Photorefractive keratectomy with intraoperative mitomycin-C application

J CATARACT REFRACT SURG - VOL 31, DECEMBER 2005

Photorefractive keratectomy with intraoperative mitomycin-C application Dong H. Lee, MD, PhD, Hak Sung Chung, MD, PhD, Young C. Jeon, MD, Sang D. Boo, MD, Young D. Yoon, MD, Jong G. Kim, MD

PURPOSE: To evaluate the efficacy and safety of photorefractive keratectomy (PRK) with intraoperative application of mitomycin-C (MMC). SETTING: Yonsei Eye Center, Seoul, South Korea. METHODS: This retrospective noncomparative case series included 536 patients (1011 eyes) who had had PRK with intraoperative application of MMC using the Nidek EC-5000 excimer laser. Preoperative and postoperative best spectacle-corrected and uncorrected visual acuities, spherical equivalent (SE) refraction, corneal haze graded by slitlamp biomicroscopy, and endothelial cell density measured by specular microscopy were evaluated. RESULTS: The mean preoperative SE was ÿ7.82 diopters (D) G 2.64 (SD); 72% of eyes (732) were more than ÿ6.00 D, and 28% (287) were more than ÿ9.00 D. The mean follow-up was 13 months (range 6 to 27 months). Six months postoperatively, the mean postoperative SE was ÿ0.14 G 0.62 D; 86% were within G0.50 D and 93% were within G1.00 D of desired refraction. Eighty-six percent had 20/20 or better visual acuity, and 98% were 20/40 or better. Regression of more than 1.00 D occurred in 78 eyes (7.6%), and it was more common in eyes with a preoperative SE of ÿ9.00 D or worse (18%). Haze occurred in 32 eyes (3.17%), but in most cases it was limited to grade 1. Grades 2 and 3 haze occurred in 3 eyes and 2 eyes, respectively. The postoperative endothelial cell density measured by specular microscopy did not show a significant difference from preoperative measurements. Delayed epithelial healing was observed in 2 eyes. CONCLUSION: Photorefractive keratectomy with intraoperative application of MMC was a safe procedure that produced excellent visual outcomes with few complications. J Cataract Refract Surg 2005; 31:2293–2298 Q 2005 ASCRS and ESCRS

Photorefractive keratectomy (PRK) has been a valuable refractive surgery technique; however, its popularity decreased as laser in situ keratomileusis (LASIK) was introduced to the refractive surgery field. Laser in situ keratomileusis has the advantage of little pain and rapid visual rehabilitation1,2 as well as reduced complications associated with corneal haze in high myopia. But it has also many disadvantages such as flap-related complications, dry eye, and ectasia.3–7 Recently, surface ablation is being performed as laser-assisted subepithelial keratectomy (LASEK) or advanced surface ablation.8–11 The pain is less, but haze is a major limitation of PRK or LASEK for moderate to high myopia. Several studies have been performed in an attempt to reduce or inhibit the formation of corneal haze.12–18 Mitomycin-C (MMC) is known to reduce corneal haze after PRK or radial keratotomy.19,20 It can also prevent the reccurrence of haze after previous surgical complications.21,22 The purpose of the present study was to evaluate the safety and Q 2005 ASCRS and ESCRS Published by Elsevier Inc.

efficacy of the prophylactic use of intraoperative application of MMC during PRK. PATIENTS AND METHODS This was a noncomparative retrospective consecutive case series study in which 1011 eyes of 536 patients who had PRK with intraoperative application of MMC at the Yonsei Eye Center, Seoul, South Korea, were enrolled. Institutional review board/ ethics committee approval was not required for this study, and all patients provided informed consent. Inclusion criteria were healthy myopic patients 18 years of age or older with no history of ocular surgery or trauma and no ocular pathology other than refractive error. Refractive error had to have been stable for at least more than 1 year. The spherical equivalent (SE) in 72% (732) of eyes were more than ÿ 6.00 diopters (D) and in 28% (287) was more than ÿ 9.00 D (Figure 1). Preoperative examinations included manifest and cycloplegic refractions, intraocular pressure, pachymetry, corneal topography, specular microscopy, measurement of scotopic pupil size, slitlamp biomicroscopic examination, and dilated fundus 0886-3350/05/$-see front matter doi:10.1016/j.jcrs.2005.05.027

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PHOTOREFRACTIVE KERATECTOMY WITH INTRAOPERATIVE MMC

Percent of eyes

50

44

40 25

30

28

20 10 0

3

0 ~ -3

- 3.1 ~ -6

-6.1 ~ -9

-9.1 ~

Preoperative Spherical equivalent refraction (D) Figure 1. Preoperative SE. Seventy-two percent (732) of eyes were more than ÿ6.00 D, and 28% (287) were more than ÿ9.00 D.

examination. In 1 group of patients, LASIK was contraindicated secondary to insufficient central corneal thickness. The second group of patients, which had sufficient central corneal thickness for LASIK, elected to have PRK instead of other possible corrective procedures such as LASIK or phakic intraocular lens implantation after a detailed discussion of advantages and disadvantages of each procedure. The ablation diameter was matched to the pupil diameter measured in a dark room. In high myopia, the ablation diameter and depth were reduced so that the residual stromal bed could be more than 350 mm or that the total ablation depth could not exceed 130 mm. In cases of small ablation zone with a large pupil, a thorough discussion about night-vision symptoms such as halo, starburst, and glare was provided before consent was obtained. Surgical Technique All PRK procedures were performed by multiple surgeons (D.H.L., Y.C.J., S.D.B., Y.D.Y.). Proparacaine hydrochloride 0.5% (Alcaine) was given as topical anesthesia, and the epithelium was removed with a spatula after the contact with 20% alcohol solution for 20 to 30 seconds. Laser ablation was performed with the Nidek EC-5000 laser. After the ablation, a ring-shaped Merocel sponge soaked with 0.02% MMC solution was applied to the ablated corneal surface for 30 seconds to 2 minutes, depending on

Accepted for publication May 18, 2005. From the Department of Ophthalmology (Lee, Jeon, Boo, Yoon, Kim), Yonsei Eye Center, Seoul, South Korea, and the Department of Ophthalmology (Chung), Feinberg School of Medicine/ Northwestern University, Chicago, Illinois, USA. Presented in part at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, April 2003, the XXth Congress of the European Society of Cataract and Refractive Surgeons, Munich, Germany, September 2003, and annual meeting of the American Academy of Ophthalmology, Anaheim, California, USA, November 2003. No author has a financial or proprietary interest in any material or method mentioned. Reprint requests to Dong H. Lee, MD, PhD, Department of Ophthalmology, Yonsei Eye Center, Keugdong Bd, 4F, Sinsadong 639-3, Kangnamgu, Seoul, South Korea, 135-896. E-mail: donghlee64@ hananet.net.

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the ablation depth (30 seconds for an ablation depth from 80 to 100 mm, 1 minute for depths from 100 to 120 mm, and 2 minutes for depths greater than 120 mm). The eye was then irrigated with cold balanced salt solution (BSS) (30 mL). A therapeutic contact lens was applied. Ofloxacin 0.3% (Tarivid) and fluorometholone 0.1% (Flumetholon) were given. The contact lens was removed at postoperative days 3 or 4 after completion of epithelial healing. Use of fluorometholone 0.1% continued for 3 months with gradual tapering (4 times per day during the first month, 3 times per day during the second month, and 2 times per day during the third month). Carboxymethylcellulose 0.3% (Refresh Plus) was given as needed through the first several months. Refraction, uncorrected (UCVA) and best corrected (BCVA) visual acuities, slitlamp biomicroscopic examination, specular microscopy (SP-2000P, Topcon), and corneal topography (ORBSCAN, ORBTEK) were performed at each follow-up visit. Unusual healing or corneal haze was recorded. Corneal haze was graded from 0 to 4 (0 Z none, 1 Z mild, 2 Z moderate, 3 Z marked, 4 Z severe). Statistical analysis was performed with paired and unpaired t test (Excel, Microsoft Corp.). RESULTS

Of 536 patients, 126 were men and 410 were women. The mean age of the patients was 29 years G 6.2 (SD) (range 19 to 49 years). The mean preoperative SE was ÿ7.82 G 2.64 D (range ÿ1.25 to ÿ17.25 D). The mean preoperative central corneal thickness was 512 G 36 mm (range 422 to 651 mm), and the mean ablation depth was 94 G 17 mm (range 25 to 130 mm). The mean follow-up period was 13 months (range 6 to 27 months). All 1011 eyes were available for the follow-up evaluation at 3 and 6 months. At the end of the study period (mean 13 months), 408 eyes had more than 6 months of follow-up (mean 16 months). At 6 months postoperatively, SE showed that 86% of the eyes were within G0.50 D and 93% of eyes were within G1.00 D (Figure 2). The scattergram of attempted versus achieved refraction showed that the distribution of SE in the mild to moderate myopia group (less than ÿ9.00 D) located with G1.00 D; however, in the high myopia group (more than ÿ9.00 D), there were more overcorrected or undercorrected eyes (Figure 3). The high myopia group showed an undercorrection rate of 18% compared to 3.4% in the moderate myopia group (ÿ5.00 to ÿ8.90 D). Six months postoperatively, UCVA was 20/20 in 86% and 20/40 or better in 98% of all cases (Figure 4). Best corrected visual acuity did not change in 73% of all cases. There was 1 line gain in 13%, 2 line gain in 5%, and 3 line gain in 1% of all cases. There was 1 line lost in 8% of all cases (Figure 5). Postoperative refraction was stable during the follow-up visits (Figure 6). Regression of more than 1.00 D occurred in 78 eyes (7.6%). Endothelial cell count was measured postoperatively with a specular microscope at 3 months (359 eyes), 6 months (96 eyes), and at the final visit (16.6 G 2.6 months; range 12 to 24 months) (34 eyes).

J CATARACT REFRACT SURG - VOL 31, DECEMBER 2005

PHOTOREFRACTIVE KERATECTOMY WITH INTRAOPERATIVE MMC

Preop SCVA

2

1

2

4

5

3

Percent of Eyes

0

Postop UCVA

120

82

0

-6 . -3 00 .1 to 0 -3 .0 -2 0 .1 to 0 -2 .0 -1 0 .1 to 0 -1 .0 -0 0 .5 to 1 -0 .5 0. 0 t 00 o +0 +0 .1 .5 to 0 +0 to .51 +1 +1 to .10 +2 +2 to .10 +3

Percent of Eyes

+/- 0.5D: 86%, +/- 1D:93% 90 80 70 60 50 40 30 20 10 0

100

89 86

94 92

99 100 100 100 100 100 100 100 100 100 100 99 98 97

80 60 30 30

40 20 0

2

2

10

13

20

25

30

40

50

60

80

100 200

Cumulative Snellen Visual Acuity(20/_)

Postoperative Spherical Equivalent Refraction(D) Figure 2. Postoperative SE at 6 months. Eighty-six percent of eyes were within G0.50 D, and 93% of eyes were within G1.00 D.

There was no significant difference at 3 months and the final visit. At 6 months, the endothelial cell count was significantly increased (Table 1). Corneal haze occurred in 32 eyes (3.17%). Among them, 27 were grade 1, 3 eyes were grade 2, and 2 eyes were grade 3. The mean ablation depth in the cornea haze group was 104.97 G 9.57 mm (range 85 to 129 mm). The mean MMC exposure time in these eyes was 1.9 G 0.3 minutes (range 30 seconds to 2 minutes). No eye lost 2 or more lines of visual acuity postoperatively. Two eyes that developed grade 3 corneal haze lost 1 line of visual acuity. Detailed corneal examinations in these 2 eyes, including topography, did not show pathologic corneal findings other than corneal haze. The group of patients with cornea haze was significantly younger than the group 20 18 16

Figure 4. Preoperative spectacle-corrected Snellen visual acuity versus postoperative uncorrected visual acuity at 6 months. Eighty-six percent of eyes were better than 20/20, and 98% of eyes were better than 20/40 after surgery.

of patients without corneal haze (27 G 6 years versus 29 G 6 years; P Z.024). The ablation depth (104.97 G 9.57 mm versus 94.11 G 17.44 mm, P Z.00047) and preoperative SE (ÿ9.33 G 2.22 D versus ÿ7.81 G 2.64 D; P Z.0014) were also significantly different between the haze group and the no haze group. Delayed epithelial healing occurred in 2 eyes. Complete epithelial healing was achieved within 10 days in each. Epithelial and subepithelial haze were found in both cases but disappeared within 1 to 2 months. DISCUSSION

Although LASIK is probably the most commonly performed refractive procedure, it should be avoided in eyes with thin corneas. There is substantial risk for developing corneal ectasia in eyes with a postoperative stromal bed depth less than 250 to 300 mm.23 In the majority of these cases, PRK or LASEK may be safely performed with significantly less risk for corneal

12

2 or more lines loss: 0%

10

Percent of Eyes

Achieved (D)

14

8 6 4 2 0 0

5

10

15

20

Attempted (D)

Figure 3. Scattergram of attempted versus achieved correction at 6 postoperative months. In low to moderate myopia, the results are closely distributed within G1.00 D. In high myopia, undercorrections were more common.

80 70 60 50 40 30 20 10 0

73

13

8

5

0

-2

-1

0

1

2

1

3

Change in Snellen Lines of Spectacle-corrected Visual acuity Figure 5. Change in spectacle-corrected visual acuity between preoperative and postoperative at 6 months. There was 1 line gain in 13%, 2 line gain in 5%, and 3 line gain in 1% of eyes. There was 1 line lost in 8%. No eye lost 2 or more lines.

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PHOTOREFRACTIVE KERATECTOMY WITH INTRAOPERATIVE MMC

2

SE refraction(D)

0 -0.14

0.00

-2

-0.13

-4 -6 -8

-7.82

-10 -12

preop

3 month

6 month

final

Time after Surgery Figure 6. Change in refraction during follow-up. Refraction was stable throughout the follow-up period. SE Z spherical equivalent.

ectasia because they provide more corneal structural support. However, PRK has the disadvantage of developing corneal haze, especially in high myopia patients. In this retrospective consecutive case-series study, there was no control group of PRK without MMC treatment. One prospective clinical trial using 36 high myopia (O7.00 D) patients (1 eye assigned to PRK with MMC and the fellow eye to PRK with artificial tear as a control group) reported that corneal haze developed in 20% of the group having PRK without MMC vs 0% of MMC-treated eyes at 1 year.24 One prospective comparative study using high myopia patients (ÿ6.00 to ÿ10.00 D) reported that a corneal haze rate, greater than grade 1, was 63% in the control group of PRK without MMC (30 eyes) and 0% in the study group of PRK with MMC (30 eyes) at 6 months postoperatively.25 Our study of 1011 eyes treated with PRK with MMC that showed that corneal haze developed in 32 eyes (3.17%). Corneal haze of more than grade 1 developed in only 5 eyes (0.49%). These studies may suggest that intraoperative use of MMC during PRK effectively reduces corneal haze development. Furthermore, none of these studies Table 1. Change in endothelial cell counts (cells/mm2) at 3 and 6 postoperative months and at final visit.

Parameter

3 Mo 6 Mo Preop Postop Preop Postop Preop Final

Number 359 of eyes Mean 2969 SD 409 Preop vs d 3 mo postop* Preop vs d 6 mo postop* Preop vs final* d *Paired t test

2296

359

96

96

34

34

2993 376 0.23

2984 380 d

3116 375 d

d

d

0.0008

d

d

d

d

d

d

0.88

3027 3039 362 430 d d

reported any toxic effect of MMC. Recently, LASEK was introduced and suggested the possibility of reducing haze in high myopia cases. However, the role of LASEK in haze prevention is not clear. Clinical studies both support and dissuade the use of LASEK as an alternative procedure. Lin et al.26 report that even in LASEK, the chance of corneal haze increases when the ratio of the ablation depth/corneal thickness is greater than 0.18. Intraoperative application of MMC is probably 1 of the most consistently effective methods to prevent haze formation after corneal ablation. Prophylactic use of MMC with PRK can be beneficial to patients with risk factors for corneal haze, such as high myopia and deep ablation depth.24,25 Mitomycin-C was first used by Schipper and coauthors16 and Talamo et al.17 in rabbit studies. Majmudar et al.19 applied MMC in patients who had corneal haze and decreased corrected visual acuity due to previous PRK or RK procedures. The authors removed the corneal scar mechanically and applied MMC, thus preventing the reformation of haze. Carones and coauthors25 also report similar cases with good results and few complications. However, these studies had relatively small numbers of cases and possible toxicity was not adequately evaluated with a satisfactory methodology such as specular microscopy. Our study evaluated 1011 cases with mean follow-up period of 13 months, and toxicity was evaluated with specular microscopy. The corneal endothelial density did not decrease at any follow-up period, and at 6 postoperative months, there was increase in cell count. The reason is not clear, but the cessation of contact lenses may be 1 reason. There have been reports of complications occurring with MMC use, such as bleb thinning, bleb perforation, and scleral melting after pterygium excision or glaucoma filtration surgery.27–29 Mitomycin-C is toxic to fibroblast and capillary endothelial cells.30,31 Mitomycin-C can induce tissue necrosis due to vascular damage; however, the cornea is avascular and fully supported by aqueous humor and tear film. It is, therefore, toxicity of MMC to the cornea, which occurs by direct contact of cells and MMC in high concentration, not avascular necrosis cascades.32,33 There has been no known case of direct toxicity associated with intraoperative use of 0.02% MMC for 2 minutes.24,25 We now use an annular sponge that is soaked with 0.02% MMC. The study began with disk sponges, but the sponge shape was changed to the annular type to increase efficacy. Jain and coauthors33 report that the annular type is more effective than the disk type. The patient is able to see through the central opening of the annular sponge, which facilitates fixation during surgery. Before the MMC application, the stromal bed was irrigated with a small amount of BSS to alleviate dryness that may induce rapid and deep MMC penetration.

J CATARACT REFRACT SURG - VOL 31, DECEMBER 2005

PHOTOREFRACTIVE KERATECTOMY WITH INTRAOPERATIVE MMC

Currently, we determine MMC application duration according to ablation depth. Specifically, 30 seconds for an ablation depth from 80 to 100 mm, 1 minute for depths from 100 to 120 mm, and 2 minutes for depths greater than 120 mm. Using this protocol of MMC application time, there has been no clinically significant corneal haze or complication over a 1-year follow-up. Corneal integrity depends on many factors including various cells such as endothelium, keratocyte, and epithelium and their cellular products such as collagen and extracellular matrix. We demonstrated that there was no change in endothelial cell density based on specular microscopy. A more comprehensive analysis of the cornea would require confocal microscopic examination or pathologic examination. In a preliminary study of 40 eyes, we found that keratocyte density in the anterior and mid stroma in PRK with MMC cases was not significantly different from cell densities in PRK without MMC (presented in the ASCRS annual meeting in 2004: ASCRS abstract #441, p112). Photorefractive keratectomy with intraoperative application of MMC produced excellent visual outcomes with almost no complications. Most high myopia patients with large pupils reported mild halos after surgery. However, none complained of significant discomfort or functional difficulty. The incidence of clinically significant corneal haze (grade 3) was very low (0.2%; 2 of 1011 eyes). Therefore, PRK with intraoperative MMC is a valuable alternative to LASIK, especially in young patients with high myopia and thin corneas.

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