Paraformaldehyde-induced Keratitis After Photorefractive Keratectomy Ioannis G. Fallikaris, M.D., M i l t i a d e s K. T s i l i m b a r i s , M.D., Maria E. Fapatzanaki, M.D., Konstantinos G. G o l e s , M.D., and D i m i t r i o s S. S i g a n o s , M.D. We examined three patients who developed keratitis after myopic photorefractive keratectomy. All patients were treated on the same day and in all three cases paraformaldehyde tablets were used for disinfection of the excimer laser iris cone. All patients developed an intense postoperative corneal inflammation that resulted in corneal opacities. In the first patient, the opacities were central and persisted for at least 4V2 months postoperatively. He became more myopic than before the operation. His best spectacle-corrected visual acuity worsened by four Snellen lines. In the other two patients, the corneal opacities were paracentral and of less density. Six months postoperatively, these opacities were barely seen. In these two patients, the postoperative best spectacle-corrected visual acuity remained unchanged or improved one Snellen line compared to the preoperative level. In all three patients, astigmatism increased postoperatively. These observations suggest that paraformaldehyde tablets are not safe for the disinfection of the excimer laser iris cone.
I ARAFORMALDEHYDE is a solid polymer of for maldehyde, a gas used for disinfection and sterilization of certain types of surgical, medi cal, and laboratory equipment. At room temp erature (20 to 28 C), paraformaldehyde gradu ally gives off gaseous formaldehyde. Gaseous
Accepted for publication May 14, 1992. From the Department of Ophthalmology, Division of Medicine, School of Health Sciences, University of Crete, Greece. This study was presented in part at the Excimer Laser Meeting, Heraklion, Crete, Greece, Nov. 1-3, 1991. Reprint requests to Ioannis G. Pallikaris, M.D., Uni versity of Crete, School of Health Sciences, Division of Medicine, Dept. of Ophthalmology, 714 09 Heraklion, Crete, Greece.
formaldehyde destroys bacteria within one or two hours. Viruses are also killed. 1 We exam ined three patients in whom intense keratitis developed after excimer laser photorefractive keratectomy for the correction of myopia. In each case, paraformaldehyde tablets were used for disinfection of the fixation-suction ring, which is integrated with the excimer laser iris diaphragm.
Patients and Methods Three patients underwent standard photore fractive keratectomy for the correction of myo pia in which a 193-nm excimer laser (Phoenix, Aesculap-Meditec GMBH, D-8501 Herolds berg, Germany) was used. The laser operated in a scanning-slit mode (repetition rate, 20 Hz; fluence at the cornea, 220 mj/cm 2 ). The optical zone was 5 mm in diameter. The magnitude of the correction was programmed by a computer that controlled both the total ablation time and the movement of a mechanical iris over the treated area. The cone that contained the me chanical iris was fixed on the globe by a suction ring that immobilized the eye. Disinfection of the mechanical iris was achieved by placing it in a plastic container in which two to three paraformaldehyde tablets (paraformaldehyde, 1 g, for disinfection by fumigation, MERK, E. Merk, D-6104 Darmstadt, Germany) were add ed, two or more hours preoperatively. Informed consent was obtained from each patient after a thorough description of the pro cedure and its risks. Before laser treatment, the corneal epitheli um was softened by using cocaine 2% eyedrops. The optical axis was marked and the epithelium was removed by means of a hockey knife within a 6-mm-diameter area. The ex posed corneal surface was irrigated with buff ered saline solution. The iris cone was then
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placed on the cornea and fixed by using the suction ring. Photorefractive keratectomy was then performed. After the procedure, the ablat ed area was carefully cleaned with a cellulose sponge. The eyes were patched until reepithelialization occurred. Postoperative examination included a slitlamp examination (and photography), keratometry, corneal topography, and autorefraction. Both uncorrected and best spectacle-corrected visual acuity were determined, after reepithelialization had occurred. Postoperatively, the subepithelial haze was graded by using the gradation scheme de scribed by Fantes and associates. 2 In this scheme, haze is graded as follows: grade 0, cornea totally clear; grade 1, haze seen with difficulty with direct and diffuse illumination; grade 2, mild haze easily visible with direct focal slit-lamp illumination; grade 3, iris details partially obscured; and grade 4, dense opacity completely obscuring the details of intraocular structures.
Case Reports Case 1 A 31-year-old man underwent standard pho torefractive keratectomy for the correction of 4 diopters of myopia in his right eye. He had been myopic since childhood and had worn hard contact lenses for the previous 20 years. He had a history of mild allergic conjunctivitis. His preoperative visual acuity was 20/100 without correction and 20/25— with the best spectacle correction. The autorefraction read ing was —3.0 —1.25 x 10 and the subjective refraction was - 3 . 7 5 - 1 . 7 5 x 175. The keratometric reading was 41.3/42.6(67). Paraformaldehyde dust was observed on the surface of the cone before application of the iris cone to the eye. The dust was carefully removed by using air flow and mechanical wiping with a cellulose sponge. On the first postoperative day, the patient had intense ocular pain. At slit-lamp examination, the cornea was edematous and cloudy and was more pronounced in the anterior stroma adjacent to the ablated area. Descemet's folds and a moderate flare (not obscuring the details) were seen in the anterior chamber. At that time, only patching was used. On postoperative day 4, no improvement was noted and cultures were performed (Fig. 1). Topical treatment with fortified antibiotics
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Fig. 1 (Pallikaris and associates). Case 1. Slit-lamp photograph three days postoperatively showing in tense corneal inflammation. (gentamicin sulfate and cefazolin sodium, ev ery half an hour) was started and the eye remained unpatched. The culture results were negative and the clinical signs and symptoms did not change with the antibiotic therapy. Furthermore, during the first postoperative days, minute opaque dots in the anterior corne al stroma were observed when using high mag nification. These dots gradually disappeared and, at the end of the third postoperative week, were no longer visible. The cause of the corneal inflammation was attributed to the paraformal dehyde dust that was noticed intraoperatively. On postoperative day 20, the treatment was changed to daily dexamethasone sodium phos phate subconjunctival injections; tobramycin sulfate eyedrops, twice daily; and tear substi tute in gel, twice daily, while the eye remained patched. The new treatment was more effective, as the corneal edema, as well as Descemet's folds, gradually subsided. On postoperative day 50, the cornea was fully reepithelialized. There was still a mild stromal edema and a subepithelial haze of grade 3 density throughout the ablated area. An opaci ty of the anterior stroma was seen in the center of the ablated area. His visual acuity was 20/64 without correction and 20/32 with best specta cle correction. The patient had to hold his head in an oblique position to attain his best visual acuity. The autorefraction reading was —0.25 - 5 . 7 5 x 43. Keratometry disclosed irregular images. The patient began treatment with topi-
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cal prednisolone acetate and tobramycin sulfate eyedrops, six times daily. One week later, the corneal edema had resolved. His visual acuity was 20/64 without correction and 20/32 with best spectacle correction, always with an oblique position of the head. The autorefraction reading was - 2 . 7 5 - 3 . 7 5 x 23 and the keratometric reading was 38.25/40.75(120). The pa tient described his vision as blurred. Four and one-half months postoperatively, his visual acuity was 20/200 without correction and 20/50 with best spectacle correction (with oblique head position). The autorefraction reading was —7.5 - 2 . 2 5 x 3, the subjective refraction reading was - 5 . 0 - 2 . 5 x 180, and the keratometric reading was 43.25/45.5(80). The cornea was normally epithelialized and uninflamed. However, a central corneal scar could be easily detected. There was a grade 2 to 3 reticulate subepithelial haze throughout the ablated area (Fig. 2). Corneal topography disclosed a central cor neal flattening immediately after epithelialization that disappeared 15 days later. On his last visit, 4% months postoperatively, the central cornea was steeper than before photorefractive keratectomy. Case 2 A 26-year-old woman underwent standard photorefractive keratectomy for the correction of 7 diopters of myopia in her right eye. She had
Fig. 2 (Pallikaris and associates). Case 1. Slit-lamp photograph 4 Vi months postoperatively showing sub epithelial haze and central opacity.
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been myopic since childhood and had worn contact lenses for the previous seven years. Her preoperative visual acuity was counting fingers at 3 m without correction and 20/200 with best spectacle correction. The autorefraction read ing was —5.75 —1.25 x 5, the subjective refrac tion reading was —6.0 —1.75 x 180, and the keratometric reading was 43.75/45.25(91). Immediately before application of the cone to the patient's eye, paraformaldehyde dust was seen on the cone surface and was carefully removed by using air flow and mechanical wip ing with a cellulose sponge. On postoperative day 5, the cornea was reepithelialized. There was stromal edema, as well as a paracentral opacity of the anterior stroma. A grade 2 subepithelial haze could also be seen. Prednisolone acetate and tobramycin sulfate eyedrops were instilled five times daily. Four days later, the corneal edema had resolved, but the opacity and the subepithelial haze did not change. Her visual acuity was 20/40 without correction and 20/25— with best spectacle cor rection. The keratometric reading was 3 8 . 5 / 41.75(95) and the autorefraction reading was - 2 . 0 x 170. Four months postoperatively, the cornea re mained well epithelialized with a less intense paracentral opacity of the anterior stroma. The subepithelial haze was graded 1. Her visual acuity was 20/32 without correction and 20/20 with best spectacle correction. The autorefrac tion reading was - 0 . 2 5 - 3 . 0 x 175 and the keratometric reading was 40.0/42.5(85). Six months postoperatively, her visual acuity was 20/32 without correction and 20/20 with best spectacle correction. The keratometric reading was 40.5/42.75(85), the autorefraction reading was - 0 . 7 5 - 2 . 5 x 175, and the subjec tive refraction reading was - 0 . 7 5 - 2 . 5 x 175. The paracentral corneal opacity was barely seen and the subepithelial haze was graded 1 (Fig. 3). Case 3 A 52-year-old woman underwent standard photorefractive keratectomy for the correction of 7 diopters of myopia in her left eye. She had been myopic since childhood and had never worn contact lenses. Her uncorrected preopera tive visual acuity was 20/200 and 2 0 / 2 5 - with best spectacle correction. The autorefraction reading was - 7 . 5 - 2 . 5 x 180, the subjective refraction reading was - 7 . 0 - 2 . 7 5 x 2, and the keratometric reading was 43.5/47.1(85). We removed the paraformaldehyde dust from
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Fig. 3 (Pallikaris and associates). Case 2. Slit-lamp photograph six months postoperatively. The corneal haze is hardly seen. the cone surface before the procedure in the previously discussed manner. On postoperative day 5, the patient had a car accident and for this reason her data on refraction were incomplete. The cornea was reepithelialized on postopera tive day 8. There was stromal edema and a paracentral opacity of the anterior stroma. A grade 2 subepithelial haze could be seen. She started treatment with topical prednisolone ac etate and tobramycin sulfate drops six times daily. Forty days postoperatively, her visual acuity was 20/64 without correction and 2 0 / 3 2 - with best spectacle correction. The autorefraction reading was - 1 . 7 5 - 4 . 5 X 180 and the keratometric reading was 39.25/42.1(93). A paracentral corneal opacity and a grade 2 subepithelial haze were also observed. Six months postoperatively, her visual acuity was 20/50 without correction and 20/20 with best spectacle correction. The autorefraction reading was —1.5 —3.25 X 10, the subjective refraction reading was —1.75 —3.5 x 10, and the keratometric reading was 39.75/43.75(92). A grade 1 subepithelial corneal haze and a paracentral opacity in the anterior corneal stro ma of much less density than in her previous visits could be seen.
Discussion The three patients were among the first at our clinic to be operated on with the excimer laser
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for the correction of myopia. As the mechanical iris cone was the only part of the laser that was in contact with the patient's eye and because autoclaving was impossible, we used paraformaldehyde tablets for disinfection of the cone. The three patients underwent the operation on the same day in the order in which they were examined. The iris cone remained in the con tainer with the paraformaldehyde tablets for 24 hours before the first operation, and for two hours before each of the next two operations. A small amount of paraformaldehyde dust could be seen on the cone surface at the end of the disinfection. Before applying the suction ring on the patient's eye, the paraformaldehyde dust was carefully removed. However, the mechani cal closure of the iris blades, as well as the air flow around the iris and suction ring, probably released incarcerated paraformaldehyde dust on the ablated corneal surface. At the end of the procedures, no paraformaldehyde dust could be detected on the ablated area. This should be expected, as the chemical spreads rapidly through the entire thickness of the stroma after its application on the cornea. Postoperatively, all three patients developed intense corneal inflammation, which lasted 50 days in the first patient. The other two patients recovered earlier. In all three patients, opacities developed in the anterior stroma. In the first patient, the corneal opacity was central and accompanied by a grade 2 to 3 reticulate haze. The final result was a 4-Snellen-line reduction of his best-corrected visual acuity. The other two patients developed a paracentral opacity that did not interfere with the final visual acu ity. The more severe reaction observed in the first patient was probably caused by accumula tion of more paraformaldehyde dust on the cone surface that resulted from the longer dis infection time. Paraformaldehyde is a polymer of formalde hyde that, in room temperature (20 to 28 C), depolymerizes to formaldehyde; their toxicity is identical. 3 Formalin, the aqueous solution of formaldehyde, has been toxic to the eye in dilutions from 1 in 1,000 to 1 in 2,000. Acciden tal application of a drop on the cornea results in extreme chemosis and keratitis, which leads to permanent opacities. Formalin experimentally applied to a rabbit cornea spreads rapidly throughout the entire thickness of the stroma; the corneal corpuscles are killed and fixed in situ to appear as minute white dots. 4 This is consistent with our observation of white
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opaque dots in the corneal stroma of our first patient. When paraformaldehyde dust was applied to the ablated area of rabbit corneas immediately after photorefractive keratectomy, it resulted in a severe inflammation, a delay of reepithelialization, and a formation of an intense subepithelial corneal haze (Pallikaris and associates, unpublished data, 1991). After observing intense corneal reactions, we stopped using paraformaldehyde tablets for disinfecting the iris cone. Of the 30 patients operated on in our clinic with the excimer laser so far, only the three patients of this study developed intense postoperative inflammation and corneal opacities. These patients, as al ready mentioned, were the first to be operated on and the only in whom paraformaldehyde tablets were used for the iris cone disinfection. Therefore, we believed the intense inflammato ry reaction and the corneal opacities were caused by the corneal toxicity of paraformalde hyde. Currently, we disinfect the lower part of the iris cone, where the suction ring is located, by immersing the cone in isopropyl alcohol solu tion 70% for 20 minutes. Isopropyl alcohol is a known disinfectant and has been an efficient means of disinfecting Goldmann tonometers against both human immunodeficiency virus type 1 and herpesviruses. There is evidence that 70% isopropyl alcohol also inactivates hepatitis B virus. 5 The regression of myopia was interesting in our first patient. The preoperative spher ical equivalent of this patient was —3.6 diop ters. Immediately after reepithelialization, the spherical equivalent was —3.1 diopters, and 4% months postoperatively, it was —8.6 diopters. This patient had the most intense inflammatory reaction, with the final amount of haze and subepithelial scarring appearing to correspond with the degree of regression. His myopia not only regressed but also actually overshot the preoperative level. This was presumably a re sult of both corneal remodeling after the in tense inflammation and secondary scar forma tion. Contracture of this scar tissue could lead to steepening of the cornea and regression of the myopic photoablative outcome. This effect, in conjunction with corneal topography meas urements, may be interesting regarding the study of regression after photoablative keratec tomy. McDonald, Frantz, and Klyce6 described a case of marked regression after myopic photo-
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refractive keratectomy that was attributed to stromal remodeling. Seiler and Wollensak 7 de scribed marked regression in eyes with marked scarring after photorefractive keratectomy. All three of our cases also showed an increase in astigmatism. The refractive astigmatism of the first patient was - 1 . 2 5 x 10 preoperatively, and —2.25 x 3 4Vi months postoperatively. The refractive astigmatism of the second patient was —1.25 x 5 preoperatively, and - 2 . 5 x 175 six months postoperatively. Finally, the re fractive astigmatism of the third patient was - 2 . 5 x 180 preoperatively, and 3.25 x 10 six months postoperatively. Corneal remodeling after the formaldehyde-induced inflammation was probably the reason for this astigmatic effect. Postoperatively, all patients were intensively treated with corticosteroids, and at least in the patients in Cases 2 and 3, this therapy was effective in preserving the photoablative myop ic correction. This effectiveness may be of inter est regarding the effect that the specific corticosteroid treatment regimen may have in modifying the wound healing response and amount of regression. The perioperative complication observed in these patients dictates careful attention to steri lization of any device that contacts the eye. Once an instrument is cleaned with a disinfec tant, there is always a chance to cause corneal damage even if only traces remain. A small amount of paraformaldehyde is enough to cause intense corneal inflammation. Mean while, it may be extremely difficult to be sure of complete paraformaldehyde removal after its fumigation; the dust of the chemical may be incarcerated in difficult-to-reach locations, as between the blades of the iris cone, for exam ple. These observations suggest that paraformal dehyde tablets are not safe for disinfection of the excimer laser iris cone or other accessories used on or around the cornea during excimer laser ablation. Contact of paraformaldehyde dust with the ablated area can lead to intense corneal inflammation, resulting in an undesir able refractive outcome, or even impairment of visual acuity after photorefractive keratectomy.
References 1. Phillips, C. R. : Gaseous sterilization. In Block, C. S. (ed.): Disinfection, Sterilization and Preserva-
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tion. Philadelphia, Lea & Febiger, 1977, pp. 5 9 3 5940. 2. Fantes, F. E., Hanna, K. D., Waring, G. O. Ill, Pouliquen, Y., Thompson, K. P., and Savoldelli, M.: Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys. Arch. Ophthalmol. 108:665, 1990. 3. Gosselin, R. E., Hodge, H. C , Smith, R. P., and Gleason, M. N. (eds.): Ingredient index. In Clinical Toxicology of Commercial Products, sec. 2, ed. 4. Baltimore, Williams and Wilkins Co., 1976, p. 125. 4. Duke-Elder, S., and MacFaul, P. A.: Injuries. Non-mechanical injuries. In Duke-Elder, S. (ed.):
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System of Ophthalmology, vol. 14, chap. 11. Lon don, Henry Kimpton, 1972, pp. 1169-1170. 5. Pepose, J. S., Linette, G., Lee, S. F., and MacRae, S.: Disinfection of Goldmann tonometers against human immunodeficiency virus type 1. Arch. Ophthalmol. 107:983, 1989. 6. McDonald, M. B., Frantz, J. M., and Klyce, S. D.: Central photorefractive keratectomy for myo pia. Arch. Ophthalmol. 108:799, 1990. 7. Seiler, T., and Wollensak, J.: Myopic photore fractive keratectomy with the excimer laser. Ophthal mology 98:1156, 1991.
OPHTHALMIC MINIATURE
Joan h a d lovely eyes, grey eyes like her father's that reminded one of the sea. In certain lights they could look almost green, as though a tide were washing over them. When we moved to H e n d o n , it was true, I did miss the sea. I used to look into Joan's eyes sometimes, w h e n she wasn't looking, and she seemed to give me back a little of the winter seas. Eyes are so vulnerable; they say things that words themselves can't say. I used to feel sad and lost looking into the greyness of Joan's gaze. It was almost a relief when her eyes weakened a n d she h a d to wear glasses. It shielded me from all her unspoken reproaches and all the unanswerable questions that lay there. Lisa St. Aubin de Terân, Joanna London, Virago Press, 1990, p . 244
I ARAFORMALDEHYDE is a solid polymer of for maldehyde, a gas used for disinfection and sterilization of certain types of surgical, medi cal, and laboratory equipment. At room temp erature (20 to 28 C), paraformaldehyde gradu ally gives off gaseous formaldehyde. Gaseous
Accepted for publication May 14, 1992. From the Department of Ophthalmology, Division of Medicine, School of Health Sciences, University of Crete, Greece. This study was presented in part at the Excimer Laser Meeting, Heraklion, Crete, Greece, Nov. 1-3, 1991. Reprint requests to Ioannis G. Pallikaris, M.D., Uni versity of Crete, School of Health Sciences, Division of Medicine, Dept. of Ophthalmology, 714 09 Heraklion, Crete, Greece.
formaldehyde destroys bacteria within one or two hours. Viruses are also killed. 1 We exam ined three patients in whom intense keratitis developed after excimer laser photorefractive keratectomy for the correction of myopia. In each case, paraformaldehyde tablets were used for disinfection of the fixation-suction ring, which is integrated with the excimer laser iris diaphragm.
Patients and Methods Three patients underwent standard photore fractive keratectomy for the correction of myo pia in which a 193-nm excimer laser (Phoenix, Aesculap-Meditec GMBH, D-8501 Herolds berg, Germany) was used. The laser operated in a scanning-slit mode (repetition rate, 20 Hz; fluence at the cornea, 220 mj/cm 2 ). The optical zone was 5 mm in diameter. The magnitude of the correction was programmed by a computer that controlled both the total ablation time and the movement of a mechanical iris over the treated area. The cone that contained the me chanical iris was fixed on the globe by a suction ring that immobilized the eye. Disinfection of the mechanical iris was achieved by placing it in a plastic container in which two to three paraformaldehyde tablets (paraformaldehyde, 1 g, for disinfection by fumigation, MERK, E. Merk, D-6104 Darmstadt, Germany) were add ed, two or more hours preoperatively. Informed consent was obtained from each patient after a thorough description of the pro cedure and its risks. Before laser treatment, the corneal epitheli um was softened by using cocaine 2% eyedrops. The optical axis was marked and the epithelium was removed by means of a hockey knife within a 6-mm-diameter area. The ex posed corneal surface was irrigated with buff ered saline solution. The iris cone was then
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placed on the cornea and fixed by using the suction ring. Photorefractive keratectomy was then performed. After the procedure, the ablat ed area was carefully cleaned with a cellulose sponge. The eyes were patched until reepithelialization occurred. Postoperative examination included a slitlamp examination (and photography), keratometry, corneal topography, and autorefraction. Both uncorrected and best spectacle-corrected visual acuity were determined, after reepithelialization had occurred. Postoperatively, the subepithelial haze was graded by using the gradation scheme de scribed by Fantes and associates. 2 In this scheme, haze is graded as follows: grade 0, cornea totally clear; grade 1, haze seen with difficulty with direct and diffuse illumination; grade 2, mild haze easily visible with direct focal slit-lamp illumination; grade 3, iris details partially obscured; and grade 4, dense opacity completely obscuring the details of intraocular structures.
Case Reports Case 1 A 31-year-old man underwent standard pho torefractive keratectomy for the correction of 4 diopters of myopia in his right eye. He had been myopic since childhood and had worn hard contact lenses for the previous 20 years. He had a history of mild allergic conjunctivitis. His preoperative visual acuity was 20/100 without correction and 20/25— with the best spectacle correction. The autorefraction read ing was —3.0 —1.25 x 10 and the subjective refraction was - 3 . 7 5 - 1 . 7 5 x 175. The keratometric reading was 41.3/42.6(67). Paraformaldehyde dust was observed on the surface of the cone before application of the iris cone to the eye. The dust was carefully removed by using air flow and mechanical wiping with a cellulose sponge. On the first postoperative day, the patient had intense ocular pain. At slit-lamp examination, the cornea was edematous and cloudy and was more pronounced in the anterior stroma adjacent to the ablated area. Descemet's folds and a moderate flare (not obscuring the details) were seen in the anterior chamber. At that time, only patching was used. On postoperative day 4, no improvement was noted and cultures were performed (Fig. 1). Topical treatment with fortified antibiotics
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Fig. 1 (Pallikaris and associates). Case 1. Slit-lamp photograph three days postoperatively showing in tense corneal inflammation. (gentamicin sulfate and cefazolin sodium, ev ery half an hour) was started and the eye remained unpatched. The culture results were negative and the clinical signs and symptoms did not change with the antibiotic therapy. Furthermore, during the first postoperative days, minute opaque dots in the anterior corne al stroma were observed when using high mag nification. These dots gradually disappeared and, at the end of the third postoperative week, were no longer visible. The cause of the corneal inflammation was attributed to the paraformal dehyde dust that was noticed intraoperatively. On postoperative day 20, the treatment was changed to daily dexamethasone sodium phos phate subconjunctival injections; tobramycin sulfate eyedrops, twice daily; and tear substi tute in gel, twice daily, while the eye remained patched. The new treatment was more effective, as the corneal edema, as well as Descemet's folds, gradually subsided. On postoperative day 50, the cornea was fully reepithelialized. There was still a mild stromal edema and a subepithelial haze of grade 3 density throughout the ablated area. An opaci ty of the anterior stroma was seen in the center of the ablated area. His visual acuity was 20/64 without correction and 20/32 with best specta cle correction. The patient had to hold his head in an oblique position to attain his best visual acuity. The autorefraction reading was —0.25 - 5 . 7 5 x 43. Keratometry disclosed irregular images. The patient began treatment with topi-
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cal prednisolone acetate and tobramycin sulfate eyedrops, six times daily. One week later, the corneal edema had resolved. His visual acuity was 20/64 without correction and 20/32 with best spectacle correction, always with an oblique position of the head. The autorefraction reading was - 2 . 7 5 - 3 . 7 5 x 23 and the keratometric reading was 38.25/40.75(120). The pa tient described his vision as blurred. Four and one-half months postoperatively, his visual acuity was 20/200 without correction and 20/50 with best spectacle correction (with oblique head position). The autorefraction reading was —7.5 - 2 . 2 5 x 3, the subjective refraction reading was - 5 . 0 - 2 . 5 x 180, and the keratometric reading was 43.25/45.5(80). The cornea was normally epithelialized and uninflamed. However, a central corneal scar could be easily detected. There was a grade 2 to 3 reticulate subepithelial haze throughout the ablated area (Fig. 2). Corneal topography disclosed a central cor neal flattening immediately after epithelialization that disappeared 15 days later. On his last visit, 4% months postoperatively, the central cornea was steeper than before photorefractive keratectomy. Case 2 A 26-year-old woman underwent standard photorefractive keratectomy for the correction of 7 diopters of myopia in her right eye. She had
Fig. 2 (Pallikaris and associates). Case 1. Slit-lamp photograph 4 Vi months postoperatively showing sub epithelial haze and central opacity.
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been myopic since childhood and had worn contact lenses for the previous seven years. Her preoperative visual acuity was counting fingers at 3 m without correction and 20/200 with best spectacle correction. The autorefraction read ing was —5.75 —1.25 x 5, the subjective refrac tion reading was —6.0 —1.75 x 180, and the keratometric reading was 43.75/45.25(91). Immediately before application of the cone to the patient's eye, paraformaldehyde dust was seen on the cone surface and was carefully removed by using air flow and mechanical wip ing with a cellulose sponge. On postoperative day 5, the cornea was reepithelialized. There was stromal edema, as well as a paracentral opacity of the anterior stroma. A grade 2 subepithelial haze could also be seen. Prednisolone acetate and tobramycin sulfate eyedrops were instilled five times daily. Four days later, the corneal edema had resolved, but the opacity and the subepithelial haze did not change. Her visual acuity was 20/40 without correction and 20/25— with best spectacle cor rection. The keratometric reading was 3 8 . 5 / 41.75(95) and the autorefraction reading was - 2 . 0 x 170. Four months postoperatively, the cornea re mained well epithelialized with a less intense paracentral opacity of the anterior stroma. The subepithelial haze was graded 1. Her visual acuity was 20/32 without correction and 20/20 with best spectacle correction. The autorefrac tion reading was - 0 . 2 5 - 3 . 0 x 175 and the keratometric reading was 40.0/42.5(85). Six months postoperatively, her visual acuity was 20/32 without correction and 20/20 with best spectacle correction. The keratometric reading was 40.5/42.75(85), the autorefraction reading was - 0 . 7 5 - 2 . 5 x 175, and the subjec tive refraction reading was - 0 . 7 5 - 2 . 5 x 175. The paracentral corneal opacity was barely seen and the subepithelial haze was graded 1 (Fig. 3). Case 3 A 52-year-old woman underwent standard photorefractive keratectomy for the correction of 7 diopters of myopia in her left eye. She had been myopic since childhood and had never worn contact lenses. Her uncorrected preopera tive visual acuity was 20/200 and 2 0 / 2 5 - with best spectacle correction. The autorefraction reading was - 7 . 5 - 2 . 5 x 180, the subjective refraction reading was - 7 . 0 - 2 . 7 5 x 2, and the keratometric reading was 43.5/47.1(85). We removed the paraformaldehyde dust from
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Fig. 3 (Pallikaris and associates). Case 2. Slit-lamp photograph six months postoperatively. The corneal haze is hardly seen. the cone surface before the procedure in the previously discussed manner. On postoperative day 5, the patient had a car accident and for this reason her data on refraction were incomplete. The cornea was reepithelialized on postopera tive day 8. There was stromal edema and a paracentral opacity of the anterior stroma. A grade 2 subepithelial haze could be seen. She started treatment with topical prednisolone ac etate and tobramycin sulfate drops six times daily. Forty days postoperatively, her visual acuity was 20/64 without correction and 2 0 / 3 2 - with best spectacle correction. The autorefraction reading was - 1 . 7 5 - 4 . 5 X 180 and the keratometric reading was 39.25/42.1(93). A paracentral corneal opacity and a grade 2 subepithelial haze were also observed. Six months postoperatively, her visual acuity was 20/50 without correction and 20/20 with best spectacle correction. The autorefraction reading was —1.5 —3.25 X 10, the subjective refraction reading was —1.75 —3.5 x 10, and the keratometric reading was 39.75/43.75(92). A grade 1 subepithelial corneal haze and a paracentral opacity in the anterior corneal stro ma of much less density than in her previous visits could be seen.
Discussion The three patients were among the first at our clinic to be operated on with the excimer laser
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for the correction of myopia. As the mechanical iris cone was the only part of the laser that was in contact with the patient's eye and because autoclaving was impossible, we used paraformaldehyde tablets for disinfection of the cone. The three patients underwent the operation on the same day in the order in which they were examined. The iris cone remained in the con tainer with the paraformaldehyde tablets for 24 hours before the first operation, and for two hours before each of the next two operations. A small amount of paraformaldehyde dust could be seen on the cone surface at the end of the disinfection. Before applying the suction ring on the patient's eye, the paraformaldehyde dust was carefully removed. However, the mechani cal closure of the iris blades, as well as the air flow around the iris and suction ring, probably released incarcerated paraformaldehyde dust on the ablated corneal surface. At the end of the procedures, no paraformaldehyde dust could be detected on the ablated area. This should be expected, as the chemical spreads rapidly through the entire thickness of the stroma after its application on the cornea. Postoperatively, all three patients developed intense corneal inflammation, which lasted 50 days in the first patient. The other two patients recovered earlier. In all three patients, opacities developed in the anterior stroma. In the first patient, the corneal opacity was central and accompanied by a grade 2 to 3 reticulate haze. The final result was a 4-Snellen-line reduction of his best-corrected visual acuity. The other two patients developed a paracentral opacity that did not interfere with the final visual acu ity. The more severe reaction observed in the first patient was probably caused by accumula tion of more paraformaldehyde dust on the cone surface that resulted from the longer dis infection time. Paraformaldehyde is a polymer of formalde hyde that, in room temperature (20 to 28 C), depolymerizes to formaldehyde; their toxicity is identical. 3 Formalin, the aqueous solution of formaldehyde, has been toxic to the eye in dilutions from 1 in 1,000 to 1 in 2,000. Acciden tal application of a drop on the cornea results in extreme chemosis and keratitis, which leads to permanent opacities. Formalin experimentally applied to a rabbit cornea spreads rapidly throughout the entire thickness of the stroma; the corneal corpuscles are killed and fixed in situ to appear as minute white dots. 4 This is consistent with our observation of white
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Paraformaldehyde-induced Keratitis
opaque dots in the corneal stroma of our first patient. When paraformaldehyde dust was applied to the ablated area of rabbit corneas immediately after photorefractive keratectomy, it resulted in a severe inflammation, a delay of reepithelialization, and a formation of an intense subepithelial corneal haze (Pallikaris and associates, unpublished data, 1991). After observing intense corneal reactions, we stopped using paraformaldehyde tablets for disinfecting the iris cone. Of the 30 patients operated on in our clinic with the excimer laser so far, only the three patients of this study developed intense postoperative inflammation and corneal opacities. These patients, as al ready mentioned, were the first to be operated on and the only in whom paraformaldehyde tablets were used for the iris cone disinfection. Therefore, we believed the intense inflammato ry reaction and the corneal opacities were caused by the corneal toxicity of paraformalde hyde. Currently, we disinfect the lower part of the iris cone, where the suction ring is located, by immersing the cone in isopropyl alcohol solu tion 70% for 20 minutes. Isopropyl alcohol is a known disinfectant and has been an efficient means of disinfecting Goldmann tonometers against both human immunodeficiency virus type 1 and herpesviruses. There is evidence that 70% isopropyl alcohol also inactivates hepatitis B virus. 5 The regression of myopia was interesting in our first patient. The preoperative spher ical equivalent of this patient was —3.6 diop ters. Immediately after reepithelialization, the spherical equivalent was —3.1 diopters, and 4% months postoperatively, it was —8.6 diopters. This patient had the most intense inflammatory reaction, with the final amount of haze and subepithelial scarring appearing to correspond with the degree of regression. His myopia not only regressed but also actually overshot the preoperative level. This was presumably a re sult of both corneal remodeling after the in tense inflammation and secondary scar forma tion. Contracture of this scar tissue could lead to steepening of the cornea and regression of the myopic photoablative outcome. This effect, in conjunction with corneal topography meas urements, may be interesting regarding the study of regression after photoablative keratec tomy. McDonald, Frantz, and Klyce6 described a case of marked regression after myopic photo-
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refractive keratectomy that was attributed to stromal remodeling. Seiler and Wollensak 7 de scribed marked regression in eyes with marked scarring after photorefractive keratectomy. All three of our cases also showed an increase in astigmatism. The refractive astigmatism of the first patient was - 1 . 2 5 x 10 preoperatively, and —2.25 x 3 4Vi months postoperatively. The refractive astigmatism of the second patient was —1.25 x 5 preoperatively, and - 2 . 5 x 175 six months postoperatively. Finally, the re fractive astigmatism of the third patient was - 2 . 5 x 180 preoperatively, and 3.25 x 10 six months postoperatively. Corneal remodeling after the formaldehyde-induced inflammation was probably the reason for this astigmatic effect. Postoperatively, all patients were intensively treated with corticosteroids, and at least in the patients in Cases 2 and 3, this therapy was effective in preserving the photoablative myop ic correction. This effectiveness may be of inter est regarding the effect that the specific corticosteroid treatment regimen may have in modifying the wound healing response and amount of regression. The perioperative complication observed in these patients dictates careful attention to steri lization of any device that contacts the eye. Once an instrument is cleaned with a disinfec tant, there is always a chance to cause corneal damage even if only traces remain. A small amount of paraformaldehyde is enough to cause intense corneal inflammation. Mean while, it may be extremely difficult to be sure of complete paraformaldehyde removal after its fumigation; the dust of the chemical may be incarcerated in difficult-to-reach locations, as between the blades of the iris cone, for exam ple. These observations suggest that paraformal dehyde tablets are not safe for disinfection of the excimer laser iris cone or other accessories used on or around the cornea during excimer laser ablation. Contact of paraformaldehyde dust with the ablated area can lead to intense corneal inflammation, resulting in an undesir able refractive outcome, or even impairment of visual acuity after photorefractive keratectomy.
References 1. Phillips, C. R. : Gaseous sterilization. In Block, C. S. (ed.): Disinfection, Sterilization and Preserva-
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tion. Philadelphia, Lea & Febiger, 1977, pp. 5 9 3 5940. 2. Fantes, F. E., Hanna, K. D., Waring, G. O. Ill, Pouliquen, Y., Thompson, K. P., and Savoldelli, M.: Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys. Arch. Ophthalmol. 108:665, 1990. 3. Gosselin, R. E., Hodge, H. C , Smith, R. P., and Gleason, M. N. (eds.): Ingredient index. In Clinical Toxicology of Commercial Products, sec. 2, ed. 4. Baltimore, Williams and Wilkins Co., 1976, p. 125. 4. Duke-Elder, S., and MacFaul, P. A.: Injuries. Non-mechanical injuries. In Duke-Elder, S. (ed.):
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System of Ophthalmology, vol. 14, chap. 11. Lon don, Henry Kimpton, 1972, pp. 1169-1170. 5. Pepose, J. S., Linette, G., Lee, S. F., and MacRae, S.: Disinfection of Goldmann tonometers against human immunodeficiency virus type 1. Arch. Ophthalmol. 107:983, 1989. 6. McDonald, M. B., Frantz, J. M., and Klyce, S. D.: Central photorefractive keratectomy for myo pia. Arch. Ophthalmol. 108:799, 1990. 7. Seiler, T., and Wollensak, J.: Myopic photore fractive keratectomy with the excimer laser. Ophthal mology 98:1156, 1991.
OPHTHALMIC MINIATURE
Joan h a d lovely eyes, grey eyes like her father's that reminded one of the sea. In certain lights they could look almost green, as though a tide were washing over them. When we moved to H e n d o n , it was true, I did miss the sea. I used to look into Joan's eyes sometimes, w h e n she wasn't looking, and she seemed to give me back a little of the winter seas. Eyes are so vulnerable; they say things that words themselves can't say. I used to feel sad and lost looking into the greyness of Joan's gaze. It was almost a relief when her eyes weakened a n d she h a d to wear glasses. It shielded me from all her unspoken reproaches and all the unanswerable questions that lay there. Lisa St. Aubin de Terân, Joanna London, Virago Press, 1990, p . 244
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