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Late Onset of Corneal Scar After Excimer Laser Photorefractive Keratectomy
Late Onset of Corneal Scar After Excimer Laser Photorefractive Keratectomy JOHN C. MEYER, MD., R. DOYLE STULTING, MD., KEITH P. THOMPSON, M.D., AND DANIEL S. DURRIE, M.D.
• PURPOSE: We studied the occurrence of late scarring after photorefractive keratectomy and its response to topical corticosteroids and debridement during the course of follow-up of 950 eyes that had photorefractive keratectomy with excimer laser. • METHODS: Five eyes of four patients developed localized corneal scars, decreased visual acuity, and increased myopia after five to 33 months of good visual acuity, with trace haze. In two eyes, scars were removed by debridement alone. In these two eyes, recurrent scars were treated by debride ment, followed by aggressive treatment with topi cal corticosteroids. Two other eyes were treat ed with topical corticosteroids alone. The fifth eye, which developed a scar after debridement to correct a subjective visual distortion after photorefractive keratectomy, was treated with debridement followed by aggressive topical corticosteroids. • RESULTS: Treatment with topical corticoste roids alone in two eyes improved uncorrected visual acuity slightly and decreased myopia, al though the scars remained unchanged. Debride ment without aggressive topical corticosteroid use resulted in rapid return of the scars and a decrease
Accepted for publication Jan. 18, 1996. From the Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia (Drs. Meyer, Stulting, and Thompson); and Hunkeler Eye Clinic, Kansas City, Missouri (Dr. Durrie). This study was supported in part by grant P30 EY06360 (Departmental Core Grant) from the National Institutes of Health, Bethesda, Mary land, and Research to Prevent Blindness, Inc., New York, New York. Reprint requests to R. Doyle Stulting, M.D., Emory University Eye Center, 1327 Clifton Rd. N.E., Atlanta, GA 30322; fax: (404) 7785128.
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in visual acuity. Subsequent debridement after aggressive topical corticosteroid treatment resulted in resolution of scars and no recurrence after discontinuation of corticosteroids in one case. In another case, the scar recurred eight months after discontinuation of topical corticosteroids. In Case 4, the scar has not recurred as the topical cortico steroid dosage has been reduced. • CONCLUSIONS: Patients who undergo photore fractive keratectomy should be counseled concern ing the risk of late scarring, reexamined frequently after photorefractive keratectomy, and treated with topical corticosteroids after corneal trauma. Longterm treatment with topical corticosteroids may be required to prevent the recurrence of scars after debridement.
T
HE EXCIMER LASER IS BECOMING INCREASINGLY popular as a device for the correction of myopia (photorefractive keratectomy)1 and for the removal of superficial corneal abnormalities (phototherapeutic keratectomy).2 Mild, anterior corneal stromal opacification is usually seen after photorefrac tive keratectomy and phototherapeutic keratectomy.3'7 Commonly referred to as haze, this opacity has been attributed to the normal healing processes. In this study, the term "haze" will be used to describe the anterior stromal opacity that typically appears within a few months after photorefractive keratectomy, reaches maximum severity at about three months, fades thereafter, does not cause topographic abnor malities, and is visually insignificant.1,5,6 Topical corti costeroids are commonly administered after photore fractive keratectomy to reduce the incidence and severity of corneal haze, although their efficacy re-
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mains controversial.8'10 The term "scar" will be used to refer to a denser, more anterior opacification that is associated with topographic abnormalities and inter feres with vision. We studied four patients who underwent excimer laser photorefractive keratectomy, in whom visually significant localized superficial corneal scars developed after long, haze-free intervals and normal early postoperative courses.
CASE REPORTS
At two centers, we reviewed the records at two centers of 950 eyes treated for myopia with the Summit ExciMed UV200LA Excimer Laser (Summit Tech nology, Inc., Waltham, Massachusetts) without fixa tion of the globe or the use of nitrogen gas to remove effluent. After topical anesthesia was administered, the central epithelium was removed with a No. 15 Bard-Parker surgical scalpel (Becton-Dickinson, Lin coln Park, New Jersey) before ablation. Fluence was 180 mj/cm2, the repetition rate was 10 Hz, and the ablation zone was 5.0 mm. Eyes were patched for one day, and patients were examined on days 1 and 3 after photorefractive keratectomy. Reepithelialization was complete by day 3 in all eyes. Additional examina tions were scheduled at one, two, three, six, 12, 18, and 24 months. Tobramycin and dexamethasone ointment was applied five times a day until the epithelial defect healed. Fluorometholone 1% drops were then instilled four times a day for one month, three times a day for one month, two times a day for two weeks, once a day for one week, every other day for one week, and finally discontinued three months postoperatively. Corneal haze was graded by an experienced observer who compared the appearance of the patient's cornea to a series of standardized photographs. Eyes with scars were treated with topical corticosteroids for various durations or mechanical epithelial debridement or both. Patients received topical anesthesia, and mechanical debridement was performed at the slit lamp. A No. 15 Bard-Parker surgical scalpel was used to remove the scar. Scraping was continued vigorously until the epithelium and scar were removed. The underlying stroma was left slightly irregular, and the ablation rings were not visible after scraping.
• CASE l: A 29-year-old woman underwent uncom plicated photorefractive keratectomy in her right eye, followed by treatment of her left eye six months later. She had a history of strabismus surgery at the age of 9 years with resultant microtropia, monofixation syn drome, and mild amblyopia in her left eye. Cycloplegic refractions were R.E.: —5.75 +0.25 x 10 and L.E.: —6.00 sphere. Best spectacle-corrected visual acuity was R.E.: 20/16 and L.E.: 20/25. For the right eye, she received 243 pulses in a 5.0-mm treatment zone diameter, for a desired correc tion of 5.9 diopters. The epithelium healed by the third day. At six months, the uncorrected visual acuity was 20/16 —1; cycloplegic refraction was — 1.00 +0.50 X 35; and best spectacle-corrected visual acuity was 20/12.5 +2. At this time, the left eye was treated with 239 pulses in a 5.0-mm treat ment zone diameter, for a desired target correction of 5.8 diopters. The epithelium healed by the third day. At the three-month visit, uncorrected visual acuity was 20/25 +2; cycloplegic refraction was —1.00 sphere; and best spectacle-corrected visual acuity was 20/20 —2. Mild haze was present. At the six-month visit for the left eye, uncorrected visual acuity had decreased to L.E.: 20/50. Cyclople gic refraction was L.E.: —1.75, and best spectaclecorrected visual acuity was L.E.: 20/30. A 2.7 X 3.0-mm scar was present in the inferonasal area of the ablation zone, and the overlying epithelium was intact. The density of the scar increased during the subsequent month, and uncorrected visual acuity decreased to 20/200. The scar was debrided and tobramycin-and-dexamethasone ointment was instilled four times a day for two days and twice daily for one additional day. The epithelial defect healed by the second day. Treatment was then continued with artificial tear supplements alone. The uncorrected visual acuity improved one month after debridement to 20/30. A manifest refrac tion of —1.00 +0.25 X 155 yielded visual acuity of 20/20 —3, and trace haze was noted without residual scar. When she was examined two months later, a 1.9 X 2.7-mm scar was present in the same area as before, and uncorrected visual acuity was again 20/200. She
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was treated with prednisolone acetate 1% four times a day to reduce the scarring. Three weeks later, uncorrected visual acuity was 20/80; best spectaclecorrected visual acuity was 20/30 —1 ( — 1.50 +1.00 x 165); and the scar appeared to be unchanged. The topical corticosteroid dose was reduced to one drop per day per week, and four weeks later the scar was unchanged. Uncorrected visual acuity was 20/200, and best spectacle-corrected visual acuity was 20/50 (-2.50 +1.25 x 165). The scar was removed again, and tobramycin-anddexamethasone ointment was instilled six times a day for seven days. The epithelial defect healed by the second day. On day 7, the ointment was discontin ued, and prednisolone acetate 1% was applied four times a day for two weeks, three times a day for three weeks, and twice a day for four weeks. One month after the last debridement, the patient attained an uncorrected visual acuity of L.E.: 20/20. When last examined, one year after the second debridement and seven months after discontinuation of corticosteroids, she had an uncorrected visual acuity of L.E.: 20/25 and a refraction of —1.75 +1.00 X 105, yielding a visual acuity of 20/20. There was trace haze and no recurrence of localized scar. The right cornea showed mild haze.
• CASE 2: A 43-year-old man underwent photorefractive keratectomy of the right eye followed six months later by treatment of the left eye. His previous ocular history was unremarkable. Preoperative visual acuity was 20/20 in each eye, with cycloplegic refrac tions of R.E.: -5.25 +0.25 x 160 and LE.: -4.50 +0.25 X 75. The right eye was treated with 201 pulses in a treatment zone 5.0 mm in diameter for a desired correction of 4.7 diopters. At six months, uncorrected visual acuity was 20/20 —2. Cycloplegic refraction was +1.00 +0.75 X 60, and best spectaclecorrected visual acuity was 20/12.5—. Trace haze was present. The left eye was then treated with 218 pulses in a treatment zone 5.0 mm in diameter for a desired correction of 5.2 diopters. In both eyes, epithelial defects healed by the third day. At the three-month visit for the left eye (nine-month visit for the right eye), trace haze was present in each eye. In the left eye, uncorrected visual acuity was 20/60 +2 and best
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spectacle-corrected visual acuity was 20/20 + 2 ( — 1.25 +0.75 x 75). At the one-year postoperative visit for the right eye, visual acuity was R.E.: 20/125 - 2 uncorrected and 20/30— with best spectacle correction (—2.50 +1.00 X 155). A localized scar was present in the inferonasal portion of the ablation zone. Visual acuity was L.E.: 20/20 —1 uncorrected with mild haze (Fig. 1). By 13 months postoperatively, uncorrected visual acuity had decreased to R.E.: 20/200. The scar in the cornea of the right eye was removed at that time with a scalpel, and tobramycin-and-dexamethasone oint ment was instilled four times a day for six days, then twice a day for two days. The epithelial defect healed by the third day. Artificial tears were then used four times a day as needed. Within five months, the scar recurred in the right eye, and a new scar appeared in the left eye (Fig. 2). Uncorrected visual acuity had decreased to R.E.: 20/400 and L.E.: 20/70 + 1 . Cycloplegic refractions were R.E.: -3.25 sphere and L.E.: -1.50 +0.50 X 130. Best spectacle-corrected visual acuity was R.E.: 20/40 and L.E.: 20/20. The right cornea was again debrided 19 months after photorefractive keratecto my; tobramycin-and-dexamethasone ointment was applied four times a day for two days; then predniso lone acetate 1% was instilled four times a day. The epithelial defect healed by the second day. Four months after the second debridement, uncor rected visual acuity was R.E.: 20/40 and L.E.: 20/200. Manifest refractions of the right eye ( +1.00 sphere) and left eye (-2.25 +0.50 x 170) yielded visual acuity of R.E.: 20/25— and L.E.: 20/20-. The scar on the right eye had not recurred as treatment continued with prednisolone acetate 1% every other day. The scar on the left eye increased slightly in size and density and was treated with prednisolone acetate 1% four times a day. Three months later, uncorrected visual acuity in the left eye had improved to 20/40 and myopia had decreased to —1.50 +0.75 X 120, yielding a visual acuity of 20/20 —2, but there was no change in the appearance of the scar. Seven months after the second debridement of the right eye, while topical fluorometholone was being used every other day and uncorrected visual acuity was R.E.: 20/20 —2, topical corticosteroids in the
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Fig. 1 (Meyer and associates). Case 2, left eye. Slit'lamp photograph (left) and videokeratograph (right) six months after photorefractive keratectomy show minimal haze and regular topography.
Fig. 2 (Meyer and associates). Case 2, left eye. Slit-lamp photograph (left) and videokeratograph (right) of the same eye shown in Figure 1, 17 months after photorefractive keratectomy, show a dense focal scar (arrow) and a corresponding increase in corneal curvature.
right eye were discontinued. The dose of prednisolone acetate 1% was decreased to twice daily in the left eye. Uncorrected visual acuity and the appearance of the corneas remained unchanged for two months. At his most recent visit eight months after discontinuation of topical corticosteroids in the right eye, 532
the patient had progressive decrease in visual acuity in the right eye. Uncorrected visual acuity at that time was R.E.: 20/200, improving to 20/30 with manifest refraction of —2.75 sphere. A focal scar was again present in the right cornea, and topical cortico steroids were again prescribed.
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• CASE 3: A 44-year-old man underwent photorefractive keratectomy in the left eye followed by treatment of the right eye six months later. His preoperative refractions were R.E.: —4.25 +0.50 X 130 and L.E.: -3.50 +0.50 X 55, with best specta cle-corrected visual acuity of 20/15 in each eye. He received 123 pulses in a treatment zone 5.0 mm in diameter, for a desired correction of 2.5 diopters in the left eye, and 193 pulses in a treatment zone 5.0 mm in diameter, for a desired correction of 4.50 diopters in the right eye. Twelve months after treat ment of the left eye and six months after treatment of the right eye, uncorrected visual acuity was R.E.: 20/25 - 2 and LE.: 20/32 - 1 . Best spectaclecorrected visual acuity was R.E.: 20/20 —2 and L.E.: 20/20 - 1 , with refractions of +1.00 +1.25 X 135 and 1.75 +1.25 X 55, respectively. Scarring was noted in the right eye 11 months after photorefractive keratectomy. Best spectacle-corrected visual acuity decreased to 20/40 (-2.00 +0.50 x 15). He was examined two months later, after using fluorometholone 0.25% four times daily for two weeks. The scar had cleared partially, uncorrected visual acuity was 20/40, and best-corrected visual acuity was 20/25 — 1 (-0.50 +1.00 X 120). Corticosteroids were tapered to twice daily application over one month, and the patient returned two months later with increasing symptoms, uncorrected visual acuity of R.E.: 20/40 —2, a slight increase in the density of the scar, best spectacle-corrected visual acuity of 20/30 —1+2, and a refraction of-1.75 +2.25 X 110. • CASE 4: A 44-year-old man underwent photore fractive keratectomy for myopia in the left eye. His preoperative cycloplegic refraction was —5.25 +0.25 x 50, and best spectacle-corrected visual acuity was L.E.: 20/20. The left eye was treated with 176 pulses in a treatment zone 4 5 mm in diameter, for a desired correction of 5.3 diopters. Postoperatively, he had a slight overcorrection that improved by 12 months to a cycloplegic refraction of +1.00 +1.25 x 035. Best spectacle-corrected visual acuity was L.E.: 20/20, and uncorrected visual acuity was 20/40 — 1. His uncor rected visual acuity varied over the next year from 20/20 to 20/40. He complained of a smudge in his inferior visual field in the left eye, despite regular topography and
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only mild haze (Fig. 3). Contact lenses did not alleviate his symptoms, and epithelial debridement wasfinallyperformed 25 months after photorefractive keratectomy to correct the problem. He failed to return for follow-up visits for nine months, and on return his uncorrected visual acuity was L.E.: 20/400 with a refraction of —3.50 sphere, yielding a visual acuity of 20/40 - 2 . There was a dense focal scar in the area that was previously debrided (Fig. 4). The scar was again debrided. Tobramycin-and-dexamethasone drops were pre scribed four times a day for two days; then treatment was continued with prednisolone acetate 1% four times a day. The epithelial defect healed by the third day. At his last visit, nine months after the second debridement, uncorrected visual acuity was L.E.: 20/20, and refraction was —0.75 sphere. There was moderate haze, and the patient still complained of smudgy vision.
RESULTS AFTER PHOTOREFRACTIVE KERATECTOMY IN THE FIVE
eyes described herein, uncorrected visual acuities of 20/20 were attained in three eyes, 20/25 in one eye, and 20/40 in one eye. Best-corrected visual acuity was 20/12.5 in one eye, 20/20 in three eyes, and 20/25 in one eye. Corneal haze was no worse than mild in all eyes. Seven to 33 months postoperatively, localized scars were noted, with corresponding topographic steepening and 2.25- to 4.50-diopter increases in myopic spherical equivalent and loss of uncorrected visual acuity. These results are given in Table 1. Debridement of the scar in Case 1 improved uncorrected visual acuity from 20/200 to 20/30. The scar recurred within two months and was treated with topical corticosteroid drops. Uncorrected visual acuity improved from 20/200 to 20/80, and best-corrected acuity to 20/30 — 1, with no change in the appear ance of the scar. A reduction in corticosteroid dose was accompanied by decreased visual acuity. A sec ond debridement after topical corticosteroid use re sulted in uncorrected visual acuity of 20/25 and decrease in myopia. The scar had not recurred seven months after discontinuation of corticosteroid use. Occurrence of a scar in Case 2 (right eye) was
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Fig. 3 (Meyer and associates). Case 4. Slit-lamp photograph (left) and videokeratograph (right) 24 months after photorefractive keratectomy show focal haze and regular topography.
Fig. 4 (Meyer and associates). Case 4. Slit-lamp photograph (left) and videokeratograph (right) of the same eye shown in Fig. 3 eight months after debridement show dense focal scar (arrow) and a corresponding increase in corneal curvature.
accompanied by an increase in myopic spherical equivalent of 2.25 diopters, decrease in uncorrected visual acuity from 20/20 —2 to 20/125 —2, and decrease in best-corrected visual acuity from R.E.: 20/12.5 to 20/30—. Debridement alone was followed by recurrence of the scar with increase in myopia and 534
decreased visual acuity. A second debridement after topical corticosteroid treatment resulted in a 4.25diopter decrease in myopic spherical equivalent, im provement of uncorrected visual acuity to 20/40, and improvement of best-corrected visual acuity to R.E.: 20/25 — . By eight months after discontinuation of
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TABLE 1 SUMMARY OF CLINICAL DATA AFTER CORNEAL SCAR
BEFORE CORNEAL SCAR MONTHS AFTER
CASE NO. (EYE)
1 (LE.) 2 (R.E.) 2 (L.E.) 3 (R.E.) 4(L.E.)
BEST UNSPECTACLECORRECTED PHOTOCORRECTED VISUAL REFRACTIVE VISUAL ACUITY ACUITY KERATECTOMY
20/25 +2 2/20 - 2 20/20 - 1 20/25 - 2 20/40-1
3 6 6 6 24
20/20 - 2 20/12.5 20/20 20/20 - 2 20/20
MANIFEST REFRACTION
-1.00 -0.25 -0.50 +1.00 -0.25
sphere +1.00 x 55 +0.75 x 160 +1.25 x 135 +1.25 x 52
topical corticosteroids, the scar had returned, with loss of unconnected visual acuity to R.E.: 20/200 and best-corrected visual acuity to 20/30. Treatment of the scar in Case 2 (left eye) with corticosteroids alone resulted in a decrease in myopic spherical equivalent of 0.875 diopter and improve ment in uncorrected visual acuity from LE.: 20/400 to 20/40, without change in the appearance of the scar. Occurrence of the scar in Case 3 (left eye) was associated with an increase in myopic spherical equivalent of 3.375 diopters and a decrease in bestcorrected visual acuity from L.E.: 20/20 —2 to 20/40. Treatment with corticosteroid drops resulted in a decrease in myopic spherical equivalent of 3.75 diop ters, improvement in best-corrected visual acuity from L.E.: 20/40 to 20/25 —1, and decrease in the density of the scar. Tapering of corticosteroids led to in creased myopia and decreased best-corrected visual acuity. Occurrence of the scar in Case 4 (left eye) was accompanied by a decrease in uncorrected visual acuity from L.E.: 20/40 to 20/400, a decrease in best-corrected visual acuity from L.E.: 20/20 to 20/40 —2, and an increase in myopic spherical equivalent of 3.875 diopters. Debridement after topical corticoste roids improved uncorrected visual acuity to L.E.: 20/20 and decreased the myopic spherical equivalent by 3.75 diopters. The scar did not recur while corticosteroid use was being tapered. Table 2 gives the results of treatment in each of the cases. Treatment of scars with debridement alone
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UNCORRECTED VISUAL ACUITY
20/200 12/125 - 2 20/200 Not available 20/400
MONTHS AFTER PHOTOREFRACTIVE KERATECTOMY
BEST SPECTACLECORRECTED VISUAL ACUITY
MANIFEST REFRACTION
7 12 17 11 33
Not available 20/3020/2020/40 20/40-2
Not available -2.50+1.00 x 155 -2.25 +0.50 x 170 -2.00 +0.50 x 15 -3.50 sphere
successfully eliminated the scars, improved visual acuity, and eliminated myopic regression in all cases, although scars recurred within months in each case. Treatment of both initial and recurrent scars with topical corticosteroids temporarily increased visual acuity and decreased myopic regression. Topical corti costeroids decreased the density of the scar slightly in one case, whereas the scar remained unchanged in another case. The beneficial effect of topical cortico steroids did not persist after reducing the dosage. Treatment of scars by debridement followed by vigor ous topical corticosteroid use resulted in improved vision, elimination of myopic regression, and resolu tion of scars without recurrence after corticosteroid use was tapered in two cases. In another case, the scar recurred within eight months after topical corticoste roids were discontinued.
DISCUSSION THE DEVELOPMENT OF CORNEAL OPACITIES AFTER COR-
neal surface ablation with the excimer laser has been previously described.3'7 Typical postoperative corneal haze appears within a few weeks as a mild, diffuse, white, anterior stromal opacity that increases in severity for two to four months and fades there after.1'5,6·8 Some authors have used the term "scar" to describe corneal opacity after photorefractive keratectomy in 0.0%u to 4.9%12 of patients. In the study by Seiler and Wollensak,12 these opacities appeared dur ing the first two to three months after surgery and resolved within one year. The time of appearance and
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TABLE 2 SUMMARY OF RESPONSE TO TREATMENT
CASE
1, Initial scar Recurrent scar
2, Initial scar (R.E.) Recurrent scar Initial scar (L.E.)
3, initial scar
4, Initial scar
DEBRIDEMENT
DURATION OF
FOLLOWED BY
FOLLOW-UP
CORTICOSTEROIDS
(MOS)
Resolution with recurrence Not applicable
Not applicable Resolution without recurrence
5* 12+
Resolution with recurrence Not applicable Not applicable
Not applicable Resolution with recurrence Not applicable
6* 15f 16*
Not applicable
Not applicable
4*
Not applicable
Resolution without recurrence
9f
CORTICOSTEROIDS ALONE
DEBRIDEMENT ALONE
Not applicable Myopia decreased, vision improved, scar unchanged Not applicable Not applicable Myopia decreased, vision improved, scar unchanged Myopia decreased, vision improved, scar density minimally decreased Not applicable
•From debridement of first scar to debridement of second scar. ♦From most recent debridement to most recent visit. •From appearance of scar to most recent visit.
resolution of these opacities suggests that they were what we have defined as haze. Extensive scarring is said to be rare.13 In a series of 285 eyes that underwent photorefractive keratectomy, Caubet5 found that an increased incidence of clinically significant corneal opacity was associated with higher attempted corrections, smaller ablation zones (<4.5 mm), being male, ablations deeper than 50 μιτι, and discontinuation of topical corticosteroids. The origin of corneal haze remains unknown. Focal areas of scar 20 μπι thick were found in rabbits treated with the excimer laser.14 Fibrinogen, fibronectin, laminin, and type III collagen are deposited in the anterior stroma of monkey corneas as they heal after excimer laser treatment.1516 Type III collagen, not normally found in the cornea, does not have the regular lamellar structure of native type I stromal collagen and may scatter light. Vacuolization of the basal epithelial cells and abnormalities of the base ment membrane have also been observed after photorefractive keratectomy.16 Increased keratocyte density and metabolic activity have been found in the stroma immediately beneath the ablated surface in animals and humans.3141718 536
The anterior stromal collagen lamellae become increasingly disorganized in rabbits up to three months after ablation. The collagen lamellae gradual ly reestablish a more regular pattern by 15 months,14 paralleling the severity of haze. Fantes and associates18 found no such collagen disorganization in monkeys. They observed, however, irregular epithelial base ment membrane and persistence of metabolically active fibroblasts with adjacent clumps of amorphous material. These abnormalities correlated with the amount of haze. The use of nitrogen gas blowers is known to produce more haze, possibly attributable to a rougher ablation surface.19 Ditzen, Anschutz, and Schroder20 reported a series of 325 eyes undergoing photorefractive keratectomy in which slower epithelial healing was associated with more haze. In that series, no cornea that healed in five to nine days was clear, and no marked haze occurred in corneas that healed in less than three days. In all four patients described herein, the epithelial defects (after photorefractive keratectomy and de bridement) healed rapidly (less than three days); haze was minimal; early postoperative courses were un eventful; and topical corticosteroids had been dis-
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continued. These cases are unusual because dense corneal scarring associated with increased myopia, decreased visual acuity, and topographic abnormality appeared at a time when haze typically fades and the results of photorefractive keratectomy are generally believed to be stable. Case 4 is particularly interesting because scarring was not present until the central corneal epithelium was removed to improve the quality of the patient's vision two years after photore fractive keratectomy. The severity of haze correlates with the degree of myopic regression in the early postoperative period after photorefractive keratectomy. Typically, however, regression halts and the refractive error is stable after six months.21 In contrast, the occurrence and recur rence of scar in the right eye of Case 2 were associated with myopic shifts of 2.25 diopters and 3.50 diopters, respectively, compared to the refractive error at six months. Some aberration in the delivery of the laser energy is a possible explanation for the late scarring in these cases. However, the right eye in Case 1, which did not develop a scar, and the right eye in Case 2, which did develop a scar, were treated consecutively, on the same day with the same laser. Case 3 was treated with a different laser on a different day. Moreover, it is difficult to understand how factors related to the delivery of laser energy would become manifest after a completely uneventful initial postoperative course. The late and rapid onset of scarring suggests an idiosyncratic healing response of the patient as a cause rather than some factor related to the laser. Presently, we are unable to identify any preoperative factors that might predict the development of visually significant corneal scarring postoperatively. No tear film abnormalities, external eye disease, underlying metabolic disorders, systemic wound-healing abnor malities (keloid formation), or trauma (except for Case 4, in which scar formation followed debridement) were found that might explain these scars. Trauma not significant enough to be noticed by the patients may have been responsible for the scarring, although verification is impossible. Cases 1 and 3 were unilateral (at the time of this study), which does not support the involvement of systemic abnormali ties in these patients. Case 2 was bilateral, which raises the possibility of a systemic explanation in this patient. VOL.121, No. 5
Topographic steepening corresponding to the area of scarring and extending slightly peripherally from each scar was noted, suggesting the possibility of keratoconus, which often results in anterior corneal scarring, as a factor in the development of scars. Keratoconus was ruled out in Cases 1 through 3 by the following factors: ( 1 ) preoperative central keratometry was less than 45.0 diopters; (2) inferiorsuperior value22 differences in keratometry 3 mm from the center were less than 1.3 diopters; and (3) there were no clinical signs of keratoconus. Preoperative topographic information was unavailable for the op erative eye in Case 4. However, the nontreated eye demonstrated asymmetric astigmatism with a central keratometry value of 45.70 diopters in the steepest meridian and a difference of 2.92 diopters from inferior to superior at 3 mm from the center. Resolu tion of scarring was accompanied by return of topog raphy to the prescar baseline, suggesting that in creased corneal curvature resulted from the scar rather than keratoconus. Corneal wound healing is ä complex process in volving epithelial cells, keratocytes, and the extracel lular matrix. The factors that invoke and regulate corneal healing probably involve multiple cellular mediators and direct cell-to-cell contact. Photorefrac tive keratectomy removes Bowman's layer, allowing direct communication between epithelial cells and keratocytes. Injuries that violate the integrity of Bowman's layer are known to result in scarring, which may be caused by interaction of epithelial cells and keratocytes.16 It is possible that the absence of Bowman's layer makes the cornea more susceptible to reactive scarring from subsequent minor injuries. Scar formation after debridement (Case 4), and in unpub lished anecdotal reports (written communication, George O. Waring III, October 1994) of increased haze or scarring in photorefractive keratectomy pa tients after excessive ultraviolet light, wind, and dust exposure, support this theory. Modulation of the healing response to photorefrac tive keratectomy is an area of great importance. Topical corticosteroids inhibit the synthesis of ante rior stromal connective tissue in rabbits after excimer laser ablation,23 but the effect of topical corticoste roids on haze in humans is controversial. In a prospective, double-masked, randomized study of 113 eyes undergoing photorefractive keratectomy, Gartry
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and associates9 found no statistically significant differ ence between anterior stromal haze in the corticosteroid-treated group and control subjects. Lohmann and associates8 found a similar degree of haze in patients who discontinued corticosteroid use prema turely after photorefractive keratectomy compared to those who used corticosteroids for three months after the procedure. In contrast, others have reported a reduced incidence of haze in patients treated with topical corticosteroids.5,10 Topical interferon-alpha 2b10 and basic fibroblast growth factor24 have also been shown to decrease the incidence of haze after photorefractive keratectomy. Eyes with marked haze after photorefractive keratectomy have been success fully treated with subsequent excimer laser photoablation.25 The effect of topical corticosteroids on myopic regression is controversial. The use of dexamethasone has been associated with less regression,26 and topical corticosteroids have been successfully used to reverse regression.27'29 Gartry, Kerr-Muir, and Marshall30 found a greater reduction in myopia in eyes treated with corticosteroids compared to controls, but statisti cal significance was lost within three months of discontinuation of corticosteroids. Schipper31 report ed two cases similar to ours in which a marked increase in myopia, corneal opacification, and a decrease in best-corrected visual acuity occurred nine to 12 months after photorefractive keratectomy. In these cases, treatment with prednisolone acetate 1% five times daily for two weeks improved best spectaclecorrected visual acuity, decreased myopia, and re duced haze. In our cases, scars developed after topical cortico steroids were discontinued. The scar tissue was rela tively superficial and could be removed by simple debridement. In one eye (Case 4), scarring occurred, and in two eyes (Cases 1 and 2), scarring recurred when debridement was not followed by topical corti costeroid treatment. There was no recurrence after debridement and subsequent vigorous topical cortico steroid use in two cases. In another case (Case 2), scarring recurred eight months after discontinuation of topical corticosteroids. Topical corticosteroids without debridement in two eyes (Cases 1 and 3) improved uncorrected visual acuity slightly but did not affect topography or the density of the scar. Furthermore, the beneficial effect of corticosteroids 538
was lost when they were discontinued. Our initial results of treatment with topical corticosteroids after debridement were encouraging. The recent recur rence of a scar in Case 2, however, raises questions about the long-term efficacy of this treatment. Cau tion must be used in prolonged topical corticosteroid use because some patients will have increased intra ocular pressure and cataract formation. At the time these five eyes were identified, about 150 eyes had been treated with photorefractive kera tectomy at Emory University and 700 eyes at the Hunkeler Eye Clinic. Thus, we estimate the incidence of late-onset corneal scarring after photorefractive keratectomy to be at least 0.6%. The true incidence of late scarring may be higher because we cannot be certain that we examined all eyes that developed scars. The loss of uncorrected and best spectaclecorrected visual acuity in our patients raises the question of whether the long-term adverse effects of excimer laser photorefractive keratectomy are yet to be discovered. Like the hyperopic shift after radial keratotomy, the true incidence of late postoperative complications after photorefractive keratectomy may not become evident until careful, long-term observa tions can be made. We suggest that observers adopt a standardized definition of haze and scar, such as we propose, to facilitate comparison of data in the future. We also recommend that patients who have under gone photorefractive keratectomy be educated con cerning the possibility of late scarring and be treated with topical corticosteroids for prolonged periods with frequent observation after debridement, retreatment, or minor corneal injuries.
REFERENCES 1. Kim JH, Hahn TW, Lee YC, Joo CK, Sah WJ. Photorefrac tive keratectomy in 202 myopic eyes: one year results. Refract Corneal Surg 1993;9 Suppl:Sll-6. 2. Campos M, Nielsen S, Szerenyi K, Garbus JJ, McDonnell PJ. Clinical follow-up of phototherapeutic keratectomy for treat ment of corneal opacities. Am J Ophthalmol 1993;115:43340. 3. Wu WCS, Stark WJ, Green WR. Corneal wound healing after 193-nm excimer laser keratectomy. Arch Ophthalmol 1991;109:1426-32. 4. McDonald MB, Frantz JM, Klyce SD, Beuerman RW, Varnell R, Munnerlyn CR, et al. Central photorefractive keratectomy for myopia. Arch Ophthalmol 1990;108:799-808. 5. Caubet E. Causes of subepithelial corneal haze over 18
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months after photorefractive keratectomy for myopia. Refract Comeal Surg 1993;9 Suppl:S65-70. Marshall J, Trokel SL, Rothery S, Krueger RR. Long term healing of the central cornea after photorefractive keratecto my using an excimer laser. Ophthalmology 1988;95:141121. Hanna KD, Pouliquen YM, Salvoldelli M, Fantes F, Thomp son KP, Waring GO III, et al. Comeal wound healing in monkeys 18 months after excimer laser photorefractive kera tectomy. Refract Corneal Surg 1990;6:340-5. Lohmann CP, Gartry DS, Muir MK, Timberlake GT, Fitzke FW, Marshall J. Corneal haze after excimer laser refractive surgery: objective measurements and functional implications. Eur J Ophthalmol 1991;1:173-80. Gartry DS, Muir MG, Lohmann CP, Marshall J. The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy: a prospec tive, randomized, double-blind trial. Arch Ophthalmol 1992;110:994-9. Morlet N, Gillies MC, Crouch R, Maloof A. Effect of topical interferon-alpha 2b on corneal haze after excimer laser photorefractive keratectomy in rabbits. Refract Corneal Surg 1993;9:443-51. Brancate R, Tavola A, Carones F, Scialdone A, Gallus G, Garancini P, et al. Excimer laser photorefractive keratectomy for myopia: results in 1165 eyes. Refract Corneal Surg 1993;9:95-104. Seiler T, Wollensak J. Results of a prospective evaluation of photorefractive keratectomy at 1 year after surgery. Ger J Ophthalmol 1993;2:135-42. Seiler T, Kriegerowski M, Kahle G, Wollensak J. Excimer laser keratomileusis for myopia correction: results and compli cations. Klin Monatsbl Augenheilkd 1991;199:153-9. Hanna KD, Pouliquen Y, Waring GO III, Savoldelli M, Cotter J, Morton K, et al. Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation. Arch Ophthalmol 1989;107:895-901. Malley DS, Steinert RF, Puliafito CA, Dobi ET. Immunofluorescence study of corneal wound healing after excimer laser anterior keratectomy in the monkey eye. Arch Ophthalmol 1990;108:1316-22. SundarRaj N, Geiss M], Fantes F, Hanna K, Anderson SC, Thompson KP, et al. Healing of excimer laser ablated monkey corneas: an immunohistochemical evaluation. Arch Ophthalmol 1990;108:1604-10. Beuerman RW, McDonald MB, Shofher RS, Munnerlyn CR, Clapham TN, Salmeron B, et al. Quantitative histologie studies of primate corneas after excimer laser photorefractive keratectomy. Arch Ophthalmol 1994;112:1103-10. Fantes FE, Hanna KD, Waring GO, Pouliquen Y, Thompson
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KP, Savoldelli M. Wound healing after excimer laser kerato mileusis (photorefractive keratectomy) in monkeys. Arch Ophthalmol 1990;108:665-8. Campos M, Cuevas K, Garbus J, Lee M, McDonnell PJ. Corneal wound healing after excimer laser ablation: effects of nitrogen gas blower. Ophthalmology 1992;99:893-7. Ditzen K, Anschutz T, Schroder E. Photorefractive keratecto my to treat low, medium, and high myopia: a multicenter study. J Cataract Refract Surg 1994;20:234-8. Piebenga LW, Matta CS, Dietz MR, Tauber ], Irvine JW, Sabates FN. Excimer photorefractive keratectomy for myopia. Ophthalmology 1993;100:1335-45. Rabinowitz Y, McDonnell P. Computer-assisted corneal topography in keratoconus. Refract Corneal Surg 1989; 5:400-8. Tuft SJ, Zabel RW, Marshall ]. Corneal repair following keratectomy: a comparison between conventional surgery and laser photoablation. Invest Ophthalmol Vis Sci 1989; 30:1769-77. Rieck P, David T, Hartman C, Renard G, Courtois Y, Pouliquen Y. Basicfibroblastgrowth factor modulates corneal wound healing after excimer laser keratomileusis in rabbits. Get J Ophthalmol 1994;3:105-11. Epstein D, Tengroth B, Fagerholm P, Hamberg-Nyström H. Excimer retreatment of regression after photorefractive kera tectomy. Am J Ophthalmol 1994;117:456-61. Fagerholm P, Hamberg-Nyström H, Tengroth B, Epstein D. Effect of postoperative steroids on the refractive outcome of photorefractive keratectomy for myopia with the Summit excimer laser. J Cataract Refract Surg 1994;20:212-5. Fitzsimmons TD, Fagerholm P, Tengroth B. Steroid treatment of myopicregression:acuterefractiveand topographic chang es in excimer photorefractive keratectomy patients. Cornea 1993;12:358-61. Tengroth B, Epstein D, Fagerholm P, Hamberg-Nyström H, Fitzsimmons T. Excimer laser photorefractive keratectomy for myopia: clinical results in sighted eyes. Ophthalmology 1993;100:739-45. Carones F, Brancate R, Venturi E, Scialdone A, Bertuzzi A, Tavola A. Efficacy of corticosteroids in reversing regression after myopic photorefractive keratectomy. Refract Corneal Surg 1993;9:S52-6. Gartry DS, Kerr-Muir MG, Marshall J. The effect of topical corticosteroids on refraction and corneal haze following excimer laser treatment of myopia, an update: a prospective, randomized double-masked study. Eye 1993;7:584-90. Schipper I. Corticosteroid treatment of regression after pho torefractive keratectomy for myopia [letter]. ] Refract Corneal Suig 1994:10:659.
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• PURPOSE: We studied the occurrence of late scarring after photorefractive keratectomy and its response to topical corticosteroids and debridement during the course of follow-up of 950 eyes that had photorefractive keratectomy with excimer laser. • METHODS: Five eyes of four patients developed localized corneal scars, decreased visual acuity, and increased myopia after five to 33 months of good visual acuity, with trace haze. In two eyes, scars were removed by debridement alone. In these two eyes, recurrent scars were treated by debride ment, followed by aggressive treatment with topi cal corticosteroids. Two other eyes were treat ed with topical corticosteroids alone. The fifth eye, which developed a scar after debridement to correct a subjective visual distortion after photorefractive keratectomy, was treated with debridement followed by aggressive topical corticosteroids. • RESULTS: Treatment with topical corticoste roids alone in two eyes improved uncorrected visual acuity slightly and decreased myopia, al though the scars remained unchanged. Debride ment without aggressive topical corticosteroid use resulted in rapid return of the scars and a decrease
Accepted for publication Jan. 18, 1996. From the Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia (Drs. Meyer, Stulting, and Thompson); and Hunkeler Eye Clinic, Kansas City, Missouri (Dr. Durrie). This study was supported in part by grant P30 EY06360 (Departmental Core Grant) from the National Institutes of Health, Bethesda, Mary land, and Research to Prevent Blindness, Inc., New York, New York. Reprint requests to R. Doyle Stulting, M.D., Emory University Eye Center, 1327 Clifton Rd. N.E., Atlanta, GA 30322; fax: (404) 7785128.
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in visual acuity. Subsequent debridement after aggressive topical corticosteroid treatment resulted in resolution of scars and no recurrence after discontinuation of corticosteroids in one case. In another case, the scar recurred eight months after discontinuation of topical corticosteroids. In Case 4, the scar has not recurred as the topical cortico steroid dosage has been reduced. • CONCLUSIONS: Patients who undergo photore fractive keratectomy should be counseled concern ing the risk of late scarring, reexamined frequently after photorefractive keratectomy, and treated with topical corticosteroids after corneal trauma. Longterm treatment with topical corticosteroids may be required to prevent the recurrence of scars after debridement.
T
HE EXCIMER LASER IS BECOMING INCREASINGLY popular as a device for the correction of myopia (photorefractive keratectomy)1 and for the removal of superficial corneal abnormalities (phototherapeutic keratectomy).2 Mild, anterior corneal stromal opacification is usually seen after photorefrac tive keratectomy and phototherapeutic keratectomy.3'7 Commonly referred to as haze, this opacity has been attributed to the normal healing processes. In this study, the term "haze" will be used to describe the anterior stromal opacity that typically appears within a few months after photorefractive keratectomy, reaches maximum severity at about three months, fades thereafter, does not cause topographic abnor malities, and is visually insignificant.1,5,6 Topical corti costeroids are commonly administered after photore fractive keratectomy to reduce the incidence and severity of corneal haze, although their efficacy re-
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mains controversial.8'10 The term "scar" will be used to refer to a denser, more anterior opacification that is associated with topographic abnormalities and inter feres with vision. We studied four patients who underwent excimer laser photorefractive keratectomy, in whom visually significant localized superficial corneal scars developed after long, haze-free intervals and normal early postoperative courses.
CASE REPORTS
At two centers, we reviewed the records at two centers of 950 eyes treated for myopia with the Summit ExciMed UV200LA Excimer Laser (Summit Tech nology, Inc., Waltham, Massachusetts) without fixa tion of the globe or the use of nitrogen gas to remove effluent. After topical anesthesia was administered, the central epithelium was removed with a No. 15 Bard-Parker surgical scalpel (Becton-Dickinson, Lin coln Park, New Jersey) before ablation. Fluence was 180 mj/cm2, the repetition rate was 10 Hz, and the ablation zone was 5.0 mm. Eyes were patched for one day, and patients were examined on days 1 and 3 after photorefractive keratectomy. Reepithelialization was complete by day 3 in all eyes. Additional examina tions were scheduled at one, two, three, six, 12, 18, and 24 months. Tobramycin and dexamethasone ointment was applied five times a day until the epithelial defect healed. Fluorometholone 1% drops were then instilled four times a day for one month, three times a day for one month, two times a day for two weeks, once a day for one week, every other day for one week, and finally discontinued three months postoperatively. Corneal haze was graded by an experienced observer who compared the appearance of the patient's cornea to a series of standardized photographs. Eyes with scars were treated with topical corticosteroids for various durations or mechanical epithelial debridement or both. Patients received topical anesthesia, and mechanical debridement was performed at the slit lamp. A No. 15 Bard-Parker surgical scalpel was used to remove the scar. Scraping was continued vigorously until the epithelium and scar were removed. The underlying stroma was left slightly irregular, and the ablation rings were not visible after scraping.
• CASE l: A 29-year-old woman underwent uncom plicated photorefractive keratectomy in her right eye, followed by treatment of her left eye six months later. She had a history of strabismus surgery at the age of 9 years with resultant microtropia, monofixation syn drome, and mild amblyopia in her left eye. Cycloplegic refractions were R.E.: —5.75 +0.25 x 10 and L.E.: —6.00 sphere. Best spectacle-corrected visual acuity was R.E.: 20/16 and L.E.: 20/25. For the right eye, she received 243 pulses in a 5.0-mm treatment zone diameter, for a desired correc tion of 5.9 diopters. The epithelium healed by the third day. At six months, the uncorrected visual acuity was 20/16 —1; cycloplegic refraction was — 1.00 +0.50 X 35; and best spectacle-corrected visual acuity was 20/12.5 +2. At this time, the left eye was treated with 239 pulses in a 5.0-mm treat ment zone diameter, for a desired target correction of 5.8 diopters. The epithelium healed by the third day. At the three-month visit, uncorrected visual acuity was 20/25 +2; cycloplegic refraction was —1.00 sphere; and best spectacle-corrected visual acuity was 20/20 —2. Mild haze was present. At the six-month visit for the left eye, uncorrected visual acuity had decreased to L.E.: 20/50. Cyclople gic refraction was L.E.: —1.75, and best spectaclecorrected visual acuity was L.E.: 20/30. A 2.7 X 3.0-mm scar was present in the inferonasal area of the ablation zone, and the overlying epithelium was intact. The density of the scar increased during the subsequent month, and uncorrected visual acuity decreased to 20/200. The scar was debrided and tobramycin-and-dexamethasone ointment was instilled four times a day for two days and twice daily for one additional day. The epithelial defect healed by the second day. Treatment was then continued with artificial tear supplements alone. The uncorrected visual acuity improved one month after debridement to 20/30. A manifest refrac tion of —1.00 +0.25 X 155 yielded visual acuity of 20/20 —3, and trace haze was noted without residual scar. When she was examined two months later, a 1.9 X 2.7-mm scar was present in the same area as before, and uncorrected visual acuity was again 20/200. She
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was treated with prednisolone acetate 1% four times a day to reduce the scarring. Three weeks later, uncorrected visual acuity was 20/80; best spectaclecorrected visual acuity was 20/30 —1 ( — 1.50 +1.00 x 165); and the scar appeared to be unchanged. The topical corticosteroid dose was reduced to one drop per day per week, and four weeks later the scar was unchanged. Uncorrected visual acuity was 20/200, and best spectacle-corrected visual acuity was 20/50 (-2.50 +1.25 x 165). The scar was removed again, and tobramycin-anddexamethasone ointment was instilled six times a day for seven days. The epithelial defect healed by the second day. On day 7, the ointment was discontin ued, and prednisolone acetate 1% was applied four times a day for two weeks, three times a day for three weeks, and twice a day for four weeks. One month after the last debridement, the patient attained an uncorrected visual acuity of L.E.: 20/20. When last examined, one year after the second debridement and seven months after discontinuation of corticosteroids, she had an uncorrected visual acuity of L.E.: 20/25 and a refraction of —1.75 +1.00 X 105, yielding a visual acuity of 20/20. There was trace haze and no recurrence of localized scar. The right cornea showed mild haze.
• CASE 2: A 43-year-old man underwent photorefractive keratectomy of the right eye followed six months later by treatment of the left eye. His previous ocular history was unremarkable. Preoperative visual acuity was 20/20 in each eye, with cycloplegic refrac tions of R.E.: -5.25 +0.25 x 160 and LE.: -4.50 +0.25 X 75. The right eye was treated with 201 pulses in a treatment zone 5.0 mm in diameter for a desired correction of 4.7 diopters. At six months, uncorrected visual acuity was 20/20 —2. Cycloplegic refraction was +1.00 +0.75 X 60, and best spectaclecorrected visual acuity was 20/12.5—. Trace haze was present. The left eye was then treated with 218 pulses in a treatment zone 5.0 mm in diameter for a desired correction of 5.2 diopters. In both eyes, epithelial defects healed by the third day. At the three-month visit for the left eye (nine-month visit for the right eye), trace haze was present in each eye. In the left eye, uncorrected visual acuity was 20/60 +2 and best
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spectacle-corrected visual acuity was 20/20 + 2 ( — 1.25 +0.75 x 75). At the one-year postoperative visit for the right eye, visual acuity was R.E.: 20/125 - 2 uncorrected and 20/30— with best spectacle correction (—2.50 +1.00 X 155). A localized scar was present in the inferonasal portion of the ablation zone. Visual acuity was L.E.: 20/20 —1 uncorrected with mild haze (Fig. 1). By 13 months postoperatively, uncorrected visual acuity had decreased to R.E.: 20/200. The scar in the cornea of the right eye was removed at that time with a scalpel, and tobramycin-and-dexamethasone oint ment was instilled four times a day for six days, then twice a day for two days. The epithelial defect healed by the third day. Artificial tears were then used four times a day as needed. Within five months, the scar recurred in the right eye, and a new scar appeared in the left eye (Fig. 2). Uncorrected visual acuity had decreased to R.E.: 20/400 and L.E.: 20/70 + 1 . Cycloplegic refractions were R.E.: -3.25 sphere and L.E.: -1.50 +0.50 X 130. Best spectacle-corrected visual acuity was R.E.: 20/40 and L.E.: 20/20. The right cornea was again debrided 19 months after photorefractive keratecto my; tobramycin-and-dexamethasone ointment was applied four times a day for two days; then predniso lone acetate 1% was instilled four times a day. The epithelial defect healed by the second day. Four months after the second debridement, uncor rected visual acuity was R.E.: 20/40 and L.E.: 20/200. Manifest refractions of the right eye ( +1.00 sphere) and left eye (-2.25 +0.50 x 170) yielded visual acuity of R.E.: 20/25— and L.E.: 20/20-. The scar on the right eye had not recurred as treatment continued with prednisolone acetate 1% every other day. The scar on the left eye increased slightly in size and density and was treated with prednisolone acetate 1% four times a day. Three months later, uncorrected visual acuity in the left eye had improved to 20/40 and myopia had decreased to —1.50 +0.75 X 120, yielding a visual acuity of 20/20 —2, but there was no change in the appearance of the scar. Seven months after the second debridement of the right eye, while topical fluorometholone was being used every other day and uncorrected visual acuity was R.E.: 20/20 —2, topical corticosteroids in the
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Fig. 1 (Meyer and associates). Case 2, left eye. Slit'lamp photograph (left) and videokeratograph (right) six months after photorefractive keratectomy show minimal haze and regular topography.
Fig. 2 (Meyer and associates). Case 2, left eye. Slit-lamp photograph (left) and videokeratograph (right) of the same eye shown in Figure 1, 17 months after photorefractive keratectomy, show a dense focal scar (arrow) and a corresponding increase in corneal curvature.
right eye were discontinued. The dose of prednisolone acetate 1% was decreased to twice daily in the left eye. Uncorrected visual acuity and the appearance of the corneas remained unchanged for two months. At his most recent visit eight months after discontinuation of topical corticosteroids in the right eye, 532
the patient had progressive decrease in visual acuity in the right eye. Uncorrected visual acuity at that time was R.E.: 20/200, improving to 20/30 with manifest refraction of —2.75 sphere. A focal scar was again present in the right cornea, and topical cortico steroids were again prescribed.
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• CASE 3: A 44-year-old man underwent photorefractive keratectomy in the left eye followed by treatment of the right eye six months later. His preoperative refractions were R.E.: —4.25 +0.50 X 130 and L.E.: -3.50 +0.50 X 55, with best specta cle-corrected visual acuity of 20/15 in each eye. He received 123 pulses in a treatment zone 5.0 mm in diameter, for a desired correction of 2.5 diopters in the left eye, and 193 pulses in a treatment zone 5.0 mm in diameter, for a desired correction of 4.50 diopters in the right eye. Twelve months after treat ment of the left eye and six months after treatment of the right eye, uncorrected visual acuity was R.E.: 20/25 - 2 and LE.: 20/32 - 1 . Best spectaclecorrected visual acuity was R.E.: 20/20 —2 and L.E.: 20/20 - 1 , with refractions of +1.00 +1.25 X 135 and 1.75 +1.25 X 55, respectively. Scarring was noted in the right eye 11 months after photorefractive keratectomy. Best spectacle-corrected visual acuity decreased to 20/40 (-2.00 +0.50 x 15). He was examined two months later, after using fluorometholone 0.25% four times daily for two weeks. The scar had cleared partially, uncorrected visual acuity was 20/40, and best-corrected visual acuity was 20/25 — 1 (-0.50 +1.00 X 120). Corticosteroids were tapered to twice daily application over one month, and the patient returned two months later with increasing symptoms, uncorrected visual acuity of R.E.: 20/40 —2, a slight increase in the density of the scar, best spectacle-corrected visual acuity of 20/30 —1+2, and a refraction of-1.75 +2.25 X 110. • CASE 4: A 44-year-old man underwent photore fractive keratectomy for myopia in the left eye. His preoperative cycloplegic refraction was —5.25 +0.25 x 50, and best spectacle-corrected visual acuity was L.E.: 20/20. The left eye was treated with 176 pulses in a treatment zone 4 5 mm in diameter, for a desired correction of 5.3 diopters. Postoperatively, he had a slight overcorrection that improved by 12 months to a cycloplegic refraction of +1.00 +1.25 x 035. Best spectacle-corrected visual acuity was L.E.: 20/20, and uncorrected visual acuity was 20/40 — 1. His uncor rected visual acuity varied over the next year from 20/20 to 20/40. He complained of a smudge in his inferior visual field in the left eye, despite regular topography and
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only mild haze (Fig. 3). Contact lenses did not alleviate his symptoms, and epithelial debridement wasfinallyperformed 25 months after photorefractive keratectomy to correct the problem. He failed to return for follow-up visits for nine months, and on return his uncorrected visual acuity was L.E.: 20/400 with a refraction of —3.50 sphere, yielding a visual acuity of 20/40 - 2 . There was a dense focal scar in the area that was previously debrided (Fig. 4). The scar was again debrided. Tobramycin-and-dexamethasone drops were pre scribed four times a day for two days; then treatment was continued with prednisolone acetate 1% four times a day. The epithelial defect healed by the third day. At his last visit, nine months after the second debridement, uncorrected visual acuity was L.E.: 20/20, and refraction was —0.75 sphere. There was moderate haze, and the patient still complained of smudgy vision.
RESULTS AFTER PHOTOREFRACTIVE KERATECTOMY IN THE FIVE
eyes described herein, uncorrected visual acuities of 20/20 were attained in three eyes, 20/25 in one eye, and 20/40 in one eye. Best-corrected visual acuity was 20/12.5 in one eye, 20/20 in three eyes, and 20/25 in one eye. Corneal haze was no worse than mild in all eyes. Seven to 33 months postoperatively, localized scars were noted, with corresponding topographic steepening and 2.25- to 4.50-diopter increases in myopic spherical equivalent and loss of uncorrected visual acuity. These results are given in Table 1. Debridement of the scar in Case 1 improved uncorrected visual acuity from 20/200 to 20/30. The scar recurred within two months and was treated with topical corticosteroid drops. Uncorrected visual acuity improved from 20/200 to 20/80, and best-corrected acuity to 20/30 — 1, with no change in the appear ance of the scar. A reduction in corticosteroid dose was accompanied by decreased visual acuity. A sec ond debridement after topical corticosteroid use re sulted in uncorrected visual acuity of 20/25 and decrease in myopia. The scar had not recurred seven months after discontinuation of corticosteroid use. Occurrence of a scar in Case 2 (right eye) was
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Fig. 3 (Meyer and associates). Case 4. Slit-lamp photograph (left) and videokeratograph (right) 24 months after photorefractive keratectomy show focal haze and regular topography.
Fig. 4 (Meyer and associates). Case 4. Slit-lamp photograph (left) and videokeratograph (right) of the same eye shown in Fig. 3 eight months after debridement show dense focal scar (arrow) and a corresponding increase in corneal curvature.
accompanied by an increase in myopic spherical equivalent of 2.25 diopters, decrease in uncorrected visual acuity from 20/20 —2 to 20/125 —2, and decrease in best-corrected visual acuity from R.E.: 20/12.5 to 20/30—. Debridement alone was followed by recurrence of the scar with increase in myopia and 534
decreased visual acuity. A second debridement after topical corticosteroid treatment resulted in a 4.25diopter decrease in myopic spherical equivalent, im provement of uncorrected visual acuity to 20/40, and improvement of best-corrected visual acuity to R.E.: 20/25 — . By eight months after discontinuation of
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TABLE 1 SUMMARY OF CLINICAL DATA AFTER CORNEAL SCAR
BEFORE CORNEAL SCAR MONTHS AFTER
CASE NO. (EYE)
1 (LE.) 2 (R.E.) 2 (L.E.) 3 (R.E.) 4(L.E.)
BEST UNSPECTACLECORRECTED PHOTOCORRECTED VISUAL REFRACTIVE VISUAL ACUITY ACUITY KERATECTOMY
20/25 +2 2/20 - 2 20/20 - 1 20/25 - 2 20/40-1
3 6 6 6 24
20/20 - 2 20/12.5 20/20 20/20 - 2 20/20
MANIFEST REFRACTION
-1.00 -0.25 -0.50 +1.00 -0.25
sphere +1.00 x 55 +0.75 x 160 +1.25 x 135 +1.25 x 52
topical corticosteroids, the scar had returned, with loss of unconnected visual acuity to R.E.: 20/200 and best-corrected visual acuity to 20/30. Treatment of the scar in Case 2 (left eye) with corticosteroids alone resulted in a decrease in myopic spherical equivalent of 0.875 diopter and improve ment in uncorrected visual acuity from LE.: 20/400 to 20/40, without change in the appearance of the scar. Occurrence of the scar in Case 3 (left eye) was associated with an increase in myopic spherical equivalent of 3.375 diopters and a decrease in bestcorrected visual acuity from L.E.: 20/20 —2 to 20/40. Treatment with corticosteroid drops resulted in a decrease in myopic spherical equivalent of 3.75 diop ters, improvement in best-corrected visual acuity from L.E.: 20/40 to 20/25 —1, and decrease in the density of the scar. Tapering of corticosteroids led to in creased myopia and decreased best-corrected visual acuity. Occurrence of the scar in Case 4 (left eye) was accompanied by a decrease in uncorrected visual acuity from L.E.: 20/40 to 20/400, a decrease in best-corrected visual acuity from L.E.: 20/20 to 20/40 —2, and an increase in myopic spherical equivalent of 3.875 diopters. Debridement after topical corticoste roids improved uncorrected visual acuity to L.E.: 20/20 and decreased the myopic spherical equivalent by 3.75 diopters. The scar did not recur while corticosteroid use was being tapered. Table 2 gives the results of treatment in each of the cases. Treatment of scars with debridement alone
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UNCORRECTED VISUAL ACUITY
20/200 12/125 - 2 20/200 Not available 20/400
MONTHS AFTER PHOTOREFRACTIVE KERATECTOMY
BEST SPECTACLECORRECTED VISUAL ACUITY
MANIFEST REFRACTION
7 12 17 11 33
Not available 20/3020/2020/40 20/40-2
Not available -2.50+1.00 x 155 -2.25 +0.50 x 170 -2.00 +0.50 x 15 -3.50 sphere
successfully eliminated the scars, improved visual acuity, and eliminated myopic regression in all cases, although scars recurred within months in each case. Treatment of both initial and recurrent scars with topical corticosteroids temporarily increased visual acuity and decreased myopic regression. Topical corti costeroids decreased the density of the scar slightly in one case, whereas the scar remained unchanged in another case. The beneficial effect of topical cortico steroids did not persist after reducing the dosage. Treatment of scars by debridement followed by vigor ous topical corticosteroid use resulted in improved vision, elimination of myopic regression, and resolu tion of scars without recurrence after corticosteroid use was tapered in two cases. In another case, the scar recurred within eight months after topical corticoste roids were discontinued.
DISCUSSION THE DEVELOPMENT OF CORNEAL OPACITIES AFTER COR-
neal surface ablation with the excimer laser has been previously described.3'7 Typical postoperative corneal haze appears within a few weeks as a mild, diffuse, white, anterior stromal opacity that increases in severity for two to four months and fades there after.1'5,6·8 Some authors have used the term "scar" to describe corneal opacity after photorefractive keratectomy in 0.0%u to 4.9%12 of patients. In the study by Seiler and Wollensak,12 these opacities appeared dur ing the first two to three months after surgery and resolved within one year. The time of appearance and
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TABLE 2 SUMMARY OF RESPONSE TO TREATMENT
CASE
1, Initial scar Recurrent scar
2, Initial scar (R.E.) Recurrent scar Initial scar (L.E.)
3, initial scar
4, Initial scar
DEBRIDEMENT
DURATION OF
FOLLOWED BY
FOLLOW-UP
CORTICOSTEROIDS
(MOS)
Resolution with recurrence Not applicable
Not applicable Resolution without recurrence
5* 12+
Resolution with recurrence Not applicable Not applicable
Not applicable Resolution with recurrence Not applicable
6* 15f 16*
Not applicable
Not applicable
4*
Not applicable
Resolution without recurrence
9f
CORTICOSTEROIDS ALONE
DEBRIDEMENT ALONE
Not applicable Myopia decreased, vision improved, scar unchanged Not applicable Not applicable Myopia decreased, vision improved, scar unchanged Myopia decreased, vision improved, scar density minimally decreased Not applicable
•From debridement of first scar to debridement of second scar. ♦From most recent debridement to most recent visit. •From appearance of scar to most recent visit.
resolution of these opacities suggests that they were what we have defined as haze. Extensive scarring is said to be rare.13 In a series of 285 eyes that underwent photorefractive keratectomy, Caubet5 found that an increased incidence of clinically significant corneal opacity was associated with higher attempted corrections, smaller ablation zones (<4.5 mm), being male, ablations deeper than 50 μιτι, and discontinuation of topical corticosteroids. The origin of corneal haze remains unknown. Focal areas of scar 20 μπι thick were found in rabbits treated with the excimer laser.14 Fibrinogen, fibronectin, laminin, and type III collagen are deposited in the anterior stroma of monkey corneas as they heal after excimer laser treatment.1516 Type III collagen, not normally found in the cornea, does not have the regular lamellar structure of native type I stromal collagen and may scatter light. Vacuolization of the basal epithelial cells and abnormalities of the base ment membrane have also been observed after photorefractive keratectomy.16 Increased keratocyte density and metabolic activity have been found in the stroma immediately beneath the ablated surface in animals and humans.3141718 536
The anterior stromal collagen lamellae become increasingly disorganized in rabbits up to three months after ablation. The collagen lamellae gradual ly reestablish a more regular pattern by 15 months,14 paralleling the severity of haze. Fantes and associates18 found no such collagen disorganization in monkeys. They observed, however, irregular epithelial base ment membrane and persistence of metabolically active fibroblasts with adjacent clumps of amorphous material. These abnormalities correlated with the amount of haze. The use of nitrogen gas blowers is known to produce more haze, possibly attributable to a rougher ablation surface.19 Ditzen, Anschutz, and Schroder20 reported a series of 325 eyes undergoing photorefractive keratectomy in which slower epithelial healing was associated with more haze. In that series, no cornea that healed in five to nine days was clear, and no marked haze occurred in corneas that healed in less than three days. In all four patients described herein, the epithelial defects (after photorefractive keratectomy and de bridement) healed rapidly (less than three days); haze was minimal; early postoperative courses were un eventful; and topical corticosteroids had been dis-
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continued. These cases are unusual because dense corneal scarring associated with increased myopia, decreased visual acuity, and topographic abnormality appeared at a time when haze typically fades and the results of photorefractive keratectomy are generally believed to be stable. Case 4 is particularly interesting because scarring was not present until the central corneal epithelium was removed to improve the quality of the patient's vision two years after photore fractive keratectomy. The severity of haze correlates with the degree of myopic regression in the early postoperative period after photorefractive keratectomy. Typically, however, regression halts and the refractive error is stable after six months.21 In contrast, the occurrence and recur rence of scar in the right eye of Case 2 were associated with myopic shifts of 2.25 diopters and 3.50 diopters, respectively, compared to the refractive error at six months. Some aberration in the delivery of the laser energy is a possible explanation for the late scarring in these cases. However, the right eye in Case 1, which did not develop a scar, and the right eye in Case 2, which did develop a scar, were treated consecutively, on the same day with the same laser. Case 3 was treated with a different laser on a different day. Moreover, it is difficult to understand how factors related to the delivery of laser energy would become manifest after a completely uneventful initial postoperative course. The late and rapid onset of scarring suggests an idiosyncratic healing response of the patient as a cause rather than some factor related to the laser. Presently, we are unable to identify any preoperative factors that might predict the development of visually significant corneal scarring postoperatively. No tear film abnormalities, external eye disease, underlying metabolic disorders, systemic wound-healing abnor malities (keloid formation), or trauma (except for Case 4, in which scar formation followed debridement) were found that might explain these scars. Trauma not significant enough to be noticed by the patients may have been responsible for the scarring, although verification is impossible. Cases 1 and 3 were unilateral (at the time of this study), which does not support the involvement of systemic abnormali ties in these patients. Case 2 was bilateral, which raises the possibility of a systemic explanation in this patient. VOL.121, No. 5
Topographic steepening corresponding to the area of scarring and extending slightly peripherally from each scar was noted, suggesting the possibility of keratoconus, which often results in anterior corneal scarring, as a factor in the development of scars. Keratoconus was ruled out in Cases 1 through 3 by the following factors: ( 1 ) preoperative central keratometry was less than 45.0 diopters; (2) inferiorsuperior value22 differences in keratometry 3 mm from the center were less than 1.3 diopters; and (3) there were no clinical signs of keratoconus. Preoperative topographic information was unavailable for the op erative eye in Case 4. However, the nontreated eye demonstrated asymmetric astigmatism with a central keratometry value of 45.70 diopters in the steepest meridian and a difference of 2.92 diopters from inferior to superior at 3 mm from the center. Resolu tion of scarring was accompanied by return of topog raphy to the prescar baseline, suggesting that in creased corneal curvature resulted from the scar rather than keratoconus. Corneal wound healing is ä complex process in volving epithelial cells, keratocytes, and the extracel lular matrix. The factors that invoke and regulate corneal healing probably involve multiple cellular mediators and direct cell-to-cell contact. Photorefrac tive keratectomy removes Bowman's layer, allowing direct communication between epithelial cells and keratocytes. Injuries that violate the integrity of Bowman's layer are known to result in scarring, which may be caused by interaction of epithelial cells and keratocytes.16 It is possible that the absence of Bowman's layer makes the cornea more susceptible to reactive scarring from subsequent minor injuries. Scar formation after debridement (Case 4), and in unpub lished anecdotal reports (written communication, George O. Waring III, October 1994) of increased haze or scarring in photorefractive keratectomy pa tients after excessive ultraviolet light, wind, and dust exposure, support this theory. Modulation of the healing response to photorefrac tive keratectomy is an area of great importance. Topical corticosteroids inhibit the synthesis of ante rior stromal connective tissue in rabbits after excimer laser ablation,23 but the effect of topical corticoste roids on haze in humans is controversial. In a prospective, double-masked, randomized study of 113 eyes undergoing photorefractive keratectomy, Gartry
CORNEAL SCAR AFTER EXCIMER LASER KERATECTOMY
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and associates9 found no statistically significant differ ence between anterior stromal haze in the corticosteroid-treated group and control subjects. Lohmann and associates8 found a similar degree of haze in patients who discontinued corticosteroid use prema turely after photorefractive keratectomy compared to those who used corticosteroids for three months after the procedure. In contrast, others have reported a reduced incidence of haze in patients treated with topical corticosteroids.5,10 Topical interferon-alpha 2b10 and basic fibroblast growth factor24 have also been shown to decrease the incidence of haze after photorefractive keratectomy. Eyes with marked haze after photorefractive keratectomy have been success fully treated with subsequent excimer laser photoablation.25 The effect of topical corticosteroids on myopic regression is controversial. The use of dexamethasone has been associated with less regression,26 and topical corticosteroids have been successfully used to reverse regression.27'29 Gartry, Kerr-Muir, and Marshall30 found a greater reduction in myopia in eyes treated with corticosteroids compared to controls, but statisti cal significance was lost within three months of discontinuation of corticosteroids. Schipper31 report ed two cases similar to ours in which a marked increase in myopia, corneal opacification, and a decrease in best-corrected visual acuity occurred nine to 12 months after photorefractive keratectomy. In these cases, treatment with prednisolone acetate 1% five times daily for two weeks improved best spectaclecorrected visual acuity, decreased myopia, and re duced haze. In our cases, scars developed after topical cortico steroids were discontinued. The scar tissue was rela tively superficial and could be removed by simple debridement. In one eye (Case 4), scarring occurred, and in two eyes (Cases 1 and 2), scarring recurred when debridement was not followed by topical corti costeroid treatment. There was no recurrence after debridement and subsequent vigorous topical cortico steroid use in two cases. In another case (Case 2), scarring recurred eight months after discontinuation of topical corticosteroids. Topical corticosteroids without debridement in two eyes (Cases 1 and 3) improved uncorrected visual acuity slightly but did not affect topography or the density of the scar. Furthermore, the beneficial effect of corticosteroids 538
was lost when they were discontinued. Our initial results of treatment with topical corticosteroids after debridement were encouraging. The recent recur rence of a scar in Case 2, however, raises questions about the long-term efficacy of this treatment. Cau tion must be used in prolonged topical corticosteroid use because some patients will have increased intra ocular pressure and cataract formation. At the time these five eyes were identified, about 150 eyes had been treated with photorefractive kera tectomy at Emory University and 700 eyes at the Hunkeler Eye Clinic. Thus, we estimate the incidence of late-onset corneal scarring after photorefractive keratectomy to be at least 0.6%. The true incidence of late scarring may be higher because we cannot be certain that we examined all eyes that developed scars. The loss of uncorrected and best spectaclecorrected visual acuity in our patients raises the question of whether the long-term adverse effects of excimer laser photorefractive keratectomy are yet to be discovered. Like the hyperopic shift after radial keratotomy, the true incidence of late postoperative complications after photorefractive keratectomy may not become evident until careful, long-term observa tions can be made. We suggest that observers adopt a standardized definition of haze and scar, such as we propose, to facilitate comparison of data in the future. We also recommend that patients who have under gone photorefractive keratectomy be educated con cerning the possibility of late scarring and be treated with topical corticosteroids for prolonged periods with frequent observation after debridement, retreatment, or minor corneal injuries.
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