Editorial

There’s more to ROP than ROPAlistair R. Fielder, FRCP, FRCS, FRCOphth

The infant born preterm is at risk of developinga number of ophthalmic problems, not just inthe eye but along the entire visual pathway and

even beyond. Some are the result solely of being borntoo soon, whereas others are complications of prematurityand its management. Finally, there are those ophthalmicproblems that are generated by these complications ortheir management. Teasing out the relative contributionsmade by each of these to an individual child in the cliniccan be difficult and sometimes impossible. Recently,investigators from the Early Treatment for Retinopathyof Prematurity (ETROP) study have reported on such di-verse topics as cataract, myopia, retinopathy of prematurity(ROP), nystagmus, cerebral vision impairment, glaucoma,and strabismus.The ETROP study recruited infants\1,251 g between

October 1, 2000, and September 30, 2002. Details ofenrolment, randomization, and treatment are describedelsewhere,1 but of the 828 infants with prethresholdROP, 401 were randomized to either early treatment(ET) at high-risk prethreshold ROP with ablative therapyor conventional management (CM) with treatment atthreshold if this was reached. The 5 papers discussed hereinpresent secondary analyses of this cohort.Cataract is classically associated with end-stage ROP, in

which a retrolental membrane abuts the posterior lenssurface. Davitt and colleagues2 have reported a ratherdifferent situation and described the development ofcataract by 6 months’ corrected age in eyes that were notend stage. They reported cataract in 8 eyes (1.9%) of366 infants who survived to 6 months’ corrected age—3ET and 5 CM eyes (3 with laser). None of the eyes hadretinal detachment, and 2 CM eyes did not receive laser.In only 1 of 6 eyes that had laser treatment did the cataractdevelop with 10 days of treatment. Although the etiology ofthese cataracts is not known, the authors postulated that itcould not always be attributed to ROP treatment.Nevertheless, 5 of the 6 eyes with cataract after treat-

ment had anterior segment complications such ashyphema, shallow anterior chamber, iris synechiae, orcorneal opacification. It is difficult to escape thereforefrom the rather obvious conclusion that perturbation of

See accompanying articles on pages 124 and 129.

Author affiliations: Department of Optometry & Visual Science, City University, London,United KingdomCorrespondence: Alistair R. Fielder, FRCP, FRCS, FRCOphth, Professor Emeritus of

Ophthalmology, Department of Optometry &Visual Science, City University, NorthamptonSquare, London EC1V 0HB, United Kingdom (email: gafielder@btinternet.com).J AAPOS 2013;17:121-123.Copyright � 2013 by the American Association for Pediatric Ophthalmology and

Strabismus.1091-8531/$36.00http://dx.doi.org/10.1016/j.jaapos.2013.03.009

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the anterior segment by either disease or its treatmentwas a factor in cataractogenesis in these cases. Cataractformation during infancy after severe acute-phase ROP isan infrequent but serious complication, but readers willbe reassured that treatment at the earlier postmenstrualage of high-risk prethreshold, as consequence of ETROP,as compared to treatment at threshold, does not, assuggested by Salgado and colleagues,3 seem to increasethe risk of anterior segment complications.

The type of glaucoma classically associated with ROP isthat associated with end-stage disease, in which theposterior segment becomes crowded with a retinaldetachment and a retrolental membrane and/or a swollenlens, and these structures displace forward the iris-lensdiaphragm. Last year Bremer and colleagues4 reportedthe development of glaucoma in 12 of 718 randomizedeyes (1.67%). The onset of this complication rangedfrom 9 months to 5 years (5 and 3 eyes, respectively).Only one child had measurable vision and of the12, 7 eyes had the classic form of glaucoma associatedwith ROP, with only 3 having a normal retinal structure.The mechanism of glaucoma in the remaining 5 eyes isunknown—the authors speculated that inflammation mayhave played a role as 4 eyes had extensive treatment,whereas 1 eye may have developed late-onset primaryglaucoma. The authors appropriately considered thedifficulty of making the diagnosis of glaucoma in theabsence of robust criteria, acknowledging that thismay result in both underdiagnosis and overdiagnosis.Glaucoma is related to the disease and not its treatment,and although it is not common after ROP, it can developin eyes with major sequelae and may not become evidentclinically for years.

In this issue of the Journal of AAPOS, Quinn and col-leagues5 report on the progression of myopia between 4and 6 years of age. Cycloplegic retinoscopy was performedat 6 and 9 months’ corrected age and then annually untilthe patients reached 6 years of age. The results of measure-ments up to 3 years in the ETROP study have beenpreviously reported,6,7 but in summary, the prevalence ofmyopia increased from 58% to 68% between 6 and 9months. Although there was little change in myopiabetween 9 months and 3 years, the frequency of highmyopia increased beyond 6 months. Eyes with ROPresidua had a greater prevalence of myopia, but ofconsiderable interest, and perhaps not intuitive, ROP zoneor plus disease were not major determinants of myopia,and even more important, there was no difference betweeneyes treated at high-risk prethreshold (ET) compared withthreshold (CM) ROP. Between 4 and 6 years of age therewas no increase in the prevalence in either myopia or highmyopia for either treatment group. The prevalence of

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myopia or high myopia was greater in ET zone 1 comparedto zone 2. Figure 1A and B (p126) shows very clearly thatmost of the change in the prevalence of myopia is between6 and 9 months, whereas for high myopia, changes continueup to 3 years, after which both the magnitude of myopia andhigh myopia are relatively stable. This finding is in contrastto theCRYO-ROP(Cryotherapy forRetinopathy ofPrema-turity) study, in which refractive state was rather static after 9months’ corrected age,8 indicating that the refractive error ofETROP eyes seems to take longer to stabilize.

Within the broader context of refractive development ininfants born prematurely, both preterm birth and ROPinfluence refractive development, and at age 10-12 yearsthere is a greater prevalence of all refractive errors: hyper-metropia, astigmatism, and myopia.9,10 It is of interest thatboth the major ROP clinical trials and follow-up studies ofpreterm infants without and with ROP show that throughchildhood, refractive state is relatively stable with a slight(1 D) shift toward myopia. Fledelius11 demonstratedarrested development of the anterior segment in thepreterm infant, even in the absence of ROP. In the presenceof severe ROP, there is growth restriction of both theanterior and posterior segments, which influences axiallength.12 Overwhelming evidence now exists that myopiais related to the ROP process itself and not its treatment.

Epidemiological studies of children born preterm havefound that the prevalence of strabismus is greater inchildren who were born prematurely and is independentlyassociated with birth weight, ROP, cerebral palsy,anisometropia, and refractive error.13,14 VanderVeen andcolleagues15 analyzed 6-year data on strabismus from 379infants with prethreshold ROP in the ETROP study.Children aged 6 years had an overall prevalence ofstrabismus of 42.2%, whereas for those with favorablefunctional and structural outcomes, it was 25.4% and34.2%, respectively, with a greater prevalence in childrenwith vision impairment or neurological damage. Moststrabismus was constant at both 9 months and 6 years,although a few resolved by the latter age—most spontane-ously and a very few due to surgery. Thus most children(59.4%) with high-risk prethreshold ROP developedstrabismus, and the risk factors for this were abnormalfixation, a history of amblyopia, anisometropia, and anunfavorable structural outcome. This study15 highlightsthe complexity of attempting to understand the pathoge-nesis of strabismus in a child born prematurely.

Worldwide, the outcome for infants with severe ROPhas been greatly improved as a consequence of theCRYO-ROP and ETROP studies, but unfortunately visualdisability still occurs. In this issue of the Journal ofAAPOS, Siatkowski and colleagues16 present characteris-tics of children with severe visual impairment but favorableretinal structural outcomes in the ETROP study. At the6-year ETROP examination, 39 of 342 children (11%)had visual acuity of #20/200: 64% had an ophthalmo-scopically normal fundus, 28% had straightening of thetemporal retinal vessels with or without macular ectopia,

46% had optic atrophy, and 8% had disk cupping (all ofthese in one or both eyes). Developmental status (WeeFIMtest) was normal in only 18%. Neuroimaging was not per-formed, so on the basis of visual and ophthalmic findings,the authors classified the children as having definiteposterior visual pathway impairment (cerebral vision im-pairment [CVI]) or probable combined anterior and poste-rior pathway disease.

For some time, nystagmus has been used to differentiatedisorders of the anterior visual pathway (nystagmuspresent) from those of the posterior visual pathway(no nystagmus). In this ETROP subgroup analysis,Siatowski and colleagues16 have excluded children withsearching or roving eye movements as not qualifying asnystagmus. But if it is not nystagmus, what is it? Riskingthe opprobrium of the entire eye movement fraternity,this writer opines that roving eye movements are indeednystagmus at the extreme end of the nystagmus spectrum.The early literature,17,18 which described that the presenceof nystagmus could be used to differentiate anterior andposterior visual pathway disorders, emphasized that itwas sustained nystagmus in primary position that wasabsent or present. Ill-sustained oscillations in eccentricpositions were excluded in this context as being presentin most patients with extensive neurological damage andthus not indicative of the location of the damage.

Of patients reported by Siatowski and colleagues,16

77% had nystagmus. The authors concluded that nystag-mus is not reliable as a marker for the localization of vi-sion defects. Because ETROP examiners were simplyasked whether nystagmus was present or absent, it isnot possible to tease out whether nystagmus wassustained in the primary position or present in eccentricpositions. Therefore, these data do not prove or disprovethe hypothesis that sustained nystagmus is not a featureof CVI. Nevertheless, as the authors state, no one wouldclaim absence of nystagmus to be the sole marker ofCVI but simply one of a constellation of clinical find-ings. This article by Siatowski and colleagues16 is veryuseful because it highlights the challenges facing the pe-diatric ophthalmologist assessing the child with reducedvision.

ETROP is a landmark clinical study that has greatlyaffected ROP treatment across the world, and it is anexample of the value that rigorous clinical researchbrings to clinical practice. ETROP investigators haveprovided important insight into the ophthalmicconsequences of preterm birth per se, ROP, its treatment,and the neurological damage that some of these childrendevelop. Clearly, for many children, there is more toROP than ROP.

References

1. Good WV; Early Treatment for Retinopathy of PrematurityCooperative Group. Final results of the Early Treatment forRetinopathy of Prematurity (ETROP) randomized trial. Trans AmOphthalmol Soc 2004;102:233-48.

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2. Davitt BV, Christiansen SP, Hardy RJ, Tung B, Good WV; EarlyTreatment for Retinopathy of Prematurity Cooperative Group. Inci-dence of cataract development by 6 months’ corrected age in the EarlyTreatment for Retinopathy of Prematurity study. J AAPOS 2013;17:49-53.

3. Salgado CM, Celik Y, VanderVeen DK. Anterior segmentcomplications after diode laser photocoagulation for prethresholdretinopathy of prematurity. Am J Ophthalmol 2010;150:6-9.

4. Bremer DL, Rogers DL, Good WV, Tung B, Hardy RJ, Fellows R.Glaucoma in the Early Treatment for Retinopathy of Prematurity(ETROP) study. J AAPOS 2012;16:449-52.

5. Quinn GE, Dobson V, Davitt BV, et al; Early Treatment for Retino-pathy of Prematurity Cooperative Group. Progression of myopia andhigh myopia in the Early Treatment for Retinopathy of PrematurityStudy: Findings at 4 to 6 years of age. J AAPOS 2013;17:124-8.

6. Davitt BV, Dobson V, Good WV, et al; for the Early Treatment forRetinopathy of Prematurity Cooperative Group. Prevalence ofmyopia at 9 months in infants with high-risk prethreshold retinopathyof prematurity. Ophthalmology 2005;112:1564-8.

7. QuinnGE,DobsonV,Davitt BV, et al; Early Treatment for Retinop-athy of Prematurity Cooperative Group. Progression of myopia andhigh myopia in the Early Treatment for Retinopathy of PrematurityStudy: Findings to 3 years of age. Ophthalmology 2008;115:1058-64.

8. Quinn GE, Dobson V, Siatkowski R, et al; Cryotherapy forRetinopathy of Prematurity Cooperative Group. Does cryotherapyaffect refractive error? Results from treated versus control eyes inthe cryotherapy for retinopathy of prematurity trial. Ophthalmology2001;108:343-7.

9. Larsson E, Rydberg A, Holmstr€om G. A population-based study ofthe refractive outcome in 10-year-old preterm and full-term children.Arch Ophthalmol 2003;121:1430-36.

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10. O’Connor AR, Stephenson TJ, Johnson A, et al. Change in refractivestate and eye size in children of birth weight less than 1701 g.Br J Ophthalmol 2006;90:456-60.

11. Fledelius HC. Pre-term delivery and subsequent ocular development.A 7-10 year follow-up of children screened 1982-84 for ROP. 4)Oculometric - and other metric considerations. Acta Ophthalmol1996;74:301-5.

12. Fledelius HC, Fledelius C. Eye size in threshold retinopathy of prema-turity, based on a Danish preterm infant series: early axial eye growth,pre- and postnatal aspects. Invest Ophthalmol Vis Sci 2012;53:4177-84.

13. O’Connor AR, Stephenson TJ, Johnson A, Tobin MJ, Ratib S,Fielder AR. Strabismus in children of birth weight less than 1701 g.Arch Ophthalmol 2002;120:767-73.

14. Holmstr€omG, Rydberg A, Larsson E. Prevalence and development ofstrabismus in 10-year-old premature children: A population-basedstudy. J Pediatr Ophthalmol Strabismus 2006;43:346-52.

15. VanderVeen DK, Bremer DL, Fellows RR, et al; Early Treatment forRetinopathy of Prematurity Cooperative Group. Prevalence andcourse of strabismus through age 6 years in participants of theEarly Treatment for Retinopathy of Prematurity randomized trial.J AAPOS 2011;15:536-40.

16. SiatkowskiRM,GoodWV,SummersCG,QuinnGE,TungB.Clinicalcharacteristics of children with severe visual impairment but favorableretinal structural outcomes from the Early Treatment for Retinopathyof Prematurity (ETROP) study. J AAPOS 2013;17:129-34.

17. Whiting S, Jan JE, Wong FKH, Flodmark O, Farrell K,McCormick AQ. Permanent cortical visual impairment in children.Dev Med Child Neurol 1985;27:730-39.

18. Fielder AR, EvansNM. Is the geniculostriate system a prerequisite fornystagmus? Eye 1988;2:628-35.