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The documents posted here were obtained in paper form from the National Eye Institute under the Freedom of Information Act. Highlightings and comments are added here for emphasis. The list of references cited for pages 1 to 3 is on page 4 of this series.
FEASIBILITY TRIAL OF LIGHT REDUCTION FOR RETINOPATHY OF PREMATURITY
MANUAL OF PROCEDURES (Title Page)
08 08 95
> Page 2-9 > 06-07-95 There is no doubt that prevention of any disease and specifically ROP is preferable to treatment. Ideally premature birth itself could be prevented by perfect prenatal care. In the absence of this, a focus on prophylaxis of ROP development in these preterm infants is the next best option.
Light reduction, if successful, offers an inexpensive, easily instituted and manageable method of contributing to ROP prophylaxis on a worldwide basis, not just in highly developed, technologically advanced countries. If unsuccessful a social, political and medical debate will be put to rest which otherwise will continue to unduly occupy the attention and effort of the public, politicians, hospital personnel, and medical researchers.
2.4 RETINAL LIGHT TOXICITY
Optical radiation interacts with biological tissues via three processes: photochemical, thermal and ionization. Thermal damage to the retina occurs with a light source intense enough to actually burn the retina, i.e., denature proteins. This effect has been known for hundreds of years. But it was not until 1966 that it was realized that light levels, much below that required for thermal effects, could also produce clear cut anatomical retinal damage.42 This is the photochemical mechanism. Ionization is also a relatively recently understood process and this occurs with extremely high energy levels such as occur with lasers. Laser energy may induce tissue plasma formation and may essentially vaporize tissue.
It is photochemical light damage that is of interest to this study. This is dependent on wavelength, intensity, and duration of stimulus and also varies with the biology of the target tissue.
There are two classes of photochemical damage to the retina.43-46 Type 1 arises from prolonged exposure to low irradiance levels of mid-visible wavelength light. Type 2 is produced by shorter wavelength light, ultraviolet and blue light, with higher irradiances > Page 2-10 > 06-07-95 and shorter durations. Type 1 centers in the photoreceptors and type 2 in the retinal pigment epithelium. However, other layers of the neural retina can also be damaged.45, 46
When comparing the scientific descriptions of photoreceptor damage from light, specific alterations in the fine structure of cells and cell components have been described, as have changes in some aspects of visual function.43 When compared together, there appears to be an enormous diversity of abnormalities ranging from photoreceptor loss to relatively subtle increases in the size and number of shed packets of outer segment disks.
Histopathologic studies have employed criteria for damage which range from mild disruption of outer segment disks to outright loss of the photoreceptor nuclei. Exposure to broad-spectrum fluorescent light can induce subtle changes in the photoreceptors consisting of a disruption of the precise ultra structural arrangement of disk membranes in the photoreceptor outer segments.47 More dramatic changes occur with longer exposures to either cyclic or continuous illumination.48 In albino rats, cyclic exposure to as little as 500 lux results in loss of most photoreceptor nuclei in the central retina within 30 days.49
Ocular pigmentation reduces, but does not eliminate, damage to photoreceptors by light, probably by partial filtering.50 The disruption of disk organization and outer segment swelling which occurs in albino mice in less than 12 hours at intensities of 250- 450 lux, takes 14 hours at 3500-4000 lux in pigmented animals.50
Another consideration is the genetic species variation in light-damage susceptibility found amongst different strains of mice and rats.51 Retinal susceptibility to light damage increases with age in the albino rat, as does dark rearing before light exposure. Ocular melanin has a protective function, presumably by the screening and absorption of light. These effects are associated with increasing rhodopsin content of the photoreceptors. Although there is extensive characterization of the factors mentioned above, little is known about the manner by which they exert their influence, partly due to an incomplete understanding of the development of metabolic function in the immature retina and the precise mechanisms of retinal light toxicity.
> Page 2-11 > 06-07-95 Light damage to photoreceptor cells is usually associated with changes in adjacent tissues. One of the earliest changes is the apparent separation of the microvilli of pigment epithelial cells, reducing the contact between the retinal pigment epithelium (RPE) and neural retina. Light induced shedding of outer segment disks results in more phagosomes. These often fuse with each other and/or with pigment granules in the RPE.50
Photochemical damage depends on absorption by a sensitizing molecule or chromophore which is then excited. Molecular bonds may then be split. This may produce positive or negative ions or generate free radicals.43, 52 This can then result in
membrane or intracellular damage depending on the site of the sensitizer molecule.55
There are many chromophores including rhodopsin, melanin, riboflavin, bilirubin, porphyrins, mitochondrial cytochrome enzymes, and rhodopsin photobleaching products.9,46,48,53,54 Whatever the sensitizer, the mechanism involves free radicals including hydroxyl radicals, singlet oxygen and superoxide radicals.43-46,53-55 The common denominator is the basic pathophysiology of oxidation, and the most sensitive structures to free radical attack are the polyunsaturated fatty acids, an essential component of biological membranes.43-46,53-55
There is little doubt, that in the adult, visible radiation can damage the lens, photoreceptors, and retinal pigment epithelium; the effect of early exposure to light on the immature visual system is unknown.
[Note : If adults can get light damage, and immature systems are inherently more vulnerable, then why not protect right away the more vulnerable people from the agent that can harm the robust ones, instead of first studying the harm?]
Following are some factors which may affect the susceptibility of the immature retina to light-induced damage.
In the adult, exposure to light decreases retinal metabolic activity which shifts from aerobic to anaerobic. Retinal blood flow and oxygen consumption are both higher in the dark than light in the human, although Hill and Houseman recorded increased flow in some cats but decreased in others in response to dark exposure.57 Raised retinal oxygen tension has been measured in the light compared to the dark in the rabbit, confirming decreased metabolic activity under these conditions. Oxygen consumption across the cat retina in the light was only 60% of that in the dark. Recently, Dorey and associates demonstrated that blue light inhibits the growth of retinal endothelial cells.58
[Note : the highest energy spike from the fluorescent nursery lamps is exactly in that blue region where mammalian eyes are most vulnerable.]
These >Page 2-12 > 06-07-95 authors stated that since light or oxygen act synergistically with dopa to inhibit endothelial cell growth, exposure to light or oxygen could exacerbate the potential for vascular damage. The levels of dopamine in the immature retina are about 1/20th of those in the adult; Hollyfield and associates have suggested that the low dopamine concentrations at birth could be partly due to very low light levels in utero.59
Biological tissues also have means for prevention or repair of free radical damage: rapid cell reproduction, free radical scavengers, membrane stabilizing compounds. Nevertheless, these systems can be overwhelmed. These protective mechanisms tend to decrease with age, however, and in pre-term organisms many of these antioxidant systems are not yet fully operational.56
In the adult, under normal conditions, the intracellular content of both superoxide dismutase and peroxidases are sufficient to remove superoxide radicals and peroxides generated by oxidative metabolism. Rilev and Slater (1969) suggested that the oxidant- antioxidant balance in the retina of a preterm neonate was critical because of the potential for light-induced auto-oxidative damage to the lipid membranes.60
Vitamin C may aid Vitamin E regeneration and its level in the preterm retina exceeds adult levels by 35-50%. In contrast retinal Vitamin E levels in the preterm neonate are low (5-12% of levels in mature tissue) particularly in the avascular regions.61 Vitamin E supplementation increases retinal tissue levels, particularly in those neonates of >27 weeks gestational age.
Preterm infants are deficient in selenium. This trace element is an essential component of both glutathione-S-transferase and glutathione peroxidase, and both enzymes play a role in the prevention of autoxidative damage.62 No age-related changes in glutathione S-transferase activity have been detected; however the specific activity of glutathione peroxidase is higher in preterm than mature retina.
Paralleling photoreceptor differentiation, a space develops between the retinal pigment epithelium, photoreceptors and MüIIer cells. This sub-retinal space appears first in the central retina at 20 weeks gestational age and by 28 weeks it covers 75% of the retinal area.63 This space contains the inter-photoreceptor matrix of which inter- >Page 2-13 > 06-07-95 photoreceptor binding protein (IRBP) is a major constituent. This protein facilitates nutrient transport, including Vitamins E and A, between the retinal pigment epithelium and the neural retina.64 Thus IRBP may have a role in protecting the retina from light damage in older preterm infants.
Although much is known regarding photochemical tissue damage, much is yet to be understood. However, there is a clear consensus that the mechanism of cell damage is via the intermediary of free radical-oxidative toxicity. This gives rise to the paradox described by Marshall. "... oxygen is essential for life but toxic, and light is essential for vision but toxic. The retina has one of the highest metabolic demands of any tissue in the body, thus the combination of light and oxygen greatly enhances the probability of deleterious reactions within its component cells." 43
[The footnote references for this chapter of the Manual are posted on page 4 in this series.]
Continue reading on page 2 for more extracts from the LIGHT-ROP Manual.
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