Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

Figure 19-8. Stage 3 ROP. A: Active, intravitreal ROP seen towards the left in a wide angle RetCam view (courtesy of Fielder 2000). B: Regressing ROP showing anterior progression of the vessels, leaving the residual intravitreal vessels behind (from the CRYO-ROP Study Atlas, with permission from E Palmer, Oregon Health & Science University.)

Figure 19-9. Residual fundus scars from ROP. A: Drawing illustrating the location and orientation of the photograph (circle) (reproduced by permission of Pediatrics NeoReviews 2001; 2:e162). B: Fundus photo in a child who recovered from ROP (from the CRYO-ROP Study Atlas, with permission from E Palmer, Oregon Health & Science University).

Figure 19-10. Diagram of progression of retinal detachment in ROP. A: The retina is partially detached, not involving the macula. B: The detachment has extended and lifted off the macular area of the retina. C: The detachment is complete, and the retina is tightly bound up behind the lens (thus the older term for this disease, “retrolental fibroplasia” or RLF39), resulting in a total retinal detachment. (Reprinted with permission from Arch Ophthalmol. 1987;105:906–912. Copyrighted 1987, American Medical Association.40)

4.CLINICAL APPROACHES TO PREVENT AND TREAT ROP

The best chance for prevention of ROP rests with obstetricians and neonatologists who work together with society to reduce the rate of preterm birth. However, because there are still many infants born prematurely, there have been many efforts to prevent and treat ROP.

4.1Preventing ROP

4.1.1Oxygen Injury

Poorly controlled administration of oxygen causes an increase in the rate of ROP, particularly if it is given when not needed.41 Since the late 1960s, the technical ability to measure arterial blood gases (and, since the 1980s, oxygen saturation) has led to better control of arterial oxygenation. Severe ROP is now restricted to only the most vulnerable: those born at less than 28 weeks’ gestation or at 28-35 weeks who have had extremely unstable medical courses.

While neonatologists have become fairly sure that the best is being done for oxygen monitoring and control,42 recent historical control or cohort publications have suggested that even more strict use of oxygen monitoring and even different saturation goals should be investigated.43,44 In a cohort study in the United Kingdom, Tin and colleagues found that a nursery using

saturation targets of 85-90% (and even allowing saturations to fall transiently as low as 70%) had much lower rates of ROP, ROP surgery, chronic lung disease, and length of stay than nurseries in their region that used saturation targets of 88-98%. Their follow-up studies revealed no differences between the nurseries for rates of survival or cerebral palsy for infants of less than 28 weeks gestation (Figure 11).44 These authors have called for careful randomized controlled trials to study the safety and

effectiveness of different oxygen saturation targets in the care of preterm infants.45,46

Figure 19-11. Outcomes from the cohort study of neonatal intensive care units (NICU) using different oxygen saturation targets. Higher saturations were 88-98%, and lower saturations were 70-90%. Mortality is in percent. ROP/CRYO = % of infants who received cryotherapy for ROP. BPD = % of infants still on oxygen at 36 weeks PMA. Vent days = days on mechanical ventilation. CP = % with cerebral palsy at 1 year of age. Figure prepared from the published data in Tin et al.44

4.1.2Antioxidants

Given the clear link between oxygen and ROP, and the deficient antioxidant defenses of the preterm infant, it is natural to have considered antioxidant protection to prevent ROP. Vitamin E is the only fat-soluble antioxidant and has been extensively tested in preterm infants in randomized controlled

trials. The results have been mostly negative, resulting in a summary recommendation that vitamin E be given to preterm infants to maintain physiologic, but not pharmacologic, serum levels.47 The disappointing impact of this potent antioxidant suggests that impaired blood flow through the maturing vascular bed may be more important than direct oxidant injury.

4.1.3Blocking Vaso-obliteration

Some of the most interesting recent benchwork in ROP has involved the exploration of means to prevent the initial vaso-obliteration. Given the nature of the infant’s growing eye, this is more likely to be successful than later interference with neovascularization. VEGF is believed to be protective for endothelial cells, preserving them during times of stress.48 In the face of rising oxygen, VEGF production is reduced, leaving the developing cells vulnerable. PDGF and IGF-1 act on/with VEGF and the VEGF receptor, promoting the survival of endothelial cells both in vitro and in vivo.49 Hellstrom et al. have identified an additional problem in the preservation of endothelial cells in that preterm infants develop low serum levels of insulin-

like growth factor-1(IGF-1) after birth. IGF-1 is required for the action of VEGF on endothelial cells.50,51 These studies are in the early stages, but hold

a great deal of promise. In my opinion, prevention of vaso-obliteration at times of relative hyperoxia would be the most useful intervention we can target.

4.1.4Restricting Light

Because of the known phototoxicity of bright light in the neuroretina, and because preterm infants normally develop in an extremely light-restricted in utero environment, investigators since the 1940s have sought to learn if restricting light exposure would reduce ROP. Unfortunately, after many studies across decades, including a final multicenter masked trial,52 it is clear that restricting light does not prevent either mild or severe ROP.53

4.1.5Other Interventions Partially Tested

When administering d-penicillamine to preterm infants to promote a fall in bilirubin, Lakatos and colleagues noted that those infants did not develop

severe ROP. In a subsequent randomized trial to test this hypothesis, the finding was confirmed in their center.54,55 This finding has yet to be

replicated, because an intravenous preparation is not yet available in the market for testing.

During studies of intravenous inositol being given to premature infants to prevent pulmonary morbidity, Hallman observed that the treated subjects had reduced mortality, lung disease, and, unexpectedly, incidence of mild or severe ROP.56 This study was replicated in the same nursery in a subsequent randomized trial57 and has been recommended for a large multicenter double masked trial.58

5.MANAGING NEOVASCULARIZATION IN ESTABLISHED ROP

Once established, and advancing to the point where retinal detachment is likely to ensue, ROP has become the target of a series of investigations to intervene and prevent progression of the disease (to promote its regression).

5.1Peripheral Ablation

The CRYO-ROP study was built upon the work of several physicians who had attempted to treat aggressive ROP with photocoagulation or cryotherapy. The rationale was to ablate the peripheral avascular retina in order to preserve the posterior retina that is most essential in vision. One hypothesis was that the peripheral retina was hypoxic as well as ischemic, generating an excessive amount of growth factors that caused the neovascularization; hopefully these could be turned off by destroying that little-used portion of the retina. The results of the multicenter cryotherapy trial demonstrated the safety and efficacy of this approach, and retinal

detachments were reduced from about one-half to about one-fourth of the eyes that reached threshold ROP.7,12,,22 Subsequently, the same peripheral

ablation using the indirect diode laser has proven to be at least as effective.59-

61

5.2Modulation of Neovascularization with Oxygen

The success of peripheral ablation with cyrotherapy was considered supportive of the “growth factor overproduction in the periphery” hypothesis. VEGF is produced under the control of the hypoxia-inducible factor-1 (HIF-1), and administration of oxygen reduces VEGF production in animal models.62,63 We believe the neovascularization is due to marginal hypoxia in the avascular retina, so the STOP-ROP multicenter study proposed64 that raising arterial oxygen levels a small amount would partially relieve that hypoxia and reduce the levels of growth factors, allowing the disease to regress. The entry criterion for the STOP-ROP study was

may be sufficiently out of normal mechanisms of control that altering oxygenation is no longer an effective approach.

5.3Early Treatment for High Risk Prethreshold ROP Study

As experience grew with treating ROP, some clinicians became convinced that treating earlier than the threshold established in the CRYO-ROP study would result in better outcomes. The concern, however, is that in treating milder disease, the number of infants that would be treated unnecessarily (i.e., that would have healed spontaneously without treatment) would be increased. The Early Treatment for high risk Prethreshold ROP Study (ETROP) tested this hypothesis in a large randomized trial (n=401). Adverse retinal outcomes were reduced from 14% to 9% of enrolled infants.4 In an extensive secondary analysis, the ETROP Study Group proposed new criteria for treatment that should result in the proportion of treated infants (among those <1.25 kg birthweight) rising from 6% to just 8%.4

6.ANTI-NEOVASCULARIZATION THERAPY IN ROP

New developments in understanding and controlling neovascularization are exciting and inspire creative approaches to controlling intraocular neovascularization in ROP. Looking at the total picture of this disease, however, brings out several key points that must be kept in mind when designing interventions.

The entire infant is growing extremely rapidly at the time acute ROP is active. Any systemic treatment that might affect growth in the rapidly differentiating infant is likely to have an unacceptably high number of side effects.

The retina of the preterm infant has an actively growing vasculature, and any preventative intervention with a broad attack that would stop the normal growth of vessels is likely to lead to further neuroretinal ischemia. The results could be the opposite of those intended. Even an intervention administered locally, and only at the point when active neovascularization is already present, must also limit itself to arresting new vessel growth in the vitreous, allowing the development of intra-retinal vessels to proceed and establish a blood supply to the peripheral retina.

Animal model studies in rodents are extremely helpful in screening potential interventions, but higher order animals with retinal vasculature more similar to humans should be used prior to preterm human trials.

7.SUMMARY

ROP is a persistent and devastating disorder resulting in lifelong visual impairment for hundreds to thousands of infants every year. Interaction between and contributions from bench scientists, physiologists, and clinical scientists studying this disease will accelerate the pace of finding ways to control vision loss from ROP.

ACKNOWLEDGMENTS

Dr. Phelps was supported in part by grant EY 09962 from the National Eye Institute, NIH.

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