Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

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the condition was designated as “retrolental fibroplasia.” As the pathoanatomy became more fully appreciated and improved classification systems were developed, the term retinopathy of prematurity was adopted. During the 10 years following Terry’s observations, ROP was seen in epidemic proportions and became the largest cause of blindness in children in the United States and a major cause of blindness throughout the developed world; approximately 7000 children in the United States alone were blinded by ROP.150 In the late 1950s and 1960s, oxygen therapy was curtailed because of its incrimination as the principal cause of ROP, and this led to a dramatic decline in the incidence of ROP. This decline was, however, associated with an adverse effect on premature infant morbidity and mortality rates.7,103 Cross25 estimated that for each case of blindness prevented approximately 16 babies died as a result of inadequate oxygenation. In the 1970s, developments in arterial blood gas monitoring made possible more careful documentation of the premature infant’s oxygen needs. However, despite improvement in oxygen tension monitoring, a “second epidemic” of ROP resulted from survival of younger and smaller preterm infants. Their lower birth weight and gestational age became recognized as ROP risk factors. The 1980s and early 1990s can be considered to be a period of progress in terms of reducing the complications from ROP, and there were numerous clinical trials of treatment with reduced nursery light levels, vitamin E, cryotherapy, and laser photocoagulation.

INCIDENCE AND NATURAL HISTORY

ROP reached epidemic proportions between 1948 and 1954.127 However, after excess oxygen was implicated as the principal cause of ROP in the 1950s, a marked decrease in the incidence of ROP occurred after curtailment of oxygen. Beginning in the mid-1960s, because of technological advances in neonatology associated with the increased survival of low birth weight infants, a steady increase in the incidence of ROP was noted.127 A report131 of survival rates specific for birth weight and gestational age for 6676 inborn neonates registered during the CRYOROP study in 1986 and 1987 who weighed less than 1251 g at birth demonstrated that overall 28-day survival increased with gestational age and birth weight, from 36.5% at 24 weeks gestation to 89.9% at 29 weeks gestation. Survival increased from

30.0% for neonates of 500 through 599 g birth weight to 91.3% for neonates of 1200 through 1250 g.

Reports of the incidence of ROP from the 1950s and 1960s are difficult to compare with those of the 1970s and 1980s due to variations in patient selection, the lack of a standard classification system, and the lack of appreciation of mild forms of ROP, which became possible with the availability of indirect ophthalmoscopy in the 1970s.29 In the 1980s, several large studies15,47 provided information on the incidence of ROP and reaffirmed that the incidence was inversely related to gestational age and birth weight. Flynn47 performed multivariate risk analysis techniques and concluded that birth weight was the strongest and most consistent predictor of acute ROP in a population of 639 infants with birth weight ranging from 600 to 1500 g. Campbell et al.15 determined the incidence of acute ROP in 2958 admissions to a tertiary hospital neonatal intensive care unit (NICU). Among 2484 survivors, acute ROP developed in 72 (2.9%); 60 (83%) of these newborns had birth weights less than 1500 g. The incidence of acute ROP among survivors with birth weights of less than 1000 g (28%) was approximately three times that of survivors with birth weights between 1001 and 1500 g (10.1%).

Accurate estimations of the incidence of blindness secondary to ROP are lacking because of the absence of an organized reporting system in the United States. Campbell et al.15 reported an overall incidence of blindness in 4.5% of 2484 surviving infants in a tertiary NICU with birth weights less than 1000 g and 1.2% of those surviving with birth weights of 1000 to 1500 g. Phelps128 estimated that approximately 546 infants were blinded from ROP in the United States during 1979 and that approximately 2100 infants would be affected annually with cicatricial sequelae including myopia, strabismus, blindness, and late retinal detachment.

Prospective studies29,42 have provided new information regarding the current incidence of various stages of ROP and have relevance in determining ROP screening protocols. Fielder et al.42 studied 572 infants weighing 1700 g, or less and noted development of acute ROP in 50.9%. All ROP stages 1 and 2 underwent complete resolution and of the 27 (4.7%) infants with stage 3–4 disease, cicatricial sequelae developed in 6. Incidence and severity increased with decreasing birth weight and gestational age.

Among premature infants, the high-risk group that was selected for the Multicenter Trial of Cryotherapy for Retinopa-

TABLE 10-2. Definitions of Retinal Vascular Development in Premature Infants, Stages of ROP, and Criteria for Enrollment in CRYO-ROP Study.

domization.28 Threshold ROP occurred in 6% of VLBW infants between 34 and 42 weeks postconception 90% of the time (median onset, 36.9 weeks).29 Thus, ROP appears, runs its course, and reaches its most damaging stages within a specific developmental time frame; in VLBW infants, this corresponds to approximately 1 to 3 months postpartum.

Of the eyes that reached threshold ROP and were randomized to no treatment, 12% developed subtotal retinal detachment (stage 4), 32.4% total retinal detachment (stage 5), and 6.9% a posterior retinal fold (grade III, Reese Classification141) 3 months after randomization.27 In eyes treated according to the CRYO-ROP study protocol, these figures were reduced to 9.9% for stage 4, 18% for stage 5, and 3.2% for a posterior retinal fold affecting the macula (as judged by masked grading of retinal photographs).27

This prospective study29 provided new insight into the development of ROP and again confirmed that ROP incidence and severity were higher in lower birth weight and gestational age categories. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events.

PATHOGENESIS

Normal Vascular Development

In infants, retinal vascular development begins at 16 weeks gestation with mesenchyme, the blood vessel precursor, growing from the disc to reach the ora nasally at 8 months and the ora temporally shortly after birth.4,48,57 On the posterior edge of the advancing mesenchyme, a primitive immature network of capillaries develops according to Ashton’s theory.4 This delicate, chicken-wire meshwork undergoes absorption and remodeling to form mature retinal arteries and veins that are surrounded by the capillary meshwork.4,48,53

The Role of Oxygen in ROP

CLINICAL FINDINGS

Campbell,14 in 1951, observed a relationship of ROP to oxygen exposure. Patz and coworkers126 confirmed the apparent role of supplementary oxygen in a controlled nursery study. In 1956, the results of the 18-hospital collaborative study chaired by Dr. V.E. Kinsey confirmed the role of oxygen as an important factor in the production of ROP.84

EXPERIMENTAL FINDINGS

Hyperoxic animal models5,125 have clearly demonstrated that the immature and incompletely vascularized retina is susceptible to oxygen toxicity, providing experimental support for the initial clinical studies implicating oxygen as a major cause of ROP. Lesions closely resembling the early stages of human ROP have been produced in the kitten, mouse, rat, and puppy models.5,125 Rearing newborn rats in variable, fluctuating supplemental oxygen also causes retinopathy.100 The immature retinal vasculature of a term newborn kitten is comparable to a 6.5-month gestational human fetus, offering the unique advantage of studying a healthy term animal subject.5

The primary effect of oxygen on the incompletely vascularized retina of the experimental animal is retinal vasoconstriction, and vaso-obliteration which may be reversible with a short duration of oxygen exposure.5,124,125 However, permanent occlusion of peripheral immature retinal vessels can occur as a result of exposure to significantly elevated arterial oxygen partial pressure for an extended period of several days.57a After sustained hyperoxia and subsequent removal of the kitten animal model to ambient air, nodules of endothelial proliferation arise from the residual vascular complexes adjacent to retinal capillaries closed during hyperoxia and canalize to form new vessels. These new vessels, similar to other proliferative retinopathies, penetrate through the internal limited membrane and proliferate on the inner retinal surfaces.

PATHOPHYSIOLOGY OF ROP

Fundamental to understanding the pathophysiology of ROP is knowledge that, in utero, the fetus is in a hypoxic state with a stable PaO2 of 22 to 24 mm Hg. This is in contrast to a full-term baby and a normal adult where the PaO2 is dramatically higher— ranging from 70 to 90 mm Hg. The developing retinal vessels grow from the optic nerve to the peripheral avascular retina. In animal models, this growth of immature retinal vessels into the peripheral avascular retina is stimulated by vascular endothelial growth factor (VEGF) (Fig. 10-1). Physiologic levels of VEGF are required to maintain vessel integrity of existing retinal vessels and to stimulate vessel growth.57a The amount of oxygen in the retinal tissue determines the amount of VEGF produced.

Low tissue oxygen, or ischemia, stimulates VEGF production;

FIGURE 10-1A–E. VEGF model of pathophysiology of ROP. (A) Drawing of immature retinal vessels in a premature infant approximately 25–28 weeks gestational age. Note that the vessels have the normal treebranching architecture. (B) Premature infant exposed to high oxygen, causing VEGF to be downregulated. The drawing shows constriction and vaso-obliteration of small vessels. (C) Over time, the peripheral avascular retina becomes ischemic from the lack of blood supply. Peripheral retinal ischemia causes an increase in local VEGF, stimulating arteriolar venous shunt formation at the junction between avascularized and vascularized retina. This represents Stage 1 to Stage 2 ROP. Note the vascular pattern of peripheral vessel straightening, or Broom-bristle pattern, indicative of a shunt associated with ROP. (D) Retinal vessels show pattern of regression as physiologic levels of VEGF stimulate normal vessel growth into the area of avascular retina. Note the normal vascular pattern of tree branching. (E) Drawing shows the effects of sustained peripheral retinal ischemia causing abnormally high levels of local VEGF. Consistently high levels of VEGF results in neovascularization (Stage 3 ROP) and dilated, tortuous posterior pole vessels (plus disease).