Effect of Acute-Phase Retinopathy of Prematurity on Grating Acuity Development in the Very Low Birth Weight Infant

Effect of Acute-Phase Retnopathy of Prematurty on Gratng Acuty Development n the Very Low Brth Weght Infant Velma Dobson* Graham E. Qurng C. Gal Summers,X Rchard A. Saunders,\ Dale L. Phelps,\\ Betty Tung,^ and Earl A. Palmer# for the Cryotherapy for Retnopathy of Prematurty Cooperatve Group Purpose. To examne the development of gratng acuty n four groups of eyes n the Multcenter Study of Cryotherapy for Retnopathy of Prematurty (CRYO-ROP): eyes wth no ROP; eyes wth less-than-prethreshold ROP; eyes wth prethreshold ROP; and eyes wth threshold ROP that were randomzed to serve as controls (not treated wth cryotherapy). Methods. Subjects were 398 chldren wth brth weghts <25 g whose acute-phase ROP was documented as part of the CRYO-ROP study. Monocular gratng acuty was measured usng the Teller acuty card procedure when chldren reached, 2, 3'/ 2, and 4'/ 2 years of age. Results. Eyes n the no-rop and less-than-prethreshold groups showed nearly dentcal acuty development. Eyes wth predreshold ROP showed mean acuty smlar to the no-rop group at and 2 years, but slghdy below the no-rop group at 3'/ 2 and 4'/ 2 years. Only 50% of eyes n the threshold untreated ROP group had measurable acuty. These eyes showed mean acuty scores that were approxmately octave below tfose of the no-rop group at all four test ages. When data from eyes wth ROP resdua or other ocular abnormaltes, and data from eyes of chldren who were unable to pass the study developmental screenng tems, were excluded, acuty development was smlar among groups. Conclusons. Mld (less-dan-prethreshold) ROP has no effect on de development of gratng acuty n chldren between and 4'/ 2 years of age. Moderate (prethreshold) ROP s assocated wth reduced acuty at 3V2 and 4'/ 2 years. In general, severe (threshold untreated) ROP results n moderate to severe reductons n acuty at all ages between and 4 '/ 2 years. However, a small number of chldren wth severe ROP show normal acuty development. Invest Ophthalmol Vs Sc. 994; 35:4236-4244. From the * Departments of Psychatry and Psychology, Unversty of Pttsburgh, Pttsburgh; the ^Dvson of Pedatrc Ophthalmology, Chldren's Hosptal of Phladelpha, and the Schee Eye Insttute, Unversty of Pennsylvana, Phladelpha, Pennsylvana; the %Departments of Ophthalmology and Pedatrcs, Unversty of Mnnesota, Mnneapols, Mnnesota; the Storm Eye Insttute, Medcal Unversty of South Carolna, Charleston, South Carolna; the ^Departments of Pedatrcs and Ophthalmology, Unversty of Rochester, Rochester, New York; the ^School of Publc Health, Unversty of Texas Health Scence Center at Houston, Texas; and the # Casey Eye Insttute, Oregon Health Scences Unversty, Portland, Oregon. Supported by Cooperatve Agreement 5 UJO EY05874 from the Natonal Eye Insttute, Natonal Insttutes of Health, Bethesda, Maryland. Submtted for publcaton fanuary 25, 994; revsed fuly 8, 994; accepted July 8, 994. Propretary nterest category: C. Presented n part at the Annual Meetng of the Assocaton for Research n Vson and Ophthalmology, Sarasota, Florda, May 993. Reprnt requests: Earl A. Palmer, MD, CRYO-ROP Headquarters, Casey Eye Insttute, Oregon Health Scences Unversty, 3375 SW Terwllger Boulevard, Portland, OR 9720-497. Jvecent modfcatons of preferental lookng technques have made t possble to quantfy gratng vsual acuty n nfants and chldren n clncal settngs. ' 2 One mportant use of these technques has been to document the outcome of treatments of ocular dsorders n nfants. Such treatments nclude cryotherapy for potentally blndng retnopathy of prematurty (ROP) experenced by some very low brth weght (VLBW) nfants 34 and vtrectomy for retnal detachment after ROP. 5 " 7 Another mportant use of preferental lookng tests of gratng acuty has been to document vsual development n chldren who had ROP durng the neonatal perod. An ntal study, n whch relatvely few patents were tested, reported that nfants who 4236 Investgatve Ophthalmology & Vsual Scence, December 994, Vol. 35, No. 3 Copyrght Assocaton for Research n Vson and Ophthalmology

Gratng Acuty After Acute-Phase ROP 4237 experenced mld-to-moderate ROP that dd not result n retnal resdua show acuty development smlar to that of nfants who dd not have ROP. 8 In contrast, chldren wth retnal resdua of more severe ROP show below-normal acuty scores. 9 ' 0 Recently, acuty testng of 340 nfants at 20 to 40 weeks corrected age (age from term due date) confrmed that there s a sgnfcant decrease n acuty wth ncreasng severty of acute-phase ROP, even n nfants who have no apparent ROP resdua." As part of the contnung follow-up of patents n the Multcenter Study of Cryotherapy for Retnopathy of Prematurty (CRYO-ROP), gratng acuty was assessed at ages, 2, 3 '/ 2, and 4 '/ 2 years n a large cohort of chldren wth brth weghts less than 25 g; ROP developed n the majorty of them durng the neonatal perod. 2 Ths artcle descrbes the development of gratng acuty n the CRYO-ROP populaton and evaluates the nfluence of severty of ROP on acuty development. MATERIALS AND METHODS CRYO-ROP Study Descrpton The CRYO-ROP study enrolled nfants wth brth weghts <25 g, born between January, 986, and November 30, 987, at 23 study centers n the Unted States. Four thousand nnety-nne nfants were enrolled n a natural hstory study of ROP. Ophthalmc examnatons began 4 to 7 weeks after brth and were repeated at defned ntervals 3 untl the retna was fully vascularzed or untl any ROP that developed had ether resolved or progressed to a severty that qualfed for enrollment n the randomzed tral of cryotherapy. Of the 4099 patents enrolled n the natural hstory study, 28 entered the randomzed porton of the tral after they developed threshold ROP, defned as at least 5 contguous or 8 cumulatve clock hours of stage 3 + ROP n zone or 2. 4 An addtonal 73 patents not born at a study hosptal also partcpated n the randomzed porton of the study. Patents wth blateral threshold ROP had one eye randomzed to cryotherapy; the other eye dd not receve cryotherapy and served as a control. Patents n whom threshold ROP developed n only one eye had that eye randomzed to cryotherapy or control. Patents Subjects n ths report are the 398 CRYO-ROP patents who had gratng acuty measured at one or more of the -, 2-, 3 '/ 2 -, and 4 '/ 2 -year follow-up examnatons. Two hundred forty-sx of the 398 patents n ths report were partcpants n the randomzed porton of the study. Each randomzed patent's gratng acuty was measured at, 2, 3 '/ 2, and 4 '/ 2 years after randomzaton at one of the 23 partcpatng study centers. Only data from the untreated eyes are reported here; data from treated eyes were excluded because our goal was to examne the natural hstory of vsual development n VLBW nfants. Eyes that underwent cryotherapy may have had an altered course of acuty development. The remanng 52 patents were partcpants n the nonrandomzed porton of the CRYO-ROP study. These patents were enrolled at one of the fve study centers (Columbus, Mnneapols, Phladelpha, Portland, and upstate New York) where patents n the nonrandomzed porton of the CRYO-ROP study were followed after the -year examnaton. Nonrandomzed patents at the remanng 8 study centers dd not receve sequental gratng acuty testng because of fundng lmtatons. The CRYO-ROP study followed the tenets of the Declaraton of Helsnk, and nformed consent was obtaned after the study was explaned to parents of partcpants. Insttutonal human expermentaton commttee approval was granted at each study center. Procedure Each patent's monocular gratng acuty was assessed usng the Teller Acuty Card procedure. Testers were unaware of the ROP status of each eye and of whether ether eye had receved cryotherapy. 56 When vson was so poor that t could not be assessed wth the standard Teller Acuty Cards, eyes were tested wth the Low Vson (LV) Teller Acuty Card, whch contans a large (25 X 23 cm) area of 2.2-cm-wde strpes. Responses to the LV card were not quantfed because the tester was allowed to hold the card at any dstance, n any part of the vsual feld, and to move the card to determne whether a response to the pattern was present. If no response to the LV card was obtaned, the tester used a penlght to evaluate whether lght percepton or no lght percepton was present. Chldren were exempt from acuty testng and both eyes were scored as havng no pattern vson f both the followng crtera were met: Physcan and parents agreed that the chld's vson was, at best, lght percepton, and both eyes had total retnal detachment, phthss bulb, or enucleaton. Also, at the 2-, 3V 2 -, and 4'/ 2 -year examnatons, a patent was exempt from acuty testng f both the physcan and the parents agreed that the chld had no lght percepton n ether eye. Vsual acuty results were consdered fnal and were entered nto the data analyses only f amblyopa had been treated accordng to the study protocol (at least 4 weeks f therapy was ongong, or at least 75 days f therapy had been prescrbed at an earler age), and substantal refractve errors had been corrected

4238 Investgatve Ophthalmology 8c Vsual Scence, December 994, Vol. 35, No. 3 for at least 4 weeks before acuty testng. By study protocol, spectacle correcton was requred for myopa greater than 4.75 D at and 2 years, greater than -3.00 D at 3'/ 2 years, and greater than -2.00 D at 4'/a years. Correcton was requred for hyperopa greater than +6.00 D at and 2 years, greater than +5.00 D at 3'/ 2 years, and greater than +4.00 D at 4'/ 2 years. Correcton was also requred for astgmatsm greater than 3.00 D at and 2 years, greater than 2.00 D at 3'/a years, and greater than.50 D at 4'/ 2 years; and for ansometropa greater than 2.00 D at, 2, 3 '/>>, and 4 '/ 2 years, f the physcan judged amblyopa to be present. 7 After acuty assessment by the vson tester at each age, a certfed study ophthalmologst conducted an eye examnaton. 7 ROP resdua were recorded on a detaled study form, and an overall ROP dagnoss was assgned, based on the Reese classfcaton and on the Internatonal Classfcaton of ROP. 37 " 9 Screenng tems selected from the Denver Developmental Screenng Examnaton were used at each age to categorze developmental status. A chld passed the developmental screenng at year f, at the tme of the study examnaton, he or she was observed to st unsupported, to grasp an object and resst havng t removed, and to respond to a sound. At 2 years, the screenng was passed f the chld, by observaton at the tme of the examnaton or by hstory, was successful at self-feedng, used three words, and could walk more than three steps. At 3'/ 2 years, the screenng was passed f the chld could copy a crcle durng the examnaton, put on a shrt and shoes by hstory, and gve frst and last names by hstory or at the tme of the examnaton. At 4% years, the screenng was passed f the chld by observaton or by hstory could answer what to do f cold, tred, and hungry, could balance on each foot for more than 3 seconds, and could follow three of four commands to place an object under, on, n front of, and behnd a char. Data Analyss To prevent the unequal representaton of patents that arses when data from one eye of some patents and both eyes of other patents are ncluded n statstcal analyses, data were ncluded from only one eye of each patent. For patents n the nonrandomzed group, the eye was selected at random. For patents n the randomzed group, the eye selected was the untreated (control) eye. No data from eyes that receved cryotherapy were ncluded n ths study of the natural hstory of vsual development n VLBW nfants. Eyes were categorzed nto four groups on the bass of the hghest acute-phase retnopathy that was observed durng the pernatal perod. The groups were: () eyes wth no ROP; (2) eyes wth ROP that was less than prethreshold; (3) eyes wth prethreshold ROP, where prethreshold ROP was defned as any stage of ROP n zone, stage 2 wth plus dsease n zone 2, stage 3 wthout plus dsease n zone 2, or fewer than 5 contguous or 8 cumulatve clock hours of stage 3 + ROP n zone or zone 2; and (4) untreated (control) eyes wth threshold ROP, as defned above. For certan analyses, descrbed n detal n the Results secton, data from eyes wth amblyopa were excluded. At the - and 2-year study vsts, amblyopa was dagnosed by abnormal fxaton behavor, compared to normal fxaton behavor n the fellow eye, n eyes wth favorable structural outcomes. ("Favorable" was defned at 2 months and older to nclude normal posteror pole, abnormal angle of temporal vessels, macular heterotopa, stage 4A retnal detachment, and reu'noschss or retnal fold outsde zone ). At the 3 '/ 2 - and 4 V 2 -year study vsts, amblyopa was dagnosed as fxaton that was not mantaned, compared to mantaned fxaton n the fellow eye, n eyes that had favorable structural outcomes. For categorzaton of acuty results, eyes were judged to have ether a "favorable" or an "unfavorable" acuty outcome. Crtera for an unfavorable outcome were: gratng acuty < 0.8 cyc/deg at year, < 2.2 cyc/deg at 2 years, or < 6.4 cyc/deg at 3'/a or 4'/ 2 years. 3 ' 47 These cut-off values are approxmately octave below the bottom of the normal range at each age. Wthn the unfavorable classfcaton, eyes were categorzed as "very low vson or blnd" f they had no lght percepton or lght percepton only, or f they detected only the 2.2-cm-wde strpes on the LV card. Eyes were categorzed as havng "poor" vson f they had measurable acuty n the unfavorable range. Wthn the favorable classfcaton, eyes were classfed as havng "normal" vson f gratng acuty was s.6 cyc/deg at year, >4.5 cyc/deg at 2 years, or sl3 cyc/deg at 3'/ 2 or 4'/ 2 years, and as havng "below normal" vson f gratng acuty was less than normal and wthn the favorable classfcaton. For calculatons of mean acuty scores and for other statstcal analyses, gratng acuty scores were converted to logarthmc values. RESULTS Success Rates Acuty testng was consdered successful f one of the followng results was obtaned: a quanttatve acuty score, ablty to resolve only the gratng on the Low Vson Card, lght percepton only, no lght percepton, or exempton from acuty testng. As shown n Table, acuty data were obtaned from 96% to 00% of eyes at each age n the four ROP groups tested. Also shown n Table are the percentages of eyes n each group wth acute-phase ROP that met study

Gratng Acuty After Acute-Phase ROP 4239 TABLE l. Success Rates for Acuty Assessment Group Number Tested Data Obtaned Data Included* Year No-ROP eyes <Prethreshold eyes Prethreshold eyes Threshold untreated eyes 223 37 7 89 22 (99.) 308 (97.2) 7 (00.0) 85 (97.9) 24 (96.8) 298 (96.8) 65 (9.5) 58 (85.4) 2 Years No-ROP eyes <Prethreshold eyes Prethreshold eyes Threshold untreated eyes 296 4 02 202 3 Years 285 (96.3) 400 (97.3) 98 (96.) 95 (96.5) 277 (97.2) 388 (97.0) 95 (96.9) 85 (94.9) No-ROP eyes <Prethreshold eyes Prethreshold eyes Threshold untreated eyes 354 484 02 207 4 Years 350 (98.9) 479 (99.0) 00 (98.0) 202 (97.6) 344 (98.3) 47 (98.3) 99 (99.0) 94 (96.0) No-ROP eyes < Prethreshold eyes Prethreshold eyes Threshold untreated eyes 385 506 06 206 384 (99.7) 503 (99.4) 04 (98.) 205 (99.5) 380 (99.0) 499 (99.2) 00 (96.2) 94 (94.6) * Data were ncluded only f refractve errors had been corrected and anblyopa had been treated accordng to study protocol (see text). f Denomnator = N (from precedng column). crtera for ncluson n the data analyss. In these eyes, amblyopa and refractve errors had been treated accordng to the study protocol. At the 2-, 3'/a-, and 4'/2~year age, 94.6% to 99.2% of eyes wth acuty data met these crtera and were ncluded n the data analyss. The lower percentages for the prethreshold (9.5%) and threshold untreated (85.4%) groups at year occurred because acuty testng was ntroduced nto the study as patents were reachng year of age. Therefore, some patents, who by study protocol requred 4 weeks of amblyopa therapy or glasses correcton before acuty testng, could not meet these requrements to allow testng of gratng acuty wthn the tme frame allotted for the -year examnaton. Acuty Results Fgure shows the dstrbuton of acuty scores at each test age for eyes n each of the four groups wth acutephase ROP: no ROP, less-than-prethreshold ROP, prethreshold ROP, and untreated eyes wth threshold ROP. Bars on the left sde of each graph show the percentage of eyes n each group that had no pattern vson (lght percepton, no lght percepton, or exempt from acuty testng) and the percentage of eyes that could detect only the gratng on the low vson card. As prevously reported for the - and 3 '/ 2 -year study vsts, 34 approxmately half of the threshold untreated eyes were classfed as havng no pattern vson. Few eyes n the remanng three groups had vson that was ths poor. The goal of ths study was to descrbe acuty development n eyes wth quantfable acuty. Eyes classfed as havng lght percepton only, no lght percepton, or low vson only do not have acuty that s quantfable wth the Acuty Card procedure, and therefore development over tme cannot be analyzed. These eyes were excluded from further analyses. Fgure 2 shows the mean acuty scores for eyes wth quantfable acuty n each of the four groups wth acute-phase ROP at each age. For comparson, Fgure 2 also shows the 95% predcton lmts for Teller Acuty Card scores obtaned from -, 2-, 3-, and 4-year-old healthy full-term chldren wth no ocular abnormaltes, who were tested by Mayer et al 20 usng a procedure smlar to that used n the present study. Acuty results from eyes wth no ROP, eyes wth lessthan-prethreshold ROP, and eyes wth prethreshold ROP are near the lower 95% predcton lmt for

4240 Investgatve Ophthalmology 8c Vsual Scence, December 994, Vol. 35, No. 3 FIGURE l. Gratng acuty results at (A) year, (B) 2 years, (C) 3 '/ 2 years, and (D) 4 '/ 2 years for eyes n the CRYO- ROP study that had no ROP, less-than-prethreshold ROP, prethreshold ROP, and threshold ROP not treated wth cryotherapy. At all ages, approxmately 50% of the eyes wth threshold ROP that comprsed the untreated control group n the CRYO-ROP study had vson that was no better than lght percepton. Defntons of unfavorable and favorable acuty outcomes, very low vson or blnd, poor, below normal (BN), and normal (Nl) groupngs, and no lght percepton (NLP), lght percepton only (LP), and detecton of low vson card (LV) are provded n the text. Numbers n parentheses ndcate the lowest acuty values, n cyc/deg, that were ncluded n the Nl and BN groupngs at each age. Normal adult gratng acuty ranges from 30 to 60 cyc/deg. Although gratng acuty and letter acuty are not always equvalent, a gratng acuty of 6 cyc/deg s usually equated to a Snellen acuty of 20/00, 2 cyc/deg s equated to 20/ 50, and 30 cyc/deg s equated to 20/20. CRYO-ROP = Cryotherapy for Retnopathy of Prematurty. healthy full-term chldren at all four ages. Acuty results from eyes n the threshold untreated group are substantally below the lower 95% predcton lmt at all ages. A repeat measures analyss of varance was conducted on the data from eyes wth measurable acuty data that met the crtera for ncluson n the study at all four ages, to determne the effect of age and severty of retnal dsease on acuty development. The numbers of eyes ncluded n ths analyss were 70, 234, 52, and 50 for the no-rop, less-than-prethreshold, prethreshold, and threshold untreated groups, respectvely. The results showed that acuty mproved wth age (F 3 = 40., P < 0.000) and that mean acuty scores dffered sgnfcantly among the groups (F 3 = 2.7, P < 0.000). There was an age by group nteracton (F 9 = 2.5, P < 0.0), ndcatng that the rate of acuty development dffered among the four groups. Post hoc analyss (Dunnett's tests) showed that there were no statstcally sgnfcant dfferences n average acuty scores between the no-rop and the less-thanprethreshold groups or between the no-rop and the prethreshold groups, at any age. However, the group of threshold untreated eyes wth measurable acuty showed lower mean scores (P < 0.05) than those of the no-rop group at all ages. Acuty Development n the Absence of Identfable Ocular and Neurodevelopmental Abnormaltes Eyes n whch ROP develops are at rsk for a varety of ocular dsorders known to nterfere wth vsual acuty. These nclude macular heterotopa, retnal fold, and retnal detachment. 90 ' 2 Also, central nervous system A. YEAR unfavorable favorable <ery L.V. or blnd poor B.N.(.S) Nl..6) n, LP.NLP LV <0.75 0.75-.5-3.0-6.0-2.0- >-24.0.49 2.99 5.99.99 23.99 B. 2 YEARS unfavorable ry L.V. or blnd favorable B.N.2.2) Nl.4.6) 20 0 0 LL - K3 = l - ~ LP.NLP LV <0.75 0.75-.5-3.0-6.0-2.0- >-24.0.49 2.99 5.99.99 23.99 3 /2 YEARS unfavorable favorable LP.NLP LV <0.75 0.75-.5-3.0-6.0-2.0- >-24.0.49 2.99 5.99.99 23.99 D. 4 /2 YEARS unfavorable favorable very L.V. or blnd B.N.6.4) NI.I3) ru. LP.NLP LV <0.75 0.75-.5-3.0-6.0-2.0- >-24.0.49 2.99 5.99.99 23.99 GRATING ACUITY (cycles/degree) CHI THRESHOLD CONTROL 883 'PRETHRESHOLD ESS PRETHRESHOLD H NO ROP abnormaltes that can affect vsual acuty, for example, ntraventrcular hemorrhage and perventrcular leukomalaca, are often found n VLBW nfants n whom severe ROP develops. 2223 A subanalyss of the present data was conducted to determne whether eyes wth severe ROP n whch abnormaltes dd not develop that would nterfere wth vson would show acuty development smlar to that of eyes wth no ROP. In ths subanalyss, data from eyes wth the followng ocular abnormaltes were excluded at the age at whch the abnormalty appeared and at all subsequent ages: corneal cloudng, cataract, aphaka, glaucoma

424 Gratng Acuty After Acute-Phase ROP or glaucoma surgery, nystagmus, vtrectomy, abnormal straghtenng of the temporal retnal vessels, macular heterotopa, partal or total retnal detachment, retnal fold, or retnoschss, even when these latter abnormaltes dd not nvolve the posteror pole. Data were excluded at all ages from eyes wth amblyopa dagnosed at any age and from eyes that had optc atrophy at the last examnaton completed. Also excluded at each age were eyes of patents who were unable to pass all the developmental screenng tems at the last examnaton completed because ths suggested neurologc mparment or developmental delay, both of whch have been assocated wth vsual mparment.24 Fgure 3 summarzes the proporton of eyes for whch a quantfable acuty score was obtaned for each group at each test age (ndcated by the heght of each bar), and the proporton of eyes wth quantfable acuty that remaned n each group after eyes from patents wth ocular or neurodevelopmental abnormaltes, as descrbed above, were excluded. As ndcated prevously (Fg. ), a quantfable acuty score was obtaned from nearly all eyes n the no-rop, less-than- cc O UJ Q -- 2.0 5 6.0 CO UJ.,. - ' '" ^A- Alll O 3.0 NO ROP D < PRETHRESHOLD T PRETHRESHOLD V THRESHOLD UNTREATED MAYER ET AL 2 0 CD _ - en n R 0 2 3 4 5 CORRECTED AGE (YEARS) FIGURE 2. Acuty development n eyes wth quantfable gratng acuty n the CRYO-ROP study. For comparson, the upper and lower dotted lnes ndcate the 95% predcton lmts for healthy full-term chldren wth no ocular abnormaltes, reported by Mayer et al.a> Less than 3% of eyes n the no-rop, less-than-prethreshold, and prethreshold groups, and approxmately 50% of eyes n the threshold untreated group, are not represented n the graph because these eyes had vson so poor that t was not quantfable wth- the acuty card procedure. Numbers of eyes n each group at the four test ages, respectvely, are: no-rop (23, 276, 344, 380), less-than-prethreshold (295, 384, 468, 496), prethreshold (64, 92, 96, 98), and threshold untreated (78, 89,94, 98). Bars ndcate ± SEM. CRYO-ROP = Cryotherapy for Retnopathy of Prematurty. n 00 ~ at ( > I O O 80 60 40 20 Age 2 as * s NO ROP 3 I I 4.8 PRETHRESH ] HO ABNORMALITIES t» 3 6 4 S PRETHRESH 2 It 4 6 THRESH UNTR QUANTIFIABLE ACUITY FIGURE 3. Percentage of eyes for whch a quantfable acuty score was obtaned for each group at each age (represented by bar heght), and percentage of eyes that remaned n each group at each age after eyes from patents wth ocular or neurodevelopmental abnormaltes were excluded (dagonally hatched porton of bars). Number above each bar ndcates total number of eyes n the group. prethreshold, and prethreshold groups, but from only half the eyes n the threshold untreated group. After eyes wth ocular abnormaltes and eyes from patents wth neurodevelopmental abnormaltes were excluded, the no-rop, less-than-prethreshold, and prethreshold groups were reduced to approxmately 60% of ther orgnal number at the 4'/2-year examnaton, whereas the threshold untreated group was reduced at the 4'/2-year examnaton to only 2% of the total number of eyes n the orgnal group. Fgure 4 presents the mean acuty scores from eyes wth no ocular abnormaltes, selected only from patents who passed the developmental screenng tems. In ths selected populaton, mean acuty scores for the no-rop and less-than-prethreshold groups are nearly dentcal and le near the lower 95% predcton lmt for healthy, full-term chldren20 at and 2 years and near the mddle of the normal range for fullterm chldren at 3 '/ 2 a n d 4 '/ 2 years. Scores from the prethreshold and threshold control groups are smlar to those of no-rop and less-than-prethreshold groups at, 2, and 4V2 years but are lower than those of the no-rop and less-than-prethreshold groups at 3 '/a years. A repeat measures analyss of varance was conducted on data from eyes n ths populaton that had gratng acuty scores at all four ages. Numbers of eyes ncluded n the analyss were 26, 56, 29, and 2 for the no-rop, less-than-prethreshold, prethreshold, and threshold untreated groups, respectvely. The results of ths selectve analyss showed that acuty mproved wth age (F3 = 3.5, P < 0.000) and that mean acuty scores dffered sgnfcantly among the groups (F3 = 2.7, P < 0.05). There was an age-bygroup nteracton (F9 = 2., P< 0.05), ndcatng that

Investgatve Ophthalmology & Vsual Scence, December 994, Vol. 35, No. 3 4242 I LU LLJ CC CD Ul Q I ' 24.0 2.0 CO LU 6.0 - > O 3.0 o < D V.5 CD 0.8 NO ROP < PRETHRESHOLD PRETHRESHOLD THRESHOLD UNTREATED MAYER ET AL.20? - 4 CORRECTED AGE (YEARS) FIGURE 4. Acuty development after excluson of data from eyes wth ocular abnormaltes and eyes of patents who were unable to pass the developmental screenng tems. Dotted lnes represent the 95% predcton lmts for healthy fullterm chldren.20 Numbers of eyes n each group at the four test ages, respectvely, are: no-rop (58, 205, 233, 260), lessthan-prethreshold (93, 253, 30, 320), prethreshold (34, 52, 55, 54), and threshold untreated (24, 2, 22, 24). the rate of acuty development dffered among the four groups. Post hoc analyses (Dunnett's tests) showed a sgnfcant dfference (P < 0.05) between mean acuty scores of the prethreshold and the norop groups at 4 '/> years and between the threshold untreated and the no-rop groups at 3 % years. Comparson of Fgures 2 and 4 shows that excluson of data from eyes of patents wth ocular or neurodevelopmental abnormaltes affected the mean vsual acuty scores of the four groups dfferently. In the norop and less-than-prethreshold groups, excluson of data from these eyes produced only a small mprovement (<0.2 octave) n mean acuty. In contrast, excluson of data from these eyes produced a substantal mprovement (0.6 to.3 octave) n the mean acuty values of the threshold untreated group. The change produced n mean acuty values of eyes n the prethreshold group was ntermedate, wth mprovements that ranged between 0. octave at 2 years to 0.3 octave at 3 '/ 2 years of age. DISCUSSION Ths artcle descrbes the natural hstory of the development of gratng acuty n a large group of chldren wth brth weghts less than 25 g. All chldren had careful documentaton of presence and severty of ROP n the neonatal perod, as well as follow-up eye examnatons and measurement of gratng acuty at, 2, 3'/ a, and 4'/a years, as part of the protocol of the Multcenter CRYO-ROP study. The results showed that more than 99% of eyes n whch ROP never developed and more than 99% of eyes n whch mld (less-than-prethreshold) ROP developed had quantfable acuty (.e., they were not blnd because of ocular or cortcal abnormaltes) at each follow-up age. As shown n Fgure, both the rate of gratng acuty development and the mean acuty scores at each of the four test ages were nearly dentcal for eyes n whch ROP never developed and for eyes n whch mld ROP developed. Thus, the presence of mld ROP durng the pernatal perod does not appear to affect the development of gratng acuty durng the frst 4'/ 2 years of lfe. Although eyes n the less-than-prethreshold groups showed acuty development smlar to that of eyes n the no-rop group, the mean acuty scores for both groups were at the low end of the normal range for healthy full-term chldren tested wth a smlar procedure20 (Fg. ). These results dffer from prevous studes, whch showed smlar monocular acuty development n preterm and full-term nfants up to year of age.2526 However, the results are n agreement wth prevous studes suggestng that 3- to 4-year-old preterm chldren show gratng acuty scores at the lower end of the normal range.26"27 The lower overall acuty scores shown by nfants wth no or mld ROP n the present study s lkely to be due to preterm brth (all nfants had brth weghts <25 g) and ts attendant llnesses and medcal complcatons. More than 96% of eyes wth moderate (prethreshold) ROP had quantfable acuty. These eyes showed mean acuty scores smlar to those of eyes wth less severe or no ROP at ages and 2 years but slghtly lower than those eyes at 3 '/ 2 a n d 4 '/a years, suggestng that defcts n gratng acuty occur n eyes wth moderate ROP but that these defcts do not become measurable untl chldren reach 3 % to 4 '/a years of age, when gratng acuty approaches adult levels. Of the eyes wth severe (threshold) ROP that served as control (untreated) eyes n the CRYO-ROP study, half had vson so poor that gratng acuty was unmeasurable, and the other half showed mean acuty scores that were approxmately octave below those of the no-rop group at all four test ages. Thus, eyes wth severe ROP showed defcts n gratng acuty that were measurable at the earlest age ( year) at whch acuty was tested n the CRYO-ROP study. Retnal resdua of ROP and other abnormaltes that can result n acuty defcts develop n many eyes wth severe ROP n the pernatal perod.9'0'2 Some nfants wth severe ROP also have central nervous system abnormaltes, such as ntraventrcular hemorrhage or perventrcular leukomalaca, that can result

Gratng Acuty After Acute-Phase ROP 4243 n acuty defcts. 22 ' 23 We conducted a subgroup analyss to determne whether eyes n whch threshold ROP developed durng the neonatal perod could show acuty development smlar to that of eyes n whch ROP never developed f the threshold ROP regressed, leavng no dentfable retnal resdua and no other ocular or nonocular abnormaltes assocated wth poor acuty were present. Ths subgroup conssted of only 2% of eyes wth severe ROP and, as shown n Fgure 4, mean gratng acuty at age 4'/ 2 years was not sgnfcantly dfferent from that of eyes n whch ROP never developed. These results suggest that, although t s not a frequent occurrence, eyes wth severe ROP can have functonal vson smlar to that of eyes n whch ROP never developed. Strengths of Ths Study Because our data were collected as part of the the prospectve Multcenter CRYO-ROP study, several mportant factors were carefully controlled. Frst, unform testng procedures were used across all study centers and across all test ages. Acuty testng was conducted by a small number of testers (seven), each of whom was traned n a standardzed fashon. Testers partcpated n bannual qualty assurance sessons, n whch testng technques were revewed and possble dfferences among testers were dentfed and corrected. 7 When testng each chld, testers were unaware of whether ROP developed n an eye durng the neonatal perod, and they also were unaware of the retnal status of an eye at the tme of the followup examnatons. 5 Second, all chldren underwent eye examnaton by a certfed study ophthalmologst accordng to a specfed schedule durng the pernatal perod. Chldren also underwent an eye examnaton by a certfed study ophthalmologst at each follow-up age at whch acuty was tested. Refractve errors that exceeded study crtera were corrected, and amblyopa was treated for at least 4 weeks before acuty testng. Thus, chldren receved close ophthalmc follow-up, whch helped to maxmze ther vsual acuty outcome. Fnally, acuty results were obtaned n a hgh proporton of eyes (more than 96% at each age), and there were few eyes for whch data had to be excluded because of nadequate correcton of refractve error or treatment of amblyopa (5% or less after the ntal test age of year) (Table ). The hgh follow-up rates ndcate that the acuty results were not based by poor testablty or by dfferental patent drop-out at the four test ages. Lmtatons of Ths Study There are two notable lmtatons n the vsual acuty data presented n ths artcle. Frst, the neurodevelopmental data on each patent were obtaned from three screenng tems asked by the study center coordnator at each age. Because chldren wth developmental delay may show vsual acuty defcts n the apparent absence of ocular abnormaltes, 24 more extensve neurodevelopmental performance testng mght have helped to dentfy non-rop-related, postretnal vsual pathway defects. A second lmtaton of the present artcle s that the type of vsual acuty measured was resoluton (gratng) acuty, not recognton (letter) acuty, whch s the "gold standard" for measurement of vsual acuty n adults. However, measurement of recognton acuty s not possble n most chldren before 2'/a to 3 years of age, and, therefore, the only way to examne systematcally the course of acuty development between and 4 V 2 years s to use a measure of resoluton acuty. Furthermore, although most normal 3'/ 2 - and 4'/ 2 -year-olds can perform a recognton acuty task, the matchng or verbal sklls requred to complete recognton acuty testng may not be present n the or developmentally delayed chld at 3'/ 2 4 '/> years. Thus, relyng on recognton acuty to examne acuty dfferences among young chldren born at a very early gestatonal age could produce based results. Conclusons In concluson, these data demonstrate that t s possble for an eye wth ROP, even threshold ROP, to show normal gratng acuty development. The probablty that an eye wll show normal gratng acuty development, however, s hghly dependent on the severty of the acute-phase ROP. Eyes wth less-than-prethreshold ROP show vsual acuty development nearly dentcal to that of eyes wth no ROP n the same populaton of VLBW chldren. In contrast, eyes wth threshold untreated ROP are unlkely to show acuty development smlar to that of eyes wth no ROP. Ffty percent of eyes n the group wth threshold untreated ROP ether had no vson or vson that was unmeasurable wth Teller Acuty Cards, and an addtonal 35% to 40% had ocular or neurodevelopmental abnormaltes often assocated wth poor vsual acuty. Only by excludng data from 85% to 90% of eyes n ths group was t possble to fnd a small sample of eyes that showed acuty development smlar to that of eyes wth no ROP. Key Words retnopathy of prematurty, gratng acuty, nfants, chldren, acuty development References. Teller DY, McDonald MA, Preston K, Sebrs SL, Dobson V. Assessment of vsual acuty n nfants and chldren: The acuty card procedure. Devel Med Chld Neurol. 986; 28:779-789.

4244 Investgatve Ophthalmology & Vsual Scence, December 994, Vol. 35, No. 3 2. Brch EE. Vsual acuty testng n nfants and young chldren. Ophthalmol Cln N Am. 989;2:369-389. 3. Cryotherapy for Retnopathy of Prematurty Cooperatve Group. Multcenter tral of cryotherapy for retnopathy of prematurty: One year outcome: Structure and functon. Arch Ophthalmol. 990; 08:408-46. 4. Cryotherapy for Retnopathy of Prematurty Cooperatve Group. Multcenter tral of cryotherapy for retnopathy of prematurty: 3 '/2-year outcome: Structure and functon. Arch Ophthalmol. 993; :339-344. 5. Qunn GE, Dobson V, Barr CC, et al. Vsual acuty n nfants after vtrectomy for severe retnopathy of prematurty. Ophthalmology. 99;98:5-3. 6. Hrose T, Katsum O, Mehta MC, Schepens CL. Vson n stage 5 retnopathy of prematurty after retnal reattachment by open-sky vtrectomy. Arch Ophthalmol. 993;lll:345-349. 7. Trese MT, Hartzer M, Ln LR, Mayer D, Regan V, Manatrey P. Vtreous and retnopathy of prematurty: Vtreous surgery and vsual results. In: Flynn JT, Tasman W, eds. Retnopathy of Prematurty: A Clncan's Gude. New York: Sprnger-Verlag; 992;83-93. 8. Luna B, Dobson V, Bglan AW. Development of gratng acuty n nfants wth regressed stage 3 retnopathy of prematurty. Invest Ophthalmol Vs Sc. 990; 3: 2082-2087. 9. Katsum O, Mehta MC, Matsu Y, Tetsuka H, Hrose T. Development of vson n retnopathy of prematurty. Arch Ophthalmol. 99; 09:394-398. 0. Brch EE, Spencer R. Vsual outcome n nfants wth ccatrcal retnopathy of prematurty. Invest Ophthalmol Vs Sc. 99;32:40-45.. Laws D, Shaw DE, Robnson J, Jones HS, Ng YK, Felder AR. Retnopathy of prematurty: A prospectve study: Revew at sx months. Eye. 992; 6:477-483. 2. Palmer EA, Flynn JT, Hardy RJ, et al. Incdence and early course of retnopathy of prematurty. Ophthalmology. 99; 98:628-640. 3. Multcenter Tral of Cryotherapy for Retnopathy of Prematurty Cooperatve Group. Manual of Procedures. Sprngfeld, VA: Natonal Techncal Informaton Servce; 985. US Dept of Commerce publcaton PB 88-63530. 4. Cryotherapy for Retnopathy of Prematurty Cooperatve Group. Multcenter tral of cryotherapy for retnopathy of prematurty: Three-montf outcome. Arch Ophthalmol. 990; 08:95-204. 5. Dobson V, Qunn GE, Bglan AW, Tung B, Flynn JT, Palmer EA. Acuty card assessment of vsual functon n the cryotherapy for retnopathy of prematurty tral. Invest Ophthalmol Vs Sc. 990;3:l702-l708. 6. Trueb L, Evans J, Hammel A, Bartholomew P, Dobson V. Assessng vsual acuty of vsually mpared chldren usng the Teller acuty card procedure. Am Orthoptc f. 992;42:49-54. 7. Multcenter Tral of Cryotherapy for Retnopathy of Prematurty (CRYO-ROP) Cooperatve Group. Manual of Procedures, Volume II: Phase II FollouhUp Study. Sprngfeld, VA: Natonal Techncal Informaton Servce; 993. US Dept of Commerce publcaton PB 93-34427. 8. Reese AB, Kng MJ, Owens WC. A classfcaton of retrolental fbroplasa. Am J Ophthalmol. 953; 36: 333-335. 9. Internatonal Commttee for the Classfcaton of the Late Stages of Retnopathy of Prematurty. An nternatonal classfcaton of retnopathy of prematurty: II: The classfcaton of retnal detachment. Arch Ophthalmol. 987; 05:906-92. 20. Mayer DL, Warner A, Beser A, Lang J, McNff K. Normatve acuty card study: I: Monocular norms. ARVO Abstracts. Invest Ophthalmol Vs Sc. 992; 33:353. 2. Mntz-Httner HA, Prager TC, Kretzer FL. Vsual acuty correlates wth severty of retnopathy of prematurty n untreated nfants weghng 750 g or less at brth. Arch Ophthalmol. 992; 0:087-09. 22. Ng YK, Felder AR, Levene MI, Trounce JQ, McLellan N. Are severe acute retnopathy of prematurty and severe perventrcular leucomalaca both schaemc nsults? Brf Ophthalmol. 989; 73:-4. 23. Procanoy RS, Garca-Prats JA, Httner HM, Adams JM, Rudolph AJ. An assocaton between retnopathy of prematurty and ntraventrcular hemorrhage n very low brth weght nfants. Ada Paedatr. 98;70:473-477. 24. Mayer DL, Fulton AB, Sossen PL. Preferental lookng acuty of pedatrc patents wth developmental dsabltes. Behav Bran Res. 983; 0:89-98. 25. Brch EE, Spencer R. Monocular gratng acuty of healthy preterm nfants. Cln Vson Sc. 99; 6:33-334. 26. Getz L, Dobson V, Luna B. Gratng acuty development n 2-week-old to 3-year-old chldren born pror to term. Cln Vson Sc. 992;7:25-256. 27. Sebrs SL, Dobson V, Hartmann EE. Assessment and predcton of vsual acuty n 3- to 4-year-old chldren born pror to term. Human Neurobol. 884; 3:87 92.