PHOTOTOXICITY AND THE CORNEA Oliver D. Schein, MD, MPH Boston, Massachusetts
The cornea is sensitive to the effects of ultraviolet (UV) light and can suffer both acute and chronic toxicity. Ultraviolet keratitis is associated with relatively short exposures to light sources such as welding arcs or tanning lamps. The corneal effects are seen within a few hours following exposure and typically will resolve within 72 hours. Chronic exposure to environmental UV light may lead to a variety of ocular surface abnormalities that rarely resolve in the absence of therapy. Ultraviolet light, while potentially destructive, also can be used therapeutically. Recently, the photoablative properties of the excimer laser have been used in corneal refractive surgery. This laser uses UV light to break chemical bonds and remove tissue. Corneal phototoxicity is a reflection of the sensitivity of the ocular surface to photochemical injury. Fortunately, effective protection in the form of UV-blocking lenses is widely available. (J Nati Med Assoc. 1992;84:579-583.) Key words * phototoxicity * cornea - ultraviolet keratitis
ULTRAVIOLET KERATITIS Unlike the majority of phototoxic syndromes involving the eye that require chronic exposure and lead to long-term cellular changes, ultraviolet (UV) keratitis is relatively rapid in both onset and resolution. The clinical syndrome is characterized by the onset of significant ocular pain and decreased acuity between 6 and 12 hours after exposure, usually to a welder's arc or a tanning lamp. A superficial punctate keratitis, typically bilateral, develops early; in severe cases, this From the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Requests for reprints should be addressed to Dr Oliver D. Schein, Wilmer Eye Institute, Johns Hopkins Institute, 600 N Wolfe St, Baltimore, MD 21205. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
is frequently followed by total epithelial desquamation. Conjunctival chemosis, lacrimation, and blepharospasm are also usually present. Corneal reepithelialization, aided by lubrication, patching of the eye, or a bandage contact lens, occurs over a 36- to 72-hour period. Long-term sequelae are rare. This is in contradistinction to damage to the epithelium from certain chemicals (eg, alkalis and strong acids) where re-epithelialization is often delayed or abnormal. The lag time between exposure and symptoms is characteristic, and is indirect evidence that the effect is photochemical rather than thermal. The absence of pain during this period has been puzzling to patients and physicians alike. This phenomenon has been studied experimentally in humans1 using corneal touch threshold measurements in humans who were exposed to subclinical doses of a focused electric-arc welding set. A significant increase in sensitivity loss was observed in all subjects. Moreover, the mean time to the peak of sensitivity loss occurred at 13/4 hours. By 4 hours, corneal sensitivity had returned to baseline in all subjects. It is quite likely that this pattern of sensory loss and return contributes to the characteristic lag in symptoms seen clinically. The action spectrum for keratitis produced by UV radiation was first measured in 1946 by Cogan and Kinsey and has been repeated in a variety of animals under several testing conditions.2-4 The action spectrum refers to a curve that relates wavelength to the amount of energy necessary to produce a threshold level of keratitis. The peak sensitivity is about 270 nm. At that wavelength, only about 0.005 J/cm2 is required to produce keratitis. This peak sensitivity, which is quite narrow, is thought to correspond to the absorption of UV light by epithelial nucleic acids and aromatic amino acids. Longer wavelength UV light requires more log units of energy to produce threshold keratitis (eg, at 320 nm, 10 J/cm2 are required). Natural sources of UV light will not cause keratitis at short exposures because the ozone layer of our atmosphere effectively blocks light of less than 290 nm. Therefore, manmade implements are the chief source of UV keratitis.5 579
PHOTOTOXICITY & THE CORNEA
ol
; o
~m
Ct. .d E o
~
~
_... ^
..
~
e
...
_,
.e_
_
s
_
CO) ct
Figure 1. Advanced climatic droplet keratopathy.
Acute UV keratitis can, however, be caused by natural sources under specific circumstances. For example, keratitis has been reported following solar eclipse burns.6 In addition, keratitis solaris has been reported after exposure to strong solar radiation at high altitudes or in snow-covered terrain. The keratitiseffective irradiance is felt to depend greatly on the characteristics of the ozone layer, the albedo of the terrain, and the altitude. For example, the higher ozone content in the spring is responsible for a 23% lower keratitis-effective irradiance compared with that during the autumn equinox. Conversely, a 25% decrease in the ozone content of the atmosphere will increase the keratitis-effective irradiance by 35% for a solar elevation of 400 and by 70% for a solar elevation of 200.7 Such effects, unfortunately, are becoming ever more relevant in light of the increasing, human-imposed stress on the ozone layer. Phototoxic effects may occur at all levels of the cornea. In the epithelium, UV light inhibits mitosis, produces nuclear fragmentation, and causes a loosening of the epithelial layer.8 These effects are compatible with the clinical presentation, and the rapid regenerative powers of the corneal epithelium account for the anticipated recovery. Effects on the corneal stroma also have been documented experimentally in the rabbit,9 where reversible damage to the stromal keratocytes has been shown. In addition, the threshold for ultrastructural damage to the corneal endothelium has been found to occur within the range typically achieved by standard UV lamps.'0 An effect on the endothelium has been indirectly established in man in a case-control study of welders in Japan where specular microscopy found a significantly greater amount of pleomorphic change (a 580
decrease in the hexagonal cell population) in the endothelial mosaic of the welders.'1 This was not associated with any observable visual or functional deficit. Before leaving the area of acute exposure to UV light and the cornea, a new application of UV light should be mentioned. Short wavelength UV light is germicidal, effecting cross-linking and breaking bonds between nucleic acids. Recently, a 253.7-nm UV light was tested for its germicidal capabilities in the disinfection of contaminated contact lenses and storage solutions.'2 The exposure time necessary to reduce a concentration of organisms from 106/mL to less than 10/mL was 30 seconds for Staphylococcus aureus, 60 seconds for Pseudomonas aeruginosa, and 84 seconds for Candida albicans. Less than 3 minutes were required to sterilize a suspension of 104/mL Acanthamoeba polyphaga. The contamination of contact lenses and related solutions is a major risk factor for ulcerative keratitis associated with soft contact lens use. Ultraviolet light disinfection may prove to be a rapid and easy method for combined disinfection of the lens and case. The short exposure time and broad germicidal effect may render this approach the method of choice in the near future.
CHRONIC SOLAR TOXICITY Chronic solar toxicity has been linked to several disorders of the ocular surface-pinguecula, pterygium, climatic droplet keratopathy (CDK), and squamous metaplasia/carcinoma. Pterygium and pinguecula are discussed elsewhere. The evidence linking actinic damage to CDK is much stronger than for squamous metaplasia/carcinoma. Climatic droplet keratopathy is also known as Labrador keratopathy and spheroidal degeneration. As Taylor has pointed out,13 these terms probably describe two separate disease processes. Spheroidal degeneration is characterized by fine golden globules in the anterior cornea or conjunctiva and may be primary in normal corneas or secondary in association with other ocular disease. 14 This is to be distinguished from Labrador keratopathy or CDK, which is characterized, in its early stages, by small gray droplets at the level of Bowman's membrane and has been associated with extremes of the climatic spectrum. The clinical findings associated with CDK range from fine, subepithelial opacities without visual effect to functional blindness from axial corneal scarring (Figure 1). Microscopically, characteristic globular lesions are found in Bowman's layer and superficial stroma. It has been conjectured that these deposits contain denatured plasma proteins, but this has not been JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
PHOTOTOXICITY & THE CORNEA
confirmed. A link with environmental factors has long been proposed because the disease, in its severe form, characteristically occurs in extreme climatic conditions and is typically limited to exposed cornea not covered by the upper or lower lids. The condition has a distinct male predominance, which has been attributed to male association with occupational exposure. In a survey in Labrador, the overall prevalence among men was 56%, and in one community, CDK was found in 100% of men older than 40 years of age.'5 A high prevalence with unusually severe disease also has been reported from the Dahlak Islands in the Red Sea. Forty-five percent of the islanders had CDK, and corneal scarring from CDK was found to be the principal cause of blindness in the area.'6 Recently, a standardized methodology for estimating occupational ocular exposure to UV radiation has been developed that combined detailed occupational histories with laboratory and field measurements.17 Taylor and associates have employed these techniques to explore the relationship between keratopathy and chronic UV exposure among Chesapeake Bay watermen in Maryland.'8 In this geographic setting, CDK was seen in 19% of the watermen, although in no case did it result in visual impairment. Logistic regression analyses established a significant association between UV light and pterygium, CDK, and pinguecula for all UV radiation bands. The association was weakest for pinguecula. Risk for CDK increased with age and UV exposure. As the authors point out, this study shed light on a number of important issues regarding phototoxicity and chronic corneal disease. First, CDK and pterygium were associated with both UV-A and UV-B exposure, unlike cortical cataract where UV-A was not found to be contributory.'9 Second, a dose-response relationship between UV radiation and CDK and pterygium, in the absence of other previously hypothesized exposures (wind, dust, etc), renders a phototoxic etiology quite convincing. Third, it is apparent that low-technology, low-expense prevention in the form of a hat or spectacles would likely be preventive. Although there is considerable evidence linking UV exposure to squamous carcinoma of the skin, this evidence is lacking for conjunctival or corneal squamous metaplasias. This may be the result of a lack of association or simply the result of the rarity of the condition and hence the difficulty of performing meaningful epidemiologic research. The indirect evidence consists largely of the known association of UV light with nonmelanoma dermatologic malignancy. These lesions occur predominantly in sun-exposed JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
Ir' t~~~~ Figure 2. Limbal conjunctival intraepithelial neoplasia.
areas of the skin. The ocular counterpart occurs in what is termed the interpalpebral exposure zone. Conjunctival squamous metaplasias, ranging from mild dysplasia to invasive squamous cell carcinoma, invariably involve the corneal limbus in this exposure zone (Figure 2). Whether this is solely because of a greater potential for malignant change in this junctional region of epithelium, analogous to the squamocolumnar junction of cervical epithelium, or because of the added effects of environmental exposure is unclear. Several studies from Africa have associated squamous cell carcinoma with pterygium.20 In one such study, 58% of patients with conjunctival carcinoma were described as having a homolateral hyperactive pterygium. The concurrence of conjunctival carcinoma and pterygium has led some to speculate that pterygium and conjunctival carcinoma lie on the same biologic pathway. However, this is not generally held, and the conversion of pterygium to carcinoma is considered to be very rare. From a clinical standpoint, however, it is important to appreciate that pterygium and carcinoma can coexist and that squamous cell carcinoma, especially in its recurrent form after surgical excision, may closely mimic pterygium in its clinical appearance (Figure 3). The conditions discussed so far have chiefly affected the ocular surface and anterior cornea. Although there is no evidence for clinically significant endothelial phototoxicity, there is some suggestive laboratory evidence linking endothelial abnormalities with the interaction of light and photosensitizing compounds. Chlorpromazine, widely used for psychiatric conditions, is known to be associated with fine deposits in multiple ocular tissues. Phototoxic and photoallergic reactions in the 581
PHOTOTOXICITY & THE CORNEA
Figure 3. Squamous carcinoma presenting as pseudopterygium.
skin are well known with this drug. Functional corneal endothelial effects have been measured in vitro with endothelial cells exposed to chlorpromazine and UV light, but analogous effects in humans have not been shown. Recently, endothelial dysfunction has been linked, in a rabbit model, to protoporphyrin photosensitization. Protoporphyrin IX is a naturally occurring photoactive compound that has been detected in the aqueous of three patients with hyphema. It is speculated that, in the setting of hyphema, corneal blood staining and endothelial dysfunction may be related to the presence of this photoactive compound and that patching might be protective.
LASERS The last decade has witnessed an explosion in the clinical application of laser technology. Laser applications represent a form of controlled phototoxicity. These applications include photocoagulation, photoradiation, photodisruption, and photoablative decomposition. A host of ocular complications from the various procedures now in use with argon, krypton, and YAG lasers have been recorded. Adverse effects have been reported for all layers of the eye. For the most part, these are the direct effects of tissue coagulation or disruption. A discussion of the complications inherent to each laser type and anatomical site is beyond the scope of this article. Neovascularization of the cornea is associated with poor vision, abnormal surface epithelium, and a high risk of graft rejection after penetrating keratoplasty. The current treatment options for the extensive neovascularization seen in conjunction with chemical bums, Stevens-Johnson syndrome, or other severe ocular 582
surface disorders are very limited. Argon lasers have been used to treat neovascularization of the cornea by direct photocoagulation. However, recurrence after routine photocoagulation is frequently noted, as with thermal cautery. A novel approach to this problem, referred to as photothrombosis of corneal neovascularization, takes advantage of phototoxic reactions and shows significant promise in animal studies. This technique relies on a photochemical interaction between rose bengal (a photosensitizing dye) and argon laser irradiation. Singlet molecules are generated with resultant direct peroxidation of lipids and proteins, leading to endothelial damage and platelet aggregation. Effective thrombosis has been achieved using this technique, and corneal clarity has been maintained. Photothrombosis is accomplished at physiologic temperatures and requires a fraction of the laser energy necessary for laser photocoagulation, thereby avoiding the tissue destruction and inflammation associated with thermal coagulation. Photothrombosis also has been associated with normalization of the corneal surface after successful occlusion of corneal neovascularization. In addition, photothrombotic occlusion of corneal vessels in a rabbit model significantly improved corneal transplantation survival. Further work is necessary, however, before broad application to patients. The photosensitizing process is efficient enough that damage to corneal stroma has been noted, presumably secondary to photochemical reactions with leaking dye. Peripheral chorioretinal scarring, perhaps an effect of deflected corneal irradiation, also has been recorded. Modification of delivery systems may be able to overcome these problems, allowing the application of this technique to patients with advanced corneal
neovascularization. There is enormous interest in the potential uses of laser technology for refractive surgery. This is a direct result of the recent development of the UV excimer laser and the process of ablative photodecomposition. In this process, UV photons directly break chemical bonds and excess energy excites the resultant molecular fragments, leading to their ablation and ejection from the surface. Controlled corneal ablation has potential application in radial keratotomy, lamellar keratectomy for diseases of the anterior cornea, and large area corneal ablation to alter corneal curvature and power in an attempt to correct ametropia. The potential application of laser surgery to large numbers of subjects, in particular those for whom refractive error is the only abnormality, renders the JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
PHOTOTOXICITY & THE CORNEA
issue of photoxicity all the more important. In addition to the planned ablation, what remote effects are possible? Different UV wavelengths can be produced depending on the choice of laser medium. The destructive effects vary significantly with the wavelength. In general, it appears that there is an increasing thermal effect with longer wavelengths and thus an increased risk for side effects. Comparative studies have shown the 193-nm excimer laser to have the most precise etching abilities. Comeal cuts with this laser show essentially no damage, on light microscopy, to corneal stroma outside of the intended ablation zone. On electron microscopy, a zone of damaged tissue is found 0.1 Lm to 0.3 ,um on either side of the ablation. In contrast, surrounding tissue damage with a 248-nm excimer laser is equivalent to those of a diamond knife set at the same depth. The 248-nm laser also produces significant endothelial trauma when used for nonpenetrating incisions. A potential secondary effect of excimer irradiation is UV-induced mutagenesis or carcinogenesis. Mutagenicity can be assayed by in vitro tests for DNA damage. This has recently been performed for the excimer laser for a variety of wavelengths. Cell-damaging effects were found to be less for lasers operating at 193 nm compared with lasers operating at 248 nm and 308 nm. Although such in vitro effects suggest a risk for carcinogenesis, this is not likely to be a problem for excimer corneal surgery for two principal reasons. First, primary corneal tumors are exceedingly rare, suggesting a relative resistance of the tissue to malignant transformation. Second, animal models for UVassociated tumors have invariably required prolonged and repeated exposures for tumor induction. Despite this encouraging information concerning the lack of distant phototoxic effects, there are certainly major obstacles to be overcome before excimer corneal surgery gains widespread application. In particular, issues relating to wound healing and corneal clarity must be addressed before this technology can be generally accepted. Literature Cited 1. Millodot M, Earlam RA. Sensitivity of the cornea after exposure to ultraviolet light. Ophthalmic Res. 1 984;1 6:325-328. 2. Cogan DG, Kinsey VE. Action spectrum for keratitis
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
produced by ultraviolet radiation. Arch Ophthalmol. 1 946;35:676-677. 3. Pitts DG. A comparative study of the effects of ultraviolet radiation on the eye. Am J Optom. 1970;50:535-546. 4. Zuclich JA. Ultraviolet induced damage in the primate cornea and retina. Curr Eye Res. 1984;3:27-34. 5. Miller D. Light and the cornea and conjunctiva. In: Miller D, ed. Clinical Light Damage to the Eye. New York, NY: Springer-Verlag; 1987:55-62. 6. Billore OP, Shroff AP, Vasavada KA. Superficial keratitis following solar eclipse burn. Indian J Ophthalmol. 1982;30:303304. 7. Blumthaler M, Ambach W, Daxecker F On the threshold radiant exposure for keratitis solaris. Invest Ophthalmol Vis Sci. 1987;28:1713-1716. 8. Millodot and Buschke W, Friedenwald JS, Moses SG. Effects of ultraviolet irradiation on corneal epithelium: mitosis, nuclear fragmentation, post-traumatic cell movements, loss of tissue cohesion. J Cell Comp Physiol. 1 945;26:147-164. 9. Ringvold A, Davanger M. Changes in the rabbit corneal stroma caused by UV-radiation. Acta Ophthalmol. 1 985;63:601 -606. 10. Ringvold A, Davanger M, Olsen EG. Changes of the corneal endothelium after ultraviolet radiation. Acta Ophthalmol. 1982;60:41-53. 11. Karai I, Matsumura S, Sadafumi T, Horiguchi S, Matsuda M. Morphological change in the corneal endothelium due to ultraviolet radiation in welders. Br J Ophthalmol. 1984;68:544548. 12. Dolman PJ, Dobrogowski MJ. Contact lens disinfection by ultraviolet light. Am J Ophthalmol. 1989;1 08:665-669. 13. Taylor HR. Aetiology of climatic droplet keratopathy and pterygium. Br J Ophthalmol. 1980;64:154-163. 14. Fraunfelder FT, Hanna C. Spheroidal degeneration of cornea and conjunctiva. Am J Ophthalmol. 1973;76:41-50. 15. Johnson GJ, Ghosh M. Labrador keratopathy: clinical and pathological findings. Can J Ophthalmol. 1975;1 0:119-135. 16. Rodger FC, Cuthill JA, Fydelor PJ, Lenham AP. Ultraviolet radiation as a possible cause of corneal degenerative changes under certain physiographic conditions. Acta Ophthalmol 1974;52:777-785. 17. Rosenthal FS, Phoon C, Bakalian AE, Taylor HR. The ocular dose of ultraviolet radiation to outdoor workers. Invest Ophthalmol Vis Sci. 1988;29:649-656. 18. Taylor HR, West SK, Rosenthal FS, Munox B, Newland HS, Emmett EA. Corneal changes associated with chronic UV irradiation. Arch Ophthalmol. 1989;107:1481-1484. 19. Taylor HR, West SK, Rosenthal FS, et al. Effect of ultraviolet radiation on cataract formation. N Engl J Med. 1988;319:1429-1433. 20. Clear AS, Chirambo MC, Hutt MSR. Solar keratosis, pterygium, and squamous cell carcinoma of the conjunctiva in Malawi. Br J Ophthalmol. 1 979;63:1 02-109.
583
The cornea is sensitive to the effects of ultraviolet (UV) light and can suffer both acute and chronic toxicity. Ultraviolet keratitis is associated with relatively short exposures to light sources such as welding arcs or tanning lamps. The corneal effects are seen within a few hours following exposure and typically will resolve within 72 hours. Chronic exposure to environmental UV light may lead to a variety of ocular surface abnormalities that rarely resolve in the absence of therapy. Ultraviolet light, while potentially destructive, also can be used therapeutically. Recently, the photoablative properties of the excimer laser have been used in corneal refractive surgery. This laser uses UV light to break chemical bonds and remove tissue. Corneal phototoxicity is a reflection of the sensitivity of the ocular surface to photochemical injury. Fortunately, effective protection in the form of UV-blocking lenses is widely available. (J Nati Med Assoc. 1992;84:579-583.) Key words * phototoxicity * cornea - ultraviolet keratitis
ULTRAVIOLET KERATITIS Unlike the majority of phototoxic syndromes involving the eye that require chronic exposure and lead to long-term cellular changes, ultraviolet (UV) keratitis is relatively rapid in both onset and resolution. The clinical syndrome is characterized by the onset of significant ocular pain and decreased acuity between 6 and 12 hours after exposure, usually to a welder's arc or a tanning lamp. A superficial punctate keratitis, typically bilateral, develops early; in severe cases, this From the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. Requests for reprints should be addressed to Dr Oliver D. Schein, Wilmer Eye Institute, Johns Hopkins Institute, 600 N Wolfe St, Baltimore, MD 21205. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
is frequently followed by total epithelial desquamation. Conjunctival chemosis, lacrimation, and blepharospasm are also usually present. Corneal reepithelialization, aided by lubrication, patching of the eye, or a bandage contact lens, occurs over a 36- to 72-hour period. Long-term sequelae are rare. This is in contradistinction to damage to the epithelium from certain chemicals (eg, alkalis and strong acids) where re-epithelialization is often delayed or abnormal. The lag time between exposure and symptoms is characteristic, and is indirect evidence that the effect is photochemical rather than thermal. The absence of pain during this period has been puzzling to patients and physicians alike. This phenomenon has been studied experimentally in humans1 using corneal touch threshold measurements in humans who were exposed to subclinical doses of a focused electric-arc welding set. A significant increase in sensitivity loss was observed in all subjects. Moreover, the mean time to the peak of sensitivity loss occurred at 13/4 hours. By 4 hours, corneal sensitivity had returned to baseline in all subjects. It is quite likely that this pattern of sensory loss and return contributes to the characteristic lag in symptoms seen clinically. The action spectrum for keratitis produced by UV radiation was first measured in 1946 by Cogan and Kinsey and has been repeated in a variety of animals under several testing conditions.2-4 The action spectrum refers to a curve that relates wavelength to the amount of energy necessary to produce a threshold level of keratitis. The peak sensitivity is about 270 nm. At that wavelength, only about 0.005 J/cm2 is required to produce keratitis. This peak sensitivity, which is quite narrow, is thought to correspond to the absorption of UV light by epithelial nucleic acids and aromatic amino acids. Longer wavelength UV light requires more log units of energy to produce threshold keratitis (eg, at 320 nm, 10 J/cm2 are required). Natural sources of UV light will not cause keratitis at short exposures because the ozone layer of our atmosphere effectively blocks light of less than 290 nm. Therefore, manmade implements are the chief source of UV keratitis.5 579
PHOTOTOXICITY & THE CORNEA
ol
; o
~m
Ct. .d E o
~
~
_... ^
..
~
e
...
_,
.e_
_
s
_
CO) ct
Figure 1. Advanced climatic droplet keratopathy.
Acute UV keratitis can, however, be caused by natural sources under specific circumstances. For example, keratitis has been reported following solar eclipse burns.6 In addition, keratitis solaris has been reported after exposure to strong solar radiation at high altitudes or in snow-covered terrain. The keratitiseffective irradiance is felt to depend greatly on the characteristics of the ozone layer, the albedo of the terrain, and the altitude. For example, the higher ozone content in the spring is responsible for a 23% lower keratitis-effective irradiance compared with that during the autumn equinox. Conversely, a 25% decrease in the ozone content of the atmosphere will increase the keratitis-effective irradiance by 35% for a solar elevation of 400 and by 70% for a solar elevation of 200.7 Such effects, unfortunately, are becoming ever more relevant in light of the increasing, human-imposed stress on the ozone layer. Phototoxic effects may occur at all levels of the cornea. In the epithelium, UV light inhibits mitosis, produces nuclear fragmentation, and causes a loosening of the epithelial layer.8 These effects are compatible with the clinical presentation, and the rapid regenerative powers of the corneal epithelium account for the anticipated recovery. Effects on the corneal stroma also have been documented experimentally in the rabbit,9 where reversible damage to the stromal keratocytes has been shown. In addition, the threshold for ultrastructural damage to the corneal endothelium has been found to occur within the range typically achieved by standard UV lamps.'0 An effect on the endothelium has been indirectly established in man in a case-control study of welders in Japan where specular microscopy found a significantly greater amount of pleomorphic change (a 580
decrease in the hexagonal cell population) in the endothelial mosaic of the welders.'1 This was not associated with any observable visual or functional deficit. Before leaving the area of acute exposure to UV light and the cornea, a new application of UV light should be mentioned. Short wavelength UV light is germicidal, effecting cross-linking and breaking bonds between nucleic acids. Recently, a 253.7-nm UV light was tested for its germicidal capabilities in the disinfection of contaminated contact lenses and storage solutions.'2 The exposure time necessary to reduce a concentration of organisms from 106/mL to less than 10/mL was 30 seconds for Staphylococcus aureus, 60 seconds for Pseudomonas aeruginosa, and 84 seconds for Candida albicans. Less than 3 minutes were required to sterilize a suspension of 104/mL Acanthamoeba polyphaga. The contamination of contact lenses and related solutions is a major risk factor for ulcerative keratitis associated with soft contact lens use. Ultraviolet light disinfection may prove to be a rapid and easy method for combined disinfection of the lens and case. The short exposure time and broad germicidal effect may render this approach the method of choice in the near future.
CHRONIC SOLAR TOXICITY Chronic solar toxicity has been linked to several disorders of the ocular surface-pinguecula, pterygium, climatic droplet keratopathy (CDK), and squamous metaplasia/carcinoma. Pterygium and pinguecula are discussed elsewhere. The evidence linking actinic damage to CDK is much stronger than for squamous metaplasia/carcinoma. Climatic droplet keratopathy is also known as Labrador keratopathy and spheroidal degeneration. As Taylor has pointed out,13 these terms probably describe two separate disease processes. Spheroidal degeneration is characterized by fine golden globules in the anterior cornea or conjunctiva and may be primary in normal corneas or secondary in association with other ocular disease. 14 This is to be distinguished from Labrador keratopathy or CDK, which is characterized, in its early stages, by small gray droplets at the level of Bowman's membrane and has been associated with extremes of the climatic spectrum. The clinical findings associated with CDK range from fine, subepithelial opacities without visual effect to functional blindness from axial corneal scarring (Figure 1). Microscopically, characteristic globular lesions are found in Bowman's layer and superficial stroma. It has been conjectured that these deposits contain denatured plasma proteins, but this has not been JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
PHOTOTOXICITY & THE CORNEA
confirmed. A link with environmental factors has long been proposed because the disease, in its severe form, characteristically occurs in extreme climatic conditions and is typically limited to exposed cornea not covered by the upper or lower lids. The condition has a distinct male predominance, which has been attributed to male association with occupational exposure. In a survey in Labrador, the overall prevalence among men was 56%, and in one community, CDK was found in 100% of men older than 40 years of age.'5 A high prevalence with unusually severe disease also has been reported from the Dahlak Islands in the Red Sea. Forty-five percent of the islanders had CDK, and corneal scarring from CDK was found to be the principal cause of blindness in the area.'6 Recently, a standardized methodology for estimating occupational ocular exposure to UV radiation has been developed that combined detailed occupational histories with laboratory and field measurements.17 Taylor and associates have employed these techniques to explore the relationship between keratopathy and chronic UV exposure among Chesapeake Bay watermen in Maryland.'8 In this geographic setting, CDK was seen in 19% of the watermen, although in no case did it result in visual impairment. Logistic regression analyses established a significant association between UV light and pterygium, CDK, and pinguecula for all UV radiation bands. The association was weakest for pinguecula. Risk for CDK increased with age and UV exposure. As the authors point out, this study shed light on a number of important issues regarding phototoxicity and chronic corneal disease. First, CDK and pterygium were associated with both UV-A and UV-B exposure, unlike cortical cataract where UV-A was not found to be contributory.'9 Second, a dose-response relationship between UV radiation and CDK and pterygium, in the absence of other previously hypothesized exposures (wind, dust, etc), renders a phototoxic etiology quite convincing. Third, it is apparent that low-technology, low-expense prevention in the form of a hat or spectacles would likely be preventive. Although there is considerable evidence linking UV exposure to squamous carcinoma of the skin, this evidence is lacking for conjunctival or corneal squamous metaplasias. This may be the result of a lack of association or simply the result of the rarity of the condition and hence the difficulty of performing meaningful epidemiologic research. The indirect evidence consists largely of the known association of UV light with nonmelanoma dermatologic malignancy. These lesions occur predominantly in sun-exposed JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
Ir' t~~~~ Figure 2. Limbal conjunctival intraepithelial neoplasia.
areas of the skin. The ocular counterpart occurs in what is termed the interpalpebral exposure zone. Conjunctival squamous metaplasias, ranging from mild dysplasia to invasive squamous cell carcinoma, invariably involve the corneal limbus in this exposure zone (Figure 2). Whether this is solely because of a greater potential for malignant change in this junctional region of epithelium, analogous to the squamocolumnar junction of cervical epithelium, or because of the added effects of environmental exposure is unclear. Several studies from Africa have associated squamous cell carcinoma with pterygium.20 In one such study, 58% of patients with conjunctival carcinoma were described as having a homolateral hyperactive pterygium. The concurrence of conjunctival carcinoma and pterygium has led some to speculate that pterygium and conjunctival carcinoma lie on the same biologic pathway. However, this is not generally held, and the conversion of pterygium to carcinoma is considered to be very rare. From a clinical standpoint, however, it is important to appreciate that pterygium and carcinoma can coexist and that squamous cell carcinoma, especially in its recurrent form after surgical excision, may closely mimic pterygium in its clinical appearance (Figure 3). The conditions discussed so far have chiefly affected the ocular surface and anterior cornea. Although there is no evidence for clinically significant endothelial phototoxicity, there is some suggestive laboratory evidence linking endothelial abnormalities with the interaction of light and photosensitizing compounds. Chlorpromazine, widely used for psychiatric conditions, is known to be associated with fine deposits in multiple ocular tissues. Phototoxic and photoallergic reactions in the 581
PHOTOTOXICITY & THE CORNEA
Figure 3. Squamous carcinoma presenting as pseudopterygium.
skin are well known with this drug. Functional corneal endothelial effects have been measured in vitro with endothelial cells exposed to chlorpromazine and UV light, but analogous effects in humans have not been shown. Recently, endothelial dysfunction has been linked, in a rabbit model, to protoporphyrin photosensitization. Protoporphyrin IX is a naturally occurring photoactive compound that has been detected in the aqueous of three patients with hyphema. It is speculated that, in the setting of hyphema, corneal blood staining and endothelial dysfunction may be related to the presence of this photoactive compound and that patching might be protective.
LASERS The last decade has witnessed an explosion in the clinical application of laser technology. Laser applications represent a form of controlled phototoxicity. These applications include photocoagulation, photoradiation, photodisruption, and photoablative decomposition. A host of ocular complications from the various procedures now in use with argon, krypton, and YAG lasers have been recorded. Adverse effects have been reported for all layers of the eye. For the most part, these are the direct effects of tissue coagulation or disruption. A discussion of the complications inherent to each laser type and anatomical site is beyond the scope of this article. Neovascularization of the cornea is associated with poor vision, abnormal surface epithelium, and a high risk of graft rejection after penetrating keratoplasty. The current treatment options for the extensive neovascularization seen in conjunction with chemical bums, Stevens-Johnson syndrome, or other severe ocular 582
surface disorders are very limited. Argon lasers have been used to treat neovascularization of the cornea by direct photocoagulation. However, recurrence after routine photocoagulation is frequently noted, as with thermal cautery. A novel approach to this problem, referred to as photothrombosis of corneal neovascularization, takes advantage of phototoxic reactions and shows significant promise in animal studies. This technique relies on a photochemical interaction between rose bengal (a photosensitizing dye) and argon laser irradiation. Singlet molecules are generated with resultant direct peroxidation of lipids and proteins, leading to endothelial damage and platelet aggregation. Effective thrombosis has been achieved using this technique, and corneal clarity has been maintained. Photothrombosis is accomplished at physiologic temperatures and requires a fraction of the laser energy necessary for laser photocoagulation, thereby avoiding the tissue destruction and inflammation associated with thermal coagulation. Photothrombosis also has been associated with normalization of the corneal surface after successful occlusion of corneal neovascularization. In addition, photothrombotic occlusion of corneal vessels in a rabbit model significantly improved corneal transplantation survival. Further work is necessary, however, before broad application to patients. The photosensitizing process is efficient enough that damage to corneal stroma has been noted, presumably secondary to photochemical reactions with leaking dye. Peripheral chorioretinal scarring, perhaps an effect of deflected corneal irradiation, also has been recorded. Modification of delivery systems may be able to overcome these problems, allowing the application of this technique to patients with advanced corneal
neovascularization. There is enormous interest in the potential uses of laser technology for refractive surgery. This is a direct result of the recent development of the UV excimer laser and the process of ablative photodecomposition. In this process, UV photons directly break chemical bonds and excess energy excites the resultant molecular fragments, leading to their ablation and ejection from the surface. Controlled corneal ablation has potential application in radial keratotomy, lamellar keratectomy for diseases of the anterior cornea, and large area corneal ablation to alter corneal curvature and power in an attempt to correct ametropia. The potential application of laser surgery to large numbers of subjects, in particular those for whom refractive error is the only abnormality, renders the JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 7
PHOTOTOXICITY & THE CORNEA
issue of photoxicity all the more important. In addition to the planned ablation, what remote effects are possible? Different UV wavelengths can be produced depending on the choice of laser medium. The destructive effects vary significantly with the wavelength. In general, it appears that there is an increasing thermal effect with longer wavelengths and thus an increased risk for side effects. Comparative studies have shown the 193-nm excimer laser to have the most precise etching abilities. Comeal cuts with this laser show essentially no damage, on light microscopy, to corneal stroma outside of the intended ablation zone. On electron microscopy, a zone of damaged tissue is found 0.1 Lm to 0.3 ,um on either side of the ablation. In contrast, surrounding tissue damage with a 248-nm excimer laser is equivalent to those of a diamond knife set at the same depth. The 248-nm laser also produces significant endothelial trauma when used for nonpenetrating incisions. A potential secondary effect of excimer irradiation is UV-induced mutagenesis or carcinogenesis. Mutagenicity can be assayed by in vitro tests for DNA damage. This has recently been performed for the excimer laser for a variety of wavelengths. Cell-damaging effects were found to be less for lasers operating at 193 nm compared with lasers operating at 248 nm and 308 nm. Although such in vitro effects suggest a risk for carcinogenesis, this is not likely to be a problem for excimer corneal surgery for two principal reasons. First, primary corneal tumors are exceedingly rare, suggesting a relative resistance of the tissue to malignant transformation. Second, animal models for UVassociated tumors have invariably required prolonged and repeated exposures for tumor induction. Despite this encouraging information concerning the lack of distant phototoxic effects, there are certainly major obstacles to be overcome before excimer corneal surgery gains widespread application. In particular, issues relating to wound healing and corneal clarity must be addressed before this technology can be generally accepted. Literature Cited 1. Millodot M, Earlam RA. Sensitivity of the cornea after exposure to ultraviolet light. Ophthalmic Res. 1 984;1 6:325-328. 2. Cogan DG, Kinsey VE. Action spectrum for keratitis
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produced by ultraviolet radiation. Arch Ophthalmol. 1 946;35:676-677. 3. Pitts DG. A comparative study of the effects of ultraviolet radiation on the eye. Am J Optom. 1970;50:535-546. 4. Zuclich JA. Ultraviolet induced damage in the primate cornea and retina. Curr Eye Res. 1984;3:27-34. 5. Miller D. Light and the cornea and conjunctiva. In: Miller D, ed. Clinical Light Damage to the Eye. New York, NY: Springer-Verlag; 1987:55-62. 6. Billore OP, Shroff AP, Vasavada KA. Superficial keratitis following solar eclipse burn. Indian J Ophthalmol. 1982;30:303304. 7. Blumthaler M, Ambach W, Daxecker F On the threshold radiant exposure for keratitis solaris. Invest Ophthalmol Vis Sci. 1987;28:1713-1716. 8. Millodot and Buschke W, Friedenwald JS, Moses SG. Effects of ultraviolet irradiation on corneal epithelium: mitosis, nuclear fragmentation, post-traumatic cell movements, loss of tissue cohesion. J Cell Comp Physiol. 1 945;26:147-164. 9. Ringvold A, Davanger M. Changes in the rabbit corneal stroma caused by UV-radiation. Acta Ophthalmol. 1 985;63:601 -606. 10. Ringvold A, Davanger M, Olsen EG. Changes of the corneal endothelium after ultraviolet radiation. Acta Ophthalmol. 1982;60:41-53. 11. Karai I, Matsumura S, Sadafumi T, Horiguchi S, Matsuda M. Morphological change in the corneal endothelium due to ultraviolet radiation in welders. Br J Ophthalmol. 1984;68:544548. 12. Dolman PJ, Dobrogowski MJ. Contact lens disinfection by ultraviolet light. Am J Ophthalmol. 1989;1 08:665-669. 13. Taylor HR. Aetiology of climatic droplet keratopathy and pterygium. Br J Ophthalmol. 1980;64:154-163. 14. Fraunfelder FT, Hanna C. Spheroidal degeneration of cornea and conjunctiva. Am J Ophthalmol. 1973;76:41-50. 15. Johnson GJ, Ghosh M. Labrador keratopathy: clinical and pathological findings. Can J Ophthalmol. 1975;1 0:119-135. 16. Rodger FC, Cuthill JA, Fydelor PJ, Lenham AP. Ultraviolet radiation as a possible cause of corneal degenerative changes under certain physiographic conditions. Acta Ophthalmol 1974;52:777-785. 17. Rosenthal FS, Phoon C, Bakalian AE, Taylor HR. The ocular dose of ultraviolet radiation to outdoor workers. Invest Ophthalmol Vis Sci. 1988;29:649-656. 18. Taylor HR, West SK, Rosenthal FS, Munox B, Newland HS, Emmett EA. Corneal changes associated with chronic UV irradiation. Arch Ophthalmol. 1989;107:1481-1484. 19. Taylor HR, West SK, Rosenthal FS, et al. Effect of ultraviolet radiation on cataract formation. N Engl J Med. 1988;319:1429-1433. 20. Clear AS, Chirambo MC, Hutt MSR. Solar keratosis, pterygium, and squamous cell carcinoma of the conjunctiva in Malawi. Br J Ophthalmol. 1 979;63:1 02-109.
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