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Retinopathy of Prematurity

A.Burloiu
Bucharest, Romania

 

Correspondence: 

A.Burloiu M.D.
“N.Malaxa” Hospital, Vergului Av. Nr.12,

Bucharest, Romania 

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Retinopathy of prematurity (ROP) has been recognized as an important cause of childhood visual impairment and blindness since the 1940’s when improved facilities and treatment increased the survival rate of premature infants. Although its incidence and severity have been decreasing in developed countries over the past two decades, both are increasing in developing nations. ROP is consequently targeted as an important but avoidable disease.

During the 1940s and 1950s, ROP, also known as retrolental fibroplasia, was the leading cause of blindness in children in the US. In 1942, Terry first reported the disease that was published in a report on the histological findings of end stage cicatricial disease. Severe ROP (initially termed "retrolental fibroplasia" or RLF) was first described during an epidemic of the disease in the 1940s (1). In 1951, Campbell suggested that the toxic effects of uncontrolled supplemental oxygen to newborns were responsible for the epidemic. She emphasized the importance of maintaining pregnancies beyond the 33rd week and avoiding the use of prophylactic oxygen therapy, advocating its use only in the treatment of cyanosis. Subsequent studies in the same decade confirmed that high levels of oxygen obliterated blood vessels in the neonatal retina. This epidemic ceased following controlled oxygen administration. In the United States alone, the proportion of blindness due to RLF fell from 50% in 1950 to 4% by 1965. Unfortunately, this decline was accompanied by an increase in neonatal deaths from atelectasis and respiratory distress secondary to hyaline membrane disease. During the late 1970s and 1980s, reports emerged of a second epidemic of ROP similar in size to the first despite the careful monitoring of oxygen delivery to neonates since the 1950s. It was concluded that this epidemic was due to increased survival rates of very low birth weight premature infants weighting 750–999 g and not to new iatrogenic factors. Survival rates for premature infants less than 27 weeks' gestation continued to improve in the 1990s and, while some studies showed greater occurrence of more severe ROP(11), more recent reports indicate a decline in incidence, severity, and progression to threshold disease in developed countries(2,3). However, ROP remains prevalent in very low birthweight infants, with as many as 12.5% of infants born between 23 and 26 weeks' gestation requiring treatment for threshold disease .

Pathophysiology: The retinal vasculature begins in the 16th week of gestation. Retinal vessels grow out of the optic disc as a wave of mesenchymal spindle cells. As these mesenchymal spindle cells lead the shunt, endothelial proliferation and capillary formation follow. These new capillaries will form the mature retinal vessels. The choroidal vessels (that are vascularized by the 6th week of gestation) supply the rest of the avascularized retina. The nasal portion of the retina is completely vascularized to the ora serrata by the 32nd week of gestation. The larger temporal area usually is completed at 40-42 weeks (term). Two theories exist on the pathogenesis of ROP. The mesenchymal spindle cells, exposed to hyperoxic extrauterine conditions, develop gap junctions. These gap junctions interfere with the normal vascular formation, triggering a neovascular response as reported by Kretzer and Hittner. Ashton theorizes that 2 phases exist. The first phase, a hyperoxic phase, causes retinal vasoconstriction and irreversible capillary endothelial cell destruction. As the area becomes ischemic, angiogenic factors, such as vascular endothelial growth factor (VEGF), is made by the mesenchymal spindle cells and ischemic retina to provide new vascular channels. These new vascular channels are not mature and do not respond to proper regulation. Although many causative factors have been proposed for ROP, only low birth weight, low gestational age, and supplemental oxygen therapy following delivery have been consistently associated with disease (4). A multicentre US study of infants born in 1986–1987 reported that of those infants weighing less than 1000 g, 81.6% developed ROP, while 46.9% of those 1000–1250 g developed the disorder. Severe disease is seen especially in babies under 26 weeks' gestation with severity increasing with decreasing gestational age. Infants conceived through fertility programmes have a higher incidence of multiple births and subsequently premature deliveries, raising the risk of ROP. Infants conceived by in vitro fertilization account for the majority of the increased risk for this group. A second at-risk group includes those infants with cerebral palsy who have a higher incidence of retinal vascular anomalies associated with both cerebral ischemia and prematurity . A number of other risk factors have been suggested as contributors to ROP although it is unclear whether these are truly independent risk factors or simply indicators of the compromised health of the neonate (4). These factors include bronchopulmonary dysplasia, the number of blood transfusions, parenteral nutrition, hypo/hypercarbia, early intubation, hypotension, patent ductus arteriosus, necrotizing enterocolitis, administration of ß blockers to mothers before delivery, intraventricular haemorrhage, poor postnatal weight gain, and Candida sepsis.

History: In 1984, a committee consisting of 23 ophthalmologists from 11 countries formed the International Classification of Retinopathy of Prematurity (ICROP). This new classification system demarcated the location of the disease into zones (1, 2, and 3) of the retina, the extent of the disease based on the clock hours (1), and the severity of the disease into stages (0-5).

ROP is categorized in zones, with stages depicting the severity of the disease. The smaller and younger the infant at birth, the more likely the disease will involve the central zones with advanced stages. ROP is categorized by the lowest zone and the highest stage observed in each eye.

Zones

  • Zone 1 is the most labile. The center of zone 1 is the optic nerve. It extends twice the distance from the optic nerve to the macula in a circle. Using a 28-diopter lens, if any portion of the optic nerve is in the same view as the ridge of ROP, that is considered zone 1. Any disease in zone 1 (even stage 0, immature) is critical and must be monitored closely. Zone 1 does not follow the ICROP rules. The area is very small and changes can occur very quickly, sometimes within days. The hallmark of the disease worsening is not the presence of neovascularization (as in other zones, as specified by the ICROP) (5,6) but is by the increasing dilation and tortuosity of the vessels. The vascularized retina seems to rise (like a soufflé) probably because of the increased arteriovenous shunting. Many ROP experts feel that any disease in zone 1, and certainly any plus disease, requires treatment.
  • Zone 2 is a circle surrounding the zone 1 circle with the nasal ora serrata as its nasal border. The disease may progress quickly but usually there are warning signs that predate the threshold by 1-2 weeks, as follows: (1) The ridge shows signs of vascular arcading (increased branching); this is usually a sign that the disease is starting to become aggressive. (2) Increasing vascular dilation and tortuosity is present (3). A “hot dog” on the ridge is seen; this is a thickened vascular ridge that may not show the typical fronds of neovascularization. Rather the demarcation of vascularized and nonvascular retina is a thickened red 3-dimensional roll. This usually is seen in posterior zone 2 (borders zone 1) and is a poor prognostic indicator (4). The Cryo- therapy for Retinopathy of Prematurity Cooperative Group (CRYO-ROP) study described threshold disease as 5 contiguous or 8 noncontiguous hours of neovascularization (stage 3) with plus disease in zone 1 or 2. Of threshold eyes left untreated, 50% would develop adverse structural outcomes (e.g., retinal detachment) 12 months after randomization.
  • Zone 3 is the crescent that the circle of zone 2 did not encompass temporally. Aggressive disease rarely is seen in this zone. Typically, this is slowly vascularizing and requires evaluations every few weeks. Many infants show inactive disease in zone 3 with a demarcation line and nonvascularized retina. This has been noted in toddlers and can be considered cicatricial peripheral disease. No ill sequelae are known to occur from this ridge (Fig..1). 

Stages

Stage 0: This is the mildest form of ROP. It is immature retinal vasculature. No clear demarcation of vascularized and nonvascularized retina is present. Only a suggestion of the border is noted on examination. In zone 1, this may appear as a vitreous haze, with the optic nerve as the only landmark. Weekly examinations should be performed. In zone 2, bimonthly examinations should be performed. In zone 3, examination every 3-4 weeks should be sufficient.

Stage 1: A fine, thin demarcation line between the vascular and avascular region is present. This line has no height and no thickness. In zone 1, this should appear as a flat, thin line (usually nasally first). No elevation from the avascular retina should be present. The retinal vessels should be smooth, thin, and supple. Weekly examinations should be performed. In zone 2, bimonthly examinations should be performed. In zone 3, examination every 3-4 weeks should be sufficient.

Stage 2: A broad, thick ridge clearly separates the vascular from the avascular retina. In zone 1, if there is any hint of pink or red in the ridge, this is an ominous sign. If there is any vessel engorgement, the disease should be considered threshold and treatment commenced within 72 hours. In zone 2, if there are no vascular changes and the ridge has no engorgement, the eye should be examined within 2 weeks. Prethreshold is defined as stage 2 with plus disease. In zone 3, examination every 3-4 weeks should be sufficient, unless of course there is any vascular tortuosity or straightening of the vascular arcades.

Stage 3: The extraretinal fibrovascular proliferation (neovascularization) may be present on the ridge, on the posterior surface of the ridge or anteriorly toward the vitreous cavity. The neovascularization gives the ridge a velvety appearance, a ragged border. In zone 1, if there is any neovascularization, it is serious and requires treatment. In zone 2, prethreshold is defined as stage 3 without plus disease, or stage 3 with less than 5 contiguous or 8 noncontiguous hours. Threshold is stage 3 with at least 5 contiguous or 8 noncontiguous hours and plus disease. In zone 3, examination every 2-3 weeks should be sufficient, unless there is any vascular tortuosity or straightening of the vascular arcades.

Stage 4: This stage is a subtotal retinal detachment beginning at the ridge. The retina is pulled anteriorly into the vitreous by the fibrovascular ridge. Stage 4A does not involve the fovea. Stage 4B involves the fovea.

Stage 5: This stage is a total retinal detachment in the shape of a funnel. Stage 5A is an open funnel. Stage 5B is a closed funnel.

Along with the changes described earlier at the leading edge of the abnormally developing retinal vasculature, additional signs indicating the severity of active ROP may occur. These include increased venous dilation and arteriolar tortuosity of the posterior retinal vessels and may later increase in severity to include iris vascular engorgement, poor pupillary dilatation (rigid pupil), and vitreous haze. This important constellation of signs in the original classification was referred to as plus disease. Subsequent multicentered clinical trials have used a "standard" photograph to define the minimum amount of vascular dilatation and tortuosity required to make the diagnosis of plus disease(8-11). This definition has been further refined in the later clinical trials in which the diagnosis of plus disease could be made if sufficient vascular dilatation and tortuosity are present in at least 2 quadrants of the eye (11). A + symbol is added to the ROP stage number to designate the presence of plus disease. For example, stage 2 ROP combined with posterior vascular dilatation and tortuosity would be written "stage 2+ ROP." There is a spectrum of ROP activity indicated by abnormal dilatation and tortuosity of the posterior pole vessels. Plus disease is the severe form of this vascular abnormality. This report defines pre-plus disease as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity and more venous dilatation than normal. Over time, the vessel abnormalities of pre-plus may progress to frank plus disease as the vessels dilate and become more tortuous. The presence of pre-plus disease can be noted beside the stage, for example, stage 2 with pre-plus disease.

Other terms mentioned with ROP include the following: Popcorn-Regressed neovascularization seen anterior to the internal limiting membrane. This is a cicatricial change and usually regresses completely over several weeks. Hot dog: A “red hot” active ridge, probably the site of increasing vascular channels. This is a critical hot area of activity. If noted on zone 1 or 2, this is an ominous sign. This area may regress with cicatrix floating in the vitreous cavity and nonpatent ghost vessels still visibly attached to the retina (a second ridge would clearly be identified anterior to this cicatrix). In less fortunate eyes, this area may be the site of a true retinal detachment.

An uncommon, rapidly progressing, severe form of ROP is designated aggressive posterior ROP (AP-ROP). If untreated, it usually progresses to stage 5 ROP. The characteristic features of this type of ROP are its posterior location, prominence of plus disease, and the ill-defined nature of the retinopathy. This rapidly progressing retinopathy has been referred previously as "type II ROP" and "Rush disease, but was not specifically included in ICROP Aggressive, posterior ROP seems to be the most appropriate term since the diagnosis can be made on a single visit and it does not require evaluation over time. Aggressive posterior retinopathy of prematurity is observed most commonly in zone I, but may also occur in posterior zone II . Early in the development of AP-ROP, the posterior pole vessels show increased dilation and tortuosity in all 4 quadrants that is out of proportion to the peripheral retinopathy. These vascular changes progress rapidly. Shunting occurs from vessel to vessel within retina and not solely at the junction between vascular and avascular retina . As a result, in AP-ROP it is often difficult to distinguish between arterioles and venules because of the significant dilation and tortuosity of both vessel types. There may also be hemorrhages at the junction between the vascularized and avascular retina. Another important feature of AP-ROP is that it usually does not progress through the classic stages 1 to 3. Aggressive posterior retinopathy of prematurity may appear as only a flat network of neovascularization at the deceptively featureless junction between vascularized and nonvascularized retina and may be easily overlooked by a less experienced observer . Aggressive posterior retinopathy of prematurity typically extends circumferentially and is often accompanied by a circumferential vessel. Performing indirect ophthalmoscopy with a 20-D condensing lens instead of a 25-or 28-D lens may help to distinguish the deceptively featureless neovascularization.

Regression of ROP

Most ROP regresses spontaneously by a process of involution or evolution from a vasoproliferative phase to a fibrotic phase. One of the first signs of stabilization of the acute phase of ROP is failure of the retinopathy to progress to the next stage (12,13). Certain morphological signs characterize the onset of regression or involution. The process of regression occurs largely at the junction of vascular and avascular retina as retinal vascularization advances peripherally. On serial examinations, the anteroposterior location of retinopathy may change from zone I to zone II or from zone II to zone III. The ridge may change in color from salmon pink to white. Involutional sequelae include a broad spectrum of peripheral and posterior retinal and vascular changes that are listed in the. The more severe the acute phase of the retinopathy, the more likely involutional changes will be severe as the disease enters what was formerly termed the "cicatricial" phase.(14) During the process of involution, conspicuous features are vascular abnormalities such as prominent areas of retinal avascularity, abnormal branching of vessels with formation of arcades, and telangiectatic vessels. Pigmentary changes may be subtle but more often become large areas of decreased or even increased pigmentation located along blood vessels and in underlying retinal pigment epithelium, as seen through an avascular retina. Circumferential retinovitreous interface changes may be seen as delicate lines or more prominent ridges. In general, the more severe the peripheral changes, the more severe the posterior pole changes. These are tractional phenomena that can vary from minor distortions of foveal architecture to severe displacements of major retinal vessels, usually temporally and often accompanied by dragging of the retina over the optic disc (macular heterotopia or ectopia). Finally, traction and rhegmatogenous retinal detachment and, rarely, exudative detachment can develop as late complications of regressed ROP.

Procedures

 A dilated fundus examination with scleral depression is necessary. The instruments used are a Sauer speculum (to keep the eyes gently open), a Flynn scleral depressor (to rotate and depress small eyes), and a 28-diopter lens (for proper identification of zones). The first part of the examination should be external, with identification of iris rubeosis, if present. The next part of the examination should be the posterior pole, with identification of any plus disease or straightening of the vascular arcades. The eye is rotated to identify the presence or absence of zone 1 disease (if the ridge and the optic nerve are present in the same view, this usually implies zone 1). If the nasal vessels are not at the nasal ora serrata, this is still zone 2. If the nasal vessels have reached the nasal ora serrata, the eye is in zone3. 

retinopaty premat

Figure 1. Zones of the retina

Screening examination for ROP

  1. Infants with a birth weight of less than 1500 g or with a gestational age of 28 weeks or less, as well as selected infants between 1500 and 2000 g with an unstable clinical course who are believed to be at high risk by their attending pediatrician or neonatologist, should have at least 2 fundus examinations performed after pupillary dilation using binocular indirect ophthalmoscopy to detect ROP. One examination is sufficient only if it unequivocally shows the retina to be fully vascularized bilaterally.
  2. Examination for ROP should be performed by an ophthalmologist with sufficient regular experience and knowledge in the examination of preterm infants for ROP to identify the location and sequential retinal changes in this disorder using binocular indirect ophthalmoscopy. The location and sequential retinal changes, if any, should be recorded using the International Classification of Retinopathy of Prematurity.
  3. The first examination should normally be performed between 4 and 6 weeks of chronologic (postnatal) age or, alternatively, within the 31st to 33rd week of postconceptional or postmenstrual age (gestational age at birth plus chronologic age), whichever is later, as determined by the infant's attending pediatrician or neonatologist. If using the postconceptional age guideline, examinations are generally not needed in the first 4 weeks after birth. The timing of the initial screening examination may be adjusted appropriately on the basis of other reliable data, such as local incidence and onset of ROP or the presence of other recognized risk factors.(11,19) The initial screening examination and subsequent examinations should be timed to permit sufficient time for treatment, including, any extra time required for transfer to another facility for treatment, if  necessary. Treatment should generally be accomplished within 72 hours of determination of the presence of threshold 1 ROP to minimize the risk of retinal detachment before treatment.(15-18).
  4. Scheduling of follow-up examinations at the recommendation of the examining ophthalmologist is best determined by the findings at the first examination using the International Classification of Retinopathy of Prematurity. For example, if the retinal vasculature is immature and extends into zone II but no retinopathy is present, follow-up examination should be planned at approximately 2- to 3week intervals until normal vascularization proceeds to zone III (i.e., in the nasal periphery, there is no retinopathy and normal vessels are present within 1 disk diameter of the ora serrata).
  5. Once an infant has been determined on first examination to be at risk for ROP, the following schedule is suggested:

A. Infants with ROP that may soon progress to threshold ROP should be examined at least weekly. These include:

1. Any infant with ROP less than threshold in zone I 2. Infants with ROP in zone II, including:

a) those with stage 3 ROP without plus disease (defined as posterior pole dilation and tortuosity of the retinal vessels);

b) those with stage 2 ROP with plus disease; and c) those with stage 3 ROP with plus disease not yet extensive enough to justify ablative surgery.

B. Infants with less severe ROP in zone II should be examined at 2-week intervals. Those without ROP but with incomplete vascularization in zone I should be seen at 1- to 2-week intervals until retinal vascularization has reached zone III or until threshold conditions are reached.

C. If the retinal vascularization is incomplete in zone II but no ROP is detected, follow-up examination should be planned at approximately 2- to 3-week intervals until vascularization proceeds into zone III.

D. Retinas with incomplete vascularization only in zone III usually mature completely; ROP in zone III normally regresses (involutes) without adverse consequences. However, the finding of normal vascularization in zone III is unusual in the initial examination of very low gestational age infants. In cases in which zone III vascular maturation seems to be present on initial examination of very low birth weight infants, this finding should be verified by at least 1 repeat examination within 2 to 3 weeks. (6,8,19,20)

  6. Infants reaching threshold 1 disease (stage 3 ROP in zone I or II in 5 or more continuous clock hours or 8 cumulative clock hours with plus disease should receive ablative therapy for at least 1 eye within 72 hours of diagnosis, generally before the onset of retinal detachment. Stage 3 ROP with vascularization in zone I or borderline zone I to II may appear different from purely zone II stage 3 disease in that proliferation may appear flat, only appearing to be significantly elevated when it has become extremely severe. In view of this difficulty in distinguishing between stages 2 and 3 in posterior regions, infants with suspected stage 3 ROP in zone I or border zone I to II with plus disease should be examined especially carefully to determine if they meet the threshold criteria noted above.

  7. Parents of infants with ROP should be informed of the nature and possible consequences of this disorder throughout the infant's hospital stay, beginning at the time of first diagnosis and continuing on an ongoing basis with updates on its progression during hospitalization.

  8. Responsibility for examination and follow-up of infants at risk for ROP must be carefully defined by each neonatal intensive care unit. Unit-specific criteria for examination for ROP should be established for each neonatal intensive care unit by consultation and agreement between neonatology and ophthalmology services. These criteria should be recorded and should automatically trigger scheduled ophthalmology examinations. If hospital discharge or transfer to another neonatal unit or hospital is contemplated before retinal maturation into zone III has taken place, the availability of appropriate follow-up ophthalmologic examination must be ensured, and specific arrangement for that examination must be made before such discharge or transfer occurs. The transferring primary physician should have the responsibility of communicating orally and in writing what eye examinations are needed and their required timing to the infant's new primary physician. The new primary physician should ascertain the current ocular examination status of the infant from the record and through communication with the transferring physician so that any necessary examinations by an ophthalmologist with regular experience and knowledge of the examination of preterm infants for ROP can be arranged promptly at the receiving facility. If responsibility for arranging follow-up after discharge is delegated to the parents, it must be clearly understood by the parents that blindness is a possible outcome, that there is a critical time window to be met if treatment is to be successful, and that timely follow-up examination is essential to successful treatment; this information should be transmitted to the parents orally and in writing. If such arrangements for follow-up after transfer or discharge cannot be made, the infant should not be transferred or discharged.

Surgical Care

Cryotherapy was the original mode of treatment (since the 1970s) (8,20,21). The procedure may be completed with general or topical anesthesia. It involves approximately 50 applications of a freezing probe under direct visualization with cryo applications to the avascular retina anterior to the fibrovascular ridge. The stress of the procedure may require assisted ventilation after the procedure. The most common complications include intraocular hemorrhage, conjunctival hematoma, conjunctival laceration, and bradycardia. Laser surgery (xenon, argon, diode) has been shown to be as effective as cryotherapy for ROP (22-25). The systemic side effects are significantly less, the ocular tissues are less traumatized, posterior zone 1 disease is treated easily, general anesthesia is not necessary, and, as many recent studies show, there is less incidence of late complications. Complications include corneal haze, burns of the iris, cataracts, and intraocular hemorrhages. Scleral buckling surgery and/or vitrectomy usually is performed for stages 4 and 5. Some surgeons recommend surgery for stage 4A, while others do not think surgery should be performed because of the risks and unproven benefit. Although some surgeons advocate surgery on Stage 5, the surgeon with the most experience (S.T. Charles, MD, personal communication) no longer recommends surgery because of the poor anatomic and visual prognosis.

Further Outpatient Care

Any premature infant should continue to be monitored until active disease has subsided. Since 20% of premature babies develop strabismus and refractive errors, a pediatric ophthalmologist should screen them every 6 months, until age 3 years. Up to 10% of premature babies may develop glaucoma in later years. Eye examinations should be a part of their annual examinations.

The prognosis of this disease is always guarded. The development of the visual system may be affected in many ways, even after the ROP has resolved. There may be macular dragging, glaucoma, strabismus, refractive errors, and amblyopia that may, even after aggressive treatment, lead to visual loss. It is important that the parents are advised repeatedly of this guarded prognosis, so that their expectations are realistic, especially in severely affected children. Many children still lose vision, even under the best circumstances.

 

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