Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

The ROP cases that progress (get worse) reach a point that is clinically termed “threshold disease,” where retinal detachment occurs about 50% of the time without intervention.2 The detachment usually starts in the area of the ridge and most often appears to be pulled up into the vitreous by traction from the neovascularization. (However, the process sometimes appears inflammatory, and a more exudative, bullous retinal detachment is seen with copious subretinal fluid and minimal traction.) Treatment with peripheral

ablation of the avascular retina as the disease begins to accelerate reduces the risk of retinal detachment.4,7,12 Once ROP begins, the more rapidly it

advances from mild to moderate disease, and the more likely it will meet criteria for surgery.13 Rapid progression is a warning sign of particularly severe disease.

The unique timing of reaching threshold ROP is of particular interest in trying to understand exactly what is happening in this disease. Despite birth anywhere between 24 and 30 weeks’ gestation, the onset of observable ROP will be delayed until around 30-33 weeks PMA, rather than at any particular chronologic age after birth. Thus a biological “clock” seems to guide the regression/progression process, rather than any specific lag time after birth, when injury presumably occurs. In Figure 3, we see that threshold ROP

appears no earlier than 31 weeks PMA and largely occurs at 36 to 40 weeks PMA.1,9 For an infant of 24 weeks, this is 12 weeks after birth, but for an

infant of 30 weeks, this is only six weeks after birth. It has been hypothesized that this critical timing could be due to the state of neuroretinal differentiation surrounding that time; that maturation of the photoreceptors at this age causes a large increase in oxygen consumption and therefore creates hypoxia in the inner layers of the avascular retina. This hypoxia then results in the release of growth factors that drive the neovascularization.14,15 This attractive hypothesis would fit well with the findings noted in Figure 3.

Many investigators have tried to learn more about ROP pathophysiology from case control studies of infants at similar gestations that do or do not develop severe ROP. The strongest predictor for ROP is shorter gestation (and therefore lower birth weight), and once statistical adjustments are made for that, all others correlations are much weaker. However, the parameter of “days receiving oxygen” is always correlated positively with rates of ROP. To confound things, days on oxygen is also associated with other indicators of severe illness in these infants, such as episodes of sepsis, shock from sepsis, hemorrhage, poor cardiac output, intracranial bleeding, etc.16-18 So while we know these other illnesses increase the risk of ROP, we have not learned what it is about them that specifically does so.

Figure 19-3. Timing of the onset of threshold ROP among those infants in which it developed. In these figures, infants are divided into three birth weight categories: <750grams, 750-999 grams, and 1000-1250 grams. The smallest infants at birth had shorter gestations than the heavier infants. A: When the onset of their threshold ROP is plotted by chronological age, the three distributions are offset, with the youngest (smallest) infants developing threshold later. B: the same data plotted by postmenstrual age. The three distributions converge, strongly suggesting a process determined by the infants’ “biological clock” or time since conception, rather than elapsed time since the preterm birth. (Reprinted from Ophthalmology, vol 98, Palmer et al.1, Copyright (1991) with permission from American Academy of Ophthalmology.)

Plus disease is a key finding in defining threshold ROP. It develops in the posterior pole and usually affects that entire portion of the eye. Because of the dilated veins and tortuous arteries in the posterior pole (Figure 4), the term most often informally applied by clinicians is that the retina appears “angry.” As the ROP reaches this stage, the risk of subsequent retinal detachment begins to climb, and treatment is planned (see below). The cause

of plus disease is unknown, yet it is one of the most important prognostic factors in ROP.1,4,13

With plus disease and vitreous traction, the retina begins to lift in one area, and this commonly proceeds over several days to a week or two to involve the entire retina (illustrated in Figure 10 below). The hypothesis for using peripheral ablation to prevent this sequence is that destruction of the neuroretina, which is putatively producing growth factors (VEGF and others) that cause neovascularization and increased permeability, will end the neovascular stimulus. The corollary to this hypothesis is that without the sustained output of these growth factors, existing vessels will regain their integrity, stop growing (involute if in the vitreous), and mature. Based on the success of such treatment in 291 infants in the CRYO-ROP study, this hypothesis has gained support.7

Figure 19-4. Fundus photos of plus disease. The optic disk is central in these photos, the veins are dilated and the arterioles tortuous. A: Standard photo of the prototypical degree of plus disease required in the CRYO-ROP study.7 (from the CRYO-ROP Study Atlas, with permission from E Palmer, Oregon Health & Science University.) B: Severe plus disease seen in an eye with zone I ROP in this wide-angle RetCam photo (with appreciation to S. Schwartz, Jules Stein Eye Institute at UCLA).

The timing of threshold ROP development at around 36-40 weeks PMA is particularly cruel for families, because it is near the baby’s due date and close to the time when these preterm infants are ready for discharge from the hospital. Just as all the other problems that have been encountered are resolving, the ROP becomes manifest.19 This can be especially shocking if the family is unaware of the possibility of ROP or if it occurs after discharge. Approximately 10-20% of surgical treatments for ROP are now occurring after the infants have already been taken home.

2.3Vision after ROP

Preterm infants have visual disturbances such as strabismus, nystagmus or cortical visual impairment more often than term infants. This may be related to central nervous system injury rather than ROP.20 Infants that never reach threshold ROP and spontaneously recover from ROP usually have good visual outcomes. In contrast, if the ROP reaches threshold level, visual function is frequently affected, even when retinal detachment does not occur. High myopia is common among these infants, and can be asymmetric, leading to amblyopia if left untreated.21 Even with corrective lenses, these infants often do not achieve normal acuity.

Maturation of visual acuity over the first four years in preterm infants with and without ROP is shown in Figure 5. Compared to infants born at term, acuity in preterm infants who never developed ROP appears to develop within the low normal range. Those with mild ROP (less than prethreshold) had almost the same outcomes. Those whose ROP was prethreshold had somewhat lower acuity, just at the lower border of the normal range. In

Figure 19-6. Representation of the visual field of the right eye of premature infant controls (never had ROP) and infants who developed threshold ROP and retained vision at 10 years.25 The widest field (Never ROP, gray) was in the controls. The outer edge of the black lines is the field of those infants who recovered from threshold ROP without cryotherapy (Threshold ROP recovered without CRYO). The slightly more constricted field (Threshold ROP, postCRYO, white) is the average measured among the infants who recovered after having cryotherapy. The figure was prepared from the data reported in Figure 2 of the article, and data from the left eyes are reflected and included.25

When peripheral ablation fails, partial or full retinal detachment follows in a surprisingly short number of days to weeks in these young patients. Scleral buckle procedures are sometimes used to attempt rescue of early detachments by reducing the distance between the sclera and detaching retina. If the retina reattaches, progression to a full retinal detachment is avoided, and vision can sometimes be retained.26 When a large or complete retinal detachment occurs, there is virtually no hope for useful vision, so in these cases, retinal surgeons have attempted vitrectomy to release and reattach the retina. After this difficult procedure, which involves removal of the lens and vitreous and dissection of the fibrous tissue from the retina, the retina sometimes successfully reattaches. However, good visual acuity is not expected.27,28 Ambulatory vision is sometimes achieved.29 This contrasts with the better success achieved when treating retinal detachment in adults. It may be that the developing retina is more sensitive to permanent injury following temporary separation from the underlying choroid. Recent surgical approaches have included aggressive treatment of early retinal detachment in the hope of heading off progression of the detachment and attempts to accomplish this with sparing of the lens.30

3.ROP PATHOPHYSIOLOGY AND NEOVASCULARIZATION

The unique feature of ROP, in contrast to other retinopathies (diabetic, sickle cell, choroidal neovascularization, etc.), is its start in an incompletely vascularized retina with only partially differentiated neuroretina and an eye that is rapidly growing. Seeking similarities and recognizing differences between ROP and the neonatal animal models of this disorder is helpful in guiding further investigations.

3.1Normal Vascularization of the Retina

The avascular, immature human retina begins to develop its first primitive vessels around 14-16 weeks (of a 40-week term gestation) and proceeds to nearly complete retinal differentiation and full vascularization by term birth. This makes the human eye similar in development to other mammalian species (sheep, goat, horse, pig, cow) born with open eyelids and fully vascularized eyes.31 Species born at term with fused eyelids (rat, mouse, cat, dog) have retinal vasculature more similar to the premature human infant, who until 24-26 weeks also has fused eyelids. Chan-Ling has published descriptions of the early vascularization of the human retina.32,33 Between the start of vascularization and term, the retina is rapidly increasing in area as the eye grows and the neuroretina differentiates. As this occurs, the developing retinal vasculature is chasing an ever-expanding horizon of retina and therefore is growing quite actively. The initial spread of the most inner plexus of vessels to the ora serrata may be seen near term, but the deeper penetrating two layers of capillaries are not seen until later; these start near the fovea and proceed peripherally.

The earliest vessels are poorly supported by additional structures and, in their primitive state, readily remodel from a primitive capillary network into a more mature and well-supported structure of arterioles, venules, and capillaries with basement membranes, pericytes, and astrocyte ensheathment.34 Many early capillaries are pruned, and the endothelial cells in them normally migrate away from these abandoned paths into ones that are to remain.

3.2ROP Sequence based on human and animal studies

3.2.1Vaso-obliteration

Throughout the body, arterial tone autoregulates the delivery of oxygen to tissues. When oxygen concentrations rise, arterial constriction reduces blood flow. As reduced blood flow delivers less oxygen, tissue levels fall, and when they begin to approach hypoxic levels, arterial tone adjusts and permits more blood flow. This fine tuned autoregulation occurs in all ‘end organ’ blood supplies, which includes nearly all tissues, except the retina. What is unique about the retinal blood supply is the choroid. It lies under the retina and provides a high blood flow, irrespective of oxygen concentration (or perhaps with minimal autoregulation). When arterial oxygen concentrations rise in the choroid, a large diffusion gradient develops so that oxygen is supplied by diffusion alone through the retina to the internal limiting membrane and vitreous. The intra-retinal arterial vessels constrict in response to the high oxygen levels, to the point of total non-perfusion in hyperbaric oxygen conditions.35 However, the delivery of oxygen from the choroid continues, and so the now non-perfused retina remains well oxygenated, or excessively so.

In the immature retina, when oxygen levels are raised (as they are in the animal models of oxygen-induced retinopathy to levels of near 400 torr), autoregulation of the early retinal arterioles occurs, and flow through the vessels stops. If this persists (usually for many hours to days), the growing vascular bed is obliterated. In the kitten and puppy models, essentially all of the retinal vessels are obliterated (Figure 7), and when the animals are returned to normal oxygen concentrations, new vessels begin to grow from the optic disk or, more rarely, from the very posterior vascular remnants.36 In the mouse or rat pup models, these patterns differ because of the persistence of the large complex hyaloid vasculature system at the time of birth. In the kitten and puppy models, the hyaloid vasculature is almost involuted by the time of birth, although oxygen-induced retinopathy causes remnants of it to sometimes persist.

Figure 19-7. India ink perfused retinal flat mounts at 7 days of age (feline model). Left: Control kitten raised in room air (the dark vessel is a remnant of the hyaloid artery). The vasculature is in 3 lobes and delicately covers about the central half of the retina, the border of which is indicated by arrows. Right: Kitten raised in 80% oxygen from day 3 to 6.5 (80 hours). The retina is largely avascular, with only two thin vascular remnants persisting.

There are questions among investigators as to whether vaso-obliteration of the anterior growing vasculature occurs in the human preterm infant during the injury phase following preterm birth, as is clearly seen in the kitten model. One school of thought is that preterm birth causes vessels to arrest growth when the in utero levels of arterial oxygen (26-40 torr) rise to extrauterine levels (40-100 torr). Alternatively, elevated oxygen levels (and other cardiovascular events affecting blood flow) may not only arrest the normal rapid growth of vessels, but also obliterate the more peripheral portion of the most immature vessels, which cannot tolerate days of decreased perfusion, as seen in animal models. This question remains unresolved, because it is technically not feasible to see these immature vessels in the living child at these gestations, and pathological tissue at this age is not available in sufficient quantities to separate normal biological variation from pathology given our current techniques. Perhaps biological markers of injury, apoptosis, regression, and growth may make this feasible in the future.

In addition to autoregulation in response to oxygen, other hypotheses about the initial vascular injury leading to vaso-obliteration and/or growth arrest are that increased oxygen may increase free radicals that are directly toxic to the endothelium or that acidosis and/or poor nutrition may impair the vessels’ ability to sustain the rapid growth.

3.2.2Repair—New Vessels and Regression

The first visible sign of ROP is the retinal vessels beginning to grow again. These new vessels and accompanying tissue should grow anteriorly within the retina, toward the ora serrata. There can be moderate to severe disorganization in this process, which is the visible ROP observed. Mild disorder leads to a thin, distinct line of demarcation between the vascular and avascular retina (not seen when the retina is merely immature and without ROP). This is referred to as stage 1 ROP. When this area of disorganization is larger, with both anterior to posterior thickness as well as vertical thickness, the resulting ridge of tissue is termed stage 2 ROP. If the new vessels escape the internal limiting membrane and grow into the vitreous, it is termed stage 3 ROP.

The first hallmark of healing in ROP (called ‘regression’) is anterior growth of the vessels beyond the line of demarcation or ridge of tissue between vascular and avascular retina. This can be seen even in cases where there has been severe intra-vitreal neovascularization (stage 3) (Figure 8).

The cloudiness of the vitreous that sometimes develops during the acute phase will then clear, and any intravitreal vessels will begin to involute (shrink), cease to be perfused, and atrophy, changing from red to white.37 The retinal vessels then grow toward the ora serrata, although more slowly than they normally would, arriving later than term. A residual scar at the line of demarcation is sometimes permanent evidence of the ROP (Figure 9).

3.2.3Failed repair—Progression

Retinal detachment in the acute phases of ROP is rare without the retina having first developed plus disease, as described above (Figure 4). The usual course of retinal detachment is to begin within days to weeks of developing plus disease with traction at the demarcation line, pulling the retina up into the vitreous toward the back of the lens. The progression from immature vessels to complete retinal detachment is shown in a teaching video available from the NIH/NEI38 and also in the panels of Figure 10.