Pathogenesis

Beginning at 16 wk of gestation, retinal angiogenesis normally proceeds from the optic disc to the periphery, reaching the outer rim of the retina (ora serrata) nasally at about 36 wk and extending temporally by approximately 40 wk. Injury to this process results in various pathologic and clinical changes. The first observation in the acute phase is cessation of vasculogenesis. Rather than a gradual transition from vascularized to avascular retina, there is an abrupt termination of the vessels, marked by a line in the retina. The line can then grow into a ridge composed of mesenchymal and endothelial cells. Cell division and differentiation might later resume, and vascularization of the retina can proceed. Alternatively, there may be progression to an abnormal proliferation of vessels out of the plane of the retina, into the vitreous, and over the surface of the retina. Cicatrization and traction on the retina can follow, leading to retinal detachment.

The risk factors associated with ROP are not fully known, but prematurity and the associated retinal immaturity at birth represent the major factors. Oxygenation, respiratory distress, apnea, bradycardia, heart disease, infection, hypercarbia, acidosis, anemia, and the need for transfusion are thought by some to be contributory factors. Generally, the lower the gestational age, the lower the birthweight, and the sicker the infant, the greater the risk is for ROP.

The basic pathogenesis of ROP is still unknown. Exposure to the extrauterine environment including the necessarily high inspired oxygen concentrations produces cellular damage, perhaps mediated by free radicals. Later in the course of the disease, peripheral hypoxia develops and vascular endothelial growth factors (VEGFs) are produced in the nonvascularized retina. These growth factors stimulate abnormal vasculogenesis, and neovascularization can occur. Because of poor pulmonary function, a state of relative retinal hypoxia occurs. This causes upregulation of VEGF, which, in susceptible infants, can cause abnormal fibrovascular growth. This neovascularization can then lead to scarring and vision loss.

Classification

The currently used international classification of ROP describes the location, extent, and severity of the disease. To delineate location, the retina is divided into three concentric zones, centered on the optic disc. Zone I, the posterior or inner zone, extends twice the disc-macular distance, or 30 degrees in all directions from the optic disc. Zone II, the middle zone, extends from the outer edge of zone I to the ora serrata nasally and to the anatomic equator temporally. Zone III, the outer zone, is the residual crescent that extends from the outer border of zone II to the ora serrata temporally. The extent of involvement is described by the number of circumferential clock hours involved.

The phases and severity of the disease process are classified into 5 stages. Stage 1 is characterized by a demarcation line that separates vascularized from avascular retina. This line lies within the plane of the retina and appears relatively flat and white. Often noted is abnormal branching or arcading of the retinal vessels that lead into the line. Stage 2 is characterized by a ridge; the demarcation line has grown, acquiring height, width, and volume and extending up and out of the plane of the retina. Stage 3 is characterized by the presence of a ridge and by the development of extraretinal fibrovascular tissue (Fig. 622-1A). Stage 4 is characterized by subtotal retinal detachment caused by traction from the proliferating tissue in the vitreous or on the retina. Stage 4 is subdivided into 2 phases: (a) subtotal retinal detachment not involving the macula and (b) subtotal retinal detachment involving the macula. Stage 5 is total retinal detachment.

Figure 622-1 Retinopathy of prematurity (ROP). A, In stage 3, there is a ridge and extraretinal vascular tissue. B, Retinal vessels are dilated and tortuous in active ROP plus disease. C, Zone 1, stage ROP with plus disease.

When signs of posterior retinal vascular changes accompany the active stages of ROP, the term plus disease is used (see Fig. 622-1B,C). Patients reaching the point of dilatation and tortuosity of the retinal vessels also often demonstrate the associated findings of engorgement of the iris, pupillary rigidity, and vitreous haze.

Clinical Manifestations and Prognosis

In >90% of at-risk infants, the course is one of spontaneous arrest and regression, with little or no residual effects or visual disability. Less than 10% of infants progress to severe disease, with significant extraretinal vasoproliferation, cicatrization, detachment of the retina, and impairment of vision.

Some children with arrested or regressed ROP are left with demarcation lines, undervascularization of the peripheral retina, or abnormal branching, tortuosity, or straightening of the retinal vessels. Some are left with retinal pigmentary changes, dragging of the retina (dragged disc), ectopia of the macula, retinal folds, or retinal breaks. Others proceed to total retinal detachment, which commonly assumes a funnel-like configuration. The clinical picture is often that of a retrolental membrane, producing leukocoria (a white reflex in the pupil). Some patients develop cataracts, glaucoma, and signs of inflammation. The end stage is often a painful blind eye or a degenerated phthisical eye. The spectrum of ROP also includes myopia, which is often progressive and of significant degree in infancy. The incidence of anisometropia, strabismus, amblyopia, and nystagmus may also be increased.

Diagnosis

Systematic serial ophthalmologic examinations of infants at risk are recommended. In 2006 the American Academy of Pediatrics (AAP) published new screening guidelines for ROP. Infants with a birth weight of <1,500 g or gestational age of ≤32 wk and selected infants with a birth weight between 1,500 and 2,000 g or gestational age of >32 wk with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk, should have retinal screening examinations. The timing of the initial screening exam is based on the infant’s age. Table 622-1 was developed from an evidence-based analysis of the Mutlicenter Trial of Cryotherapy for ROP. The examination can be stressful to fragile preterm infants, and the dilating drops can have untoward side effects. Infants must be carefully monitored during and after the examination. Some neonatologists and ophthalmologists advocate the use of topical tetracaine and/or oral sucrose to reduce the discomfort and stress to the infant. Follow-up is based on the initial findings and risk factors but is usually at 2 wk or less.

Table 622-1 TIMING OF FIRST EYE EXAMINATION BASED ON GESTATIONAL AGE AT BIRTH

Treatment

In selected cases, cryotherapy or laser photocoagulation of the avascular retina reduces the more-severe complications of progressive ROP. Advances in vitreoretinal surgical techniques have led to limited success in reattaching the retina in infants with total retinal detachment (stage 5 ROP), but the visual results are often disappointing. The Early Treatment for Retinopathy of Prematurity cooperative study demonstrated the importance of plus disease and the presence of posterior retinal involvement in the determination of when to treat ROP. This study also supported the fact that laser is the treatment modality of choice. Peripheral retinal ablation should be considered for any eye with type 1 ROP. Serial examinations are indicated for any eye with type 2 ROP; treatment is considered if type 2 progresses to type 1 or if threshold ROP develops. Intravitreal bevacizumab, an inhibitor of vascular endothelial growth factor, may also have a role in treatment.

Prevention

Prevention of ROP ultimately depends on prevention of premature birth and its attendant problems. The association between ROP and oxygen saturation has been studied for decades. More-recent research has focused on keeping severely premature infants at lower oxygen saturation (85-92%) at age <34 wk and maintaining them at higher oxygen saturation (92-97%) at age >34 wk. This reduction in oxygen saturation early in the infant’s life effectively reduces the phase I hyperoxia and can stimulate the retina to develop normally. The reversal of the hypoxic phase II by elevating the oxygen saturation might ultimately decrease the incidence of severe ROP by down-regulating the secretion of VEGF. Most likely, a multicenter, prospective, randomized study will need to be performed to answer this question. Some investigators have suggested supplemental vitamin E for its antioxidant properties in infants at risk for ROP. Its efficacy has not been proved; at certain dosage levels, it can produce untoward side effects (Chapter 91.2).

Pathogenesis

During development of the eye, the hyaloid artery extends from the optic disc to the posterior aspect of the lens; it sends branches into the vitreous and ramifies to form the posterior portion of the vascular capsule of the lens. The posterior portion of the hyaloid system normally regresses by the 7th fetal mo and the anterior portion regresses by the 8th fetal mo. Small remnants of the system, such as a tuft of tissue at the disc (Bergmeister papilla) or a tag of tissue on the posterior capsule of the lens (Mittendorf dot), are common findings in healthy persons. More-extensive remnants and associated complications constitute PFV. Two major forms are described, anterior PFV and posterior PFV. Variability is great, and mixed or intermediate forms occur.

Clinical Manifestations

The usual clinical feature of anterior PFV is the presence of a vascularized plaque of tissue on the back surface of the lens in an eye that is microphthalmic or slightly smaller than normal. The condition is usually unilateral and can occur in infants with no other abnormalities and no history of prematurity. The fibrovascular tissue tends to undergo gradual contracture. The ciliary processes become elongated, and the anterior chamber can become shallow. The lens usually is smaller than normal and may be clear but often develops cataracts and can swell or absorb fluid. Large or anomalous vessels of the iris may be present. The anterior chamber angle can have abnormalities. In time, the cornea can become cloudy.

Anterior PFV is usually noted in the 1st wk or mo of life. The most common presenting signs are leukocoria (white pupillary reflex), strabismus, and nystagmus. The course is usually progressive and the outcome poor. Major complications are spontaneous intraocular hemorrhage, swelling of the lens caused by rupture of the posterior capsule, and glaucoma. The eye might eventually deteriorate. The spectrum of posterior PFV includes fibroglial veils around the disc and macula, vitreous membranes and stalks containing hyaloid artery remnants projecting from the disc, and meridional retinal folds. Traction detachment of the retina can occur. Vision may be impaired, but the eye is usually retained.

Treatment

Surgery is performed in an effort to prevent complications, to preserve the eye and a reasonably good cosmetic appearance, and, in some cases, to salvage vision. Surgical treatment usually involves aspirating the lens and excising the abnormal tissue. If useful vision is to be attained, refractive correction and aggressive amblyopia therapy are required. In some cases, the affected eye is enucleated because distinguishing between this white mass and retinoblastoma can be difficult. Ultrasonography and CT are valuable diagnostic aids.

Clinical Manifestations

The clinical manifestations of retinoblastoma vary, depending on the stage at which the tumor is detected. The initial sign in the majority of patients is a white pupillary reflex (leukocoria). Leukocoria results because of the reflection of light off the white tumor. The second most common initial sign of retinoblastoma is strabismus. Less-common presenting signs include pseudohypopyon (tumor cells layered inferiorly in front of the iris) caused by tumor seeding in the anterior chamber of the eye, hyphema (blood layered in front of the iris) secondary to iris neovascularization, vitreous hemorrhage, and signs of orbital cellulitis. On examination, the tumor appears as a white mass, sometimes small and relatively flat, sometimes large and protuberant. It might appear nodular. Vitreous haze or tumor seeding may be evident.