British Journal of Ophthalmology, 1987, 71, 837-843

Natural history of retinopathy of prematurityW E SCHULENBURG, A PRENDIVILLE, AND R OHRI

From the Departments ofSurgery and Paediatrics, Hammersmith Hospital, London W12 OHS

SUMMARY Sixty-nine infants at risk of developing retinopathy of prematurity (ROP) were enteredinto a prospective study to assess the incidence and natural history of the disease. Seventeen infantsdeveloped ROP, and in six eyes the disease progressed to stage IV ROP. The natural regression ofa pupillary membrane and physiological vitreous haze was not influenced by the onset of ROP.Progression from stage I to stage III was rapid and the rate was influenced by the zone affected.Congestion and tortuosity of vessels in the posterior pole always signified stage III ROP.Progression from stage III to stage IV ROP was slower; it was characterised by the development ofvitreoretinopathy, signified by the sudden onset of a vitreous haze. Iris congestion associated withpoor mydriasis may be a grave sign indicating imminent retinal detachment. Cicatricial ROP can bedivided into retinal and vitreoretinal cicatricial disease directly related to the stage of active diseasereached. ROP is characterised by its self limiting nature, but the stage at which it becomes inactivevaries and will influence the final outcome.

Retinopathy of prematurity (ROP) remains a per-sistent problem threatening visual development to agreater or lesser extent in the premature infant. ' Withthe advent of vitreoretinal surgery successfulanatomical results have been reported in eyes withadvanced cicatricial disease.2 The functional successin these eyes is doubtful, and whether surgery shouldbe advised in such cases may pose an ethical question.A renewed interest has developed in the treatment ofROP by cryosurgery during the active stage ofretinopathy.?' One of the problems experienced withcryosurgery is the lack of specific selection criteria fortreatment at the appropriate time. The typical retinalchanges characteristic of ROP and their evolutionhave been well reported in the past.67 Neverthelesswe still have a poor understanding of the naturalhistory of the disease and cannot explain the strikingphenomenon of spontaneous regression. A betterunderstanding of the disease is of fundamentalimportance if treatment of it in the acute stage isplanned in the future. We report our experience ofthe natural history of ROP.

Materials and methods

Sixty-nine patients at risk of developing ROPCorrespondence to W E Schulenburg, FRCS, Lower MedicalCorridor, Hammersmith Hospital, Du Cane Road, London W12OHS.

admitted to the Neonatal Intensive Care Unit at theHammersmith Hospital between May 1983 andFebruary 1985 were entered into a prospective studyto determine the incidence and natural history of thedisease. The criteria for selecting high risk infantswere the following: infants with a gestational agebelow 30 weeks and/or a birth weight below 1500 g.All other infants admitted to the unit during the studyperiod not fulfilling these criteria and exposed tooxygen were also examined, but none of themdeveloped ROP.Eye examination was scheduled at three weeks

after birth if the infant's condition allowed, and it wasrepeated at weekly intervals by one of the authors(WES) as long as the infant remained in the IntensiveCare Unit. Selected infants were examined at morefrequent intervals-that is, progressive stage IIIROP on serial examination. Mydriasis was achievedby the instillation of phenylephrine 2X5% drops andcyclopentolate 1% drops one hour and 30 minutesbefore examination. The fundus was examined byindirect ophthalmoscopy with the aid of a 28 dioptrelens and scleral indentation only where indicated-that is, to differentiate between zone II and zone IIIdisease or where inadequate information wasobtained without indentation. We found that scleralindentation was essential whenever the infantspeculum was used, resulting in blepharospasm and aBell's phenomenon. When the lids were praised open

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by the examiner, blepharospasm was not stimulatedand adequate information could be obtained with alittle patience. This technique was also followed withfundus photography, and no sedation was required.Retinal changes were recorded with a Zeiss funduscamera in selected eyes only.

After discharge the infants entered into the studywere re-examined in the outpatients department atregular intervals. Ocular findings associated withprematurity were recorded and included thepresence of a pupil membrane (tunica vasculosalentis) and a physiological peripheral vitreoushaze.ROP changes were recorded in accordance with

the international classification as soon as it becameavailable. Stage I is characterised by the formation ofa demarcation line, stage II by the formation of aretinal lesion with height and volume extending outof the retinal plane, stage III by an increase in heightand volume of the retinal lesion associated withfibrovascular proliferation, and stage IV when retinaldetachment develops. The retinal lesion is localisedby dividing the retina into three zones centred roundthe optic disc. Zone I consists of a circle with theradius twice the optic disc-macula distance, zone II ismore peripheral and extends from the edge of zone Ito the edge of a circle with a radius of the optic disc-nasal-ora distance, and zone III is a crescentperipheral io the edge of zone II and does not involvethe nasal 3 clock hours of the retina.8 Iris vascularchanges and changes in pupil dynamics associatedwith ROP were recorded.The time of onset was recorded when a demarca-

tion line developed. As regression is a gradualprocess, it was difficult to be precise about the time itstarted. Thus, in relating the age of the infant to thestage of ROP, the age at which the maximum stageROP had developed was used instead of the age atregression, to enable more accurate comparisonbetween individual eyes. Infants whose eyes reachedstage III plus with no evidence of regression on serialexamination were entered into a paired eye study toassess the value of cryosurgery, the results of whichwill form part of a future study. Selection of thesecases for cryosurgical treatment was based on theexperience of Kingham previously reported.9 Thecontrol eye only was considered to the end stage ofROP in this study on the natural history, and alltreated eyes excluded as soon as treatment wasapplied.

Results

INCIDENCEOf 69 high risk infants 17 (24-5%) developed somedegree of ROP. All cases were bilateral and sym-

metrical with the exception of two cases. In one ofthese the more severely affected eye had a persistentposterior hyaloid artery, and, in the second, one eyeprogressed to stage III and the second eye to stage IIROP only. In 34 eyes visual function was lost inseven, five of which did not receive cryosurgery, andthe natural history could be followed from the time ofonset to advanced cicatricial disease with a totalretinal detachment. These included one case withbilateral zone I ROP and three control eyes with zofieII ROP. One infant with zone I ROP was too ill to beconsidered for cryosurgery and eventually died at theage of 4 months. In 11 out of 17 infants no retinopathywas present at the initial examination.

PUPILLARY MEMBRANE AND VITREOUS HAZEIn 28 out of 34 eyes that eventually developed ROPa pupillary membrane was present at the initialexamination. A physiological peripheral vitreoushaze was present at the initial examination in 20 outof 34 eyes and cleared within four to five weeks afterbirth. The mean age at which regression of thepupillary membrane and peripheral vitreous hazetook place was equal for both the ROP and non-ROPgroups.

RETINAL VASCULAR CHANGESIn four eyes of two infants the onset of a demarcationline was observed to be preceded by dilatation andincreased tortuosity of peripheral capillaries directlybehind the margin of vasogenesis. A demarcationline (stage I) developed within one to two weeksthereafter in these eyes. Since the conclusion of thisstudy we have observed that these minor vascularchanges were present in the majority of eyes thatdeveloped ROP and probably always precede theonset of stage I as defined. These changes mayregress and do not necessarily indicate the onset ofROP. The low incidence reported in this study doesnot represent the true incidence, as it did not formpart of the data collection sheet and was thus notspecifically documented. It was added late in thestudy and referred to as 'pre-ROP' changes. In eighteyes of four infants, including one who finallyprogressed to end stage ROP in both eyes, filecapillaries were identified on the retinal surfacedirectly behind the demarcation line one week afterdiagnosis. These capillaries were fragile and gave riseto small preretinal haemorrhages in three of the eighteyes (Fig. 1). None of the eyes in this study developeda temporary retinal detachment of non-vascularisedretina.

Progression to stage II ROP was characterised bythe early development of a retinal shunt lesion withan associated progressively increasing congestionand tortuosity of the peripheral retinal vasculature,

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839Natural history ofretinopathy ofprematurity

Fig. 1 Stage IROP with apreretinal haemorrhagefromabnormal surface retinal capillaries.

Fig. 3 Globularshunt lesions extendingposterior towardsthe qptic disc. Zone II Stage IIIROP.

slowly extending further posteriorly towards theposterior pole.

Congestion and tortuosity of the retinal vascula-ture increased proportionately to the increasing sizeof the retinal shunt lesion. Such involvement of theposterior pole and optic disc always indicated stageIII ROP (Fig. 2) as previously reported.67 In pro-gressive stage III ROP the retinal shunt lesion was

Fig. 2 Zone if stage 111 ROP with characteristic posteriorpole congestion and increased retinal vascular tortuosity.

Fig. 4 Vitreous hazepreceding retinal detachment andsignifying the onset ofvitreoretinopathy. Zone IIstage IIIplus ROP.

seen on serial examination to increase in volume anddevelop a fibrovascular component at the base of thelesion that projected into the vitreous perpendicularto the retina. One case with zone II stage III ROPalso developed multiple globular shunt lesions on theretinal surface posterior to the main circumferentiallesion in both eyes (Fig. 3). This clinical appearancehas been well documented."'

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Fig. 5 Iris congestion with poor mydriasis. Zone IIstage IIIplus ROP.

VITREORETINOPATHYSix eyes progressed to stage IV ROP and includedtwo zone I, one zone III, and three zone II retino-pathy eyes. In the three untreated zone II eyes, andboth the zone I eyes that progressed to stage IV,retinal detachment was preceded by the sudden onsetof a vitreous haze one week before retinal detach-ment developed (Fig. 4). This characteristic vitreouschange was associated with a small intragel haemorr-hage from one of the retinal lesions in one eye.Clinical evidence of forward traction on the retinalshunt lesion was clearly defined by the configurationof the blood in the vitreous. This eye finally pro-gressed to a total retinal detachment. This vitreouschange was not observed in the zone III eye thatprogressed to retinal detachment but would havebeen missed if it was present and localised to theaffected temporal retina.

IRIS CHANGES AND PUPIL DYNAMICSIris congestion with a poor response to mydriaticsdeveloped in five eyes, three zone II and two zone Ieyes, with progressive stage III ROP on serialexamination (Fig. 5). All five of these eyes pro-gressed to stage IV ROP with extensive retinaldetachment.

RETINAL CHANGES IN REGRESSIONRegression was characterized by a decrease in retinalvascular congestion and tortuosity associated with asimultaneous decrease in volume of the retinal shuntlesion. The formation of a 'brushborder', as pre-viously reported by Flynn et al.,6 often coincided

Fig. 6 'Brushborder' characteristic ofearly regression.

with, or followed shortly after this vascular deconges-tion, signifying a return to normal retinal vasogenesis(Fig. 6). The newly forming retinal vasculatureperipheral to the site of the retinal shunt lesion had acharacteristically stretched or wishbone configura-tion which was distinctly different from the normalretinal vasculature as previously reported.6 In oneinfant this second phase of retinal vascularisationbecame arrested for two weeks in both eyes when atemporary second demarcation line formed.

In the five eyes that progressed to extensive retinaldetachment the retinal shunt tissue decreased involume and changed in colour from a characteristicorange to yellow soon after retinal detachment haddeveloped. Coinciding with this process a simultane-ous transgel traction developed, pulling the retina(rim of purse string) up against the posterior lenssurface. At this open funnel stage of retinal detach-ment it seemed to be purely tractional in origin.Exudative detachment followed two to three weekslater when the retinal detachment changed incharacter to a bullous closed funnel retinal detach-ment. No retinal breaks were observed in any of thereported eyes.

STAGE ROP RELATED TO AGE OF INFANT FORZONES I, II, AND IIIThe age at onset of ROP was similar for the threezones, with an average age of 6-5 weeks. Furtherprogression had a striking similarity in all threezones, with a relatively rapid development up tostage III, followed by a relatively long intervalbetween the onset of stage III and progression to

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841Natural history ofretinopathy ofprematurity

Stage Stage

Zone I IV Zone II

IVI

0 2 4 6 8 10 12 14 160 2 4 6 8 10 12 14 16

Age (weeks) Age (weeks)

StageSv Zone III

,,, / at / Fig.7 Ageofinfant(weeks)relatedtothestageofROPforzones I, II, and III.

I 2 | / / / / Tablel MeandurationofROPinweeksforzonesII,and III at the different stages ofevolution ofthe retinal lesion

Zone II Age at onset Stage I Stage III Stage IV

0 2 4 6 8 10 12 14 16 18 20 in weeks 7.5 (2)* 10(2) 14-5 (2)Age ( weeks) Time interval in Stage I to III 2-5 weeks

progression Stage III to IV 4-5 weeksOverall duration 7 weeks

active ROPstage IV ROP (Fig. 7, Table 1). However, in general, Zone IIprogression to stage III was more rapid in zone I ROP Age at onset Stage I Stage III Stave IVand slowest in zone III ROP, with a duration of 2 5 in weeks 6-6(16) 9.6(16) 13-6(3)weeks in zone I, 3-0 weeks in zone II, and 5.4 weeks Time interval in Stage I to III 3 weeksin zone III before stage III was reached. Progression progression Stage III toIV 4 weeksfrom stage III to stage IV ROP followed after a active ROP weeks

duration of 4*5 weeks in zone I, 4-0 weeks in zone II Zone IIand 7*1 weeks in zone III ROP. The mean overall Age at onset Stage I Stage III Stage IVduration before the maximum stage was reached was in weeks 7-5 (16) 12.9(5) 20(1)7-0 weeks for zones I and II and 9-4 weeks for zone III Time interval in Stage I to III 5-4weeksROP. The number of eyes included in this study was progression Stage III to IV 7-1 weeks

Overall duration 12-5 weekstoo small to allow statistical analysis, but confirms a active ROPtrend in the rate of development through the differ-ent stages for zones I, II, and III. *Numberof eyes in parentheses.

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Table 2 Retinalsequelae in infants in whom the diseaseprocess did notprogress beyond stage IIIROP

Retinalsequelae Case no.

1 2 3 4 5 6 7

Optic disc dragging + + + +Pre-retinal fibrosis + +Wishbone vessels + + + +Increased tortuosity + + + +Zone III II II III III II IIStage (maximum) III III III III II III III

SEQUELAEPermanent retinal sequelae were recorded in seveninfants who did not progress to stage IV or vitreo-retinal ROP (Table 2). These findings were recordedat the age of 6 to 18 months when co-operation waspoor and accurate clinical examination of the fundusdifficult. The reported results may thus not be anaccurate representation of the true incidence ofpermanent retinal sequelae in this group. Retinalchanges were related either to the retinal vasculatureor to residual fibrous tissue on the retinal surface atthe previous site of a retinal shunt lesion, with orwithout associated surface traction on the retina. Ofthe five eyes that progressed to vitreoretinal ROP,and finally developed a total retinal detachment, alldeveloped microphthalmos with anterior displace-ment of the iris-lens diaphragm and shallowing of theanterior chamber. In one infant with zone II ROPand an obliterated anterior chamber band kerato-pathy developed in both eyes.

Discussion

No cases ofROP presented outside the defined groupof high risk infants, so the adopted criteria wereaccurate in identifying infants at risk of developingROP.

Vascular congestion in the posterior pole wasconfirmed as an important clinical sign which acted asan indicator of the activity of the shunt lesion andindicated whether it was still in an active phase.Similarly, decreased congestion and tortuosityindicated early regression. These characteristicposterior pole changes may thus be a helpful clinicalsign to paediatricians screening infants for ROP whomay not be familiar with the indirect ophthalmoscopeand scleral indentation, necessary for accurategrading. Furthermore, iris congestion associatedwith a poor mydriatic response should be regarded asa warning sign that the disease process has reached anadvanced stage, when further progression to stage IVbecomes a real danger.From the observations made in this study it became

evident that the disease process in ROP is self

limiting, with a clinically identifiable time of onsetand an end stage when the disease process becomesinactive regardless of the stage of ROP previouslyreached. Permanent retinal sequelae are directlyrelated to the maximum stage reached. In advancedROP, stage III and stage III plus, the severity ofcicatricial ROP will depend on whether or notvitreoretinopathy had developed. In eyes wherethe disease remained confined to the retina only,cicatricial ROP will be limited to relatively minorpreretinal fibrosis and associated surface tractionalretinal changes. Those eyes that continue to progressafter stage III had been reached will ultimatelydevelop vitreoretinopathy with severe consequences.Mousel reported a similar vitreous change in one casebut referred to it as an 'inflammatory reaction'."Cicatricial disease is characterised by extensivetangential and transgel retinal traction and invariablyprogresses to extensive retinal detachment and blind-ness in zones I and II ROP. In zone III disease it isconfined to the temporal periphery only and willresult in varying degrees of temporal retinal dragrelated to the stage and volume of the retinal lesion atthe time of regression. A localised temporal retinaldetachment may develop in these eyes. It would thusbe practical to classify cicatricial disease in two maincategories, retinal and vitreoretinal cicatricial disease(Fig. 8). Infants at risk of developing ROP should bescreened at regular intervals after the age of 4 weeks.In cases that had progressed to stage III ROP serialexamination by the same clinician is of fundamentalimportance to identifying early signs of either regres-sion or progression if cryosurgery is planned.A critical stage is reached at three to four weeks

after the onset of stage III ROP, especially in zone Iand II ROP, where a higher incidence of a moreadvanced stage disease can be expected. If no sign of

Active retinopathy

Stage I

Stage

Without vitreoretinopathy or

Regression (inactive ROP)

Retinal cicatricial sequelaePreretinal fibrous scarOptic disc dragging

Macular displacementIncreased tortuosity of retinal

bloodvesselsPeripheral 'wishbone' vessels

With vitreoretinopathy

Regression (inactive ROP)I

Vitreoretinal cicatricialsequelae

Localised retinal detachmentTotal/subtotal retinal

detachmentMicrophthalmosSecondary glaucoma

Corneal decompensationFig. 8 A schematic representation ofthe development ofcicatricialROP.

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regression can be detected on serial examination atthis stage, a real danger of further progression tovitreoretinopathy exists, and cryosurgical interven-tion should be considered.A better understanding of the natural history of

ROP may enable us to establish more accurateselection criteria in eyes considered for cryosurgicalintervention. Not only will this enable us to assess theeffectiveness of cryosurgery more accurately, butalso prevent unnecessary treatment in future.

The authors thank Mr David McLeod for his advice in preparing thismanuscript and Mr John Arnold for his excellent photographicassistance. This work was supported by a locally organised researchgrant and the colour prints by 3M.

References

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2 Machemar R. Closed vitrectomy for severe retrolental fibro-plasia. Ophthalmology 1983; 90: 436-41.

3 Reisner SH, Amir I, Shohat M, Krikler R, Nissenkorn 1, Ben-Sira I. Retinopathy of prematurity: incidence and treatment.Arch Dis Child 1985; 60:698-701.

4 Patz A. Current therapy of RLF. Ophthalmology 1983; 90:425-7.

5 Ben-Sira I, Nissenkorn I, Grunwald E, Yassur Y. Treatment ofacute retrolental fibroplasia by cryopexy. BrJ Ophthalmol 1980;64: 758-62.

6 Flynn JT, O'Grady GE, Kushner BJ, Cantolino S, Milam W.Retrolental fibroplasia: I. Clinical observations. ArchOphthalmol 1977; 95; 217-23.

7 Flynn J. Acute proliferative retrolental-fibroplasia: evolution ofthe lesion. Graefes Arch Clin Exp. Ophthalmol 1975; 195:101-11.

8 Committee for the Classification of Retinopathy of Prematurity.An international classification of retinopathy of prematurity.Arch Ophthalmol 1984; 102: 1130-4.

9 Kingham JD. Acute retrolental fibroplasia. II. Treatment bycryo-surgery. Arch Ophthalmol 1978; 96: 2049-53.

10 Garoon I, Epstein G, Segall M, Rabb M, LaFranco F, Quirk T.Vascular tufts in retrolental fibroplasia. Ophthalmology 1980;87: 1128-32.

11 Mousel DK. Cryo-therapy for retinopathy of prematurity. Apersonal retrospective. Ophthalmology 1985; 92: 375-8.

Acceptedfor publication 13 August 1986.

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