Extracts from the Manual of Procedures for the 1995-8 LIGHT-ROP clinical trial
by Drs. Reynolds, Spencer, et al.
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Timing of ROP unrelated to oxygen enrichment
Excess light may enhance effect of oxygen on retina
Light toxicity and ROP are the same type of damage
Hospitals are careless about nursery light levels
Short-wavelength light is particularly dangerous
Preemie light exposures higher than normal for adults
Preemies are more vulnerable to light than adults
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2.5 THE PATHOPHYSIOLOGIC MECHANISM OF ROP
ROP is a disorder of the immature retinal vasculature, and once the retina is fully vascularized the risk for its development has passed. Although our understanding of ROP is incomplete, there are two major theories of its pathogenesis. The first developed in the 1950s has as its basis, retinal endothelial cell damage, while the second which arose in the 1980s is based on damage to mesenchymal spindle cells.
The retinal endothelial cell damage theory of ROP development arose out of the pioneering work of Ashton and Patz.65-67 Independently these workers showed that in the experimental animal ROP developed in two phases. In the first, oxygen induced vasoconstriction resulted in excessive capillary retraction, vaso-obliteration, and disintegration of retinal endothelial cells. Whether endothelial cell damage is due to a direct cytotoxic action of oxygen67 or is the ischemic consequence of reduced blood flow consequent upon the vasoconstriction has yet to be fully elucidated.66 The second, vasoproliferative, phase develops after removal from the oxygen rich environment, and the return to normal atmospheric air. By now many endothelial cells have been lost, and the angiogenic process commences in the remaining cells which proliferate profusely. This phase is > Page 2-13 > 06 07 95 simply the consequence of the previous vaso-obliteration and is not in itself due directly to oxygen.
The changes described above were observed in the experimental animal, and do not correspond closely to the situation in the human infant. Thus the development of ROP and its progression are determined predominantly by postconceptional age rather than neonatal events, and bear no temporal relation to placement in an oxygen enriched environment.
Kretzer and Hittner developed a new theory based on human experiences. Unable to detect endothelial cell damage, their theory hinges on oxidative damage to spindle cells.68-70 Mesenchymal spindle cells derived from the hyaloid artery, invade the nerve fiber layer and migrate centrifugally. As these primitive cells migrate, they differentiate into endothelial cells and form new vessels. This process in humans is distinctly different from animal models. These newly formed endothelial cells form the developing, expanding vasculature. It is this interface of differentiating mesenchymal spindle cells and newly forming endothelium that is the site of insult in ROP. Increased oxygenation with free radical generation overwhelms the immature antioxidant systems of the preterm retina. Loss of control over differentiation occurs and the damaged mesenchymal cells form abnormal neovascular shunts.
The electron microscopic finding these authors used to assess cell damage in the mesenchymal spindle cells was an increase in spindle cell gap junctions. This has been misunderstood but serves only as an indicator of cell membrane dysfunction. Gap junctions, themselves, are not integral to the pathogenesis.70
In either theory, Ashton's or Kretzer's and Hittner's, the common denominator is the cytotoxicity of oxygen via free radical production and the lack of mature antioxidant mechanisms to deal with this in the youngest pre-term infants.
Proponents of both theories have implicated light as an additional factor, and ir 1980 Patz wrote that "excess light exposure may theoretically enhance the oxygen effect on the premature retina and deserves further study."66
> Page 2-15 > 06 07 95 What is known about retinal light toxicity points to free radical oxidative damage. The most convincing evidence about the pathogenesis of ROP points to free radical oxidative damage. The same free radicals are generated in each process. Although the relative contributions of both increased oxygen and light are unknown, it is plausible that these are additive, and the basis of our primary question.
2.6 LIGHT AND ROP
2.6.1 ENVIRONMENTAL AND BIOLOGIC FACTORS THAT POTENTIATE NEONATAL LIGHT EXPOSURE
Several factors are at work which subject the very low birthweight infant, in a typical neonatal intensive care unit to an inordinate amount of ambient light under biologic conditions that may potentiate a detrimental effect of light.
22.214.171.124 Ambient light levels are highly variable in NICUs but tend to be high.71-77 Each NICU will differ from another but within units there is also tremendous variation. The number of fluorescent bulbs that are illuminated, the number, position, and shading of windows, the cycling or non-cycling of light on a diurnal basis, all vary. In the afternoon on a sunny day, one infant housed near a window received 2500 foot candles (about 25,000 lux).69 Clearly, this is extreme, but the large majority of infants receive much greater illumination than the recommended 100 foot candles.78, 79
[Note: The recommendations from the American Academy of Pediatrics have called for 60 foot-candles since 1988, so the study authors' ignorance about such basic data relevant to the subject of their alleged inquiry illustrates their slipshod work.]
126.96.36.199 Premature infants exposed to this amount of ambient light do not have the normal aversion responses. Eyelid closure is not normal in these infants and the youngest babies keep their eyelids open the longest time.80
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188.8.131.52 Premature infants also lack the protective mechanism of pupillary miosis in response to light. Infants less than 30-34 weeks post-conceptional age manifest this absence of miosis and additionally their resting pupil size is larger.81-87
184.108.40.206 Phototherapy for hyperbilirubinemia is performed with high intensity, short wavelength light. This is a particularly dangerous combination. Eyes are normally occluded for the duration of therapy. However, the occluders may be malpositioned for more than 50% of the time. Additionally, no shielding is provided to reduce reflected or scattered light to the infant neighbors." 8
This information indicates that the preterm neonate can be exposed to high levels of illumination, indeed abnormally high even for the adult. Furthermore this neonate has yet to develop aversive reflexes and mechanisms to reduce this high light dose.
2.6.2 BIOLOGIC FACTORS THAT POTENTIATE LIGHT TOXICITY IN PREMATURE INFANTS
220.127.116.11 Retinal location variations in ROP frequency may relate to enhanced light exposure in the nasal and temporal quadrants.84, 85
18.104.22.168 Photochemical retinal toxicity is potentiated by increasing temperature and increasing oxygen concentration.55, 86 Light induced photo-oxidative damage appears additive to oxidative damage from increased oxygen concentrations. This is an example of a synergistic effect of light and oxygen in promoting oxidative damage.
> Page 2-17 > 06-07-95 22.214.171.124 Pigmentation appears to be a factor. Hypopigmented animals are more susceptible to retinal light damage.87 Caucasian premature infants are relatively hypopigmented. There is also a racial variation in ROP incidence. In the CRYO-ROP study, Black infants had significantly less prethreshold (13.1% vs. 20.5%) and threshold (3.2% vs. 7.5%) ROP than did Caucasian infants.88 This may relate to genetic differences in susceptibility, unknown factors, or the difference in response to light toxicity due to differences in pigmentation.
126.96.36.199 Protoporphyrin IX is a photoactive compound (a chromophore or sensitizer) which produces reactive oxygen species when exposed to light. Levels of this molecule are significantly increased in erythrocytes in preterm infants as compared to full term infants.89 This compound represents at least 95% of free porphyrin in the blood90 and would be presumed to be in high concentration at the retinal interface of mesenchyme- endothelial cell differentiation. It has also been demonstrated that there is a light dependent generation of superoxide radicals and hydroxyl radicals from human erythrocytes with normal levels of protoporphyrin IX.91, 92 More to the point, light-mediated retinal injury has been demonstrated in protoporphyric mice.93
188.8.131.52 As noted in section 2.4, antioxidant systems are often functional only in part, if at all, in premature organisms. This has been noted with retinal vitamin E,94 retinal cytochrome oxidases,95 deficient iron-binding capacity,96 and mitochondrial superoxide dismutase.97
184.108.40.206 Retinal blood flow and oxygen consumption are higher in the dark,98, 99 thus under light conditions the retina is rendered relatively hyperoxic.100
> Page 2-18 > 06 07 95 220.127.116.11 Blue light inhibits retinal endothelial cell growth.58 This is synergistic with oxygen and may exacerbate the potential for vascular damage.
Premature infants thus not only receive more light, but also biologically control the potential light toxicity less well.
2.6.3 ANIMAL STUDIES OF LIGHT AND ROP
One of the problems in finding a relationship between light and ROP has been the lack of a good animal model of ROP in which to study this question. The two best studied animal models are in the kitten and the mouse. In both of these animal models, retinal neovascularization is induced in 100% of subjects by exposing full-term newboms to oxygen tensions sufficiently high to guarantee neovascularization in all animals. Thus, this effect of high tensions of inspired oxygen is likely to overwhelm any potentially more subtle influences such as light exposure.101
This has been the case in the work by Kremer et al.102 in the kitten model. In their work no significant difference was found in the extent of preretinal vasoproliferation in kittens with oxygen induced retinopathy and varying amounts of light exposure. In other recent work with the murine animal model for ROP, Wesolowski et al. also did not find that light exposure exacerbated the neovascular response.103
Most recently Sadda et al. demonstrated photo sensitization-induced retinopathy in beagle puppies.104 In the presence of Rose Bengal, the light irradiated eye developed ROP like retinal changes. The control non-irradiated fellow eye exhibited normal vascular development. This is strong evidence that light induced free radicals can mimic the retinal changes induced by oxygen in the newborn puppies.
[The footnote references for this chapter are posted on page 4 in this series.]
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