Retinopathy of Prematurity
J. ARCH MCNAMARA and WILLIAM TASMAN
Table Of Contents
EPIDEMIOLOGY AND DEMOGRAPHICS
AN INTERNATIONAL CLASSIFICATION FOR RETINOPATHY OF PREMATURITY
SCREENING FOR RETINOPATHY OF PREMATURITY
RETINAL DETACHMENT IN RETINOPATHY OF PREMATURITY
|Retinopathy of prematurity (ROP) was first described in 1942 by Terry.1 He named the disease retrolental fibroplasia (RLF). Many different etiologies
were proposed for RLF, including an infection that was either
primary or transmitted from the mother,2 vitamin E deficiency,3 and anoxia.3,4 In the early 1950s, hyperoxia was implicated in the growing incidence (described
as an “epidemic”) of RLF. Kinsey and Zacharias5 reported retrospective data that implicated oxygen, vitamins, and iron
in the increasing incidence of RLF. Campbell6 in Australia and Crosse and Evans7 in England presented both prospective and retrospective evidence that
supported oxygen as a causative factor. Ashton8 verified these clinical findings by producing RLF changes in kittens exposed
to high oxygen concentrations. In the mid-1950s, controlled clinical
trials showed a significant decrease in the incidence of RLF by
limiting the amount of inspired oxygen. Patz and colleagues,9,10 Lanman,11 and a national multicenter clinical trial in the United States coordinated
by Kinsey12 concluded that limiting oxygen was essential.|
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.
|EPIDEMIOLOGY AND DEMOGRAPHICS|
|From 1943 to 1951, an estimated 7000 infants in the United States were
blinded by ROP. Phelps15 estimated that approximately 546 babies were blinded by ROP in 1979. In 1950, the
survival rate of infants with a birth weight of less than 1000 g
was 8%, but Phelps16 reported that the survival rate rose to approximately 35% in 1980. Currently, a
fetus at or beyond 25 weeks of gestation or with a weight of 700 g
or more has a better than 50% chance of survival.17 These small infants are most susceptible to ROP. Campbell and colleagues18 found that the incidence of acute ROP among surviving premature babies
who weighed less than 1000 g at birth was three times that of survivors
with birth weights between 1001 and 1500 g.|
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 Multicenter Trial of Cryotherapy for Retinopathy of Prematurity reported
an incidence of ROP of 65.8% in the 4099 infants weighing less than 1250 g
at birth who were examined within that study.28 Of infants weighing less than 1000 g at birth, the incidence of ROP was 81.6%. ROP
incidence and severity were higher in lower birth weight
and gestational age categories. In Tasman's study on the natural
history of ROP, all babies who became blind weighed under 1000 g.29 In the report of the Multicenter Trial of Cryotherapy for Retinopathy
of Prematurity, the timing of disease development correlated more closely
with postconceptional age than with postnatal age, suggesting that
level of maturity is more of a determining factor than postnatal environmental
influences.28 Disease level of a severity that required treatment (“threshold
disease,” see later for definition) occurred in 6% of the overall
group. The average postconceptional age of onset of threshold disease
was 37 weeks with 95% of infants who reached threshold doing so by 42 weeks. Most
infants who develop ROP undergo regression of their disease, and
for those who do, ROP lasts approximately 15 weeks.30 Infants who go on to regression from mild ROP (less than stage 2, see
later for classification), usually undergo complete resolution.31 There is an increased incidence of strabismus in those infants compared
with those who are full term, but this may result from central nervous
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.
|AN INTERNATIONAL CLASSIFICATION FOR RETINOPATHY OF PREMATURITY|
|A classification system for acute
ROP, devised by 23 ophthalmologists from 11 different countries, was published
and widely accepted in 1984.20 This system,
the International Classification of Retinopathy of Prematurity (ICROP),
easily replaced previous classifications32,
33, 34, 35,
36, 37, 38,
39, 40 because
a much greater understanding of ROP had been gained since their publication.
Before the 1984 classification, it was not possible to compare treatment
results, since it was not clear what stage of the disease was being treated.
The 1984 classification clearly defines the location of the disease
in the retina as well as the extent of the developing vasculature
that is involved.
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).
|SCREENING FOR RETINOPATHY OF PREMATURITY|
|A useful screening protocol for ROP has been reported through a joint statement
of the American Academy of Pediatrics, the American Association
for Pediatric Ophthalmology and Strabismus, and the American Academy
of Ophthalmology.42,43 These guidelines represent a work in progress, and further modifications
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.
|Japanese investigators were the
first to describe successful treatment of the active stages of acute ROP.46,
47, 48, 49,
50 Investigators in Israel51
and Canada52 later showed positive results
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 associates64a 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.
|RETINAL DETACHMENT IN RETINOPATHY OF PREMATURITY|
|Retinal detachments in ROP typically are tractional with or without an
exudative component. Progressive fibrous proliferation causes tractional
detachment of the retina. The tractional force often is circumferential, and
the retina may detach as if a purse string were being tightened. Additionally, exuberant fibrovascular proliferation may lead to subretinal
serous fluid accumulation. Rhegmatogenous retinal detachments
are rare but may present years later as a delayed complication of the
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.
|Several late complications of ROP
are well recognized.113, 114,
117 These include myopia, retinal pigmentation,
dragging of the retina, lattice-like degeneration, retinal folds, retinal
holes, and retinal detachment. Late retinal detachment typically occurs
in the mid-teen years and results from progressive vitreoretinal traction
with subsequent retinal hole formation. Most of the patients are significantly
myopic (8 D or more), but the myopia is not axial. Most retinal breaks are
located temporally (87% in Tasman's series of 24 eyes116,117).
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 differential diagnosis of ROP differs depending on the stage of the
disease. In its earlier stages, conditions that lead to peripheral retinal
vascular changes and retinal dragging should be considered. In its
more advanced stages, the differential diagnosis of a white pupillary
reflex must be considered.|
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.
|The increased survival rate of low birth weight infants has led to an increased incidence of ROP. However, great strides have been made in the management of ROP with the advent of the international classification of this disease. The information obtained from the Cryo-ROP study has shown that treatment is beneficial. Laser therapy for threshold disease is replacing cryotherapy for managing that level of ROP. For more advanced disease, favorable treatment results also are being obtained. Scleral buckling for stage 4 and open-funnel stage 5 ROP has led to anatomic reattachment in 60% to 75% of eyes. Surgery for closed-funnel stage 5 ROP remains controversial. A success rate (reattachment of the retina) of 35% has been achieved by various investigators using both open-sky and closed techniques, but long-term these eye do poorly. Although the visual outcomes of interventions for the more advanced stages of ROP are poor, they are better than the alternative of no possibility for vision. Ongoing investigation will lead to fewer infants being blinded by this devastating disease.|
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