Over the next several years, oxygen use was curtailed, and the incidence of RLF dropped dramatically. However, brain damage and death among premature infants rose. Cross¹³ estimated that, in the United States, for every case of possible blindness from RLF that was prevented, 16 infants died. As a more rational approach to the use of oxygen in premature infants was adopted in the mid-1960s, RLF reappeared.¹⁴ This, however, coincided with dramatic advances in technology that allowed smaller and smaller babies to be saved. During the 1970s and 1980s, an increasing incidence of RLF occurred despite increasingly sophisticated techniques of monitoring blood oxygen levels. Phelps¹⁵ suggests that both a relative and absolute increase in the incidence of ROP has occurred. It was in the 1980s that ROP became accepted as the name for RLF, a term that has now been discarded.

Despite meticulous monitoring of oxygen therapy with current sophisticated techniques, ROP still occurs.¹⁹ No safe means to prevent ROP has been found.²⁰ In a prospective, randomized, double-masked trial comparing vitamin E (tocopherol) to placebo, no difference was found in the incidence of ROP between the treated and the placebo group.²¹ Light exposure has been offered as a factor in causing ROP, yet a prospective, randomized, multicenter study comparing infants in typical nursery lighting to those in reduced light failed to show any difference in the incidence of ROP.²² Five hundred infants are blinded by ROP each year in the United States. Prematurity per se and its associated low birth weight is the cause of most cases of ROP in contrast to the implied overzealous use of oxygen, as had been suggested. Other factors associated with the development of ROP (but not necessarily causally related) include sepsis, hypoxia, acidosis, and intraventricular hemorrhage.

Smith has pointed out that ROP occurs in two phases.²³ In the first phase, the infant experiences a relative hyperoxia in room air. Retinal vasculature stops growing, and vascular endothelial growth factor (VEGF) decreases. In the second phase, peripheral maturing retina becomes hypoxic because it is nonperfused, and VEGF increases. Neovascularization then responds to the increased VEGF. Smith has shown that in the retina of the mouse model, the VEGF usually is ahead of the neovascularization.²³ Indeed, she postulates that regression of persistent fetal vasculature may be related to increased VEGF.

A growing concern is the increasing incidence of ROP in middle-income countries. Because living conditions and access to medical technology have improved in these countries, more premature infants are surviving. Hence, there is a greater incidence of ROP. In North and South America and Europe, it is becoming the major cause of infant blindness.²⁴, ²⁵, ²⁶, ²⁷

The most common form of regression of ROP is continued growth of the retinal vasculature anteriorly with gradual fading of the disease at the border of posterior vascularized and anterior avascular retina. Another more dramatic sign of regression is the growth of vessels beyond the ridge (Fig. 1). The vessels penetrate into the avascular retina as an arteriole with an accompanying venule. As the vessels grow beyond the ridge, the dilation and tortuosity of vessels just posterior to the shunt and in the posterior pole diminish.

To define location, the retina was divided into three zones with the optic nerve as the center, since retinal vascular growth proceeds from the disc toward the ora serrata (Fig. 2). Zone I consists of a circle, the radius of which extends from the disc to twice the distance from the disc to the center of the macula (twice the disc-fovea distance in all directions from the optic disc). Zone II extends from the edge of zone I peripherally to a point tangential to the nasal ora serrata and around to an area near the temporal anatomic equator. Zone III is the residual temporal crescent of retina anterior to zone II. This is the zone that is vascularized last in the premature eye, and it is the zone most frequently involved with ROP. The extent of disease is specified as hours of the clock (see Fig. 2). The second parameter specified in the 1984 classification is staging of the disease, that is, the degree of abnormal vascular response observed. Four stages were recognized, and staging for the eye as a whole receives the stage of the most severe manifestation of ROP present. Stage 1 (demarcation line) is defined as a thin but definite structure that separates avascular retina anteriorly from the vascularized retina posteriorly. Abnormal branching or arcading vessels are seen leading up to the line. It is flat and white and is in the plane of the retina. Stage 2 (ridge) is present when the line of stage 1 has grown, has height and width, and occupies a volume extending up out of the plane of the retina. The ridge may be pink or white, and vessels may leave the plane of the retina to enter it. Small tufts of new vessels may be seen on the surface of the retina posterior to the ridge. These vessels do not constitute fibrovascular growth, which is a necessary condition for stage 3 ROP. Stage 3 (ridge with extraretinal fibrovascular proliferation) exists when extraretinal fibrovascular proliferation is added to the ridge of stage 2 ROP (Fig. 3). Stage 3 is arbitrarily further subdivided into mild, moderate, and severe. Stage 4 (retinal detachment) is the addition of retinal detachment to stage 3 findings. Traction or exudation cause the retinal detachment.

Progressive vascular incompetence, occurring with the changes at the edge of the abnormally developing retinal vasculature, is noted by increasing dilation and tortuosity of the peripheral retinal vessels, iris vascular engorgement, pupillary rigidity, and vitreous haze. When the vascular changes are so marked that the posterior veins are enlarged and the arterioles are tortuous, a plus sign is added to the ROP stage number (Fig. 4). Subsequent to the initial ICROP report, completion of the classification of ROP led to the publication of the classification of retinal detachment.⁴¹ Stage 4 was expanded to stage 4A and 4B. Stage 4A (Fig. 5) represents extrafoveal retinal detachment, which is a concave traction type of retinal detachment in the periphery without involvement of the macula. These detachments generally are located in anterior zone II or III. Stage 4B (Fig. 6) is a partial retinal detachment including the fovea, which usually extends in the form of a fold from the disc through zone I to involve zones II and III. Stage 5 retinal detachments are total and always funnel shaped. Stage 5 is subdivided based on the shape of the funnel. The funnel is divided into anterior and posterior parts, allowing for four subdivisions, depending on whether the funnel is open or narrow in both parts of the funnel.

Although regression was not part of the classification, the committee recognizes that it is the most common outcome of ROP. The various patterns of regression were believed to be too numerous to classify; they are listed in (Table 1).

TABLE 1. Findings in Regressed Retinopathy of Prematurity

  Peripheral Changes
  Vascular
  Failure to vascularize peripheral retina
  Abnormal, nondichotomous branching of retinal vessels
  Vascular arcades with circumferential interconnection
  Telangiectatic vessels
  Retinal
  Pigmentary changes
  Vitreoretinal interface changes
  Thin retina
  Peripheral folds
  Vitreous membranes with or without attachment to retina
  Lattice-like degeneration
  Retinal breaks
  Traction/rhegmatogenous retinal detachment
  Posterior Changes
  Vascular
  Vascular tortuosity
  Straightening of blood vessels in temporal arcade
  Decrease in angle of insertion of major temporal arcade
  Retinal
  Pigmentary changes
  Distortion and ectopia of macula
  Stretching and folding of macula in macular region leading to periphery
  Vitreoretinal interface changes
  Vitreous membranes
  Dragging of retina over disc
  Traction/rhegmatogenous retinal detachment

Infants recommended for screening are those with a birth weight of less than or equal to 1500 g or with a gestational age of 28 weeks or less. Additionally, infants weighing over 1500 g, with an unstable clinical course believed to be at high risk by the attending pediatrician or neonatologist, should have a dilated indirect ophthalmoscopic examination. Considering that the guidelines are a work in progress, Wright and colleagues⁴⁴ point out that a gestational age cutoff of 28 weeks or less may be overly restrictive. In their retrospective study of 707 infants, 10 of 74 infants with stage 2 ROP, 5 of 63 with stage 3 ROP, and 1 of 4 with stage 4 ROP had a gestational age greater than 28 weeks. The British guidelines are more inclusive than the American, recommending screening for infants weighing 1500 g or less or those born at a gestational age of 31 weeks or less.⁴⁵

The American guidelines further state that the examination should be done between 4 and 6 weeks of chronologic age or between 31 and 33 weeks' postconceptional age. Follow-up examinations are determined by the findings at the first examination using the ICROP. For example, if the retinal vasculature is immature and in zone II but no disease is present, follow-up examination should be planned at approximately 2- to 4-week intervals until vascularization proceeds into zone III. Infants with ROP in zone I should be seen at least every week until involution of ROP occurs and normal vascularization proceeds to zone II. Infants with immature vessels (without ROP) detected in zone I should be seen at least every 1 to 2 weeks until normal vascularization proceeds to zone III or the risk of attaining threshold has passed.

Follow-up examinations should be performed until either complete retinal neovascularization occurs or two successive 2-week examinations show stage 2 ROP in zone III. Infants then should be followed every 4 to 6 weeks until fully vascularized. Infants who develop threshold disease (see later) should be considered for ablative therapy of at least one eye within 72 hours of diagnosis.

Examinations usually take place in the intensive care nursery (ICN). Monitoring of infants by the ICN staff is essential. Examination should take place no sooner than 1 hour after feeding to avoid the risk of vomiting and aspiration. We use homatropine hydrobromide 2% and phenylephrine hydrochloride 2.5% every 15 minutes three times 1 hour before examination. This allows for an adequate interval of dilation and frequently overcomes iris vascular engorgement in cases of severe stage 3+ ROP. Topical anesthesia with proparacaine or tetracaine is administered, and a lid speculum is inserted. Anterior segment examination followed by indirect ophthalmoscopic examination with a 20, 25, 28, or 40 diopter (D) lens then is performed.

The degree of dilation should be noted on anterior segment examination. Poor dilation may reflect iris vascular engorgement, implying active ROP. This often is mistaken for iris neovascularization. Careful record keeping, preferably on a standardized form, noting the zone, the stage of each 30-degree sector, and the presence or absence of “plus” disease, should be performed. When regression occurs, those signs also should be noted. Noting follow-up arrangements is important, preferably in the doctor's orders, so that future examinations are not missed.

Initially, acceptance of this form of therapy was slow, but it later gained acceptance in the United States.^32,53, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸ To resolve any doubt concerning the value of cryotherapy for ROP, the National Eye Institute supported a multicenter prospective randomized clinical investigation called the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (abbreviated as CRYO-ROP Study). The preliminary results were so favorable that a special expedited publication was released in 1988.^59,60

In the CRYO-ROP Study, eligible patients were those who weighed less than 1251 g at birth. Examinations commenced at 4 to 6 weeks of age and were repeated every 2 weeks unless the ROP reached a prethreshold stage: zone I, any stage; zone II, stage 2 (ridge) with plus disease; or zone II, stage 3 (ridge with extraretinal fibrovascular proliferation) less than threshold. Examinations then were repeated at least weekly until progression to threshold disease. Threshold disease was defined as at least five contiguous or eight cumulative 30-degree sectors (clock hours) of stage 3 ROP in zones I or II in the presence of plus disease (Fig. 7). The risk of blindness at threshold was predicted to be 50%. Once threshold disease was reached, the affected eye was randomly assigned to either treatment or observation. If cryotherapy was assigned, then treatment was performed within 72 hours to minimize the risk of progression to stage 4 ROP before treatment could be performed.

In the CRYO-ROP Study, the choice of anesthesia was left to the treating physician. When performing cryotherapy, we almost exclusively treated our patients under local anesthesia with infiltration of the subconjunctival space with 0.5% or 1% lidocaine. For cryotherapy, conjunctival incisions rarely are necessary, especially if anterior therapy is performed first, since this softens the globe, allowing for the cryoprobe to be placed further posteriorly. For those still using cryotherapy, the standard retinal cryoprobe was used most often in the study, but a cataract probe and the newer neonatal probes are equally effective. Contiguous single spots of cryotherapy should be applied to the avascular retina anterior to the ridge, but the ridge itself should not be treated because of the possibility of inducing a hemorrhage. The endpoint for the freeze should be sudden whitening of the retina, and the avascular retina should be treated for 360 degrees. The number of applications range from 35 to 50. We now use laser with topical anesthesia in the ICN with monitoring by a neonatologist.

Seven days after treatment, the treated eye should be re-examined to assess the effects of treatment. Retreatment is indicated if there are untreated (skip) areas and persistent plus disease in association with either of the following characteristics: segmental shallow retinal detachment (suggesting continued adjacent disease activity) in the areas skipped, or progression of extraretinal fibrovascular proliferation (increasing floridity of the ridge) contiguous with a skipped area. When retreatment is performed, it should be applied only to previously untreated areas in sectors of continued activity. This rarely has been necessary since switching to laser treatment.

Preliminary results of the CRYO-ROP Study were based on a 3-month follow-up of eligible infants within the study. The mean birth weight of randomly assigned patients was 800 g, the mean gestational age was 26 weeks, and the mean chronologic age at randomization was 11 weeks. An unfavorable outcome was defined as (1) a retinal fold involving the macula, (2) a retinal detachment involving zone I of the posterior pole, or (3) retrolental tissue or “mass.” There was a 49.3% statistically significant overall reduction in the unfavorable outcome rate at 3 months in the treated versus the untreated eyes (21.8% compared with 43.0%).⁶⁰ Subsequent reports of the Cryo-ROP Study show persistence of a favorable outcome with treatment. At 1 year, there was a 45.8% reduction in the unfavorable structural outcome rate in eyes of patients randomly assigned to treatment compared with control eyes.⁶¹ There was a continued positive effect on structural outcome as a result of treatment as infants were followed at 3½ and 5½ years after randomization.^62,63 As children became older and visual acuities could be obtained, there was a similar overall beneficial effect on vision in the treated compared with the control eyes.^62,63 However, there were fewer treated eyes than control eyes in the best visual outcome group (20/40 or better) at 5½ years, suggesting a possible adverse effect of cryotherapy on visual acuity or the fact that the untreated eyes never reached as advanced a stage as the treated eyes.⁶³

Ocular complications recorded within the CRYO-ROP Study were not serious, but a 9% incidence of bradycardia or arrhythmia within the study underscores the need for both careful monitoring and performance of the treatment in a facility where resuscitation can be achieved immediately. Greven and Tasman⁶⁴ report on the occurrence of rhegmatogenous retinal detachment after cryotherapy for ROP that was administered in the manner described in the CRYO-ROP Study. Detachment occurred 1 to 4 years after treatment. Three infants developed rhegmatogenous retinal detachments with breaks located at the posterior edge of cryotherapy. Two of the retinas were reattached with a scleral buckling procedure, but useful vision was regained only in one eye. In the third eye, progression to total inoperable retinal detachment occurred despite scleral buckling.

Quinn and associates^64a have shown that visual field loss is less than 10% when older children who had cryotherapy are tested.

The recommendation of the CRYO-ROP Study was that at least one eye of symmetrical cases at threshold should receive cryotherapy. Surgeons should use their own clinical judgment beyond that recommendation. Our personal recommendation is to treat all eyes that have reached threshold. If both eyes have reached threshold, then the eye with the more advanced disease may be treated first, and the second eye treated a few days later if the first eye is beginning to respond to treatment.

Certain eyes can be identified to have an unfavorable prognosis before treatment. In 1977, Uemura⁴⁰ identified a fulminently progressive form of ROP. These eyes had what is known as zone I vascularization with plus disease. This form of ROP sometimes is referred to as “rush disease” because of the rapid nature of its progression.

When the CRYO-ROP Study was conceived, portable laser photocoagulation through an indirect ophthalmoscope was not available. Since that time, several investigators⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰ have reported on the use of argon laser and, recently, diode laser photocoagulation for the treatment of ROP. This method of treatment has replaced cryotherapy in the management of some other retinal disorders and currently is in widespread clinical use for managing ROP (Fig. 8). The structural results are reported to be comparable to cryotherapy in several studies.

Laser is particularly useful in the management of zone I and posterior zone II disease. Most often, conjunctival incisions are necessary to get a cryotherapy probe posterior enough to treat zone I disease. This problem is obviated with laser delivery. Results of treatment of zone I disease in the Cryo-ROP Study are poor, whereas success rates of 80% to 90% have been reported in managing zone I disease with laser.⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵ Ridges in zone I or posterior zone II disease often are wider, with more defined vasculature than in zone II disease (Fig. 9). Zone I disease can be determined with a + 25 D lens. The disc is visualized at one rim of the lens, and avascular retina can be seen at the opposite rim when zone I disease is present (Fig. 10). A This occurs at a significant rate in the eyes of the smallest infants (500 g) with a gestation of 22 to 26 weeks. There may be an associated persistence of fetal vasculature (Fig. 11).

In a study of 19 infants who were randomly assigned to immediate laser or observation until threshold disease was reached, the unfavorable anatomic outcome rate was 16% for early treatment eyes and 18% for control eyes.⁷⁵ Eighty-eight percent of control eyes reached threshold disease. There does not seem to be a clear-cut advantage to early treatment of posterior ROP so long as prompt treatment at threshold disease can be assured.

Good visual results are more likely to occur after laser for threshold ROP than after cryotherapy.^76,77 At an average follow-up point of 5.8 years, Connolly and colleagues report a 6.91 times greater chance that an eye treated with laser will have visual acuity of 20/50 or better when compared with its fellow eye treated with cryotherapy.⁷⁶ Similarly, there is a lesser degree of myopic refractive error in infants treated with laser.⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰

Laser photocoagulation can be delivered in the ICN. We usually perform the procedure under topical anesthesia with sedation. Fentanyl citrate is an ideal agent. The neonatologist calculates the appropriate dose, and continuous cardiopulmonary monitoring is done with a nurse constantly in attendance at the bedside. As when using cryotherapy, pupils can be dilated with one drop of homatropine hydrobromide 2% and phenylephrine hydrochloride 2.5% given every 15 minutes for three doses starting 1 hour before the treatment. A lid speculum is inserted into the conjunctival cul de sac. Assisting personnel and other personnel in the treatment area of the nursery should wear appropriate protective eye wear. Using a scleral depressor to rotate the eye, the peripheral retina is brought into view through the laser indirect ophthalmoscope, and laser applications are applied throughout the anterior avascular zone for 360 degrees. The portable diode laser units are ideal for this treatment. We generally start with a 200-mW power setting at 0.2 seconds' duration. Critical focus onto the retina is essential to decrease the risk of laser absorption by tissues other than the desired area of treatment, especially when a persistent tunica vasculosa lentis is present (Fig. 12). Power is increased in 50-mW increments to achieve a dull white spot on the retina. Applications are placed approximately one burn width apart. The number of applications depends mainly on the location of the termination of the vascularized retina. Zone I disease often requires over 2000 applications. The average number of applications in mid-zone II disease is approximately 950. If both eyes are at threshold, we generally treat both eyes in one session. Approximately 20 minutes are required to complete laser treatment on one eye.

Reports of cataract after laser for ROP have tempered enthusiasm for this method of treatment.⁸¹, ⁸², ⁸³, ⁸⁴, ⁸⁵, ⁸⁶ However, the incidence of cataract is likely to be low (less that 0.5% in our experience) and may be related to the ability of the treating physician to maintain adequate focus on the retina.

The systemic risks associated with laser treatment may be fewer than those associated with cryotherapy because laser is less stressful on the infant. Cryotherapy often causes severe postoperative periorbital and orbital edema. With laser photocoagulation, there is virtually no swelling.

Infants with stage 3 ROP may progress to retinal detachment anterior to the ridge (stage 4A). This detachment of the nonvascularized retina may disappear as the retinal vessels grow into the avascular zone.

The management of retinal detachment in ROP remains controversial.⁸⁷ However, scleral buckling may be useful in some cases of progressive stage 4A, 4B, and open-funnel stage 5 ROP.⁸⁸, ⁸⁹, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴ Greven and Tasman⁹⁰ report successful reattachment in 13 of 22 eyes (59%) with stages 4B and 5 ROP. The technique involved cryotherapy to the avascular zone of retina, drainage of subretinal fluid, and encirclement of the globe. Of their patients achieving anatomic reattachment with follow-up of 18 months or more, 4 of 10 (40%) had 20/400 or better visual acuity. Anatomic success after scleral buckling in ROP is defined as macular reattachment (full attachment of the retina between the vascular arcades). The success rate varies. In the larger published series,^88,89,^90,92,93,95 it is between 54% and 75%. Trese⁹³ notes a decreasing incidence of anatomic success from stages 4A to 5 (70% for stage 4A, 67% for stage 4B, and 40% for stage 5). Greater reattachment rates have been achieved in all studies when additional vitreous or scleral buckling surgery was performed. Children who have successful retinal reattachment after scleral buckling surgery should have their encircling band divided at 3 to 6 months after the surgery to allow for continued eye growth and to prevent intrusion of the band later in life.

More severe forms of total retinal detachment are not amenable to repair with scleral buckling alone. In these cases, a closed or partially closed funnel with severe fibrous proliferation prevents apposition of the retina to the retinal pigment epithelium with buckling techniques even in association with drainage of subretinal fluid. Both open and closed vitrectomy techniques have been used in the management of these retinal detachments. Each has advantages and disadvantages. The main advantage to open-sky vitrectomy (vitreous surgery through a trephined opening in the cornea) is easy access and visualization of the anterior retina and epiretinal membranes. The disadvantages are lack of control of intraocular pressure and difficulty in posterior manipulation. Closed vitrectomy has the advantages of intraocular pressure maintenance, minimal tissue dissection, and good visualization of the posterior pole. The disadvantages are poor visualization in the retinal periphery and restricted manipulation of instruments.

Schepens⁹⁶ and Hirose⁹⁷ pioneered subtotal open-sky vitrectomy for stage 5 ROP. The main advantage of open-sky vitrectomy over a closed approach is the ability to remove the membrane in the far periphery, where a strong adhesion to the detached retina exists. At surgery, a corneal button is first removed and stored in a tissue culture medium. After removing the lens by intracapsular extraction with a cryoprobe, the membrane is dissected from the surface of the retina starting just posterior to the ciliary processes. Hyaluronic acid is injected to flatten the retina, and the corneal button is sewn back in place. The membrane usually can be removed from the retina in one piece. Using the open-sky technique, Tasman and coworkers⁹⁸ documented a reattachment rate of 34.7% in 23 eyes. Hirose and colleagues⁹⁹ report on the visual results of 55 eyes of 50 infants whose retinas were reattached using the open-sky technique for stage 5 ROP. Using the visual acuity measurement technique of preferential looking, they found that 32 of 55 eyes (58%) were able to discriminate stationary objects. Eighteen of those eyes (32%) had motion perception, and 5 (9%) had light perception. Although visual acuities were low, they were useful to these patients.

Several authors¹⁰⁰, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴ advocate a closed approach for management of stage 5 ROP. Charles operated on 1237 patients with advanced-stage 4B or stage 5 disease (95% stage 5) using this technique from 1977 to 1999 (Charles S, personal communication, March 11, 1999). He removes the lens with the vitrectomy instrument and then segments the hyaloid membranes by making pie-shaped cuts. The membranes then are delaminated from the surface of the retina and circumcised peripherally near the ora serrata to eliminate anterior loop traction. Charles now performs simultaneous bilateral surgery if both eyes have stage 5 ROP to decrease anesthesia risk. Surgery for both eyes takes less than 1 hour. Using this technique, Charles reports a 35% reattachment rate. Ambulatory vision (ability to recognize faces) was present in 15% of patients with reattachment.¹⁰⁵ Maguire and Trese recommend a lens-sparing approach in selected cases with posterior proliferation and attached peripheral retina.¹⁰⁶ When using this technique, incisions should be directed parallel with the visual axis and care must be taken to avoid moving the instruments across the midline because the lens may be struck.¹⁰⁷

Although the anatomic success rates with these interventions are encouraging, the visual results are disappointing.^102,103,108, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹² However, without reattachment, no vision is possible. Because of these poor outcomes, emphasis should be placed on prevention of retinal detachment in premature infants.¹¹⁰

Fortunately, the need for vitrectomy has decreased because of laser treatment. The reasons for poor visual results in these infants remain speculative. Some infants may have had cerebral dysfunction as a result of the complications of prematurity (e.g., intraventricular hemorrhage).⁹⁰ The maculae in these infants are immature to begin with, and detachment may have had a more devastating effect on photoreceptors and their development than it would in an adult. Amblyopia likely plays a role as well.

Secondary angle closure glaucoma is another late complication of ROP. In mild cases, this may be cured with laser iridotomy. In severe cases, it usually is secondary to severe shallowing of the anterior chamber angle from retrolental fibrovascular proliferation, as first reported by Blodi.¹¹⁸ Both medical (topical corticosteroid)¹¹⁹ and surgical (lensectomy)¹²⁰ treatments have met with success. Smith and Shivitz¹²¹ report three cases of angle closure glaucoma in adults with stable regressed ROP. All cases responded to peripheral iridectomy or iridotomy. In this regard YAG laser iridotomy has proved effective.

Occasional patients followed for many years eventually lose vision for obscure reasons. Tasman and Brown¹²² report on two monocular patients who gradually lost vision over the course of years. One patient's remaining good eye had 20/30 vision with a highly myopic correction. Initial examination revealed retinal pigment epithelial change in the posterior pole with macular heterotopia but no significant vessel dragging. The patient was followed for 14 years, and over the course of the last 4 years of follow-up, vision gradually diminished to 20/400. The visual field was constricted. Fluorescein angiography demonstrated marked increasing retinal pigment epithelial alterations that progressed over the years. In a discussion of this article, Irvine added similar cases including two with cystoid macular edema, presumably from tangential traction on the retina.¹²³

Many adult patients with ROP also develop cataracts. We have followed 26 such eyes after cataract surgery with posterior chamber intraocular lenses and most have done well. The cataracts generally are nuclear.

The clinical setting often provides the diagnosis. Infants with ROP typically were premature and of low birth weight with a history of variable oxygen exposure. There is no hereditary pattern.

Familial exudative vitreoretinopathy usually is an autosomal dominant peripheral fundus disorder that is asymptomatic in 80% of cases. It also may be inherited in an X-linked fashion, in which case Norrie's disease must be included in the differential diagnosis, since one mutation in the Norrie disease protein gene (NDA) may lead to confusion with FEVR. Peripheral nonvascularization with straightening and anastomosis of the vessels occurs in a fibrillar pattern at the junction between perfused and nonperfused retina, and there may be dragging of the retina. Regression, such as occurs in ROP, typically does not occur in familial exudative vitreoretinopathy. The peripheral retina remains avascular, but progression to more severe changes such as tractional retinal detachment and neovascular glaucoma may occur.¹²⁴ Patients with familial exudative vitreoretinopathy are normally full term at birth with no history of respiratory difficulties and supplemental oxygen exposure. If familial exudative vitreoretinopathy is suspected in an older child or adult, examination of asymptomatic family members often reveals peripheral fundus lesions.

Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an X-linked dominant condition that may simulate ROP in female infants. The disease is lethal in male infants. In the first month, infants may have dilated, tortuous retinal vessels with peripheral retinal nonperfusion. Hemorrhage may be present at the junction of vascularized and avascularized retina. Other ocular anomalies include strabismus, cataract, myopia, nystagmus, blue sclera, and corneal opacities. Vesicular skin eruptions, which later turn into depigmented areas, are seen. Central nervous system disorders include seizures, spastic paralysis, mental retardation, and cortical blindness.

Patients with X-linked retinoschisis may develop a dragged retina in the first year of life. The dragging may be associated with vitreous hemorrhage. Examination of the fellow eye and electroretinography (showing a decreased b wave) are helpful in making the diagnosis. Family history frequently is positive.

The differential diagnosis of stage 5 ROP is that of a white pupillary reflex (leukocoria). This includes congenital cataract, fetal vasculature, retinoblastoma, ocular toxocariasis, intermediate uveitis, Coats' disease, advanced X-linked retinoschisis, and vitreous hemorrhage.

1. Terry T: Extreme prematurity and fibroplastic overgrowth of persistent vascular sheath behind each crystalline lens: I. Preliminary report. Am J Ophthalmol 25:203, 1942

2. James L, Lanman J: History of oxygen therapy and retrolental fibroplasia. Pediatrics 57:590, 1976

3. Owens W, Owens E: Retrolental fibroplasia in premature infants: II. Studies on prophylaxis of disease, use of alpha-tocopheral acetate. Am J Ophthalmol 32:1631, 1949

4. Kline B: Histopathologic aspects of retrolental fibroplasia. Arch Ophthalmol 41:553, 1949

5. Kinsey V, Zacharias L: Retrolental fibroplasia incidence in different localities in recent years and a correlation of the incidence with treatment given the infants. JAMA 139: 572, 1949

6. Campbell K: Intensive oxygen therapy as a possible cause of retrolental fibroplasia: A clinical approach. Med J Aust 2:48, 1951

7. Crosse V, Evans P: Prevention of retrolental fibroplsia. Arch Ophthalmol 48:83, 1952

8. Ashton N, Ward B, Serpell G: Role of oxygen in genesis of retrolental fibroplasia: Preliminary report. Br J Ophthalmol 49:225, 1953

9. Patz A: Mead Johnson award address: The role of oxygen in retrolental fibroplasia. Pediatrics 19:504, 1957

10. Patz A, Hoech L, de la Cruz E: Studies on the effect of high oxygen administration in retrolental fibroplasia: I. Nursery observations. Am J Ophthalmol 35:1248, 1952

11. Lanman J, Guy L, Dancis J: Retrolental fibroplasia and oxygen therapy. JAMA 155:223, 1954

12. Kinsey V: Retrolental fibroplasia: Cooperative study of retrolental fibroplasia and the use of oxygen. Trans Assoc Acad Ophthalmol Otolaryngol 59:15, 1955

13. Cross K: Cost of preventing retrolental fibroplasia? Lancet 2:954, 1973

14. American Academy of Pediatrics Committee on Fetus and Newborn: History of oxygen therapy and retrolental fibroplasia. Pediatrics 57(Suppl):591, 1976

15. Phelps D: Retinopathy of prematurity: An estimate of vision loss—1979. Pediatrics 67:924, 1981

16. Phelps D: Vision loss due to retinopathy of prematurity. Lancet i:606, 1981

17. Hack M, Fanaroff A: Outcomes of extremely low birth weight infants between 1982 and 1988. N Engl J Med 321:1642, 1989

18. Campbell P, Bull M, Ellis F: Incidence of retinopathy of prematurity in a tertiary newborn intensive care unit. Arch Ophthalmol 101:1686, 1983

19. Flynn J, Bancalari E, Bawol R et al: Retinopathy of prematurity: A randomized, prospective trial of transcutaneous oxygen monitoring. Ophthalmology 94:630, 1987

20. The Committee for the Classification of Retinopathy of Prematurity: An international classification of retinopathy of prematurity. Arch Ophthalmol 102:1130, 1984

21. Committee on Fetus and Newborn: Vitamin E and the prevention of retinopathy of prematurity. Pediatrics 76: 315, 1985

22. Reynolds J, Hardy R, Kennedy K et al: Lack of efficacy of light reduction in preventing retinopathy of prematurity. N Engl J Med 338:1572, 1998

23. Smith L: VEGF and ROP: Pathophysiology and treatment. International Congress of Opthalmology, Amsterdam, Holland, June 22, 1998

24. Gilbert C, Canovas R, Kocksch R et al: Causes of blindness and severe visual impairment in children in Chile. Dev Med Child Neurol 36:334, 1994

25. Gilbert C, Foster A: Causes of blindness in children attending four schools for the blind in Thailand and the Phillippines: A comparison between urban and rural blind school populations. Int Ophthalmol 17:229, 1993

26. O'Sullivan J, Gilbert C, Foster A: The causes of childhood blindness in South Africa. S Afr Med J 87:1691, 1997

27. Gilbert C, Rahi J, Eckstein M et al: Retinopathy of Prematurity in Middle Income Countries. Lancet 350:12, 1997

28. Palmer E, Flynn J, Hardy R et al: Incidence and early course of retinopathy of prematurity. Ophthalmology 98: 1628, 1991

29. Tasman W: The natural history of active retinopathy of prematurity. Ophthalmology 91:1499, 1984

30. Flynn J, Bancalari E, Bachynski B et al: Retinopathy of prematurity: Diagnosis, severity, and natural history. Ophthalmology 94:620, 1987

31. Schaffer D, Quinn G, Johnson L: Sequelae of arrested mild retinopathy of prematurity. Arch Ophthalmol 102:373, 1984

32. Kingham J: Acute retrolental fibroplasia. Arch Ophthalmol 95:39, 1977

33. Reese A, King M, Owens W: A classification of retrolental fibroplasia. Am J Ophthalmol 36:1333, 1953

34. Cantolino S, Curran J, Van Caden T et al: Acute retrolental fibroplasia: Classification and objective evaluation of incidence, natural history and resolution by fundus photography and intravenous fluorescein angiography. Perspect Ophthalmol 2:175, 1978

35. Hindle NW: International classification of retrolental fibroplasia: A proposal. Can J Ophthalmol 17:107, 1982

36. Keith G: Retrolental fibroplasia: A new classification of the developing and cicatricial changes. Aust J Ophthalmol 7:189, 1979

37. McCormick A: Retinopathy of prematurity. Curr Probl Pediatr 7:1, 1977

38. Patz A: Retrolental fibroplasia. Surv Ophthalmol 14:1, 1969

39. Schaffer D, Johnson L, Quinn G et al: A classification of retrolental fibroplasia to evaluate vitamin E therapy. Ophthalmology 86:1749, 1979

40. Uemura Y: Current status of retrolental fibroplasia: Report of the Joint committee for the study of RLF. Jpn J Ophthalmol 21:366, 1977

41. The International Committee for the Classification of the Late Stages of Retinopathy of Prematurity: An international classification of retinopathy of prematurity: II. The classification of retinal detachment. Arch Ophthalmol 105:906, 1987

42. Screening examination of premature infants for retinopathy of prematurity: A joint statement of the American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology. Ophthalmology 104:888, 1997

43. Fierson W, Palmer E, Biglan A et al: Retinopathy of prematurity guidelines [letter]. Ophthalmology 105:941, 1998

44. Wright K, Anderson M, Walker E et al: Should fewer premature infants be screened for retinopathy of prematurity in the managed care era? Pediatrics 102:31, 1998

45. Report of a Working Party of the Royal College of Ophthalmologists and the British Association of Perinatal Medicine. Early Hum Dev 46:239, 1996

46. Yamashita Y: Studies on retinopathy of prematurity: III. Cryocautery for retinopathy of prematurity. Jpn J Ophthalmol 26:385, 1972

47. Majima A, Takahashi M, Hibino Y: Clinical observations of photocoagulation on retinopathy of prematurity. Jpn J Ophthalmol 30:93, 1976

48. Nagata M, Yamagishi N, Ikeda S: Summarized results of the treatment of acute proliferative retinopathy of prematurity during the past 15 years at Tenri Hospital. Acta Soc Ophthalmol Jpn 86:1236, 1982

49. Sasaki K, Yamashita Y, Maekawa T et al: Treatment of retinopathy of prematurity in active stages by cryocautery. Jpn J Ophthalmol 20:384, 1976

50. Takagi I: Treatment of acute retrolental fibroplasia. Nippon Ganka Gakkai Zasshi 82:323, 1978

51. Ben-Sira I, Nissenkorn I, Grunwald E et al: Treatment of acute retrolental fibroplasia by cryopexy. Br J Ophthalmol 64, 1980

52. Hindle N: Cryotherapy for retinopathy of prematurity to prevent retrolental fibroplasia. Can J Ophthalmol 17:207, 1982

53. Kingham J: Acute retrolental fibroplasia: Treatment by cryosurgery. Arch Ophthalmol 96:2049, 1978

54. Mousel D, Hoyt C: Cryotherapy for retinopathy of prematurity. Ophthalmology 87:1121, 1980

55. Mousel D: Cryotherapy for retinopathy of prematurity: A personal retrospective. Ophthalmology 92:375, 1985

56. Palmer E, Goodman S: A pilot randomized trial of cryotherapy for retinopathy of prematurity. Invest Ophthalmol Vis Sci 28(Suppl):105, 1987

57. Payne J, Patz A: Treatment of acute retrolental fibroplasia. Trans Am Acad Ophthalmol Otolaryngol 76:1234, 1972

58. Reisner S, Amir J, Shohat M et al: Retinopathy of prematurity: Incidence and treatment. Arch Dis Child 60:698, 1985

59. Tasman W: Multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 106:463, 1988

60. Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: Preliminary results. Arch Ophthalmol 106: 471, 1988

61. Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: 1-year outcome. Structure and function. Arch Ophthalmol 108:1408, 1990

62. Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: 3-½ year outcome. Structure and function. Arch Ophthalmol 111:339, 1993

63. Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: Snellen visual acuity and structural outcome at 5 ½ years after randomization. Arch Ophthalmol 114:417, 1996

64. Greven C, Tasman W: Rhegmatogenous retinal detachment following cryotherapy for retinopathy of prematurity. Arch Ophthalmol 107:1017, 1989

64a. Quinn GE, Dobson V, Hardy RJ, et al: Visual fields measured with double-arc perimetry in eyes with threshold retinopathy of prematurity from the cryotherapy for retinopathy of prematurity trial. The CRYO-Retinopathy of Prematurity Cooperative Group. Ophthalmol 103:1432, 1996

65. McNamara J, Tasman W, Brown G et al: Laser photocoagulation for stage 3+ retinopathy of prematurity. Ophthalmology 98:576, 1991

66. McNamara J, Tasman W, Vander J et al: Diode laser photocoagulation for retinopathy of prematurity: Preliminary results. Arch Ophthalmol 110:1714, 1992

67. Iverson D, Trese M, Orgel I et al: Laser photocoagulation for threshold retinopathy of prematurity. Arch Ophthalmol 108:1342, 1991

68. Landers M, Toth C, Semple H et al: Treatment of retinopathy of prematurity with argon laser photocoagulation. Arch Ophthalmol 110:44, 1992

69. Goggin M, O'Keefe M: Diode laser for retinopathy of prematurity: Early outcome. Br J Ophthalmol 77:559, 1993

70. Seiberth V, Linderkamp O, Vardarli I et al: Diode laser photocoagulation for stage 3+ retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 233:489, 1995

71. Hammer M, Pusateri T, Hess J et al: Threshold retinopathy of prematurity. Transition from cryopexy to laser treatment. Retina 15:486, 1995

72. Noonan C, Clarke D: Trends in the management of stage 3 retinopathy of prematurity. Br J Ophthalmol 80:278, 1996

73. Fleming T, Runge P, Charles S: Diode laser photocoagulation for prethreshold, posterior retinopathy of prematurity. Am J Ophthalmol 114:589, 1992

74. Capone AJ, Diaz-Rohena R, Sternberg PJ et al: Diode laser photocoagulation for zone I threshold retinopathy of prematurity. Am J Ophthalmol 116:444, 1993

75. Vander J, Handa J, McNamara J et al: Early treatment of posterior retinopathy of prematurity: A controlled trial. Ophthalmology 104:1731, 1997

76. Connolly B, McNamara J, Sharma S et al: A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology 105:1628, 1998

77. White J, Repka M: Randomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: 3-year outcome. J Pediatr Ophthalmol Strabismus 34:83, 1997

78. Laws F, Laws D, Clark D: Cryotherapy and laser treatment for acute retinopathy of prematurity: Refractive outcomes. A longitudinal study. Br J Ophthalmol 81:12, 1997

79. Knight-Nanan D, O'Keefe M: Refractive outcome in eyes with retinopathy of prematurity treated with cryotherapy or diode laser: 3-year follow up. Br J Ophthalmol 80:998, 1996

80. Algawi A, Goggin M, O'Keefe M: Refractive outcome following diode laser versus cryotherapy for eyes with retinopathy of prematurity. Br J Ophthalmol 78:612, 1994

81. Drack A, Burke J, Pulido J et al: Lenticular opacities as a complication of argon laser photocoablation in an infant with retinopathy of prematurity. Am J Ophthalmol 113: 583, 1992

82. Christiansen S, Bradford J: Cataract in infants treated with argon laser photocoagulation for threshold retinopathy of prematurity. Am J Ophthalmol 120:264, 1995

83. Pogrebniak A, Bolling J, Stewart M: Argon laser-induced cataract in an infant with retinopathy of prematurity [letter]. Am J Ophthalmol 117:261, 1994

84. Campolattaro B, Lueder T: Cataract in infants treated with argon laser photocoagulation for threshold retinopathy of prematurity. Am J Ophthalmol 119:175, 1995

85. Capone AJ, Drack A: Transient lens changes after diode laser photocoablation for retinopathy of prematurity [letter]. Am J Ophthalmol 118:533, 1994

86. Simons B, Wilson M, Hertle R et al: Bilateral hyphemas and cataracts after diode laser retinal photoablation for retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 35:185, 1998

87. Tasman W: Retinal detachment in retinopathy of prematurity. In Silverman W, Flynn J (eds): Contemporary Issues in Fetal and Neonatal Medicine: Retinopathy of Prematurity, p 232. Boston: Blackwell Scientific Publications, 1985

88. McPherson A, Mintz-Hittner H, Lemos R: Retinal detachment in young premature infants with acute retrolental fibroplasia: Thirty-two new cases. Ophthalmology 89:160, 1982

89. Topilow H, Ackerman A, Wang F: The treatment of advanced retinopathy of prematurity by cryotherapy and scleral buckling surgery. Ophthalmology 92:379, 1985

90. Greven C, Tasman W: Scleral buckling in stages 4B and 5 retinopathy of prematurity. Ophthalmology 97:817, 1990

91. Wicharz A, Paulmann H, Stojanov D: Ergebnisse der operativen therapie forgeschrittener Stadien der retinopathia prämaturorum. Fortschr Ophthalmol 88:477, 1991

92. Noorily S, Small K, de Juan E et al: Scleral buckling surgery for stage 4B retinopathy of prematurity. Ophthalmology 1992; 99:263

93. Trese M: Scleral buckling for retinopathy of prematurity. Ophthalmology 101:23, 1994

94. Ricci B, Santo A, Ricci F et al: Scleral buckling surgery in stage 4 retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 234(Suppl):S38, 1996

95. Sucheski B, Tasman W, Vander J et al: Visual outcomes of scleral buckling for stage 4B and 5 retinopathy of prematurity. Ophthalmology (submitted for publication)

96. Schepens C: Clinical and research aspects of subtotal open-sky vitrectomy. Am J Ophthalmol 91:143, 1981

97. Hirose T, Schepens C: Open-sky vitrectomy in severe retinal detachment caused by advanced retinopathy of prematurity. Ophthalmology 91(Suppl):32, 1984

98. Tasman W, Borrone R, Bolling J: Open-sky vitrectomy for total retinal detachment in retinopathy of prematurity. Ophthalmology 94:449, 1987

99. Hirose T, Katsumi O, Mehta M et al: Vision in stage 5 retinopathy of prematurity after retinal reattachment by open-sky vitrectomy. Arch Ophthalmol 111:345, 1993

100. Charles S: Retinopathy of Prematurity, p 158. Baltimore: Williams & Wilkins, 1987

101. de Juan E Jr, Machemer R: Retinopathy of prematurity: Surgical technique. Retina 7:63, 1987

102. Choi W, Yu Y: Surgical management for stage 5 retinopathy of prematurity. Korean J Ophthalmol 8:37, 1994

103. Mintz-Hittner H, O'Malley R, Kretzer F: Long-term form idedtification vision after early, closed, lensectomy-vitrectomy for stage 5 retinopathy of prematurity. Ophthalmology 104:454, 1997

104. Trese M, Droste P: Long-term postoperative results of a consecutive series of stages 4 and 5 retinopathy of prematurity. Ophthalmology 105:992, 1998

105. Charles S: Vitrectomy for stage 5 retinopathy of prematurity. American Academy of Ophthalmology Annual Meeting, New Orleans, 1989

106. Maguire A, Trese M: Lens-sparing vitreoretinal surgery in infants. Arch Ophthalmol 110:284, 1987

107. McNamara J: Retinopathy of prematurity. In Tasman W (ed): Clinial Decisions in Medical Retinal Diseases, p 224. Philadelphia: Mosby, 1996

108. Seaber J, Machemer R, Eliott D et al: Long-term visual results of children after initially successful vitrectomy for stage V retinopathy of prematurity. Ophthalmology 102: 199, 1995

109. Fuchino Y, Hayashi H, Kono T et al: Long-term follow-up of visual acuity in eyes with stage 5 retinopathy of prematurity after closed vitrectomy. Am J Ophthalmol 120:308, 1995

110. Quinn G, Dobson V, Barr C et al: Visual acuity of eyes after vitrectomy for ROP: Follow-up at 5-½ years. Ophthalmology 103:595, 1996

111. Knight-Nanan D, Algawi K, Bowell R et al: Advanced cicatricial retinopathy of prematurity: Outcome and complications. Br J Ophthalmol 80:343, 1996

112. Choi W, Yu Y: Antomical and visual results of vitreous surgery for advanced retinopathy of prematurity. Korean J Ophthalmol 12:60, 1998

113. Faris B, Tolentino F, Freeman H et al: Retrolental fibroplasia in the cicatricial stage: Fundus and vitreous findings. Arch Ophthalmol 1971:661, 1971

114. Nissenkorn I, Yassur Y, Mashkowski D et al: Myopia in premature babies with and without retinopathy of prematurity. Br J Ophthalmol 67:170, 1983

115. Tasman W: Late complications of retrolental fibroplasia. Trans Am Acad Ophthalmol Otolaryngol 86:1724, 1979

116. Tasman W: Retinal detachment in retrolental fibroplasia. Graefes Arch Clin Exp Ophthalmol 195:129, 1975

117. Tasman W: Vitreoretinal changes in cicatricial retrolental fibroplasia. Trans Am Ophthalmol Soc 68:548, 1970

118. Blodi F: Symposium: Retrolental fibroplasia (retinopathy of prematurity): Management. Trans Am Acad Ophthalmol Otolaryngol 59:367, 1955

119. Kushner B, Sondheimer S: Medical management of glaucome associated with cicatricial retinopathy of prematurity. Am J Ophthalmol 94:313, 1982

120. Pollard Z: Lensectomy for secondary angle-closure glaucoma in advanced cicatricial retrolental fibroplasia. Ophthalmology 91:395, 1984

121. Smith J, Shivitz I: Angle-closure glaucoma in adults with cicatricial retinopathy of prematurity (ROP). Arch Ophthalmol 102:371, 1984

122. Tasman W, Brown C: Progressive visual loss in adults with retinopathy of prematurity (ROP). Trans Am Ophthalmol Soc 86:367, 1988

123. Irvine A: Progressive visual loss in adults with retinopathy of prematurity (ROP). Trans Am Ophthalmol Soc 86:375, 1988

124. Benson W: Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 93:473, 1995