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

whereas high tissue oxygen levels down-regulate VEGF production and halt vessel growth. If the immature retina is exposed to persistent hyperoxia, the immature vessels will stop growing. The more immature the infant, the larger the area of avascular retina. Prolonged exposure to high levels of oxygen will result in vasoconstriction and, eventually, vaso-obliteration as the vessels involute due to lack of VEGF.57a This lack of normal vessel growth leaves the peripheral retina without adequate blood supply.

Over time, usually several weeks, the avascular retina becomes ischemic and stimulates VEGF production. If the area of avascular retina is relatively small, physiologic VEGF levels are produced and stimulate normal retinal vessel growth. If, on the other hand, the area of avascular retina is large and large amounts of VEGF are produced, this induces the immature retinal vessels to sprout arterial venous (AV) shunts at the border between the vascularized and avascular retina (ROP Stages 1 and 2). Regression occurs if VEGF stimulates normal vascularization past the AV shunt into the avascular retina. Extremely large areas of avascular retina, on the other hand, upregulates VEGF stimulating neovascularization of the AV shunt (ROP Stage 3). Sustained high levels of VEGF can even cause vasodilatation and tortuosity of existing posterior pole vessels (PLUS disease), iris vessel dilatation, and rubeosis iridis. Treatment of Stage 3 ROP with cryotherapy or laser therapy is directed at obliterating the peripheral avascular retina, thus lowering levels of VEGF.57a Reducing VEGF levels will result in regression of neovascularization and reduce the chances of an unfavorable outcome. Extensive neovascularization of the retina can cause retinal fibrovascular proliferation, scarring, and retinal detachment (ROP Stages 4 and 5).

Despite environmental risk factors, or a genetic predisposition that contributes to the development of ROP, hyperoxia in very low birth weight premature infants early in the NICU course remains a possible risk factor for

ROP.6,30a,39a,40,49,57a,59,79a,97,110,140a,143a,144,147c Tin et al.79a reported ROP

outcomes on premature infants less than 28 weeks gestation and showed that by strictly curtailing the oxygen dose, the incidence of threshold ROP was reduced four-fold. Hong, Wright, et al.30a reported a significant decrease in severe ROP after institution of a protocol for strict curtailment of oxygen in premature infants under 1500 grams. Oxygen was kept between 83% to 90% O2 saturation, and oxygen curtailment was started in the delivery

room. Over the last 3 years in this level III NICU, over 300 premature infants were examined for ROP and none of the premature infants on the new protocol for curtailed oxygen developed threshold ROP. Perhaps with the use of low stable oxygen delivery, severe ROP can be reduced.30a Careful attention to mortality and morbidity in clinical trials will be needed to determine if this is feasible. Fluctuating arterial oxygen tension has also been associated with a greater risk of developing progressive ROP.144a

RISK FACTORS

Many reports have confirmed that gestational age and birth weight are key risk factors for the development of ROP.15,19,29,33,51,65,84,100,131 Although oxygen supplementation has been recognized as a risk factor for the development of ROP since the 1950s, this association has been difficult to define in terms of the duration and concentration of oxygen. Shohat et al.148 could not demonstrate a significant association between babies with ROP and the duration of supplemental oxygen or the mean maximum oxygen concentration required. A multicentered cooperative study84 found an association between ROP and oxygen supplementation but could not relate the incidence of ROP to arterial PO2 levels. However, Flynn et al.50,52 correlated the incidence and severity of ROP with the duration of exposure to different ranges of oxygen tension as measured by transcutaneous oxygen monitoring (tcPO2) in 101 premature infants with birth weights between 500 and 1300 g. There was a significant association between the amount of time that the tcPO2 was greater than or equal to 80 mm Hg and the incidence and severity of ROP.52

Because ROP has occurred in the absence of supplemental oxygen,100,148 in association with cyanotic heart disease,78 and in anencephalic infants,1 these observations suggest determinant factors other than supplemental oxygen as the etiology for ROP. Shohat et al.148 examined 32 possible risk factors in 34 infants with ROP and noted the following factors significantly associated with ROP: apnea with mask and bag ventilation; prolonged parenteral nutrition; number of blood transfusions; and episodes of hypoxemia, hypercarbia, and hypocarbia. Gunn et al.63 found several factors significantly associated with ROP in 27 infants, including apnea requiring bag and mask resuscitation with oxygen, septicemia, degree of illness, blood transfusion, and

mechanical ventilation. Hammer et al.65 reviewed 47 potential risk factors in a prospective study of 328 high-risk neonates. Only 4 were significant: ventilator hours, xanthine administration, birth weight, and maternal bleeding. Darlow et al.36 prospectively determined risk factors in 69 infants with acute retinopathy. On multiple logistic regression analysis, three variables made statistically significant independent contributions to the risk of any acute retinopathy: gestational age, principal hospital caring for the infant, and treatment with indomethacin. They speculated that the larger level III units obtained better results because their size and experience enabled them to provide a better overall quality of care. Charles et al.19 reported a 72% incidence of ROP in infants under 1200 g from a lowincome, inner-city population. Significant risk factors observed were low birth weight, short gestation period, extended supplemental oxygen administration, intraventricular hemorrhage, respiratory distress syndrome, and sepsis. In addition, they speculated that limited prenatal care and other maternal factors such as inadequate nutrition may have contributed to the high incidence of ROP in their study. Sieberth and Linderkamp confirmed that low birth weight, low gestational age, artificial ventilation longer than 7 days, high-volume blood transfusion, and surfactant increased risk of ROP in 402 infants less than or equal to 1500 gm.147a Maternal preeclampsia, antepartum betamethasone, and vitamin E therapy decreased risk.

In the CRYO-ROP study,33 an increased risk of reaching threshold ROP was found associated with lower birth weight, younger gestational age, white race, multiple births, and being born outside a study center nursery. The risk of an unfavorable macular outcome was increased with zone I ROP, “plus” disease, the severity of the stage, and the amount of circumferential involvement. A higher risk also was associated with a rapid rate of progression of ROP to prethreshold disease, but not with the postconceptional age at which ROP was first noted.

Light has also been discussed as a possible risk factor for ROP.6,59,144 One prospective study59 concluded that the high level of ambient illumination commonly found in the hospital nursery may be one factor contributing to ROP. However, the multi-center, randomized light–ROP study found no difference in incidence or severity of ROP between infants fitted with light-blocking goggles shortly after birth and those exposed to ambient nursery light.39a,143a In addition, an infant with complete cataracts was noted to have threshold ROP immediately

after cataract surgery.140c Because very little light had ever reached this infant’s retinas, at most light may play a mild cofactor role. Some authors have found a correlation between mutations in the Norrie disease gene, the full expression of which leads to congenital retinal detachment, and severe ROP.147c

INTERNATIONAL CLASSIFICATION OF ROP

Because of significant observations during the past three decades, it became evident that the Reese141 and other classification systems did not adequately describe the early active stages of ROP. The traditional term, retrolental fibroplasia, described only the severe late cicatricial changes and was inappropriate for the acute phase of this disease. In 1984, 23 ophthalmologists from 11 countries formed a committee and cooperated in developing the International Classification of Retinopathy of Prematurity (ICROP).173 This new classification involves three parameters: (1) the location (zone) of the disease in the retina, (2) the extent (clock hours) of the developing vasculature involved, and (3) the severity (stage) of abnormal vascular response observed. The development of a uniform anatomic classification system allowed the results of treatment techniques to be compared by clinicians and researchers worldwide.

The location of ROP is described by three zones (Fig. 10-2). Zone I (posterior pole or inner zone) is a posterior circle centered on the disc, and extends twice the distance from the disc to the center of the macula in all directions. The zone is defined by the most posterior location of disease. If, therefore, any ROP is found in zone I, the eye is a “zone I eye.” A circle, centered on the disc, with a radius equal to the distance to the nasal ora serrata, defines the boundary between zone II and zone III. We like the CRYO-ROP study approach whereby zones II and III are divided by a convention, rather than by a structure. The convention is that zone II extends all the way from the zone I perimeter to the ora serrata on the nasal side. There is no zone III at the nasal meridian, and only a sliver of it in the oblique nasal quadrants. Zone III is basically a temporal crescent, yet is defined by what is observed nasally. If ROP is present nasally, then the eye cannot be a “zone III eye.” On the other hand, if vessels reach the ora nasally and there is no ROP there, but ROP

FIGURE 10-2. Scheme of retina of right eye (RE) and left eye (LE) shows zone borders and clock hours employed to describe location and extent of retinopathy of prematurity. (From The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130–1134, with permission.)

is present temporally, this is apparently categorized as “zone III ROP,” no matter where it is located. This convention is only implied in the International Classification, but it is not entirely clear whether it would be still called zone III even if the temporal ROP were located very far posteriorly. In practice, this rarely, if ever, occurs and in the CRYO-ROP study, whenever the vessels were maturely developed on the nasal side and no ROP was located there, all such eyes were categorized as zone III eyes.26

The extent of the disease is specified as hours of the clock (see Fig. 10-2). As the observer looks at each eye, the 3-o’clock position is to the right and nasal in the right eye and temporal in the left eye, and the 9-o’clock position is to the left and temporal in the right eye and nasal in the left eye.

The severity of ROP is defined by five stages. Stage 1 is defined as a thin whitish demarcation line abruptly separating vascularized retina posteriorly from the more peripheral avascular retina, which usually has a blanched or opalescent appearance (Tables 10-3 and 10-4). The demarcation line is within the plane of the retina and is usually associated with abnormal branching or arcading of retinal vessels leading up to it (Fig. 10- 3). If the demarcation line takes on height and width, occupies a volume, and extends out of the plane of the retina it is termed

FIGURE 10-5. Extraretinal fibrovascular proliferative tissue of stage 3. (Courtesy of Cryotherapy for Retinopathy of Prematurity Cooperative Group.)

“ragged” and is termed stage 3 ROP (Fig. 10-5). The eye is evaluated in terms of twelve 30°“clock-hour” sectors, and the predominant stage in each sector is noted and the eye is categorized according to the highest stage of ROP observed. Thus, for example, if there are 10 sectors of stage 2 and 2 sectors of stage 3, the eye is categorized as a “stage 3 eye.” The unifying principle underlying ICROP is that the more posterior the disease and the greater the amount of retinal vascular involvement, the more serious the disease.

Progressive vascular incompetence, occurring along with the changes described 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. If this progressive vascular incompetence is so marked that the posterior veins are enlarged and arteries tortuous, this characterizes “plus” disease, and a plus sign ( ) is added to the ROP stage number (Fig. 10-6). Progression of ROP may be rapid if plus disease involves zone I or posterior zone II.

The first publication in 1984 by the International Committee defined stage 4 ROP as an unequivocal detachment of the retina caused by exudation, traction, or both.173 In 1987, another

international committee expanded the description of the features of the retinal detachment (stage 4).174 This elaboration was based on further surgical observations and study of pathological specimens.101 Stage 4A was defined as a concave, tractional type of subtotal retinal detachment occurring in the periphery without involvement of the macula (extrafoveal). The detachment may be circumferential, extending for 360°, or segmental, and extending for less than 360°. The prognosis for vision for this type of detachment is good providing there is no extension into the macula. If the partial detachment extended posteriorly to involve the macula, this was termed stage 4B, and the prognosis for vision for this type of subtotal detachment is poor. Stage 5 is a total funnel-shaped retinal detachment. For descriptive purposes the retinal detachment can be subdivided into an anterior and posterior part based on the configuration of the funnel (see Table 10-3). The most common configuration is a concave detachment with the funnel open both anteriorly and posteriorly. The other configurations in decreasing order of frequency are narrow–narrow, open–narrow, and narrow–open. If opaque retrolental membranes prevent visualization of the fundus, ultrasonography may be helpful in defining the configuration of the funnel.38,137

Although regression with or without vascular or cicatricial sequelae is the most common outcome of ROP, the International Committee decided that classification of such a wide variety of changes was impossible. However, they realized the importance of identifying these changes and recommended recording the broad spectrum of peripheral and posterior retinal and vascular changes (Table 10-4). The vascular changes include retinal avascularity, abnormal retinal branching, and telangiectatic retinal vessels (Fig. 10-7). The retinal changes include pigmentary changes, vitreoretinal interface changes, and tractional forces that may cause dragging and displacement of retinal vessels and ectopia of the macula (Fig. 10-8). Traction and rhegmatogenous retinal detachment may also develop as late complications of regressed ROP. In general, the more severe the acute disease in terms of location, extent, and stage, the more serious the resulting regressed peripheral and posterior retinal and vascular sequelae.