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Corneal opacity after repeated photorefractive keratectomy
Corneal opacity after repeated photorefractive keratectomy Kyu Sik Kim, MD, Ja Young Lee, MD, Sung Kun Chung, MD, Nam Ho Baek, MD ABSTRACT Corneal opacity developed in an eye that had photorefractive keratectomy (PRK) with a 193 nm excimer laser 5 times over 3 years. Six months after the last PRK, a partial penetrating keratoplasty was performed. The cornea was stained and immunohistochemically evaluated for collagen types. Light microscopy showed thickening of epithelial layers, proliferation of subepithelial fibroblasts, and the absence of Bowman’s membrane. Transmission electron microscopy showed irregular collagen lamellae and electron-dense deposits adjacent to keratocytes. The staining was positive for Alcian blue, and immunohistochemistry was positive for type IV and VI collagen. This case suggests that corneal opacity after repeated PRK is the result of deposits of type IV and VI collagen and acidic mucoprotein in the extracellular matrix. J Cataract Refract Surg 2001; 27:1128 –1131 © 2001 ASCRS and ESCRS
P
hotorefractive keratectomy (PRK) is distinguished from other corneal surgery techniques by its ability to successfully correct myopia and astigmatism and because it results in a flat surface.1– 4 However, complications can occur. These include subepithelial corneal opacity in the visual axis and a decrease in the corrective effect over time. The cause of these problems is not clear; however, they are associated with collagen and glycosaminoglycan deposits generated by activated corneal subepithelial cells and with remodeling of the wound.5 We studied the degeneration of corneal collagen fiber and its histopathology in a case of corneal opacity occurring after repeated PRK.
Accepted for publication November 22, 2000. From the Department of Ophthalmology, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. Supported by The Catholic Foundation for Eye Research. Reprint requests to Sung Kun Chung, MD, Department of Ophthalmology, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul #62, Yoido-dong, Youngdeungpo-ku, Seoul, 150-713, Korea. E-mail: [email protected]. © 2001 ASCRS and ESCRS Published by Elsevier Science Inc.
Case Report A 47-year-old man presented at St. Mary’s Hospital with decreased visual acuity in the right eye. He had no systemic illness. He had PRK, 5 times in the right eye and 3 times in the left eye (Table 1). The procedures were performed with a VISX Twenty-Twenty 193 nm excimer laser using an energy of 160 mJ/cm2, repetition rate of 5 Hz, and depth of 32.8 to 76.8 m in right eye and 40.8 to 76.8 m in the left eye. On admission, best corrected visual acuity was 0.02 in the right eye and 0.3 in the left eye. A corneal stromal opacity was evident in the right eye (Figure 1). The anterior chamber was deep and clear and the lens was clear in both eyes. Intraocular pressure was 12 mm Hg in the right eye and 11 mm Hg in the left eye. A diagnosis of corneal opacity was made and conductive penetrating keratoplasty (PKP) performed in the right eye 22 months after the last PRK. After the PKP, a histopathologic examination of the recipient cornea was done. Light microscopy showed partially hypertrophied corneal epithelial cells, effacement of Bowman’s membrane, and corneal subepithelial fibrosis (Figure 2). Transmission electromicroscopy showed marked irregularity of the collagen layer and electron-dense deposits around the corneal stromal cells (Figure 3). Fibrous tissue stains were positive with Alcian blue (Figure 4) but not with periodic acid-Schiff, Masson trichrome, 0886-3350/01/$–see front matter PII S0886-3350(01)00878-6
CASE REPORTS: KIM
Table 1. Data on the PRK procedures. Refraction Eye/Date of PRK
Manifest
Cycloplegic
Ablation (D)
Ablation Depth (m)
K1/K2
⫺10.25 –2.25 ⫻ 66
⫺11.00 –1.25 ⫻ 60
⫺10.00
76.8
43.0/43.9
Right May 2, 1992 December 5, 1992
⫺4.50 –1.25 ⫻ 105
⫺5.00 –0.75 ⫻ 68
⫺5.00
41.5
40.0/40.6
February 7, 1994
⫺5.25 –1.75 ⫻ 68
⫺4.75 –0.75 ⫻ 76
⫺5.00
48.7
39.5/40.0
June 5, 1994
⫺4.05 –0.25 ⫻ 86
⫺2.00 –1.50 ⫻ 64
⫺2.75
32.8
40.0/40.3
November 5, 1994
⫺6.25 –0.25 ⫻ 103
⫺5.50 –1.50 ⫻ 75
⫺5.00
59.5
40.7/41.1
⫺12.50 –1.25 ⫻ 67
⫺12.50 –1.25 ⫻ 65
⫺10.00
76.8
43.7/44.1
January 9, 1993
⫺6.50 –1.25 ⫻ 73
⫺6.50 –0.75 ⫻ 82
⫺6.50
40.8
39.8/40.5
October 16, 1993
⫺6.75 –0.25 ⫻ 109
⫺6.50 –1.00 ⫻ 92
⫺6.25
60.0
39.4/39.8
Left February 29, 1992
Figure 1. (Kim) A corneal stromal opacity that developed after
Figure 2. (Kim) Light microscopy shows increased stromal fibrosis
repeated PRK.
(arrows) at the subepithelial level (hematoxylin & eosin; original magnification ⫻100).
Congo red, or oil red O. The immunohistochemistry stain was negative for type III (monoclonal antibody to human collagen III murin immunoglobulin [Ig] M) and type VII (monoclonal anticollagen type VII Ig GG1) collagen. It was positive for type IV (antihuman collagen IV Ig G2b) and type VI (mouse antihuman type VI antibody) collagen (Figures 5 and 6). Seven days postoperatively, the patient was discharged with a visual acuity of 0.4 in the right eye. At the last follow-up 93 days postoperatively, the patient reported no visual problems and the graft cornea was clear.
In particular, the argon–fluoride excimer laser ablates the corneal surface without causing temperatureinduced degeneration. Marshall and coauthors1 propose that PRK maintains corneal clarity without initiating a wound-healing process. In addition, PRK results in minimal corneal stromal injury.5–7 However, corneal opacity caused by wound-healing after PRK has been reported in an animal model.3 Corneal subepithelial opacity has also been reported in human eyes, as has a diminution in the corrective effect over time. Photorefractive keratectomy yields better corneal clearance and is safer than radial keratotomy.1,3,6 Wound healing, which is similar in both methods,8,9
Discussion Photorefractive keratectomy is superior to other surgical techniques in flattening the corneal surface.1– 4
J CATARACT REFRACT SURG—VOL 27, JULY 2001
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CASE REPORTS: KIM
Figure 3. (Kim) Transmission electron microscopy shows amor-
Figure 4. (Kim) Light microscopy shows thick mucopolysaccha-
phous electron-dense deposits (arrows) around fibroblasts in the stroma (original magnification ⫻6000).
ride deposits (arrows) under the healing epithelium (Alcian blue; original magnification ⫻100).
Figure 5. (Kim) Immunohistochemical staining of type IV collagen with antihuman collagen type IV Ig G2b antibody (original magnification ⫻100).
Figure 6. (Kim) Immunohistochemical staining of type VI collagen with mouse antihuman type VI antibody (original magnification ⫻100).
begins about 24 hours postoperatively, when fibronectin and fibrinogen appear on the corneal surface. The fibronectin and fibrinogen serve as vehicles for corneal epithelial cell migration and attachment.8,10 Fibronectin and laminin are closely related to corneal cell activation during the wound-healing process.10,11 Collagen exists on the normal corneal stroma and comprises type I, II, III, V, and VI.12,13 Type III collagen is newly formed, found in the area of the wound lesion,14 and persists after wound healing. In our case, immunohistochemical staining was negative for collage type III and VII but positive for type IV and VI. Type III collagen is known to exist on corneal
parenchyma; however, it appears that the amount in our specimen was too small to be stained. The opacified cornea contains hyaluronic acid in the place of keratan sulfate proteoglycan. In other words, the deficiency of keratan sulfate proteoglycan results in corneal opacity,15 and corneal opacity is significantly associated with corneal macular dystrophy.16,17 In a report of a rabbit model study, Tuft and coauthors18 suggest that collagen regenerates to a depth between 15 and 75 m. This regeneration is similar to the epithelial hyperplasia that occurs after PRK. Goodman et al.19 propose that collagen deposition is associated with corneal opacity and is proportional to its depth.
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CASE REPORTS: KIM
However, Hanna et al.20 report that corneal opacity does not develop if the corneal parenchyma is not damaged. New collagen deposits form when the corneal parenchyma is injured. Wound healing after PRK is dependent on the smoothness of the ablation surface and the homogeneity of the excimer laser. In our case, corneal opacity developed after repeated PRK. Thus, type IV collagen, which is not present in the parenchyma of the normal corneal, was found. Corneal parenchyma injury results in the deposition of abnormal collagen, which induces corneal opacity. This opacity is also due to the Alcian-bluestained acidic mucoprotein deposit on the extracellular matrix.
References 1. Marshall J, Trokel S, Rothery S, Krueger RR. Photoablative reprofiling of the cornea using an excimer laser: photorefractive keratectomy. Lasers Ophthalmol 1986; 1:21– 48 2. Kerr-Muir MG, Trokel SL, Marshall J, Rothery S. Ultrastructural comparison of conventional surgical and argon fluoride excimer laser keratectomy. Am J Ophthalmol 1987; 103:448 – 453 3. Aron-Rosa DS, Boerner CF, Bath P, et al. Corneal wound healing after excimer laser keratotomy in a human eye. Am J Ophthalmol 1987; 103:454 – 464 4. Gabay S, Slomovic A, Jares T. Excimer laser-processed donor corneal lenticules for lamellar keratoplasty. Am J Ophthalmol 1989; 107:47–51 5. Hanna KD, Chastang JC, Pouliquen Y, et al. Excimer laser keratectomy for myopia with a rotating-slit delivery system. Arch Ophthalmol 1998; 106:245–250 6. Marshall J, Trokel SL, Rothery S, Krueger RR. Longterm healing of the central cornea after photorefractive keratectomy using an excimer laser. Ophthalmology 1988; 95:1411–1421 7. L’Esperance FA, Warner JW, Telfair WB, et al. Excimer laser instrumentation and technique for human corneal surgery. Arch Ophthalmol 1989; 107:131–139 8. Fujikawa LS, Foster CS, Gipson IK, Colvin RB. Base-
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
ment membrane components in healing rabbit corneal epithelial wounds: immunofluorescence and ultrastructural studies. J Cell Biol 1984; 98:128 –138 Suda T, Nishida T, Ohashi Y, et al. Fibronectin appears at the site of corneal stromal wound in rabbits. Curr Eye Res 1981/82; 1:553–556 Fujikawa LS, Foster CS, Gipson IK, et al. Fibronectin in healing rabbit cornea wounds. Lab Invest 1981; 45:120 – 129 Ohashi Y, Nakagawa S, Nishida T, et al. Appearance of fibronectin in rabbit cornea after thermal burn. Jpn J Ophthalmol 1983; 27:547–555 Zimmermann DR, Trueb B, Winterhalter KH, et al. Type VI collagen is a major component of the human cornea. FEBS Lett 1986; 197:55–58 Cintron C, Hong B-S. Heterogeneity of collagens in rabbit cornea: type IV collagen. Invest Ophthalmol Vis Sci 1988; 29:760 –766 Von der Mark K, Von der Mark H, Timpl R, Trelstad RL. Immunofluorescent localization of collagen types I, II, and III in the embryonic chick eye. Dev Biol 1977; 59:75– 85 Hassell JR, Cintron C, Kublin C, Newsome DA. Proteoglycan changes during restoration of transparency in corneal scars. Arch Biochem Biophys 1983; 222:362– 369 Nakazawa K, Hassell JR, Hascall VC, et al. Defective processing of keratan sulfate in macular corneal dystrophy. J Biol Chem 1984; 259:13751–13757 Klintworth GK, Meyer R, Dennis R, et al. Macular corneal dystrophy; lack of keratan sulfate in serum and cornea. Ophthalmic Paediatr Genet 1986; 7:139 –143 Tuft SJ, Zabel RW, Marshall J. Corneal repair following keratectomy; a comparison between conventional surgery and laser photoablation. Invest Ophthalmol Vis Sci 1989; 30:1769 –1777 Goodman GL, Trokel SL, Stark WJ, et al. Corneal healing following laser refractive keratectomy. Arch Ophthalmol 1989; 107:1799 –1803 Hanna KD, Pouliquen Y, Waring GO III, et al. Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation. Arch Ophthalmol 1989; 107:895– 901
J CATARACT REFRACT SURG—VOL 27, JULY 2001
1131
P
hotorefractive keratectomy (PRK) is distinguished from other corneal surgery techniques by its ability to successfully correct myopia and astigmatism and because it results in a flat surface.1– 4 However, complications can occur. These include subepithelial corneal opacity in the visual axis and a decrease in the corrective effect over time. The cause of these problems is not clear; however, they are associated with collagen and glycosaminoglycan deposits generated by activated corneal subepithelial cells and with remodeling of the wound.5 We studied the degeneration of corneal collagen fiber and its histopathology in a case of corneal opacity occurring after repeated PRK.
Accepted for publication November 22, 2000. From the Department of Ophthalmology, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. Supported by The Catholic Foundation for Eye Research. Reprint requests to Sung Kun Chung, MD, Department of Ophthalmology, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul #62, Yoido-dong, Youngdeungpo-ku, Seoul, 150-713, Korea. E-mail: [email protected]. © 2001 ASCRS and ESCRS Published by Elsevier Science Inc.
Case Report A 47-year-old man presented at St. Mary’s Hospital with decreased visual acuity in the right eye. He had no systemic illness. He had PRK, 5 times in the right eye and 3 times in the left eye (Table 1). The procedures were performed with a VISX Twenty-Twenty 193 nm excimer laser using an energy of 160 mJ/cm2, repetition rate of 5 Hz, and depth of 32.8 to 76.8 m in right eye and 40.8 to 76.8 m in the left eye. On admission, best corrected visual acuity was 0.02 in the right eye and 0.3 in the left eye. A corneal stromal opacity was evident in the right eye (Figure 1). The anterior chamber was deep and clear and the lens was clear in both eyes. Intraocular pressure was 12 mm Hg in the right eye and 11 mm Hg in the left eye. A diagnosis of corneal opacity was made and conductive penetrating keratoplasty (PKP) performed in the right eye 22 months after the last PRK. After the PKP, a histopathologic examination of the recipient cornea was done. Light microscopy showed partially hypertrophied corneal epithelial cells, effacement of Bowman’s membrane, and corneal subepithelial fibrosis (Figure 2). Transmission electromicroscopy showed marked irregularity of the collagen layer and electron-dense deposits around the corneal stromal cells (Figure 3). Fibrous tissue stains were positive with Alcian blue (Figure 4) but not with periodic acid-Schiff, Masson trichrome, 0886-3350/01/$–see front matter PII S0886-3350(01)00878-6
CASE REPORTS: KIM
Table 1. Data on the PRK procedures. Refraction Eye/Date of PRK
Manifest
Cycloplegic
Ablation (D)
Ablation Depth (m)
K1/K2
⫺10.25 –2.25 ⫻ 66
⫺11.00 –1.25 ⫻ 60
⫺10.00
76.8
43.0/43.9
Right May 2, 1992 December 5, 1992
⫺4.50 –1.25 ⫻ 105
⫺5.00 –0.75 ⫻ 68
⫺5.00
41.5
40.0/40.6
February 7, 1994
⫺5.25 –1.75 ⫻ 68
⫺4.75 –0.75 ⫻ 76
⫺5.00
48.7
39.5/40.0
June 5, 1994
⫺4.05 –0.25 ⫻ 86
⫺2.00 –1.50 ⫻ 64
⫺2.75
32.8
40.0/40.3
November 5, 1994
⫺6.25 –0.25 ⫻ 103
⫺5.50 –1.50 ⫻ 75
⫺5.00
59.5
40.7/41.1
⫺12.50 –1.25 ⫻ 67
⫺12.50 –1.25 ⫻ 65
⫺10.00
76.8
43.7/44.1
January 9, 1993
⫺6.50 –1.25 ⫻ 73
⫺6.50 –0.75 ⫻ 82
⫺6.50
40.8
39.8/40.5
October 16, 1993
⫺6.75 –0.25 ⫻ 109
⫺6.50 –1.00 ⫻ 92
⫺6.25
60.0
39.4/39.8
Left February 29, 1992
Figure 1. (Kim) A corneal stromal opacity that developed after
Figure 2. (Kim) Light microscopy shows increased stromal fibrosis
repeated PRK.
(arrows) at the subepithelial level (hematoxylin & eosin; original magnification ⫻100).
Congo red, or oil red O. The immunohistochemistry stain was negative for type III (monoclonal antibody to human collagen III murin immunoglobulin [Ig] M) and type VII (monoclonal anticollagen type VII Ig GG1) collagen. It was positive for type IV (antihuman collagen IV Ig G2b) and type VI (mouse antihuman type VI antibody) collagen (Figures 5 and 6). Seven days postoperatively, the patient was discharged with a visual acuity of 0.4 in the right eye. At the last follow-up 93 days postoperatively, the patient reported no visual problems and the graft cornea was clear.
In particular, the argon–fluoride excimer laser ablates the corneal surface without causing temperatureinduced degeneration. Marshall and coauthors1 propose that PRK maintains corneal clarity without initiating a wound-healing process. In addition, PRK results in minimal corneal stromal injury.5–7 However, corneal opacity caused by wound-healing after PRK has been reported in an animal model.3 Corneal subepithelial opacity has also been reported in human eyes, as has a diminution in the corrective effect over time. Photorefractive keratectomy yields better corneal clearance and is safer than radial keratotomy.1,3,6 Wound healing, which is similar in both methods,8,9
Discussion Photorefractive keratectomy is superior to other surgical techniques in flattening the corneal surface.1– 4
J CATARACT REFRACT SURG—VOL 27, JULY 2001
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CASE REPORTS: KIM
Figure 3. (Kim) Transmission electron microscopy shows amor-
Figure 4. (Kim) Light microscopy shows thick mucopolysaccha-
phous electron-dense deposits (arrows) around fibroblasts in the stroma (original magnification ⫻6000).
ride deposits (arrows) under the healing epithelium (Alcian blue; original magnification ⫻100).
Figure 5. (Kim) Immunohistochemical staining of type IV collagen with antihuman collagen type IV Ig G2b antibody (original magnification ⫻100).
Figure 6. (Kim) Immunohistochemical staining of type VI collagen with mouse antihuman type VI antibody (original magnification ⫻100).
begins about 24 hours postoperatively, when fibronectin and fibrinogen appear on the corneal surface. The fibronectin and fibrinogen serve as vehicles for corneal epithelial cell migration and attachment.8,10 Fibronectin and laminin are closely related to corneal cell activation during the wound-healing process.10,11 Collagen exists on the normal corneal stroma and comprises type I, II, III, V, and VI.12,13 Type III collagen is newly formed, found in the area of the wound lesion,14 and persists after wound healing. In our case, immunohistochemical staining was negative for collage type III and VII but positive for type IV and VI. Type III collagen is known to exist on corneal
parenchyma; however, it appears that the amount in our specimen was too small to be stained. The opacified cornea contains hyaluronic acid in the place of keratan sulfate proteoglycan. In other words, the deficiency of keratan sulfate proteoglycan results in corneal opacity,15 and corneal opacity is significantly associated with corneal macular dystrophy.16,17 In a report of a rabbit model study, Tuft and coauthors18 suggest that collagen regenerates to a depth between 15 and 75 m. This regeneration is similar to the epithelial hyperplasia that occurs after PRK. Goodman et al.19 propose that collagen deposition is associated with corneal opacity and is proportional to its depth.
1130
J CATARACT REFRACT SURG—VOL 27, JULY 2001
CASE REPORTS: KIM
However, Hanna et al.20 report that corneal opacity does not develop if the corneal parenchyma is not damaged. New collagen deposits form when the corneal parenchyma is injured. Wound healing after PRK is dependent on the smoothness of the ablation surface and the homogeneity of the excimer laser. In our case, corneal opacity developed after repeated PRK. Thus, type IV collagen, which is not present in the parenchyma of the normal corneal, was found. Corneal parenchyma injury results in the deposition of abnormal collagen, which induces corneal opacity. This opacity is also due to the Alcian-bluestained acidic mucoprotein deposit on the extracellular matrix.
References 1. Marshall J, Trokel S, Rothery S, Krueger RR. Photoablative reprofiling of the cornea using an excimer laser: photorefractive keratectomy. Lasers Ophthalmol 1986; 1:21– 48 2. Kerr-Muir MG, Trokel SL, Marshall J, Rothery S. Ultrastructural comparison of conventional surgical and argon fluoride excimer laser keratectomy. Am J Ophthalmol 1987; 103:448 – 453 3. Aron-Rosa DS, Boerner CF, Bath P, et al. Corneal wound healing after excimer laser keratotomy in a human eye. Am J Ophthalmol 1987; 103:454 – 464 4. Gabay S, Slomovic A, Jares T. Excimer laser-processed donor corneal lenticules for lamellar keratoplasty. Am J Ophthalmol 1989; 107:47–51 5. Hanna KD, Chastang JC, Pouliquen Y, et al. Excimer laser keratectomy for myopia with a rotating-slit delivery system. Arch Ophthalmol 1998; 106:245–250 6. Marshall J, Trokel SL, Rothery S, Krueger RR. Longterm healing of the central cornea after photorefractive keratectomy using an excimer laser. Ophthalmology 1988; 95:1411–1421 7. L’Esperance FA, Warner JW, Telfair WB, et al. Excimer laser instrumentation and technique for human corneal surgery. Arch Ophthalmol 1989; 107:131–139 8. Fujikawa LS, Foster CS, Gipson IK, Colvin RB. Base-
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
ment membrane components in healing rabbit corneal epithelial wounds: immunofluorescence and ultrastructural studies. J Cell Biol 1984; 98:128 –138 Suda T, Nishida T, Ohashi Y, et al. Fibronectin appears at the site of corneal stromal wound in rabbits. Curr Eye Res 1981/82; 1:553–556 Fujikawa LS, Foster CS, Gipson IK, et al. Fibronectin in healing rabbit cornea wounds. Lab Invest 1981; 45:120 – 129 Ohashi Y, Nakagawa S, Nishida T, et al. Appearance of fibronectin in rabbit cornea after thermal burn. Jpn J Ophthalmol 1983; 27:547–555 Zimmermann DR, Trueb B, Winterhalter KH, et al. Type VI collagen is a major component of the human cornea. FEBS Lett 1986; 197:55–58 Cintron C, Hong B-S. Heterogeneity of collagens in rabbit cornea: type IV collagen. Invest Ophthalmol Vis Sci 1988; 29:760 –766 Von der Mark K, Von der Mark H, Timpl R, Trelstad RL. Immunofluorescent localization of collagen types I, II, and III in the embryonic chick eye. Dev Biol 1977; 59:75– 85 Hassell JR, Cintron C, Kublin C, Newsome DA. Proteoglycan changes during restoration of transparency in corneal scars. Arch Biochem Biophys 1983; 222:362– 369 Nakazawa K, Hassell JR, Hascall VC, et al. Defective processing of keratan sulfate in macular corneal dystrophy. J Biol Chem 1984; 259:13751–13757 Klintworth GK, Meyer R, Dennis R, et al. Macular corneal dystrophy; lack of keratan sulfate in serum and cornea. Ophthalmic Paediatr Genet 1986; 7:139 –143 Tuft SJ, Zabel RW, Marshall J. Corneal repair following keratectomy; a comparison between conventional surgery and laser photoablation. Invest Ophthalmol Vis Sci 1989; 30:1769 –1777 Goodman GL, Trokel SL, Stark WJ, et al. Corneal healing following laser refractive keratectomy. Arch Ophthalmol 1989; 107:1799 –1803 Hanna KD, Pouliquen Y, Waring GO III, et al. Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation. Arch Ophthalmol 1989; 107:895– 901
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