated with worse visual acuity, regardless of whether retinal ablation was performed to treat the severe acute-phase ROP. However, within each ROP residua category, there was a wide range of visual acuity results.

Conclusions  This is the first report of the relation between visual acuity (Early Treatment of Diabetic Retinopathy Study charts) and structural abnormalities related to ROP in a large group of eyes that developed threshold ROP in the perinatal period. Visual deficits are greater in eyes with more severe retinal residua than in eyes with mild or no residua. However, severity of ROP residua does not predict the visual acuity of an individual eye because within a single residua category, acuity may range from near normal to blind.

Eyes that developed retinopathy of prematurity (ROP) during the neonatal period frequently show abnormal retinal structure that persists into adulthood, often accompanied by deficits in visual acuity.^1-8 Several studies have shown that, in general, severity of the retinal residua, particularly in the posterior pole, is predictive of the degree of deficit in visual acuity.^9-13 However, these studies have also shown that, a wide range of visual acuity can be found for each category of retinal residua (eg, abnormally straightened temporal retinal vessels, macular heterotopia, retinal fold, or partial retinal detachment), and conversely, that within each level of visual acuity (eg, normal, slightly below normal, well below normal, or blind), retinal residua of a wide range of severity may be represented.^9-13

Eyes that developed severe acute-phase ROP (threshold, defined as at least 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone I or II in the presence of plus disease) are at particularly high risk for developing retinal residua of ROP.¹⁴ The multicenter trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) enrolled and followed 291 children who developed threshold ROP in 1 or both eyes.¹⁵ Comparison of retinal structure and visual acuity for black-and-white gratings at ages 1 and 3½ years, as well as retinal structure and letter visual acuity at 3½ years (tested with charts containing the letters H, O, T, and V), was reported for 69 eyes with macular heterotopia or retinal fold in 59 of the study participants.¹² The results showed that eyes with macular heterotopia tended to have less visual acuity impairment than eyes with retinal fold. However, there was a wide range of visual acuity in both groups, with considerable overlap between the 2 groups. Furthermore, when physicians experienced in clinical manifestations of ROP were asked to predict visual acuity based on the appearance of the posterior pole, they could not reliably predict either the grating acuity or letter acuity of eyes with macular heterotopia or retinal fold.

To date, reports from the CRYO-ROP study describing visual acuity in eyes with varying severity of retinal residua of ROP have been limited to descriptions of grating acuity^12,13 and to data based on measures of recognition acuity (the HOTV test) that can be used with young children.¹³ No data have been reported for children old enough to be tested with standard adult measures of letter recognition acuity, such as the Early Treatment Diabetic Retinopathy Study (ETDRS) charts.¹⁶

This article is based on results obtained at the 10-year follow-up visit of visual acuity testing and eye examinations of participants in the randomized CRYO-ROP study. The purpose is to compare recognition visual acuity with the appearance of the posterior pole of the retina in eyes that developed threshold ROP during the neonatal period and were randomized to receive cryotherapy or to serve as controls. The comparison is based on visual acuity testing with ETDRS charts¹⁶ and examinations of the posterior pole.⁸ Data are also presented from a subset of CRYO-ROP study participants who did not develop ROP and none of whom had retinal residua of ROP at the 10-year follow-up examination.

The CRYO-ROP study enrolled 291 children who developed severe (threshold) ROP in 1 or both eyes.¹⁵ All weighed less than 1251 g at birth, and were born between January 1, 1986, and November 30, 1987. The 240 children who developed threshold ROP in both eyes had 1 eye randomized to receive cryotherapy within 72 hours and the fellow eye served as a control. The 51 children who developed threshold ROP as the worse stage in only 1 eye had that eye randomized to receive cryotherapy or to serve as a control. Long-term follow-up of the 255 surviving study participants was conducted when children reached 10 years of age.⁸ Subjects in this report were the 247 CRYO-ROP study patients who participated in the 10-year follow-up examination at one of the 23 centers in the randomized trial of cryotherapy, and a reference group of 102 of the 104 CRYO-ROP study participants from the Philadelphia center who did not develop ROP during the neonatal period.

The research was approved by the institutional review board at each participating center and was conducted according to the principles outlined in the Declaration of Helsinki. The parent or guardian provided written informed consent prior to entry into the study and prior to each follow-up phase.

For this article, data were analyzed from monocular recognition visual acuity assessments and fundus examinations conducted at the 10-year follow-up examination.

Monocular best-corrected recognition visual acuity was assessed when children were 10 years of age by testers who were masked to current and neonatal ocular status.⁸ Testing was conducted using the ETDRS charts,¹⁶ and visual acuity was estimated as the smallest letter size for which the child correctly identified at least 3 of a maximum of 5 letters.⁸ Children were exempt from acuity testing and their visual acuity was coded as “blind” in both eyes if both of the following criteria were met: (1) both the physician and the parent(s) agreed that the child's vision was, at best, light perception, and (2) both eyes had total retinal detachment, phthisis bulbi, or enucleation.

Each child's eyes were examined by a study certified ophthalmologist who determined the presence and severity of retinal residua of ROP, other structural ocular abnormalities, and refractive error. The examining ophthalmologist categorized ROP status for each eye according to the following categories: (1) no or only mild retinal residua (ie, zone I and near periphery posterior to vortex veins appear normal, including angle of retinal vessels), (2) abnormally straightened temporal retinal vessels, (3) macular heterotopia, (4) retinal fold or partial retinal detachment sparing the macula, (5) partial retinal detachment including the macula), or (6) total retinal detachment.⁸

Data from eyes with nonretinal, ophthalmic potential causes of reduced visual acuity (aphakia/pseudophakia, cataract, glaucoma, and corneal clouding) and eyes with total retinal detachment or enucleation were excluded from the analysis. Also excluded were data from eyes that underwent vitrectomy for total retinal detachment because previous reports have shown that the appearance of the posterior pole is not predictive of visual acuity after vitrectomy.^17,18 Data from both the treated and the control eyes of children in the randomized trial were included in the analysis. For analysis of data from children in the no-ROP reference group, 1 eye was selected at random for inclusion.

At the 10-year examination, data were obtained from 247 children; 202 were in the group that had developed threshold ROP in both eyes and had 1 eye treated with cryotherapy and the other eye served as a control. The remaining 45 children had developed threshold ROP in only 1 eye; in 25 children, the eye was randomized to receive cryotherapy and in 20 children, the eye was randomized to serve as a control. Thus, data were available at 10 years for 227 treated eyes and 222 control eyes.

As presented in Table 1, data from 88 treated eyes and 119 control eyes were excluded, largely based on total retinal detachment. This left data from 139 treated eyes and 103 control eyes that were included in this article. Among the 102 children from the Philadelphia center who did not develop ROP and were tested at 10 years, visual acuity results were provided by all except for 1 child who was unable to identify the letters on the ETDRS charts.

The Figure shows a scatterplot of the visual acuity results for eyes in each retinal residua category and for eyes in the no-ROP group. Medians and interquartile ranges are provided in Table 2 for each category. In general, worse visual acuity scores were associated with more severe retinal residua. However, within each category, there was a wide range of visual acuity results.

Also shown in the Figure are the visual acuity results of treated eyes compared with control eyes. When the eye examination showed only mild or no-ROP residua, a greater number of treated eyes than control eyes had visual acuity in the range of 20/100 and worse. This is reflected quantitatively in Table 2, which shows that the median acuity for treated eyes with only mild or no-ROP residua was 20/40, compared with 20/32 in control eyes (a 1-line difference on the ETDRS chart). In the no-ROP reference group, in which no eyes had retinal residua of ROP, the median visual acuity was 20/20 and nearly all eyes had visual acuity of 20/40 or better.

In contrast to results from treated vs control eyes with mild or no-ROP residua, results from eyes with more severe residua showed median acuity values that were better in treated eyes than in control eyes. As presented in Table 2, the median acuity for treated eyes with abnormally straightened temporal retinal vessels was 2 lines (0.2 log unit) better than the median acuity for control eyes. For macular heterotopia, the median acuity was greater than 5 lines (0.5 log unit) better in treated eyes than in control eyes. Similarly, although the number of eyes in each group is small, the median acuity in treated eyes with retinal fold or partial retinal detachment not involving the macula was 4 lines better than that in control eyes, and the median acuity in treated eyes with partial retinal detachment involving the macula was 5 lines better than that in control eyes.

The results of this study confirm previous reports indicating that there is a positive correlation between severity of retinal residua of ROP and degree of functional (visual acuity) deficits in eyes that had severe ROP during the neonatal period.^9-13 In addition, these results, based on data from a large group of 10-year-old children, indicate that this correlation is present both for eyes with severe acute-phase ROP that were treated with peripheral retinal ablation and for eyes with severe acute-phase ROP that did not receive peripheral retinal ablation. It is important to recognize, however, that the correlation between retinal structure and visual function is not necessarily predictive of the relation between retinal structure and visual function in an individual eye because within each category of ROP residua, data from individual eyes show a large range of visual acuity scores (Figure).

A unique aspect of this study is the comparison of retinal structure and visual function in cryotherapy-treated and control eyes, both of which had severe acute-phase ROP. Among eyes that had only mild or no retinal residua of ROP, control eyes tended to have better visual acuity than treated eyes. This difference in functional outcome in treated vs control eyes with good retinal outcomes could result from cryotherapy-related preservation of good retinal structure in some eyes in which severe ROP may have prevented normal visual acuity development. Among eyes with more severe residua, treated eyes tended to have better visual acuity than control eyes, suggesting that cryotherapy preserves visual function in eyes with moderate to severe residua of ROP.

One question that cannot be answered with the present data is whether nonretinal visual system abnormalities contributed to the poor visual acuity results shown by some eyes, especially those with only mild or no retinal residua of ROP. Previous reports have indicated that ROP can be associated with other adverse perinatal events such as periventricular leukomalacia¹⁹ and intraventricular hemorrhage,²⁰ which in turn are associated with cortical visual impairment.^21,22 Unfortunately, no data on periventricular leukomalacia or intraventricular hemorrhage were available on CRYO-ROP study participants and no specific measures of intelligence were included in the 10-year CRYO-ROP study examination.

In conclusion, the results of this study provide the first data on the relation between ETDRS visual acuity and retinal structural abnormalities related to ROP in a large group of eyes that developed threshold ROP in the perinatal period. In general, visual deficits are greater in eyes with more severe retinal residua than in eyes with mild or no residua. However, the severity of the ROP residua does not predict the visual acuity of an individual eye because within a single residua category, visual acuity can range from near normal to blind. Variability in the visual acuity results may be related to nonretinal visual system abnormalities and/or to subtle retinal abnormalities, such as retinal pigmentation, that were not reflected in the recorded categories of retinal residua of ROP.

Correspondence: Velma Dobson, PhD, Department of Ophthalmology, University of Arizona, 655 N Alvernon, Suite 108, Tucson, AZ 85711 (vdobson@eyes.arizona.edu).

Submitted for Publication: December 21, 2004; final revision received March 16, 2005; accepted March 27, 2005.

Financial Disclosure: None.

Funding/Support: This study was supported by cooperative agreement U10 EY05874 from the National Eye Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md.