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15-Year Outcomes Following Threshold Retinopathy of Prematurity

15-Year Outcomes Following Threshold Retinopathy of Prematurity ObjectiveTo report the ocular structure and visual acuity outcomes at age 15 years, and the incidence of retinal detachment between 10 and 15 years of age, for patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP).MethodsSubjects were 254 survivors from 291 preterm children with birth weights less than 1251 g and severe (threshold) retinopathy of prematurity (ROP) in one or both eyes, who participated in the CRYO-ROP trial. At age 15 years, unfavorable ocular structure was posterior retinal fold or worse judged by study-certified ophthalmologists. Unfavorable distance visual acuity was 20/200 or worse measured by study-certified testers using Early Treatment of Diabetic Retinopathy Study recognition acuity charts.ResultsThirty percent of treated eyes and 51.9% of control eyes (P<.001) had unfavorable structural outcomes. Between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes. Unfavorable visual acuity outcomes were found in 44.7% of treated and 64.3% of control eyes (P<.001).ConclusionThe benefit of cryotherapy for treatment of threshold ROP, for both structure and visual function, was maintained across 15 years of follow-up. New retinal detachments, even in eyes with relatively good structural findings at age 10 years, suggest value in long-term, regular follow-up of eyes that experience threshold ROP.In 1988, the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) reported statistically significant preliminary evidence that ablation of the peripheral nonvascularized retina of premature infants affected with “threshold” retinopathy of prematurity (ROP) was safe and effective.This has been confirmed over time,and cryotherapy (and more recently laser therapy) has become established as standard care for threshold ROP.However, uncertainty has remained concerning the stability of benefit as the affected children grow and develop. Indeed, ocular and visual complications related to ROP have been known to occur after the first decade of life. Long-term complications in eyes with a history of ROP have been reported to include late retinal detachments,retinal degenerative conditions,pigment abnormalities,cataracts,glaucoma,band keratopathy,and microphthalmos.Although several authorshave endorsed careful long-term follow-up of patients born very prematurely, the medical literature does not provide incidence data regarding the delayed (late) sequelae. Most published reports consist of small case series of adverse effects, without the denominator data needed to determine incidence. Thus, indications for long-term evaluation of patients with ROP have been based on clinical judgment rather than on prospectively collected data. The CRYO-ROP sample size and detailed prospective analysis of eyes with severe ROP offer a unique opportunity to provide data on the 15-year outcome of eyes with severe ROP. Certain aspects of clinical examinations that document such complications are far more feasible to complete in adolescents than in younger children. In addition, techniques and equipment used for clinical ultrasonography have progressed during the past decade, giving us an accepted tool to systematically evaluate the retinal periphery in eyes in which there is a poor view of the fundus. This final assessment of treated and control eyes in the CRYO-ROP population at 15 years of age provides definitive data on the long-term ocular and visual outcomes of treated and untreated eyes with severe (threshold) ROP.METHODSPATIENTSThe study population originates with the 291 infants who were enrolled in the randomized CRYO-ROP. All were born prematurely between January 1, 1986, and November 30, 1987; had birth weights less than 1251 g; and developed threshold ROP. Those who were found to have threshold ROP in both eyes at the same examination (the bilateral threshold group; n = 240) were assigned at random to receive cryotherapy to one eye and no cryotherapy to the other eye. If threshold ROP was observed in only one eye while the other eye had less severe findings (the asymmetric group; n = 51), the threshold eye was randomly assigned to receive cryotherapy or no cryotherapyand is included in threshold eyes reported herein. Randomization occurred at an average postmenstrual age of 37.7 weeks(gestational plus postnatal age) (ie, shortly before the typical due date of full-term birth [40 weeks]).Of the 254 surviving members of the randomized cohort, 198 were eligible for examination at approximately 15 years after randomization. The remaining 56 were exempted from examination because of blindness and total retinal detachment in the studied eyes at a previous study examination, and their data are carried over for inclusion in this 15-year analysis.Informed consent was obtained from parents before initial study entry, before randomization, and before each of the follow-up phases. Also, assent was requested from the children prior to the 15-year examination. Complete details concerning patients, sample-size determination, standardization of ROP classification, eligibility for randomization, and cryotherapy technique are documented in previous publications.STRUCTURAL OUTCOMEEach child underwent a standardized, comprehensive eye examination performed by a study-certified ophthalmologist. Ultrasonography was required for both eyes if the view of the fundus was obscured in one or both eyes. At the conclusion of the examination, the ophthalmologist categorized any residua of ROP that were observed in the posterior retina,using the definitions in Figure 1.Figure 1.Structural outcome categories.FUNCTIONAL OUTCOME: VISUAL ACUITYThe primary functional outcome, distance recognition visual acuity, was evaluated by linear Snellen (letter) testing with the visual acuity charts that were used in the Early Treatment Diabetic Retinopathy Study (ETDRS) (Lighthouse, Inc, New York, NY).These charts give results in units of the log of the minimum angle of resolution. The ETDRS charts are a modified version of the standard Snellen chart. Because most ophthalmologists are familiar with the term Snellento describe letter recognition visual acuity testing, we have used this term to refer to the charts, associated testing procedures, and results.Prior to testing, the child underwent manifest refraction using a chart other than the ETDRS charts, or if manifest refraction was not possible, noncycloplegic retinoscopy was conducted. If either the sphere or the cylinder of the refractive error differed by more than 0.50 diopters from the glasses that the child was wearing, the child’s best-corrected visual acuity was tested while wearing trial frames or lens carriers clipped to the current glasses to achieve best correction.Best-corrected visual acuity was measured by study-trained and study-certified testers at each study center. Acuity was recorded as the Snellen value of the line containing the smallest letter size for which the child could identify correctly 3 of the 5 letters on the line.Prior to testing, each child was given a pretest requiring the binocular identification of 10 individual letters 6 cm in height (at a distance of 0.7-1.5 m) either by name or by matching to a lap board. If the child correctly identified 9 of 10 consecutive letters, monocular distance acuity testing was undertaken using the distance ETDRS charts. Standard test distance was 4 m, but testing at 1 m or 0.5 m was permitted if needed to obtain an acuity measurement. Children who could not pass the pretest were developmentally unable, were uncooperative, or had extremely low form-discrimination visual capability.Monocular testing of the right eye was conducted first and began with the 20/200 line on ETDRS chart 1. The child was asked to identify all letters on each line until a line was reached on which the child could read none of the letters. Testing of the right eye was followed by testing of the left eye, beginning with the 20/200 line on ETDRS chart 2. Children who were unable to perform Snellen acuity testing on one or both eyes had the untestable eye or eyes assessed for the presence of light perception and gross pattern vision. Light perception was tested with a pen light, a Finoff light, or an indirect ophthalmoscope. If light perception was present, the tester presented the lowest spatial frequency (0.32 cycle/cm) Teller acuity card.Test distance was 55 cm but the card could be moved to 38 cm or 19 cm if necessary to detect pattern vision.Testers were masked to the location of the grating on the card until they presented the card enough times to determine whether the child could detect the grating with the eye that was being tested. An eye in which detection of the grating stripes was confirmed (but in which ETDRS acuity could not be measured) was coded as visual acuity of 20/200 or worse (ie, an unfavorable visual acuity outcome). This coding was based on data from the CRYO-ROP examination at 5.5 years, in which all children were tested with both ETDRS acuity charts and grating acuity cards.DATA ANALYSISA Mantel-Haenszel test combining data from participants with bilateral threshold disease and participants with asymmetric threshold disease was used to compare the outcome for treated eyes and control eyes.Outcome data were tabulated from the 1- to 15-year visits to examine the pattern over time and to report detachments that occurred between the 10- and 15-year visits. Also, a scatter diagram was used to show the relationship between visual outcome at the 10-year and the 15-year visit.RESULTSAt the 10-year outcome visit,198 of the 255 surviving CRYO-ROP participants had residual vision in at least one eye that had developed threshold ROP;this qualified them for the 15-year outcome assessment (Figure 2). An additional 57 children were exempted from participation in the 15-year examination because of blindness and total retinal detachment in the studied eyes, as determined at a previous study examination. Children who had bilateral threshold ROP (both eyes included in the study) were exempted only if both eyes met the criteria of blindness and total retinal detachment. One of the children in the exempted group died between the 10-year and 15-year study examinations; thus, there were 56 children in the exempted group at 15 years. Of the 198 participants with sight, 163 were examined at 15 years, including 136 in the bilateral threshold ROP group (one eye treated with cryotherapy and the fellow eye serving as a control) and 27 children in the asymmetric group. Data from the 163 examined children and the 56 participants with predetermined unfavorable outcomes are included in the present outcome analysis, for a total sample of 202 treated eyes and 197 control eyes (Figure 2).Figure 2.Flowchart showing the status of eligible infants with respect to follow-up at 15 years. ROP indicates retinopathy of prematurity.OPHTHALMOSCOPYTable 1shows the outcome of the fundus examination for the 189 treated eyes and 190 control eyes in which residua of ROP could be categorized. The primary data in Table 1 overrepresent the proportion of eyes with retinal detachment in the study population. This is owing to inclusion of data from all eyes of the 56 participants exempted from the 15-year examination because of a prior determination of blindness and total retinal detachment, yet inclusion of data from only a partial sample (163) of the 198 participants known to have vision in at least one study eye at previous examinations (Figure 2). To compensate for this bias, a sampling weight, 163 (82.3%) of 198 participants, rather than 100%, of exempted eyes was computed to correct for the missed examinations among the participants with sight. In essence, this adjustment assumes that had the same follow-up protocol been used for all participants, only 82.3% of the exempted eyes would have been followed up. After adjustment by this weighting factor, the percentage of eyes showing an unfavorable structural outcome at 15 years was 30.0% (54/180) for treated eyes and 51.9% (94/181) for control eyes (P<.001).Table 1. Categorization of Retinal Residua of ROP at 15-Year ExaminationOutcome Category*No. of Treated EyesAdjusted TotalNo. of Control EyesAdjusted TotalFavorable1604122915334284A3126387Unfavorable4B364C3251165A413602Vitrectomy214Exempt50 (41)†5450 (41)†94Unable to gradeNot gradable137Total202180197181Abbreviation: ROP, retinopathy of prematurity.*See Figure 1for definitions of retinal outcome categories. Outcome category was determined by ultrasonography in 4 eyes that afforded an inadequate view of the fundus. In 2 cases for which it was indicated, ultrasonography was not performed.†Adjusted from 50 to 41 (82.3%) for disproportionate structural follow-up rates (see “Ophthalmoscopy” subsection of the “Results” section in text).Among the group of participants with bilateral threshold ROP (one eye was randomized to cryotherapy and the fellow eye served as a control) were 50 who showed discordant outcomes in their 2 eyes (not shown in Table 1). Of these participants with bilateral threshold ROP, 43 had a favorable structural outcome in the treated eye and an unfavorable structural outcome in the control eye and 7 had an unfavorable structural outcome in the treated eye and a favorable structural outcome in the control eye.VISUAL ACUITYVisual acuity results were obtained for 160 of the 163 children examined. Data were also included from the 56 participants who were exempted from the 15-year examination owing to blindness and total retinal detachment documented on a previous examination. As shown in Table 2, a sampling weight (160 [80.8%] of 198 participants), rather than 100%, of exempted eyes was applied to correct for the missed examinations among the sighted participants. Once again, this assumes that had the participant been studied according to the follow-up protocol at 15 years, only 80.8% would have been followed up. With this adjustment, the results showed unfavorable visual acuity outcomes at the 15-year examination in 44.7% (85/190) of treated eyes and 64.3% (119/185) of control eyes (P<.001).Table 2. Recognition Visual Acuity (VA) Outcome at 15-Year ExaminationVA OutcomeNo. of Treated EyesAdjusted TotalNo. of Control EyesAdjusted TotalFavorable 20/20 or better1218 Worse than 20/20 but 20/40 or better3427 Worse than 20/40 but 20/60 or better237 Worse than 20/60 but better than 20/200361051466Unfavorable Equal to or worse than 20/2001617 Equal to or worse than 20/200 (not quantifiable with ETDRS charts)*1312 Blind1650 Exempt50 (40)†8550 (40)†119Total200190195185Abbreviation: ETDRS, Early Treatment of Diabetic Retinopathy Study.*Eyes in which a recognition acuity score was not obtained owing to VA worse than 20/200 at 0.5 m or to the child’s neurodevelopmental delay, but in which the tester was able to verify detection of the 0.32-cycle/cm grating on the Teller acuity card.†Adjusted from 50 to 40 (80.8%) for disproportionate VA follow-up rates (see “Visual Acuity” subsection of “Results” section in text).Among the group of participants with bilateral threshold ROP, there were 66 who showed discordant visual acuity outcomes between their fellow eyes (not shown in Table 2). Of these, 52 had a favorable visual acuity outcome in the treated eye and an unfavorable visual acuity outcome in the control eye and 14 had an unfavorable visual acuity outcome in the treated eye and a favorable visual acuity outcome in the control eye.COMPARISON OF TREATED AND CONTROL EYES OVER TIMETable 3provides a cross-sectional analysis of data on the percentage of treated and control eyes that showed an unfavorable structural outcome at the 1-, 3.5-, 5.5-, 10-, and 15-year CRYO-ROP examinations. There is a gradual increase in the percentage found to be unfavorable in both treatment groups, as well as a small increase with time in the percentage difference in unfavorable structural outcomes between treated and control eyes.Table 3. Summary of Structural and Recognition Visual Acuity Outcomes From 1-Year Examination to 15-Year Examination*CRYO-ROP Examination, yUnfavorable Structural OutcomesUnfavorable Visual Acuity OutcomesTreated EyesControl EyesDifferenceTreated EyesControl EyesDifference125.144.719.6†††3.526.145.419.346.6‡57.5‡10.9‡5.526.945.418.547.161.714.61027.247.920.744.462.117.715§30.051.921.944.764.319.6Abbreviation: CRYO-ROP, Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.*Values are expressed as percentages.†Recognition visual acuity not measured at 1 year.‡Crowded HOTV Recognition Visual Acuity Test used.§Adjusted for disproportionate follow-up rates (see “Ophthalmoscopy” and “Visual Acuity” subsections of “Results” section).Table 3also presents the proportion of treated and control eyes with unfavorable visual acuity results at the 4 outcome ages at which recognition visual acuity was measured (ages 3.5, 5.5, 10, and 15 years). Comparison in visual acuity across time requires interpretation because the crowded HOTV recognition visual acuity test was used at the 3.5-year examination while the ETDRS acuity charts were used at the older ages and because ETDRS visual acuity could not be assessed in about 15% of patients at the 5.5-year examination. However, comparison of results between the 10-year and 15-year examinations, in which ETDRS visual acuity results were obtained from nearly all sighted eyes, showed little change over time in the proportion of treated eyes with unfavorable outcomes but an increase over time in the proportion of control eyes showing an unfavorable visual acuity outcome. In addition, there was an increase in the percentage difference of unfavorable acuity outcomes between treated and control eyes.Examination of the results from the 10-year examination for the 201 treated eyes and the 196 control eyes that were tested at 15 years showed that structural outcome at 10 years was in category 1, 2, or 3 (ie, no worse than macular ectopia) (Figure 1) for 134 treated eyes and 92 control eyes. As presented in Table 4, among this group of eyes with favorable outcomes at 10 years, there were 6 treated eyes (4.5%) and 7 control eyes (7.7%) that developed a retinal fold, retinal detachment, or the posterior pole was obscured by an ROP-related abnormality (category 4C or 5A) between the 10-year and 15-year examinations. Among this group of 13 eyes with a significant change in structural outcome, 4 had an essentially normal posterior pole (category 1), 2 had abnormally straightened temporal retinal vessels (category 2), and 7 had macular ectopia (category 3) at the 10-year examination. Of the 13, there were 5 structurally unfavorable eyes in which the fundus could not be directly viewed (1 in category 4C, 2 in category 5, and 2 in category 5A) at the 15-year examination. These 5 eyes had cataracts, and the examiner could not see posterior to the lens. None of these eyes underwent any type of surgery subsequent to outcomes determined at 10 years. All 5 underwent ultrasonography to categorize their 15-year outcome, and 3 showed total retinal detachment. Both control eyes in category 5 showed total retinal detachment. The treated eye classified as 4C (view of posterior pole blocked) had band keratopathy and moderate corneal stromal opacity, with posterior vitreous abnormalities on ultrasonography. Of the 2 treated eyes in category 5A (all fundus view obstructed), 1 had total retinal detachment with band keratopathy and corneal stromal opacity. The remaining eye had moderate corneal stromal opacity with a corneal diameter of 8 mm and a pupil that dilated only to 2 mm, but ultrasonography did not demonstrate retinal detachment.Table 4. New Appearance of Serious Structural Sequelae Between the 10-Year and 15-Year Examinations15-Year ExaminationNo. of Eyes With Structural Outcome Categories 1, 2, or 3 at 10 y*Treated EyesControl EyesNo retinal fold or detachment12784Retinal fold or detachment6 (4.5%)7 (7.7%)4A234B124C105025A20Unable to grade11Total13492*See Figure 1for definitions of retinal outcome categories.Figure 3provides a comparison between visual acuity results at the 10-year and 15-year examinations for treated eyes and control eyes. For most treated eyes, there was little change in acuity with age. However, 3 eyes that had measurable acuity at 10 years (20/160, 20/1280, and 20/1600) were blind at 15 years. Two of these eyes had total retinal detachment, and the third had the posterior pole obscured by an ROP-related abnormality (category 4C) at the 15-year examination. In 1 eye that could not be tested at 10 years because the child could not perform the ETDRS visual acuity pretest by naming or matching 6-cm high letters, a visual acuity of 20/640 was measured at the 15-year examination.Figure 3.Comparison of visual acuity at 10 years vs at 15 years in (A) eyes treated with cryotherapy and (B) control eyes (not treated with cryotherapy). The diagonal line indicates equal acuity at the 2 ages. Blind indicates being unable to identify letters on the 20/200 line when tested at a distance of 0.5 m at 15 years (equivalent to 20/1600) and unable to detect the grating on the 0.32-cycle/cm Teller acuity card. At 10 years, testing at 0.25 m or 0.125 m was permitted, allowing quantification of acuity down to 20/6400 equivalent; CPP (10-year examination), cannot pass pretest (ie, the child was unable to identify large letters presented at a near distance; vision was better than light perception when tested with Teller acuity cards,but recognition (letter) acuity could not be quantified; TAC (15-year examination), Teller acuity card, better vision than light perception but not quantifiable on recognition acuity testing; 0.32-cycle/cm Teller acuity card was used because child was neurodevelopmentally delayed or because vision was too poor to allow recognition of the 20/200 letter at 0.5 m.For control eyes (Figure 3B), visual acuity was also generally stable between the 10-year and 15-year examinations, with most eyes showing little change in acuity with age. Four eyes that had measurable acuity at 10 years (20/400, 20/500, 20/1600, and 20/5120) were blind at 15 years. The 2 eyes that had acuities of 20/500 and 20/5210 at 10 years had total retinal detachment at 15 years. The remaining 2 eyes had macular ectopia (category 3) at the 15-year examination. Macular ectopia alone is not ordinarily associated with blindness; the eye that had an acuity of 20/400 at 10 years had microcornea in the presence of uniocular high myopia at 15 years, and the eye that had an acuity of 20/1600 at 10 years underwent vitrectomy (without retinal detachment) prior to age 7 years. One eye that was found to be blind at 10 years showed measurable acuity of 20/500 at the 15-year examination. This eye had macular ectopia at the 10-year examination, and although posterior pole status could not be formally categorized at the 15-year examination, there was extreme vascular attenuation and extensive pigmentary degeneration.COMMENTThis article presents the final results of assessment of ocular structure and visual function for the eyes of children who participated in CRYO-ROP. The results confirm the benefit of peripheral retinal ablation for severe (threshold) ROP that was reported in previous publications from CRYO-ROP.At 15 years, there remained a decrease of more than 40% in unfavorable structural outcomes and a decrease of approximately 30% in unfavorable visual acuity outcomes in treated eyes, as compared with control eyes.Comparison of structural outcome results at 15 years with results from prior study examinations (Table 3) showed that although the benefit of peripheral retinal ablation persists across time, there was a gradual increase in unfavorable structural outcomes between the 1-year and 15-year outcome assessments. In treated eyes, this increase averaged 0.35% per year, while it averaged 0.51% per year in control eyes. For visual acuity outcomes, comparison of results across time is possible only between the 10- and 15-year examinations because of differences in visual acuity tests and in testability of study participants at earlier vs later study examinations. Comparison of outcomes between 10 and 15 years (Table 3) showed that visual acuity of treated eyes remained virtually stable during this 5-year interval, with an average increase in unfavorable outcomes of only 0.06% per year, while the visual acuity of control eyes showed an increase in unfavorable outcomes that averaged 0.44% per year.An important goal of the 15-year outcome assessment was to determine the incidence of retinal detachment in both treated and control eyes during the preteen and early teenage years. As summarized in Table 4, new retinal detachments were observed in both treated and control eyes. These adverse events occurred in eyes that were judged at the 10-year examination to have normal or nearly normal posterior poles or macular ectopia without folding. These developments indicate the importance of continued follow-up of eyes with a history of severe acute-phase ROP, even in the absence of observable posterior pole residua as late as age 10 years.Results from CRYO-ROP examinations conducted at 3.5, 5.5, and 10 years indicated that eyes that were saved from blindness by cryotherapy developed visual acuity that was better than 20/200 but worse than the normal range for age.This finding was confirmed at the 15-year examination, in which the incidence of blindness was reduced from 55.1% (102/185) in control eyes to 36.3% (69/190) in treated eyes, while the proportion of eyes with visual acuity between 20/20 and 20/200 was increased from 25.9% (48/185) in the control group to 48.9% (93/190) in the treated group. Thirty eyes had visual acuity of 20/20 or better at the 15-year examination (Table 2). These data show that it is possible to achieve normal adult visual acuity following threshold ROP. Overall, the data suggest that the benefit of cryotherapy occurred primarily among eyes that would likely have been blind without treatment and that visual acuity was improved in these eyes to better than 20/200 but not necessarily to 20/20 or better.In summary, examination of ocular structure and visual function in a large cohort of children who had severe ROP early in life indicated that the benefit of cryotherapy persists well into the second decade of life. However, the results also indicated that ROP may represent a lifelong disease since a number of eyes, both cryotherapy-treated and noncryotherapy-treated, developed retinal detachment, blindness, and other ROP-related complications between ages 10 and 15 years. These results highlight the need for continued ophthalmologic follow-up of children with a history of severe ROP.Correspondence:Earl A. Palmer, MD, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197 (palmere@ohsu.edu).Submitted for Publication:September 1, 2004; final revision received November 3, 2004; accepted November 3, 2004.Funding/Support:The CRYO-ROP is supported by cooperative agreement EY05874 from the National Eye Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md. Indirect support has come from unrestricted grants from Research to Prevent Blindness, New York, NY.Cryotherapy for Retinopathy of Prematurity Cooperative GroupWriting CommitteeEarl A.PalmerMD, (chair); Robert J.HardyPhD; VelmaDobsonPhD; Dale L.PhelpsMD; Graham E.QuinnMD; C. GailSummersMD; Carol P.KromBA; BettyTungMS.Clinical CentersThe CRYO-ROP investigators who participated during the 15-year examination period are as follows:The Children&apos;s Hospital, Birmingham, Ala: Frederick J. Elsas, MD (principal investigator); Michelle Mizell; Brooke Williams, CPA; Douglas Witherspoon, MD (coinvestigators). Children&apos;s Hospital National Medical Center, Georgetown University Medical Center, George Washington University Medical Center, and Washington Hospital; Washington, DC:William S. Gilbert, MD (principal investigator); David Plotsky, MD (coprincipal investigator); Patricia Ann Mercer, MPA (coinvestigator). Jackson Memorial Hospital, Miami, Fla:Hilda Capó, MD (principal investigator); Mimi Garcia; Rose Anne Johnson, RN; Timothy G. Murray, MD (coinvestigators). University of Illinois Eye and Ear Infirmary, Chicago, Ill, Loyola University, Maywood, Ill, and Lutheran General Hospital, Parkwood, Ill:Lawrence M. Kaufman, MD, PhD (principal investigator); Nydia Santiago; Katrice Weaver, CO; Michael Shapiro, MD (coinvestigators). Riley Hospital, Wishard Memorial Hospital, and University Hospital; Indianapolis, Ind:Naval Sondhi, MD (principal investigator); Melissa Fields, COT (coinvestigator). University of Louisville Hospital, Norton Kosair Children&apos;s Hospital; Louisville, Ky:Charles C. Barr, MD (principal investigator); Diane Denning, BA, COT; Craig H. Douglas, MD; Peggy H. Fishman, MD; Gregory K. Whittington, PsyS (coinvestigators). Tulane Medical Center, New Orleans, La:Robert A. Gordon, MD (principal investigator); James G. Diamond, MD; Elaine Eckols; Deborah Farrae; Debbie Neff, LPN (coinvestigators). The Johns Hopkins Hospital, Baltimore, Md:Michael X. Repka, MD (principal investigator); Sheena Broome, OC, COA; Julia A. Haller, MD; Stephen P. Kraft, MD (coinvestigators). William Beaumont Hospital and Children&apos;s Hospital of Michigan; Detroit:John D. Baker, MD (principal investigator); Michael T. Trese, MD (coprincipal investigator); Patricia Manatrey, RN (coinvestigator). Fairview-University Medical Center, Minneapolis, Minn:C. Gail Summers, MD (principal investigator); Donna K. Knobloch; Jane D. Lavoie, CO; Timothy W. Olsen, MD (coinvestigators). Upstate New York Center: Rochester, Syracuse, Buffalo: University of Rochester, Rochester:Dale L. Phelps, MD (principal investigator); Karen Atkins, Ernest Guillet, MD; Robert Hampton, MD; Cassandra Horihan; Gary Markowitz, MD; Walter Merriam, MD; Robert Olsen, MD; Sheree Seeley; Richard Simon, MD; Donald H. Tingley, MD; Paul Torrisi, MD (coinvestigators). Duke Eye Center, Durham, NC:Edward G. Buckley, MD (principal investigator); Malcolm M. (Greg) Anderson, Jr, PAC; Lois Duncan, CO (coinvestigators). Cincinnati, Ohio:Miles J. Burke, MD (principal investigator). Columbus Children&apos;s Hospital, Ohio State University Hospital, Columbus:Gary L. Rogers, MD (principal investigator); Don L. Bremer, MD (coprincipal investigator); Rae R. Fellows, MEd; Alan D. Letson, MD; Mary Lou Kachmer McGregor, MD; Teresa Rinehart (coinvestigators). Casey Eye Institute, Oregon Health & Science University, Portland:Earl A. Palmer, MD (principal investigator); Lee R. Hunter, MD (Jacksonville, Fla); Carol P. Krom, Eileen Royster (coinvestigators). Children&apos;s Hospital of Philadelphia, Pa:Graham E. Quinn, MD (principal investigator); Gary C. Brown, MD; Jane C. Edmond, MD; Brian J. Forbes, MD; Jamie Koh, RN, MSN; Albert M. Maguire, MD; Sheryl J. Menacker, MD; Monte D. Mills, MD; William Tasman, MD; Martin C. Wilson, MD; Terri L. Young, MD; Sonia Zhu (coinvestigators). University of Pittsburgh, The Eye and Ear Institute of Pittsburgh, Children’s Hospital of Pittsburgh; Pittsburgh, Pa:Kenneth P. Cheng, MD (principal investigator); Kim Bauer; Margaret Schramm, MS, MPH (coinvestigators). Medical University Hospital, Charleston, SC:Richard A. Saunders, MD (principal investigator); Lisa Langdale, RN, MSN; Kimberley D. Lenhart, COA; Amy K. Hutchinson, MD; M. Edward Wilson, MD (coinvestigators). Vanderbilt University Hospital, Nashville, Tenn:Sean P. Donahue, MD, PhD (principal investigator); Cindy L. Foss, BBA; Michael Redmond, MD; Robbin Sinatra, MD; Elizabeth Vargas, COT (coinvestigators). Methodist Medical Center, Parkland Memorial Hospital, St Paul Hospital, Medical City Dallas Hospital, and Presbyterian Hospital; Dallas, Tex:Rand Spencer, MD (principal investigator); Jean Arnwine; Sally Arceneaux; Joel N. Leffler, MD (coinvestigators). University of Texas Health Science Center-Medical Center, San Antonio:W. A. J. van Heuven, MD (principal investigator); Maria B. Montéz, RN, MSHP (coinvestigator). University of Utah Hospital, Salt Lake City:Robert O. Hoffman, MD (principal investigator); Susan Bracken, RN, BS; Andrew Jordan, MD; Pat Remington; Michael Teske, MD (coinvestigators).Resource Centers, Project Officers or Managers, Principal Investigators, Study Chairman, and CoinvestigatorsNational Eye Institute, Bethesda, Md:Donald F. Everett, MA (project officer). Casey Eye Institute, Oregon Health & Science University, Portland:Earl A. Palmer, MD (principal investigator and study chairman); Carol Krom; Sandra Newton (project managers). School of Public Health, Coordinating Center for Clinical Trials, University of Texas Health Science Center, Houston:Robert J. Hardy, PhD (principal investigator); Betty Tung, MS (project manager). University of Arizona School of Medicine, Tucson:Velma Dobson, PhD (principal investigator); Graham E. Quinn, MD (coinvestigator).CommitteesExecutive committee: permanent members:Earl A. Palmer, MD (chair); Velma Dobson, PhD; Rae R. Fellows, MEd; Robert J. Hardy, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD; C. Gail Summers, MD. Ex-officio members:Donald F. Everett, PhD; Carol P. Krom, BA; Betty Tung, MS.Editorial committee: permanent members:Earl A. Palmer, MD (chair); Velma Dobson, PhD; Robert J. Hardy, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD; C. Gail Summers, MD. Ex-officio members:Carol P. Krom, BA; Betty Tung, MS.REFERENCESCryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter Trial of Cryotherapy for Retinopathy of Prematurity: preliminary results.Arch Ophthalmol19881064714792895630Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter Trial of Cryotherapy for Retinopathy of Prematurity: three-month outcome.Arch Ophthalmol19901081952042405827Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter Trial of Cryotherapy for Retinopathy of Prematurity: one-year outcome—structure and function.Arch Ophthalmol1990108140814162222274Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter Trial of Cryotherapy for Retinopathy of Prematurity: 3½-year outcome—structure and function.Arch Ophthalmol19931113393448447743Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter Trial of Cryotherapy for Retinopathy of Prematurity: Snellen visual acuity and structural outcome at 5½ years after randomization.Arch Ophthalmol19961144174248602778Cryotherapy for Retinopathy of Prematurity Cooperative GroupOphthalmological outcomes at 10 years.Arch Ophthalmol20011191110111811483076Cryotherapy for Retinopathy of Prematurity Cooperative GroupContrast sensitivity in eyes with threshold ROP from the CRYO-ROP trial.Arch Ophthalmol20011191129113311483078Cryotherapy for Retinopathy of Prematurity Cooperative GroupEffect of ablative cryotherapy for threshold retinopathy of prematurity: results of Goldmann perimetry at age 10 years.Arch Ophthalmol20011191120112511483077Laser therapy for retinopathy of prematurity: the Laser ROP Study Group.Arch Ophthalmol19941121541568311759JEWhiteMXRepkaRandomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: 3-year outcome.J Pediatr Ophthalmol Strabismus19973483879083952BPConnollyJAMcNamaraSSharmaCDRegilloWTasmanA comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity.Ophthalmology1998105162816319754168BMFarisRJBrockhurstRetrolental fibroplasia in the cicatricial stage: the complication of rhegmatogenous retinal detachment.Arch Ophthalmol19698260655819383GSHarrisRetinopathy of prematurity and retinal detachment.Can J Ophthalmol1976112125946163LLaatikainenATarkkanenHHarjuNetzhautablösung bei kindern und jugendlichen.Klin Monatsbl Augenheilkd198418512166548270SRSneedJSPulidoSFBlodiJGClarksonHWFlynnJrWFMielerSurgical management of late-onset retinal detachments associated with regressed retinopathy of prematurity.Ophthalmology1990971791832326006WTasmanVitreoretinal changes in cicatricial retrolental fibroplasia.Trans Am Ophthalmol Soc1970685485945538153WTasmanRetinal detachment in retrolental fibroplasia.Albrecht Von Graefes Arch Klin Exp Ophthalmol19751951291391079704RLWinslowWTasmanJuvenile rhegmatogenous retinal detachment.Ophthalmology197885607618580955RWitmerGiant retinal tears in retrolental fibroplasia and Marfan&apos;s syndrome.Mod Probl Ophthalmol197920279281317663MMBrownGCBrownJSDukerWTasmanJJAugsburgerExudative retinopathy of adults: a late sequela of retinopathy of prematurity.Int Ophthalmol1994-1995182812857607809WTasmanGCBrownProgressive visual loss in adults with retinopathy of prematurity (ROP).Trans Am Ophthalmol Soc1988863673792979023WTasmanGCBrownProgressive visual loss in adults with retinopathy of prematurity.Graefes Arch Clin Exp Ophthalmol19892273093112777098BCFishburneKLWinthropJERobertsonAtrophic fundus lesions associated with untreated retinopathy of prematurity.Am J Ophthalmol19971242472499262554TJKrolickiWTasmanCataract extraction in adults with retinopathy of prematurity.Arch Ophthalmol19951131731777864749BJKushnerThe sequelae of regressed retinopathy of prematurity.In: Silverman WA, Flynn JT, eds. Retinopathy of Prematurity. Boston, Mass: Blackwell; 1985:239-248GSummersDLPhelpsBTungOcular cosmesis in retinopathy of prematurity.Arch Ophthalmol1992110109210971497522WTasmanLate complications of retrolental fibroplasia.Ophthalmology1979861724174095419DRJohnsonKCSwanRetrolental fibroplasia—a continuing problem.Trans Pac Coast Otoophthalmol Soc Annu Meet1966471291336012560BJKushnerCiliary block glaucoma in retinopathy of prematurity.Arch Ophthalmol1982100107810797092646BJKushnerSSondheimerMedical treatment of glaucoma associated with cicatricial retinopathy of prematurity.Am J Ophthalmol1982943133176896960AJMichaelSRPesinLJKatzWTasmanManagement of late-onset angle-closure glaucoma associated with retinopathy of prematurity.Ophthalmology199198109310981891218ZFPollardSecondary angle-closure glaucoma in cicatricial retrolental fibroplasia.Am J Ophthalmol1980896516536892865ZFPollardLensectomy for secondary angle-closure glaucoma in advanced cicatricial retrolental fibroplasia.Ophthalmology1984913953986546979JSmithIShivitzAngle-closure glaucoma in adults with cicatricial retinopathy of prematurity.Arch Ophthalmol19841023713726546679DEBravermanWESnyderA case report and review of band keratopathy.Metab Pediatr Syst Ophthalmol19871039413151218JCohenJEAlfanoLDBoshesCPalmgrenClinical evaluation of school-age children with retrolental fibroplasia.Am J Ophthalmol196457415714106901JCMerrittENKraybillRetrolental fibroplasia: a five-year experience in a tertiary perinatal center.Ann Ophthalmol19861865673754104Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)Manual of Procedures, Vol IV, Phase IV Follow-up Study.Springfield, Va: National Technical Information Service; 2003. US Dept of Commerce publication PB2003-310650FLFerrisIIIAKassoffGHBresnickIBaileyNew visual acuity charts for clinical research.Am J Ophthalmol19829491967091289DYTellerMAMcDonaldKPrestonSLSebrisVDobsonAssessment of visual acuity in infants and children: the acuity card procedure.Dev Med Child Neurol1986287797893817317VDobsonGEQuinnAWBiglanBTungJTFlynnEAPalmerAcuity card assessment of visual function in the cryotherapy for retinopathy of prematurity trial.Invest Ophthalmol Vis Sci199031170217082211019RJHardyBRDavisThe design, analysis, and monitoring of an ophthalmological clinical trial.In: ASA Proceedings of the Biopharmaceutical Section. Alexandria, Va: American Statistical Association. 1989:248-253 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

15-Year Outcomes Following Threshold Retinopathy of Prematurity

JAMA Ophthalmology , Volume 123 (3) – Mar 1, 2005

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References (23)

Publisher
American Medical Association
Copyright
Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/archopht.123.3.311
pmid
15767472
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Abstract

ObjectiveTo report the ocular structure and visual acuity outcomes at age 15 years, and the incidence of retinal detachment between 10 and 15 years of age, for patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP).MethodsSubjects were 254 survivors from 291 preterm children with birth weights less than 1251 g and severe (threshold) retinopathy of prematurity (ROP) in one or both eyes, who participated in the CRYO-ROP trial. At age 15 years, unfavorable ocular structure was posterior retinal fold or worse judged by study-certified ophthalmologists. Unfavorable distance visual acuity was 20/200 or worse measured by study-certified testers using Early Treatment of Diabetic Retinopathy Study recognition acuity charts.ResultsThirty percent of treated eyes and 51.9% of control eyes (P<.001) had unfavorable structural outcomes. Between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes. Unfavorable visual acuity outcomes were found in 44.7% of treated and 64.3% of control eyes (P<.001).ConclusionThe benefit of cryotherapy for treatment of threshold ROP, for both structure and visual function, was maintained across 15 years of follow-up. New retinal detachments, even in eyes with relatively good structural findings at age 10 years, suggest value in long-term, regular follow-up of eyes that experience threshold ROP.In 1988, the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) reported statistically significant preliminary evidence that ablation of the peripheral nonvascularized retina of premature infants affected with “threshold” retinopathy of prematurity (ROP) was safe and effective.This has been confirmed over time,and cryotherapy (and more recently laser therapy) has become established as standard care for threshold ROP.However, uncertainty has remained concerning the stability of benefit as the affected children grow and develop. Indeed, ocular and visual complications related to ROP have been known to occur after the first decade of life. Long-term complications in eyes with a history of ROP have been reported to include late retinal detachments,retinal degenerative conditions,pigment abnormalities,cataracts,glaucoma,band keratopathy,and microphthalmos.Although several authorshave endorsed careful long-term follow-up of patients born very prematurely, the medical literature does not provide incidence data regarding the delayed (late) sequelae. Most published reports consist of small case series of adverse effects, without the denominator data needed to determine incidence. Thus, indications for long-term evaluation of patients with ROP have been based on clinical judgment rather than on prospectively collected data. The CRYO-ROP sample size and detailed prospective analysis of eyes with severe ROP offer a unique opportunity to provide data on the 15-year outcome of eyes with severe ROP. Certain aspects of clinical examinations that document such complications are far more feasible to complete in adolescents than in younger children. In addition, techniques and equipment used for clinical ultrasonography have progressed during the past decade, giving us an accepted tool to systematically evaluate the retinal periphery in eyes in which there is a poor view of the fundus. This final assessment of treated and control eyes in the CRYO-ROP population at 15 years of age provides definitive data on the long-term ocular and visual outcomes of treated and untreated eyes with severe (threshold) ROP.METHODSPATIENTSThe study population originates with the 291 infants who were enrolled in the randomized CRYO-ROP. All were born prematurely between January 1, 1986, and November 30, 1987; had birth weights less than 1251 g; and developed threshold ROP. Those who were found to have threshold ROP in both eyes at the same examination (the bilateral threshold group; n = 240) were assigned at random to receive cryotherapy to one eye and no cryotherapy to the other eye. If threshold ROP was observed in only one eye while the other eye had less severe findings (the asymmetric group; n = 51), the threshold eye was randomly assigned to receive cryotherapy or no cryotherapyand is included in threshold eyes reported herein. Randomization occurred at an average postmenstrual age of 37.7 weeks(gestational plus postnatal age) (ie, shortly before the typical due date of full-term birth [40 weeks]).Of the 254 surviving members of the randomized cohort, 198 were eligible for examination at approximately 15 years after randomization. The remaining 56 were exempted from examination because of blindness and total retinal detachment in the studied eyes at a previous study examination, and their data are carried over for inclusion in this 15-year analysis.Informed consent was obtained from parents before initial study entry, before randomization, and before each of the follow-up phases. Also, assent was requested from the children prior to the 15-year examination. Complete details concerning patients, sample-size determination, standardization of ROP classification, eligibility for randomization, and cryotherapy technique are documented in previous publications.STRUCTURAL OUTCOMEEach child underwent a standardized, comprehensive eye examination performed by a study-certified ophthalmologist. Ultrasonography was required for both eyes if the view of the fundus was obscured in one or both eyes. At the conclusion of the examination, the ophthalmologist categorized any residua of ROP that were observed in the posterior retina,using the definitions in Figure 1.Figure 1.Structural outcome categories.FUNCTIONAL OUTCOME: VISUAL ACUITYThe primary functional outcome, distance recognition visual acuity, was evaluated by linear Snellen (letter) testing with the visual acuity charts that were used in the Early Treatment Diabetic Retinopathy Study (ETDRS) (Lighthouse, Inc, New York, NY).These charts give results in units of the log of the minimum angle of resolution. The ETDRS charts are a modified version of the standard Snellen chart. Because most ophthalmologists are familiar with the term Snellento describe letter recognition visual acuity testing, we have used this term to refer to the charts, associated testing procedures, and results.Prior to testing, the child underwent manifest refraction using a chart other than the ETDRS charts, or if manifest refraction was not possible, noncycloplegic retinoscopy was conducted. If either the sphere or the cylinder of the refractive error differed by more than 0.50 diopters from the glasses that the child was wearing, the child’s best-corrected visual acuity was tested while wearing trial frames or lens carriers clipped to the current glasses to achieve best correction.Best-corrected visual acuity was measured by study-trained and study-certified testers at each study center. Acuity was recorded as the Snellen value of the line containing the smallest letter size for which the child could identify correctly 3 of the 5 letters on the line.Prior to testing, each child was given a pretest requiring the binocular identification of 10 individual letters 6 cm in height (at a distance of 0.7-1.5 m) either by name or by matching to a lap board. If the child correctly identified 9 of 10 consecutive letters, monocular distance acuity testing was undertaken using the distance ETDRS charts. Standard test distance was 4 m, but testing at 1 m or 0.5 m was permitted if needed to obtain an acuity measurement. Children who could not pass the pretest were developmentally unable, were uncooperative, or had extremely low form-discrimination visual capability.Monocular testing of the right eye was conducted first and began with the 20/200 line on ETDRS chart 1. The child was asked to identify all letters on each line until a line was reached on which the child could read none of the letters. Testing of the right eye was followed by testing of the left eye, beginning with the 20/200 line on ETDRS chart 2. Children who were unable to perform Snellen acuity testing on one or both eyes had the untestable eye or eyes assessed for the presence of light perception and gross pattern vision. Light perception was tested with a pen light, a Finoff light, or an indirect ophthalmoscope. If light perception was present, the tester presented the lowest spatial frequency (0.32 cycle/cm) Teller acuity card.Test distance was 55 cm but the card could be moved to 38 cm or 19 cm if necessary to detect pattern vision.Testers were masked to the location of the grating on the card until they presented the card enough times to determine whether the child could detect the grating with the eye that was being tested. An eye in which detection of the grating stripes was confirmed (but in which ETDRS acuity could not be measured) was coded as visual acuity of 20/200 or worse (ie, an unfavorable visual acuity outcome). This coding was based on data from the CRYO-ROP examination at 5.5 years, in which all children were tested with both ETDRS acuity charts and grating acuity cards.DATA ANALYSISA Mantel-Haenszel test combining data from participants with bilateral threshold disease and participants with asymmetric threshold disease was used to compare the outcome for treated eyes and control eyes.Outcome data were tabulated from the 1- to 15-year visits to examine the pattern over time and to report detachments that occurred between the 10- and 15-year visits. Also, a scatter diagram was used to show the relationship between visual outcome at the 10-year and the 15-year visit.RESULTSAt the 10-year outcome visit,198 of the 255 surviving CRYO-ROP participants had residual vision in at least one eye that had developed threshold ROP;this qualified them for the 15-year outcome assessment (Figure 2). An additional 57 children were exempted from participation in the 15-year examination because of blindness and total retinal detachment in the studied eyes, as determined at a previous study examination. Children who had bilateral threshold ROP (both eyes included in the study) were exempted only if both eyes met the criteria of blindness and total retinal detachment. One of the children in the exempted group died between the 10-year and 15-year study examinations; thus, there were 56 children in the exempted group at 15 years. Of the 198 participants with sight, 163 were examined at 15 years, including 136 in the bilateral threshold ROP group (one eye treated with cryotherapy and the fellow eye serving as a control) and 27 children in the asymmetric group. Data from the 163 examined children and the 56 participants with predetermined unfavorable outcomes are included in the present outcome analysis, for a total sample of 202 treated eyes and 197 control eyes (Figure 2).Figure 2.Flowchart showing the status of eligible infants with respect to follow-up at 15 years. ROP indicates retinopathy of prematurity.OPHTHALMOSCOPYTable 1shows the outcome of the fundus examination for the 189 treated eyes and 190 control eyes in which residua of ROP could be categorized. The primary data in Table 1 overrepresent the proportion of eyes with retinal detachment in the study population. This is owing to inclusion of data from all eyes of the 56 participants exempted from the 15-year examination because of a prior determination of blindness and total retinal detachment, yet inclusion of data from only a partial sample (163) of the 198 participants known to have vision in at least one study eye at previous examinations (Figure 2). To compensate for this bias, a sampling weight, 163 (82.3%) of 198 participants, rather than 100%, of exempted eyes was computed to correct for the missed examinations among the participants with sight. In essence, this adjustment assumes that had the same follow-up protocol been used for all participants, only 82.3% of the exempted eyes would have been followed up. After adjustment by this weighting factor, the percentage of eyes showing an unfavorable structural outcome at 15 years was 30.0% (54/180) for treated eyes and 51.9% (94/181) for control eyes (P<.001).Table 1. Categorization of Retinal Residua of ROP at 15-Year ExaminationOutcome Category*No. of Treated EyesAdjusted TotalNo. of Control EyesAdjusted TotalFavorable1604122915334284A3126387Unfavorable4B364C3251165A413602Vitrectomy214Exempt50 (41)†5450 (41)†94Unable to gradeNot gradable137Total202180197181Abbreviation: ROP, retinopathy of prematurity.*See Figure 1for definitions of retinal outcome categories. Outcome category was determined by ultrasonography in 4 eyes that afforded an inadequate view of the fundus. In 2 cases for which it was indicated, ultrasonography was not performed.†Adjusted from 50 to 41 (82.3%) for disproportionate structural follow-up rates (see “Ophthalmoscopy” subsection of the “Results” section in text).Among the group of participants with bilateral threshold ROP (one eye was randomized to cryotherapy and the fellow eye served as a control) were 50 who showed discordant outcomes in their 2 eyes (not shown in Table 1). Of these participants with bilateral threshold ROP, 43 had a favorable structural outcome in the treated eye and an unfavorable structural outcome in the control eye and 7 had an unfavorable structural outcome in the treated eye and a favorable structural outcome in the control eye.VISUAL ACUITYVisual acuity results were obtained for 160 of the 163 children examined. Data were also included from the 56 participants who were exempted from the 15-year examination owing to blindness and total retinal detachment documented on a previous examination. As shown in Table 2, a sampling weight (160 [80.8%] of 198 participants), rather than 100%, of exempted eyes was applied to correct for the missed examinations among the sighted participants. Once again, this assumes that had the participant been studied according to the follow-up protocol at 15 years, only 80.8% would have been followed up. With this adjustment, the results showed unfavorable visual acuity outcomes at the 15-year examination in 44.7% (85/190) of treated eyes and 64.3% (119/185) of control eyes (P<.001).Table 2. Recognition Visual Acuity (VA) Outcome at 15-Year ExaminationVA OutcomeNo. of Treated EyesAdjusted TotalNo. of Control EyesAdjusted TotalFavorable 20/20 or better1218 Worse than 20/20 but 20/40 or better3427 Worse than 20/40 but 20/60 or better237 Worse than 20/60 but better than 20/200361051466Unfavorable Equal to or worse than 20/2001617 Equal to or worse than 20/200 (not quantifiable with ETDRS charts)*1312 Blind1650 Exempt50 (40)†8550 (40)†119Total200190195185Abbreviation: ETDRS, Early Treatment of Diabetic Retinopathy Study.*Eyes in which a recognition acuity score was not obtained owing to VA worse than 20/200 at 0.5 m or to the child’s neurodevelopmental delay, but in which the tester was able to verify detection of the 0.32-cycle/cm grating on the Teller acuity card.†Adjusted from 50 to 40 (80.8%) for disproportionate VA follow-up rates (see “Visual Acuity” subsection of “Results” section in text).Among the group of participants with bilateral threshold ROP, there were 66 who showed discordant visual acuity outcomes between their fellow eyes (not shown in Table 2). Of these, 52 had a favorable visual acuity outcome in the treated eye and an unfavorable visual acuity outcome in the control eye and 14 had an unfavorable visual acuity outcome in the treated eye and a favorable visual acuity outcome in the control eye.COMPARISON OF TREATED AND CONTROL EYES OVER TIMETable 3provides a cross-sectional analysis of data on the percentage of treated and control eyes that showed an unfavorable structural outcome at the 1-, 3.5-, 5.5-, 10-, and 15-year CRYO-ROP examinations. There is a gradual increase in the percentage found to be unfavorable in both treatment groups, as well as a small increase with time in the percentage difference in unfavorable structural outcomes between treated and control eyes.Table 3. Summary of Structural and Recognition Visual Acuity Outcomes From 1-Year Examination to 15-Year Examination*CRYO-ROP Examination, yUnfavorable Structural OutcomesUnfavorable Visual Acuity OutcomesTreated EyesControl EyesDifferenceTreated EyesControl EyesDifference125.144.719.6†††3.526.145.419.346.6‡57.5‡10.9‡5.526.945.418.547.161.714.61027.247.920.744.462.117.715§30.051.921.944.764.319.6Abbreviation: CRYO-ROP, Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.*Values are expressed as percentages.†Recognition visual acuity not measured at 1 year.‡Crowded HOTV Recognition Visual Acuity Test used.§Adjusted for disproportionate follow-up rates (see “Ophthalmoscopy” and “Visual Acuity” subsections of “Results” section).Table 3also presents the proportion of treated and control eyes with unfavorable visual acuity results at the 4 outcome ages at which recognition visual acuity was measured (ages 3.5, 5.5, 10, and 15 years). Comparison in visual acuity across time requires interpretation because the crowded HOTV recognition visual acuity test was used at the 3.5-year examination while the ETDRS acuity charts were used at the older ages and because ETDRS visual acuity could not be assessed in about 15% of patients at the 5.5-year examination. However, comparison of results between the 10-year and 15-year examinations, in which ETDRS visual acuity results were obtained from nearly all sighted eyes, showed little change over time in the proportion of treated eyes with unfavorable outcomes but an increase over time in the proportion of control eyes showing an unfavorable visual acuity outcome. In addition, there was an increase in the percentage difference of unfavorable acuity outcomes between treated and control eyes.Examination of the results from the 10-year examination for the 201 treated eyes and the 196 control eyes that were tested at 15 years showed that structural outcome at 10 years was in category 1, 2, or 3 (ie, no worse than macular ectopia) (Figure 1) for 134 treated eyes and 92 control eyes. As presented in Table 4, among this group of eyes with favorable outcomes at 10 years, there were 6 treated eyes (4.5%) and 7 control eyes (7.7%) that developed a retinal fold, retinal detachment, or the posterior pole was obscured by an ROP-related abnormality (category 4C or 5A) between the 10-year and 15-year examinations. Among this group of 13 eyes with a significant change in structural outcome, 4 had an essentially normal posterior pole (category 1), 2 had abnormally straightened temporal retinal vessels (category 2), and 7 had macular ectopia (category 3) at the 10-year examination. Of the 13, there were 5 structurally unfavorable eyes in which the fundus could not be directly viewed (1 in category 4C, 2 in category 5, and 2 in category 5A) at the 15-year examination. These 5 eyes had cataracts, and the examiner could not see posterior to the lens. None of these eyes underwent any type of surgery subsequent to outcomes determined at 10 years. All 5 underwent ultrasonography to categorize their 15-year outcome, and 3 showed total retinal detachment. Both control eyes in category 5 showed total retinal detachment. The treated eye classified as 4C (view of posterior pole blocked) had band keratopathy and moderate corneal stromal opacity, with posterior vitreous abnormalities on ultrasonography. Of the 2 treated eyes in category 5A (all fundus view obstructed), 1 had total retinal detachment with band keratopathy and corneal stromal opacity. The remaining eye had moderate corneal stromal opacity with a corneal diameter of 8 mm and a pupil that dilated only to 2 mm, but ultrasonography did not demonstrate retinal detachment.Table 4. New Appearance of Serious Structural Sequelae Between the 10-Year and 15-Year Examinations15-Year ExaminationNo. of Eyes With Structural Outcome Categories 1, 2, or 3 at 10 y*Treated EyesControl EyesNo retinal fold or detachment12784Retinal fold or detachment6 (4.5%)7 (7.7%)4A234B124C105025A20Unable to grade11Total13492*See Figure 1for definitions of retinal outcome categories.Figure 3provides a comparison between visual acuity results at the 10-year and 15-year examinations for treated eyes and control eyes. For most treated eyes, there was little change in acuity with age. However, 3 eyes that had measurable acuity at 10 years (20/160, 20/1280, and 20/1600) were blind at 15 years. Two of these eyes had total retinal detachment, and the third had the posterior pole obscured by an ROP-related abnormality (category 4C) at the 15-year examination. In 1 eye that could not be tested at 10 years because the child could not perform the ETDRS visual acuity pretest by naming or matching 6-cm high letters, a visual acuity of 20/640 was measured at the 15-year examination.Figure 3.Comparison of visual acuity at 10 years vs at 15 years in (A) eyes treated with cryotherapy and (B) control eyes (not treated with cryotherapy). The diagonal line indicates equal acuity at the 2 ages. Blind indicates being unable to identify letters on the 20/200 line when tested at a distance of 0.5 m at 15 years (equivalent to 20/1600) and unable to detect the grating on the 0.32-cycle/cm Teller acuity card. At 10 years, testing at 0.25 m or 0.125 m was permitted, allowing quantification of acuity down to 20/6400 equivalent; CPP (10-year examination), cannot pass pretest (ie, the child was unable to identify large letters presented at a near distance; vision was better than light perception when tested with Teller acuity cards,but recognition (letter) acuity could not be quantified; TAC (15-year examination), Teller acuity card, better vision than light perception but not quantifiable on recognition acuity testing; 0.32-cycle/cm Teller acuity card was used because child was neurodevelopmentally delayed or because vision was too poor to allow recognition of the 20/200 letter at 0.5 m.For control eyes (Figure 3B), visual acuity was also generally stable between the 10-year and 15-year examinations, with most eyes showing little change in acuity with age. Four eyes that had measurable acuity at 10 years (20/400, 20/500, 20/1600, and 20/5120) were blind at 15 years. The 2 eyes that had acuities of 20/500 and 20/5210 at 10 years had total retinal detachment at 15 years. The remaining 2 eyes had macular ectopia (category 3) at the 15-year examination. Macular ectopia alone is not ordinarily associated with blindness; the eye that had an acuity of 20/400 at 10 years had microcornea in the presence of uniocular high myopia at 15 years, and the eye that had an acuity of 20/1600 at 10 years underwent vitrectomy (without retinal detachment) prior to age 7 years. One eye that was found to be blind at 10 years showed measurable acuity of 20/500 at the 15-year examination. This eye had macular ectopia at the 10-year examination, and although posterior pole status could not be formally categorized at the 15-year examination, there was extreme vascular attenuation and extensive pigmentary degeneration.COMMENTThis article presents the final results of assessment of ocular structure and visual function for the eyes of children who participated in CRYO-ROP. The results confirm the benefit of peripheral retinal ablation for severe (threshold) ROP that was reported in previous publications from CRYO-ROP.At 15 years, there remained a decrease of more than 40% in unfavorable structural outcomes and a decrease of approximately 30% in unfavorable visual acuity outcomes in treated eyes, as compared with control eyes.Comparison of structural outcome results at 15 years with results from prior study examinations (Table 3) showed that although the benefit of peripheral retinal ablation persists across time, there was a gradual increase in unfavorable structural outcomes between the 1-year and 15-year outcome assessments. In treated eyes, this increase averaged 0.35% per year, while it averaged 0.51% per year in control eyes. For visual acuity outcomes, comparison of results across time is possible only between the 10- and 15-year examinations because of differences in visual acuity tests and in testability of study participants at earlier vs later study examinations. Comparison of outcomes between 10 and 15 years (Table 3) showed that visual acuity of treated eyes remained virtually stable during this 5-year interval, with an average increase in unfavorable outcomes of only 0.06% per year, while the visual acuity of control eyes showed an increase in unfavorable outcomes that averaged 0.44% per year.An important goal of the 15-year outcome assessment was to determine the incidence of retinal detachment in both treated and control eyes during the preteen and early teenage years. As summarized in Table 4, new retinal detachments were observed in both treated and control eyes. These adverse events occurred in eyes that were judged at the 10-year examination to have normal or nearly normal posterior poles or macular ectopia without folding. These developments indicate the importance of continued follow-up of eyes with a history of severe acute-phase ROP, even in the absence of observable posterior pole residua as late as age 10 years.Results from CRYO-ROP examinations conducted at 3.5, 5.5, and 10 years indicated that eyes that were saved from blindness by cryotherapy developed visual acuity that was better than 20/200 but worse than the normal range for age.This finding was confirmed at the 15-year examination, in which the incidence of blindness was reduced from 55.1% (102/185) in control eyes to 36.3% (69/190) in treated eyes, while the proportion of eyes with visual acuity between 20/20 and 20/200 was increased from 25.9% (48/185) in the control group to 48.9% (93/190) in the treated group. Thirty eyes had visual acuity of 20/20 or better at the 15-year examination (Table 2). These data show that it is possible to achieve normal adult visual acuity following threshold ROP. Overall, the data suggest that the benefit of cryotherapy occurred primarily among eyes that would likely have been blind without treatment and that visual acuity was improved in these eyes to better than 20/200 but not necessarily to 20/20 or better.In summary, examination of ocular structure and visual function in a large cohort of children who had severe ROP early in life indicated that the benefit of cryotherapy persists well into the second decade of life. However, the results also indicated that ROP may represent a lifelong disease since a number of eyes, both cryotherapy-treated and noncryotherapy-treated, developed retinal detachment, blindness, and other ROP-related complications between ages 10 and 15 years. These results highlight the need for continued ophthalmologic follow-up of children with a history of severe ROP.Correspondence:Earl A. Palmer, MD, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197 (palmere@ohsu.edu).Submitted for Publication:September 1, 2004; final revision received November 3, 2004; accepted November 3, 2004.Funding/Support:The CRYO-ROP is supported by cooperative agreement EY05874 from the National Eye Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md. Indirect support has come from unrestricted grants from Research to Prevent Blindness, New York, NY.Cryotherapy for Retinopathy of Prematurity Cooperative GroupWriting CommitteeEarl A.PalmerMD, (chair); Robert J.HardyPhD; VelmaDobsonPhD; Dale L.PhelpsMD; Graham E.QuinnMD; C. GailSummersMD; Carol P.KromBA; BettyTungMS.Clinical CentersThe CRYO-ROP investigators who participated during the 15-year examination period are as follows:The Children&apos;s Hospital, Birmingham, Ala: Frederick J. Elsas, MD (principal investigator); Michelle Mizell; Brooke Williams, CPA; Douglas Witherspoon, MD (coinvestigators). Children&apos;s Hospital National Medical Center, Georgetown University Medical Center, George Washington University Medical Center, and Washington Hospital; Washington, DC:William S. Gilbert, MD (principal investigator); David Plotsky, MD (coprincipal investigator); Patricia Ann Mercer, MPA (coinvestigator). Jackson Memorial Hospital, Miami, Fla:Hilda Capó, MD (principal investigator); Mimi Garcia; Rose Anne Johnson, RN; Timothy G. Murray, MD (coinvestigators). University of Illinois Eye and Ear Infirmary, Chicago, Ill, Loyola University, Maywood, Ill, and Lutheran General Hospital, Parkwood, Ill:Lawrence M. Kaufman, MD, PhD (principal investigator); Nydia Santiago; Katrice Weaver, CO; Michael Shapiro, MD (coinvestigators). Riley Hospital, Wishard Memorial Hospital, and University Hospital; Indianapolis, Ind:Naval Sondhi, MD (principal investigator); Melissa Fields, COT (coinvestigator). University of Louisville Hospital, Norton Kosair Children&apos;s Hospital; Louisville, Ky:Charles C. Barr, MD (principal investigator); Diane Denning, BA, COT; Craig H. Douglas, MD; Peggy H. Fishman, MD; Gregory K. Whittington, PsyS (coinvestigators). Tulane Medical Center, New Orleans, La:Robert A. Gordon, MD (principal investigator); James G. Diamond, MD; Elaine Eckols; Deborah Farrae; Debbie Neff, LPN (coinvestigators). The Johns Hopkins Hospital, Baltimore, Md:Michael X. Repka, MD (principal investigator); Sheena Broome, OC, COA; Julia A. Haller, MD; Stephen P. Kraft, MD (coinvestigators). William Beaumont Hospital and Children&apos;s Hospital of Michigan; Detroit:John D. Baker, MD (principal investigator); Michael T. Trese, MD (coprincipal investigator); Patricia Manatrey, RN (coinvestigator). Fairview-University Medical Center, Minneapolis, Minn:C. Gail Summers, MD (principal investigator); Donna K. Knobloch; Jane D. Lavoie, CO; Timothy W. Olsen, MD (coinvestigators). Upstate New York Center: Rochester, Syracuse, Buffalo: University of Rochester, Rochester:Dale L. Phelps, MD (principal investigator); Karen Atkins, Ernest Guillet, MD; Robert Hampton, MD; Cassandra Horihan; Gary Markowitz, MD; Walter Merriam, MD; Robert Olsen, MD; Sheree Seeley; Richard Simon, MD; Donald H. Tingley, MD; Paul Torrisi, MD (coinvestigators). Duke Eye Center, Durham, NC:Edward G. Buckley, MD (principal investigator); Malcolm M. (Greg) Anderson, Jr, PAC; Lois Duncan, CO (coinvestigators). Cincinnati, Ohio:Miles J. Burke, MD (principal investigator). Columbus Children&apos;s Hospital, Ohio State University Hospital, Columbus:Gary L. Rogers, MD (principal investigator); Don L. Bremer, MD (coprincipal investigator); Rae R. Fellows, MEd; Alan D. Letson, MD; Mary Lou Kachmer McGregor, MD; Teresa Rinehart (coinvestigators). Casey Eye Institute, Oregon Health & Science University, Portland:Earl A. Palmer, MD (principal investigator); Lee R. Hunter, MD (Jacksonville, Fla); Carol P. Krom, Eileen Royster (coinvestigators). Children&apos;s Hospital of Philadelphia, Pa:Graham E. Quinn, MD (principal investigator); Gary C. Brown, MD; Jane C. Edmond, MD; Brian J. Forbes, MD; Jamie Koh, RN, MSN; Albert M. Maguire, MD; Sheryl J. Menacker, MD; Monte D. Mills, MD; William Tasman, MD; Martin C. Wilson, MD; Terri L. Young, MD; Sonia Zhu (coinvestigators). University of Pittsburgh, The Eye and Ear Institute of Pittsburgh, Children’s Hospital of Pittsburgh; Pittsburgh, Pa:Kenneth P. Cheng, MD (principal investigator); Kim Bauer; Margaret Schramm, MS, MPH (coinvestigators). Medical University Hospital, Charleston, SC:Richard A. Saunders, MD (principal investigator); Lisa Langdale, RN, MSN; Kimberley D. Lenhart, COA; Amy K. Hutchinson, MD; M. Edward Wilson, MD (coinvestigators). Vanderbilt University Hospital, Nashville, Tenn:Sean P. Donahue, MD, PhD (principal investigator); Cindy L. Foss, BBA; Michael Redmond, MD; Robbin Sinatra, MD; Elizabeth Vargas, COT (coinvestigators). Methodist Medical Center, Parkland Memorial Hospital, St Paul Hospital, Medical City Dallas Hospital, and Presbyterian Hospital; Dallas, Tex:Rand Spencer, MD (principal investigator); Jean Arnwine; Sally Arceneaux; Joel N. Leffler, MD (coinvestigators). University of Texas Health Science Center-Medical Center, San Antonio:W. A. J. van Heuven, MD (principal investigator); Maria B. Montéz, RN, MSHP (coinvestigator). University of Utah Hospital, Salt Lake City:Robert O. Hoffman, MD (principal investigator); Susan Bracken, RN, BS; Andrew Jordan, MD; Pat Remington; Michael Teske, MD (coinvestigators).Resource Centers, Project Officers or Managers, Principal Investigators, Study Chairman, and CoinvestigatorsNational Eye Institute, Bethesda, Md:Donald F. Everett, MA (project officer). Casey Eye Institute, Oregon Health & Science University, Portland:Earl A. Palmer, MD (principal investigator and study chairman); Carol Krom; Sandra Newton (project managers). School of Public Health, Coordinating Center for Clinical Trials, University of Texas Health Science Center, Houston:Robert J. Hardy, PhD (principal investigator); Betty Tung, MS (project manager). University of Arizona School of Medicine, Tucson:Velma Dobson, PhD (principal investigator); Graham E. Quinn, MD (coinvestigator).CommitteesExecutive committee: permanent members:Earl A. Palmer, MD (chair); Velma Dobson, PhD; Rae R. Fellows, MEd; Robert J. Hardy, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD; C. Gail Summers, MD. Ex-officio members:Donald F. Everett, PhD; Carol P. Krom, BA; Betty Tung, MS.Editorial committee: permanent members:Earl A. Palmer, MD (chair); Velma Dobson, PhD; Robert J. Hardy, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD; C. Gail Summers, MD. Ex-officio members:Carol P. 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JAMA OphthalmologyAmerican Medical Association

Published: Mar 1, 2005

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