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Retreatment for significant regression after excimer laser photorefractive keratectomy
Retreatment for Significant Regression after Excimer Laser Photorefractive Keratectomy A Prospective, Randomized, Masked Trial David S. Gartry, MD, FRCOphth, D. Frank P. Larkin, MD, FRCOphth, Adrian R. Hill, PhD, FCOptom, Linda A. Ficker, BSc, FRCOphth, Arthur D. McG. Steele, FRCS, FRCOphth Purpose: Regression, a gradual partial or complete return to the myopic state, remains a common complication of excimer laser photorefractive keratectomy (PRK) and limits the predictability of refractive outcome, especially in high myopia. An estimated 10% to 20% of patients, therefore, request a repeat PRK procedure. This study was designed to provide patient selection criteria and guidelines for successful retreatment. Methods: One hundred six patients who had regressed were randomized to I of 4 retreatment groups comprising (1) those with minimal haze after their first PRK who received an exact retreatment; (2) those with minimal haze treated with a 50% deliberate overcorrection; (3) those with significant haze (-->2+ haze) given an exact retreatment; and (4) those with significant haze who received a 50% overcorrection. A Visx 20/20 laser was used in each case. Mean follow-up after retreatment was 12 months (range, 6 - 1 8 months). Results: Deliberate overcgrrection (groups 2 and 4) resulted in a statistically significantly better refractive outcome (P = 0.026 at 6 months). Analysis of variance showed that significant haze after the first PRK was the most important predictor of a poor outcome after retreatment, other factors being high original myopia, marked regression, and loss of best-corrected visual acuity. Conclusions: A retreatment PRK procedure for significant regression will reduce residual myopia significantly in the majority of patients, and a deliberate ovemorrection (50%) reduces the chance of further regression. However, patients with high myopia who have regressed beyond approximately -3.50 diopters originally and who show significant anterior stromal haze ( > 2 + ) should be retreated only with great caution, because of the risk of further regression, haze, and loss of visual acuity. Ophthalmology 1998; 105:131-141
In 1983, Trokel, Srinivasan, and Braren ~ published the first article describing the possible role of the excimer laser in corneal surgery. Numerous laboratory studies followed, and photorefractive keratectomy (PRK) for the treatment of myopia has gained in popularity over the past 7 years since the first clinical exposures commenced.-'- ~ It has been estimated that several hundred thousand patients have been treated worldwide, and the procedure was given official limited approval by the Food and Drug Administration recently. Despite the current enthusiasm for excimer laser corneal surface reprofiling, individual patient variation in the wound-healing response limits predictability of refractive outcome, especially when attempts are made to treat moderate-to-high myopia (i.e., greater than approximately - 6 . 0 0 diopters [D]). z-5 As a
Originally received: November 1, 1995. Revision accepted: August 6, 1997. From the Cornea Service, Moorfields Eye Hospital, London, England. Presented in part at the American Academy of Ophthalmology Annual Meeting, Atlanta, Georgia, November 1995. The authors have no proprietary interest in the products or techniques described in this article. Reprint requests to David S. Gartry, MD, FRCOphth, The Cornea Service, Moorfields Eye Hospital, City Road, London ECIV 2PD, UK.
consequence of this variability, a significant number of patients regress back toward the myopic state. Given that it is likely (after approval by the Food and Drug Administration) that even greater numbers of patients will undergo PRK in the future and that regression will remain a significant problem, the number of patients requesting retreatment also will increase. From published series, it can be estimated that between 10% and 20% of patients undergoing PRK will have, what they consider to be, a significant amount of residual myopia and will want to have this eliminated. 2-'4 In the series reported here, 106 patients were retreated as part of a prospective, randomized, masked study. These patients were recruited from a cohort of approximately 1000 post-PRK patients at the time of the study's commencement and therefore represent approximately 10% of the total number. This "retreatment frequency" or incidence will vary from center to center and will depend on a number of factors, including the upper limit of myopia treated, the type of laser, the maximum ablation zone diameter used, and the threshold of both patient and surgeon in requesting and performing a PRK retreatment. In view of the increasing absolute numbers of patients with significant regression', it is important to adopt a retreatment strategy based on the results of controlled studies. This study was designed,
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Ophthalmology Volume 105, Number l, January 1998 Table 1. Change in Refraction with Time after the First Photorefractive Keratectomy Procedt, re for the Group as a Whole (n = 106) and According to the "Haze" Subgrouping (n = 52 with Minimal Haze = 1+ or Less, and n = 54 with Significant Haze = 2+ or More Subjective Haze Grading): Mean _+ SD Mean Spherical Equivalent [D (SD)]
Time (mos) Before first PRK 1 3 6 12
Whole Group (n = 106)
-6.73 +0.41 -1.78 -3.01 -3.41
(2.87) (1.53) (2.12) (2.07) (2.21)
Minimal Haze Group (n = 52)
-4.97 -0.65 -1.42 -1.59 -1.89
(I.68) (1.37) (0.77) (0.83) (0.62)
Significant Haze Group (n = 54)
-7.37 +0.72 -I.96 -3.67 -3.92
(2.91) (1.37) (2.17) (1.89) (2.07)
SD = standard deviation; PRK = photorefractive keratectomy.
therefore, to p r o v i d e patient selection criteria for ret r e a t m e n t P R K by e v a l u a t i n g the o u t c o m e o f r e t r e a t m e n t in terms o f several likely " p r e d i c t o r s " or variables, n a m e l y , (1) the a m o u n t o f anterior stromal haze present after the first P R K , (2) the loss o f best-corrected visual acuity ( B C V A ) ; (3) the a m o u n t o f original m y o p i a ; (4) the a m o u n t o f regression before retreatment; and (5) the effect o f a deliberate o v e r c o r r e c t i o n p r o g r a m m e d d u r i n g the retreatment in an attempt to c o m p e n s a t e for the already p r o v e n t e n d e n c y for regression to occur.
Materials and Methods Study Design After Ethics Committee approval, 106 patients who had requested retreatment for significant regression after PRK were recruited into the study. Patients then were divided into two groups based on the amount of anterior stromal haze present after the first PRK: group A, those with minimal or no haze ( < 2 + ) , and group B, those with significant haze (=-2+). Each patient then was randomized to one of two subgroups: group 1, those patients who received a retreatment in which the laser was programmed to correct 100% of the residual myopia (i.e., an exact retreatment), and group 2, those patients who received a retreatment in which the laser was programmed to correct 150% of the residual myopia (i.e., a deliberate overcorrection). The study design, therefore, comprised four groups: 1. G r o u p A1 - Those with minimal haze (-<1 +) in which a repeat PRK was carried out and the computer was programmed to correct the existing amount of residual myopia exactly. 2. G r o u p A2 - Just as for group A1, except that the laser was programmed to overcorrect by 50%. For example, a patient who was - 6 . 0 0 D originally and regressed back to - 2 . 0 0 D would receive a - 3 . 0 0 D retreatment. 3. G r o u p B1 - Those with significant haze (---2+) treated with an exact PRK correction (i.e., the amount programmed into the laser matched exactly the residual myopia as for group A1). 4. G r o u p B2 - Those with significant haze treated with a deliberate 50% overcorrection. The mean preoperative (original) refraction and the mean refraction at various intervals after the first PRK procedure are given in Table 1. For the group as a whole (n = 106), the mean
132
original spherical equivalent was - 6 . 7 3 D, whereas at 1 year, regression to -3.41 D had occurred. After division into the two main subgroups (i.e., by the amount of anterior stromal haze generated after the first PRK), the minimal haze group had a mean spherical equivalent of - 4 . 9 7 D (n = 52) and regressed back to - 1 . 8 9 D at 1 year, whereas the significant haze group (n = 54), as might be expected, was more myopic originally ( - 7 . 3 7 D) and regressed to - 3 . 9 2 D at 12 months (Table I). Figures IA through C show these same changes in refraction with time graphically. Preretreatment Assessment
Photorefractive
Keratectomy
Of the 106 patients enrolled in this study, 100 had been treated originally with a Visx 20/20 excimer laser (Visx Inc., Sunnyvale, CA), using a 5-mm-diameter ablation zone, as part of the Moorfields Phase [] Program. Six patients had been part of an early cohort (phase I) treated with an Excimed UV200 excimer laser (Summit Technology, Waltham, MA) using 4.5-mm or 5-mm ablation zones. All patients were at least 6 months post-first PRK, and in the majority (95%) of patients (96 of 106), follow-up was 1 year or more. The primary indication for retreatment was significant regression relative to the original myopia, which led to the patients' request for treatment of their residual myopia. Preretreatment assessment included (1) subjective refraction/slit-lamp examination and intraocular pressure measurement; (2) computerized videokeratography Eye-Map system (Alcon, Fort Worth, TX) to exclude significant ablation zone decentration; (3) optical pachymetry; and (4) anterior segment photography. Patients were counseled carefully in a similar fashion to those in other PRK cohorts within the Moorfields excimer laser research programs. In particular, the investigational and, essentially, experimental nature of the retreatment study was emphasized and the possibility of repeated regression and loss of BCVA after retreatment explained fully. It was considered essential that patients undergoing retreatment had entirely realistic expectations in relation to the uncertainty of the refractive outcome. The importance of randomization to one of the two main treatment groups (i.e., overcorrection or exact correction) also was explained in detail, and each patient was required to read and sign a six-page background information and consent form, approved by the Moorfields Eye Hospital Ethics Committee, before surgery. The Procedure A Visx 20/20 laser (Visx Inc.) was used throughout with a fluence of 180 mJ/cm-" at the corneal plane, a pulse repetition
G a r t r y et al •
Retreatment for Regression after Excimer Laser PRK
rate of 5 Hz, and a beam diameter of 6 mm in each case. Manual epithelial debridement was performed and the retreatment carried out as for a standard PRK procedure by one of the two surgeons (DSG, DFPL) responsible for the study.
Postoperative Monitoring and Topical Regimen Patients were seen on days I and 7; months 1, 3, 6, 12, 18; and annually thereafter. A standardized postoperative topical treatment regimen was used for all patients and comprised instillation of diclofenac sodium 0.1%, chloramphenicol 0.5%, and homatropine 2% eyedrops and betamethasone ointment immediately after the procedure and application of a pad. This was removed the next day, and the following regimen was used: dexamethasone 0.1% eyedrops four times daily for 1 week, then twice daily for 3 weeks, and chloramphenicol 0.5% eyedrops four times daily for 1 week.
Resul~ Figures 2A through C show the change in refraction with time after PRK retreatment for (A) the group as a whole (n = 106), (B) those patients with minimal haze after the first PRK (n = 52), and (C) those patients with significant haze after the first PRK procedure (n = 54). When compared with Figure I A, the
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progress of the whole group after the first PRK retreatment on average resulted in a greater proximity to emmetropia (i.e., - 1 . 7 5 D) after retreatment compared with - 3 . 4 1 D after the first PRK (Tables 1 and 2). It is evident, however, that patients with minimal or no haze after the first procedure achieve the best refractive results (Fig 2B), whereas those in groups B 1 and B2 (i.e., with significant haze) regress as before (Fig 2C). Figure 3 shows the effect of exact treatment versus deliberate 50% overcorrection in terms of (A) the mean refraction versus time for the 2 groups and (B) a scattergram of the 65 patients for whom I-year data are available. When,comparing the patients who received a deliberate 50% overcorrection as a whole (groups A2 and B2 combined) with those receiving an exact correction (groups A1 and B1 combined), the overcorrected groups were statistically significantly closer to emmetropia at all stages of follow-up (P = 0.026 at 6 months, n = 106; P = 0.032 at I year, n = 65). Table 3 provides a summary of the results at 6 months. Figures 4A and B are scattergrams for the four subgroups and show the effect of overcorrection versus exact correction at the 6-month stage (minimum follow-up for all 106 patients enrolled in the study). Those patients with minimal haze before retreatment are shown in Figure 4A (AI and A2), whereas those with a haze grade of 2+ or greater before retreatment are shown in Figure 4B (B 1 and B2). Table 4 summarizes the results from these scattergrams. Table 4 shows that deliberate overcorrection in the minimal haze group resulted in a statistically significantly better outcome at 6 months (i.e.,
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Complications Loss of Best-corrected Snellen Visual Acuity. Figures 5A and B show the change in B C V A (A) after the first PRK procedure and (B) after the retreatment procedure. After the first PRK (at
a minimum follow-up period of 1 year), 32% and 10% of patients lost one or two lines of BCVA, respectively, whereas approximately 15% lost one or two lines and 5.6% lost three lines after retreatment. Because the loss of B C V A proved to be cumulative in some of these cases, there were instances of a four-line loss of B C V A compared with that of the original acuity (i.e., the BCVA) before the first PRK procedure. Table 5 documents the eight patients with the worst outcome in our retreatment series in terms of loss of BCVA, anterior stromal
Table 2. Change in Refraction with Time Following Retreatment for the Group as a Whole (n = 106) and According to the Subjective "Haze" Subgrouping (n = 52 with Minimal Haze = I + or Less, and n = 54 with Significant Haze = 2"+ or Greater): Mean _+ SD Mean Spherical Equivalent [D (SD)] Time (mos) Before retreatment 1 3 6 12 18 SD = standard deviation.
134
Whole Group (n = 106) -3.41 +1.31 -0.39 -1.37 -1.69 -1.75
(2.21) (1.78) (2.09) (2.12) (2.06) (2.0I)
Minimal Haze Group (n = 52) -1.89 +0.47 -0.27 -0.28 -0.37 -0.4I
(0.62) (0.97) (0.75) (0.56) (0.47) (0.69)
Significant Haze Group (n = 54) -3.92 +1.72 -0.25 -1.93 -3.97 -4.14
(2.07) (1.97) (2.54) (2.38) (2.10) (2.34)
G a r t r y et al • R e t r e a t m e n t for R e g r e s s i o n after E x c i m e r Laser P R K 5
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haze preretreatment and postretreatment, and original amount of myopia present. The 6-month datapoints for these individuals are highlighted in Figure 4B. Three patients lost a total of four lines of BCVA after retreatment when assessed at the 6-month stage. Significantly; the mean preoperative myopia (i.e., before their first PRK procedure) for these eight patients was -9.53 D (range, - 5 . 5 0 D to -13.625 D), and the mean subjective haze grading after the first procedure was 2.88+. Analysis of variance showed that the presence of significant anterior stromal haze ( > 2 + subjectively) after the first procedure was the most important predictor of a poor outcome after retreatment, being just over four times more influential in contributing to the variance in the data than overtreatment or exact treatment. As shown in Figures 1C and 2C, those patients with significant anterior stromal haze after the first PRK ( ~ 2 + ) have greater variation in refractive outcome, as shown by the larger standard deviations, and more regression after both the first PRK and the retreatment procedure.
Discussion Since the first suggestion that e x c i m e r lasers might be suited to corneal refractive surgery, ] numerous laboratory
Table 3. The Mean Refraction Spherical Equivalent Following the First Photorefractive Keratectomy Compared with the Refraction Following Retreatment at 6 Months of Follow-up (n = 106) for Both Exact Treatment and Deliberate Overcorrection Subgroups: Mean _+ SD Group
Exact (n = 55) Overcorrection (n = 51)
Refraction (SE) after First PRK
Refraction (SE) after Retreatment
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-1.64 m 2.07
-2.82 --. 1.72
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SD = standard deviation; PRK = photorefractive keratectomy; SE = spherical equivalent.
and clinical studies have been performed. 2-32 It has been estimated that over the past 7 years since the first clinical exposures,-'- ~ several hundred thousand procedures have been undertaken worldwide, and e x c i m e r laser P R K has b e c o m e an accepted form of treatment for low-to-moderate amounts of myopia. Previous studies have shown, however, that although predictability is reasonable up to approximately - 6 . 0 0 D, it is by no means impossible for patients with lower degrees o f m y o p i a to experience significant regression (loss o f refractive effect) in which their refractive status goes some or all o f the way back to their preoperative level .2-5.24 The problem o f regression is more marked in high myopia, and predictability o f refractive outcome is limited severely in these patients. As seen in Table 6, which provides a s u m m a r y of selected published series with reasonable numbers o f patients and length o f follow-up, 2-6's'932-23 the majority o f centers classify m y o p i a into four grades for the purpose o f description o f results: 1. 2. 3. 4.
Low myopia: up to - 3 . 0 0 D Moderate myopia: from - 3 . 1 0 to - 6 . 0 0 D High myopia: from - 6 . 1 0 to - 9 . 0 0 D Extreme myopia: above - 9 . 1 0 D
In practice, the majority o f patients treated worldwide have been below - 9 . 0 0 D. On averaging the results from these different centers (Table 6), regression is shown to increase with increasing attempted change in refraction. As a guide to counseling prospective patients, Table 7 summarizes the average a c c u r a c y - p r e d i c t a b i l i t y o f the procedure for low, moderate, and high m y o p i a taken from the results in Table 6. It is, o f course, possible that variability in refractive outcome will be reduced and predictability, therefore, improved by the use o f a standard 6m m - d i a m e t e r ablation zone in keeping with the improved results reported when b e a m diameters were increased to 5 m m from the original 3.5 m m or 4 mm. 3° Peer-reviewed
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published results of studies with reasonable follow-up and substantial numbers of patients treated with 6-mm zones are awaited. In a questionnaire survey of 182 post-PRK patients from the original United Kingdom trials (treatment range, - 2 . 0 0 D to - 7 . 0 0 D and ablation zone diameter of only 4 mm, with a minimum follow-up of 18 months), 154 (85%) were pleased with the outcome. 2'3'24 Of the remaining ~8 patients, 24 cited regression as the chief cause of their dissatisfaction. Other reasons given much less commonly were the pain of the procedure, lengthy rehabilitation time, reduced BCVA, and night vision problem's. The overall level of satisfaction was therefore surprisingly high and would have been even higher had regression been less and predictability greater. Because there are ever-increasing numbers of patients seeking and
.Table 4. Comparison of Refractive Outcome at 6 Months Following Exact Tt:eatment and Deliberate Overcorrection (as for Table 3) [Groups A1 and A2 (Minimal Haze) and B1 and B2 (Significant Haze)]: Mean + SD
Group
Refraction (SE) after First PRK
Minimal haze exact (A1) Minimal haze overcorrection (A2) Significant haze exact (BI) Significant haze overcorrection (B2)
- 1 . 9 6 -'- 0.72 (n = 25) - 1 . 7 7 + 0.60 (n = 27) - 4 . 1 0 + 1.95 (n = 27) -3.85 + 2.12 (n = 27)
Refraction (SE) after Retreatment at 6-mo Stage -0.72 +- 0.94 +0.04 -+ 0.83 -2.2
+- 1.95
-0.81 + 1.46
SD = standard deviation; PRK = photorefractive keratectomy; SE = spherical equivalent.
136
undergoing PRK, it is inevitable that a significant number will regress partly or, in a minority of cases, totally back toward their original refraction. We have found that subsequent to the commencement of the study reported here, 320 (15%) of our cohort of more than 2000 patients in the Moorfields programs requested retreatment for elimination of residual myopia. If this figure is representative, then centers performing PRK will find that retreatment becomes an important part of their practice. This prospective study was designed, therefore, to determine a logical rationale for excimer laser PRK retreatment. M e c h a n i s m of Regression Regression is caused by the corneal wound-healing response that, as would be expected from first principles, differs from patient to patient and results in variation in refractive outcome and incidence of complications, even among patients with similar or identical errors of refraction. 2-5 In addition, as shown in Tables 6 and 7, regression is a much greater problem when higher degrees of myopia are treated and is the main factor limiting predictability of outcome in these patients. This decreasing predictability with the-treatment of increasing amounts of myopia is likely to be caused by a combination of the increased depth of ablation and, therefore, the volume of tissue removed, the ablation zone edge profile, and the healing characteristics of the more myopic eye. The wound-healing response post-PRK is a combination of epithelial hyperplasia and the deposition of an amorphous material beneath the epithelium. 2'3'25-2s The relative contributions of these two components have been shown to be dependent on technical parameters in laser manufacture, for example, beam diameter, which affects both edge profile and volume of tissue removed. 29'3° Each of these factors is discussed below.
G a r t r y et al • R e t r e a t m e n t for Regression after E x c i m e r Laser P R K [n = 106)
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Epithelial Hyperplasia. Animal studies have shown that epithelial hyperplasia can be considerable after P R K - - a s much as double the normal thickness. ~ Examples have been cited in which loss of epithelium 2 to 3 months after surgery in eyes showing significant regression has resulted in a return to the relatively overcorrected state. 2'3 This then was followed by a similar pattern of exponential regression as seen in the months before the epithelial loss. Anterior Stromal Haze. In animal models, anterior stromal haze was found to be caused by collagen deposition between the epithelium and the photoablated surface. as This layer of material probably contributes to the appearance of anterior stromal haze that c o m m o n l y is seen at slit-lamp examination after surgery. Recent work suggests that this layer consists of new mucopolysaccharides and glycosaminoglycans as well as new, disorganized collagen. Haze is maximal between 3 and 6 months post-PRK and is correlated moderately well with both the amount of myopia treated (depth of ablation, coefficient
of correlation, r = 0.71) and regression (r = 0 . 7 5 ) . 3.4 The greater the amount of anterior stromal haze, in general, the greater the loss of refractive effect or regression. It had been hoped that this wound-healing response could be modified pharmacologically, but to date, the results of prospective, randomized, double-masked studies investigating the role of topical corticosteroids post-PRK have not shown a statistically significant long-term beneficial effect on either refractive outcome or anterior stromal haze. 4`s
In most cases, it is likely that regression is caused by a combination of the two key corneal wound-healing factors (i.e., epithelial hyperplasia and anterior stromal haze). It may be difficult to determine the relative contributions made by each component in an individual patient. When considering a rationale for retreatment, however, these different aspects of corneal wound healing can be taken into account and two basic assumptions made in the design of this study:
Table 5. Preoperative and Postoperative Details of Patients with Marked Total Loss of Bestcorrected Visual Acuity (BCVA) Patient No.
Original Myopia (D)
Haze Before Retreatment
Loss of BCVA
Haze After Retreatment
Final Loss of BCVA
1 2 3 4 5 6 7 8
-6.625 -5.50 -8.00 - 11.00 -11.625' -9.00 -13.625 -10.875
3 3 4 2 2 4 3 2
-1 -2 -1 - 1 -1 0 -1 0
3 2 3 1 2 3 3 2.5
-4 -2 -2 -3 -2.5 -4 -4 -2
137
Ophthalmology Volume 105, Number I, January 1998 T a b l e 6. Excimer Laser Photorefractive Keratectomy for Myopia: Selected Summary of Main Published Refraction mad Visual Acuity Results
Author/Year Seiler et al, 1991 s
Laser Type (Beam Diameter)
No. of Patients
Follow-up
Treatment Range (D)
Gartry et al, 1991: and 19923
Summit (3.5 ram) Summit (4.0 ram)
26 120
1 yr 1 yr to 1 yr, 10 mos
Gartry et al, 19924 and 1993 s
Summit (4.0 mm)
113
I yr rain
Salz et al, 1993 n
Visx (5.0 and 5.5 mm)
12 71 77 133 61 81 total 32 126
2 yrs 1 yr < 1 yr 2 yrs (mean) 1 yrs
- I . 2 5 to - 8 . 3 7 - 1 . 0 0 to - 1 0
6 mos 2 yrs
up to - 6 . 0 0 -1.25 to ?-I0
176
1 yr
Piebenga et al, 199313 Ficker et al, 19936
Visx (5.0 ram) Summit (4.5 and 5.0 mm)
Taylor et al, 199314 Seiler et al, 1994 Is
Visx (6 ram) Summit (4.5 and 5.0 ram)
-1.40 -2.00 -4.00 -6.00 -3.00
to - 9 . 2 5 to - 3 . 0 0 to - 5 . 0 0 to - 7 . 0 0 and - 6 . 0 0 groups
- 1 . 2 5 to - 7 . 5 0
Les Jardinset al, 1994J6't
Meditec (5 ram)
63
> 6 mos
- 1 . 2 5 to - 9 . 0 0
Kim et al, 199417't Rogers et al, 19941s't
Summit (5.0 ram) Summit (3.6 to 5.0 ram)
45 14
2 yrs I yr
- 2 . 0 0 to - 6 . 0 0 -10.25 to -20.50
Shimizu et al, 19941~'? •
Summit (4.5 mm)
I yr
-2.00 to-7.50
Orssaud et al, 1994'°'i"
Summit (5.0 ram)
11 low 45 medium 41 high 176
6 mos mean
- 1 . 0 0 to - 8 . 5 0
Maguen et al, 199421 Epstein et aL, 1944 z2 update (see also Tengroth et al 9)
Visx (? 6.0 ram) Summit (4.3 or 4.5 ram)
240 495
1 yr mean 2 yrs min
- 1 . 0 0 to -7.75 -1.25 to - 7 . 5 0
Dutt et al, 1994,3
Summit (5 ram)
35
I yr
- 1 . 5 0 to - 6 . 1 0
(continues)
1. Those patients who have regressed significantly and have minimal anterior stromal haze are likely to have relatively greater epithelial hyperplasia to account for their regression. "2. Those patients exhibiting greater amounts of corneal haze have regressed because of the relatively greater amounts of mucopolysaccharide and glycosaminoglycans _+ collagen deposited.
T a b l e 7. Average Refractive Outcome Following Photorefractive Keratectomy Published Results from T a b l e 1
Preoperative Myopia (D) Range
% of Patients within + 1 D
- 1.00 to - 3 . 0 0 - 3 . 1 0 to - 6 . 1 0 - 6 . 1 0 to - 9 . 0 0
90 72 40
138
of Attempted Correction
Aims of the Study On the basis of the above assumptions, when considering the likely retreatment problems, the following three main questions were addressed: 1. Do those patients with little or no anterior stromal haze behave differently after retreatment compared to "aggressive hazers"? 2. In cases with significant regression, can a more satisfactory result be achieved with a repeat procedure in which only the residual myopia is treated, or is an overcorrection (or "fudge factor") required? It was hypothesized that overcorrection might be needed to offset the tendency of epithelial hyperplasia in the clear corneal group and the generation of new tissue in the significant haze group. The profile of the ablation zone produced during PRK has an influence on corneal wound healing and accounts for the lower incidence of regression when larger ablation diameters are used. 3° A deliberate overcorrection alters
Gartry et al • R e t r e a t m e n t for Regression after Excimer Laser PRK
Table 6 (continued). Refractive Outcome* (%) Within + I D of Intended
92% 83% 45% 30% 56% 20% 88% 73%
overall low medium high low high
Unaided Vision >6 mo
96% 56% low 49% medium 13% high NR
No. of Lines of BCVA Lost (Snellen, %) >2
Comment
Nil 3
Nil Nil
1 corneal graft needed, slow healing in SLE Regression prop to degree of myopia
6
Nil
Steroids of no statistically significant benefit
I
7.7 15 9
2
93% 79% at 1 yr
17
1.4
Nil
75% overall 81% overall
75% overall NR
8 15
Nil Nil
Nil Nil
Role of steroids questioned Regression prop to degree of myopia
88% overall 97.6% low 92% medium 34% high 91% low 62% medium 41% high 91.1% overall
88% ovemll NR
25 6
19 I
Nil Nil
Complications intolerable above -6.00 D
71% overall
NR
100% low 76% medium 44% high 100% low 86% medium 43% high 79% overall 87.5% overall
NR
89% overall 91% overall
80% overall
94% overall
NR
8
14%
NR
NR
4
NR
NR
NR
50% lost a "variable" amount of BCVA and were re-treated Nil Nil Nil
8 18 73
"Quality" of VA reduced in 22% of patients Significant scarring in 50% of patients Predictability better in low myopia
NR 0.4 only
9 38 4 - 7 at 1 yr Nil
NR NR NR Nil
1 potentially serious corneal infection Stabilization between 1.5 and 2 yrs
Nil at 1 yr
Nil
Nil
Loss of BCVA in first 4 mos only
BCVA = best-corrected visual acuity; NR = not reported; VA = visual acuity. * For the purposes of comparison betaveen series, "low" (myopia) is up to -3.00 D, "medium" from -3.10 to -6.00 D, and "high" is greater tb,'m -6.10 D. "t"Proceedings papers (no peer-review process).
the edge profile of the wound, and it was hypothesized that this would be of some benefit in those patients with a proven tendency to regress. 3. Which factors, identifiable after the first PRK, are important predictors of success or failure after a second treatment? As yet, no prospective, controlled studies of retreatment have been reported in the literature. Reports to date relate relatively small numbers of retreatment procedures for regression. 3~-33 In 1 of these studies, 9 (59%) of 17 patients were within + 1.00 D of emmetropia at 6 months, and once again there was marked individual variation after the surgery. 32 To date, no attempt has been made to relate the individual initial wound-healing response after the first PRK in a prospective, randomized, controlled study to either retreatment strategy or identification of predictors of outcome. As can be seen from Tables 1 and 2 anl:l Figures 1 and 2, the initial mean refraction for the 106 patients enrolled into this study was -6.73 D, and the mean refraction (regression) before retreatment was - 3 . 1 4 D. After retreatment, this
figure improved to - 1.75 D. Retreatment could therefore be described as beneficial overall. It also can be seen from Table 2, however, that those patients with minimal haze achieve a result after retreatment, which is relatively close to emmetropia (-0.41 D at 18 months) as compared to the group with significant haze after the first PRK (-4.14 D at 18 months, slightly worse on average than before retreatment). It would seem that the outcome of retreatment closely parallels the outcome of the first PRK in that those patients who generate a large amount of anterior stromal haze tend to do the same after a retreatment with a predicted loss of BCVA and repeat regression. A greater percentage of patients receiving a deliberate overcorrection at retreatment were within __ 1.00 D of the intended refraction (Table 3, Fig 3). The difference was statistically significant when comparing groups A1 and B 1 with A2 and B2 overall (P = 0.026 at 6 months and 0.032 at 1 year). Interestingly, despite the deliberate 50% overcorrection in approximately half of the patients, no patient had significant, sustained overcorrection-hyper-
139
Ophthalmology Volume 105, Number I, January 1998 metropia beyond 1 year (Fig 2A). Table 4 and Figures 4A and B allow comparisons between groups A1 and A2 (minimal haze) and B1 and B2 (significant haze), respectively. In both cases, a statistically significantly better refractive outcome was achieved in the groups undergoing deliberate overcorrection (A2 and B2, P = 0.04 and 0.027, respectively). Eight patients showed a significant loss of BCVA at 6 months (Table 5) after retreatment, which ranged from one to four lines of Snellen. These patients had been in the significant haze group (Fig 4B) and all had moderateto-high myopia before their first PRK ( - 5 . 5 to -13.625 D, mean - 9 . 5 3 D). Analysis of variance showed that anterior stromal haze after the first PRK is highly correlated with refractive outcome after retreatment and is four times more important to the outcome than overtreatment or exact treatment. Those patients with 2+ or more of haze after the first PRK have a high probability of regressing after retreatment and generating a similar amount of haze again with a concomitant loss of BCVA. We concl'ude that in the majority of patients, a retreatment PRK procedure for significant regression will reduce myopia further and that a deliberate 50% overcorrection, or fudge factor, is effective in achieving a better refractive outcome. Patients with relatively little anterior stromal haze after their first PRK procedure can, on average, be expected to generate little haze after retreatment and will, again on average, have regressed by only modest amounts. Overcorrection also is of benefit in those patients with significant haze after their first PRK. However, care must be taken when considering retreatment in these patients. Risk factors that are important predictors of a poor outcome after retreatment are (1) high myopia originally; (2) regression beyond approximately - 3 . 5 0 D; (3) significant anterior stromal haze after the first PRK ( > grade 2+); and (4) loss of BCVA after the first procedure. We consider that patients with these risk factors, especially if including loss of BCVA, should be retreated with great caution (if at all), pending the results of further trials. There is a significant risk of regression, haze, and ppfurther loss of BCVA in this group. Acknowledgment. The authors thank the Excimer Laser Group, Moorfields Eye Hospital, for their contributions to this paper.
References 1. Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol 1983;96:710-5. 2. Gartry DS, Kerr Muir MG, Marshall J. Photorefractive keratectomy with an argon fluoride excimer laser: a clinical study. J Refract Corneal Surg 1991;7:420-35. 3. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser photorefractive keratectomy--18 month follow-up. Ophthalmology 1992;99:1209-19. 4. Gartry DS, Kerr Muir MG, Lohmann CP, Marshall J. The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy. A prospective, randomized, double-blind trial. Arch Ophthalmol 1992; 110:944-52.
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5. 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;7:58490. 6. Ficker LA, Bates AK, Steele AD, et al. Excimer laser photorefractive keratectomy for myopia: 12 month follow-up. Eye 1993;7:617-24. 7. Seiler T, Kahle G, Kriegerowski M. Excimer laser (193 nm) myopic keratomileusis in sighted and blind human eyes. J Refract Corneal Surg 1990;6:165-73. 8. Seiler T, Wollensak J. Myopic photorefractive keratectomy with the excimer laser. One-year follow-up. Ophthalmology 1991;98:1156-63. 9. Tengroth B, Epstein D, Fagerholm P, et al. Excimer laser photorefractive keratectomy for myopia. Clinical results in sighted eyes. Ophthalmology 1993; 100:739-45. 10. Sher NA, Chen V, Bowers RA, et al. The use of the 193nm excimer laser for myopic photorefractive keratectomy in sighted eyes. A multicenter study. Arch Ophthalmol 1991 ; 109:1525-30. 11. McDonald MB, Liu JC, Byrd TJ, et al. Central photorefractive keratectomy for myopia. Partially-sighted and normally sighted eyes. Ophthalmology 1991 ;98:1327-37. 12. Salz JJ, Maguen E, Nesbum AB, et al. A two-year experience with excimer laser photorefractive keratectomy for myopia. Ophthalmology 1993; 100:873-82. 13. Piebenga LW, Matta CS, Deitz MR, et al. Excimer photorefractive keratectomy for myopia. Ophthalmology 1993; 100:1335-45. 14. Taylor HR, Guest CS, Kelly P, Alpins NA for the Excimer Laser and Research Group. Comparison of excimer laser treatment of astigmatism and myopia. Arch Ophthalmol 1993; 111:1621-6. 15. Seiler T, Holschbach A, Derse M, et al. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology 1994; 101:153- 60. 16. Leroux les Jardins SL, Auclin F, Roman S, et al. Results of photorefractive keratectomy on 63 myopic eyes with six months minimum follow-up. J Cataract Refract Surg 1994; 20(Suppl):223-8. 17. Kim JH, Hahn TW, Lee YC, Sah WJ. Excimer laser photorefractive keratectomy for myopia: 2-year follow-up. J Cataract Refract Surg 1994;20(Suppl):229-33. 18. Rogers CM, Lawless MA, Cohen PR. Photorefractive keratectomy for myopia of more than - 1 0 diopters. J Refract Corneal Surg 1994; 10(2 Suppl):Sl71-3. 19. Shimizu K, Amano S, Tanaka S. Photorefractive keratectomy for myopia: one-year follow-up in 97 eyes. J Refract Corneal Surg 1994; 10(2 Suppl):S178-87. 20. Orssaud C, Ganem S, Binaghi M, et al. Photorefractive keratectomy in 176 eyes: one-year follow-up. J Refract Corneal Surg 1994; 10(2 Suppl):S199-205. 21. Maguen E, Salz JJ, Nesburn AB, et al. Results of excimer laser photorefractive keratectomy for the correction of myopia. Ophthalmology 1994; 101:1548-57. 22. Epstein D, Fagerholm P, Hamberg-Nystrom H, Tengroth B. Twenty-four-month follow-up of excimer laser photorefractive keratectomy for myopia. Refractive and visual acuity results. Ophthalmology 1994; 101:1558-64. 23. Dutt S, Steinert RF, Raizman MB, Puliafito CA. One-year results of excimer laser photorefractive keratectomy for low to moderate myopia. Arch Ophthalmo! 1994; 112:1427-36. 24. Gartry DS. Treating myopia with the excimer laser: the present position. BMJ 1995; 310(6985):979-85. 25. Tuft SJ, Zabel RW, Marshall J. Corneal repair following
G a r t r y et al • Retreatment for Regression after Excimer Laser PRK
26.
27.
28.
29.
keratectomy. A comparison between conventional surgery and laser photoablation. Invest Ophthalmol Vis Sci 1989; 30:1769-77. Lohmann C, Gartry D, Kerr Muir M, et al. "Haze" in photorefractive keratectomy: its origins and consequences. Lasers and Light in Ophthalmology 1991;4:15-34. Lohmann CP, Gartry DS, Muir MK, et al. Comeal haze after excimer laser refractive surgery: objective measurements and functional implications. Eur J Ophthalmol 1991;1:173-80. Lohmann CP, Timberlake GT, Fitzke FW, et al. Corneal light scattering after excimer laser photorefractive keratectomy: the objective measurements of haze. J Refract Corneal Surg 1992;8:114-21. Gauthier CA, Epstein D, Holden BA, et al. Epithelial alter-
30.
31. 32. 33.
ations following photorefractive keratectomy for myopia. J Refract Surg 1995; 11:113-8. O'Brart DP, Gartry DS, Lohmann CP, et al. Excimer laser photorefractive keratectomy for myopia: comparison of 4.00- and 5.00-millimeter ablation zones. J Refract Corneal Surg 1994; 10:87-94. Lawless MA, Cohen PR, Rogers CM. Retreatment of undercorrected photorefractive keratectomy for myopia. J Refract Corneal Surg 1994; 10(2 Suppl):S 174-7. Epstein D, Tengroth B, Fagerholm P, Hamberg-Nystrom H. Excimer retreatment of regression after photorefractive keratectomy. Am J Ophthalmol 1994; 117:456-61. Sutton G, Kalski RS, Lawless MA, Rogers C. Excimer retreatment for scarfing and regression after photorefractive keratectomy for myopia. Br J Ophthalmol 1995;79:756-9.
Historical Vignette Richard Liebreich (1830-1917) enjoyed an amazing career in ophthalmology. He was a medical student under Helmholtz when that physician did his early work with the ophthalmoscope. He became the right-hand man of von Graefe at his famous clinic in Berlin. Liebreich next moved to Paris, where he reached the pinnacle of success at the court of Emperor Napoleon III. He operated on the Emperor's mother-in-law and cured her of acute glaucoma in the era prior to the discovery of local anesthesia. After the fall of Napoleon III in 1870, Liebreich became the head of ophthalmology at St. Thomas HoSpital and Medical School in London. Later, he returned to Paris, where he worked as a painter and sculptor. He maintained a limited ophthalmologic practice and treated patients as famous as the Impressionist artist Claude Monet.*
*Historical vignette prepared by James Ravin, MD, of Toledo, Ohio.
141
In 1983, Trokel, Srinivasan, and Braren ~ published the first article describing the possible role of the excimer laser in corneal surgery. Numerous laboratory studies followed, and photorefractive keratectomy (PRK) for the treatment of myopia has gained in popularity over the past 7 years since the first clinical exposures commenced.-'- ~ It has been estimated that several hundred thousand patients have been treated worldwide, and the procedure was given official limited approval by the Food and Drug Administration recently. Despite the current enthusiasm for excimer laser corneal surface reprofiling, individual patient variation in the wound-healing response limits predictability of refractive outcome, especially when attempts are made to treat moderate-to-high myopia (i.e., greater than approximately - 6 . 0 0 diopters [D]). z-5 As a
Originally received: November 1, 1995. Revision accepted: August 6, 1997. From the Cornea Service, Moorfields Eye Hospital, London, England. Presented in part at the American Academy of Ophthalmology Annual Meeting, Atlanta, Georgia, November 1995. The authors have no proprietary interest in the products or techniques described in this article. Reprint requests to David S. Gartry, MD, FRCOphth, The Cornea Service, Moorfields Eye Hospital, City Road, London ECIV 2PD, UK.
consequence of this variability, a significant number of patients regress back toward the myopic state. Given that it is likely (after approval by the Food and Drug Administration) that even greater numbers of patients will undergo PRK in the future and that regression will remain a significant problem, the number of patients requesting retreatment also will increase. From published series, it can be estimated that between 10% and 20% of patients undergoing PRK will have, what they consider to be, a significant amount of residual myopia and will want to have this eliminated. 2-'4 In the series reported here, 106 patients were retreated as part of a prospective, randomized, masked study. These patients were recruited from a cohort of approximately 1000 post-PRK patients at the time of the study's commencement and therefore represent approximately 10% of the total number. This "retreatment frequency" or incidence will vary from center to center and will depend on a number of factors, including the upper limit of myopia treated, the type of laser, the maximum ablation zone diameter used, and the threshold of both patient and surgeon in requesting and performing a PRK retreatment. In view of the increasing absolute numbers of patients with significant regression', it is important to adopt a retreatment strategy based on the results of controlled studies. This study was designed,
131
Ophthalmology Volume 105, Number l, January 1998 Table 1. Change in Refraction with Time after the First Photorefractive Keratectomy Procedt, re for the Group as a Whole (n = 106) and According to the "Haze" Subgrouping (n = 52 with Minimal Haze = 1+ or Less, and n = 54 with Significant Haze = 2+ or More Subjective Haze Grading): Mean _+ SD Mean Spherical Equivalent [D (SD)]
Time (mos) Before first PRK 1 3 6 12
Whole Group (n = 106)
-6.73 +0.41 -1.78 -3.01 -3.41
(2.87) (1.53) (2.12) (2.07) (2.21)
Minimal Haze Group (n = 52)
-4.97 -0.65 -1.42 -1.59 -1.89
(I.68) (1.37) (0.77) (0.83) (0.62)
Significant Haze Group (n = 54)
-7.37 +0.72 -I.96 -3.67 -3.92
(2.91) (1.37) (2.17) (1.89) (2.07)
SD = standard deviation; PRK = photorefractive keratectomy.
therefore, to p r o v i d e patient selection criteria for ret r e a t m e n t P R K by e v a l u a t i n g the o u t c o m e o f r e t r e a t m e n t in terms o f several likely " p r e d i c t o r s " or variables, n a m e l y , (1) the a m o u n t o f anterior stromal haze present after the first P R K , (2) the loss o f best-corrected visual acuity ( B C V A ) ; (3) the a m o u n t o f original m y o p i a ; (4) the a m o u n t o f regression before retreatment; and (5) the effect o f a deliberate o v e r c o r r e c t i o n p r o g r a m m e d d u r i n g the retreatment in an attempt to c o m p e n s a t e for the already p r o v e n t e n d e n c y for regression to occur.
Materials and Methods Study Design After Ethics Committee approval, 106 patients who had requested retreatment for significant regression after PRK were recruited into the study. Patients then were divided into two groups based on the amount of anterior stromal haze present after the first PRK: group A, those with minimal or no haze ( < 2 + ) , and group B, those with significant haze (=-2+). Each patient then was randomized to one of two subgroups: group 1, those patients who received a retreatment in which the laser was programmed to correct 100% of the residual myopia (i.e., an exact retreatment), and group 2, those patients who received a retreatment in which the laser was programmed to correct 150% of the residual myopia (i.e., a deliberate overcorrection). The study design, therefore, comprised four groups: 1. G r o u p A1 - Those with minimal haze (-<1 +) in which a repeat PRK was carried out and the computer was programmed to correct the existing amount of residual myopia exactly. 2. G r o u p A2 - Just as for group A1, except that the laser was programmed to overcorrect by 50%. For example, a patient who was - 6 . 0 0 D originally and regressed back to - 2 . 0 0 D would receive a - 3 . 0 0 D retreatment. 3. G r o u p B1 - Those with significant haze (---2+) treated with an exact PRK correction (i.e., the amount programmed into the laser matched exactly the residual myopia as for group A1). 4. G r o u p B2 - Those with significant haze treated with a deliberate 50% overcorrection. The mean preoperative (original) refraction and the mean refraction at various intervals after the first PRK procedure are given in Table 1. For the group as a whole (n = 106), the mean
132
original spherical equivalent was - 6 . 7 3 D, whereas at 1 year, regression to -3.41 D had occurred. After division into the two main subgroups (i.e., by the amount of anterior stromal haze generated after the first PRK), the minimal haze group had a mean spherical equivalent of - 4 . 9 7 D (n = 52) and regressed back to - 1 . 8 9 D at 1 year, whereas the significant haze group (n = 54), as might be expected, was more myopic originally ( - 7 . 3 7 D) and regressed to - 3 . 9 2 D at 12 months (Table I). Figures IA through C show these same changes in refraction with time graphically. Preretreatment Assessment
Photorefractive
Keratectomy
Of the 106 patients enrolled in this study, 100 had been treated originally with a Visx 20/20 excimer laser (Visx Inc., Sunnyvale, CA), using a 5-mm-diameter ablation zone, as part of the Moorfields Phase [] Program. Six patients had been part of an early cohort (phase I) treated with an Excimed UV200 excimer laser (Summit Technology, Waltham, MA) using 4.5-mm or 5-mm ablation zones. All patients were at least 6 months post-first PRK, and in the majority (95%) of patients (96 of 106), follow-up was 1 year or more. The primary indication for retreatment was significant regression relative to the original myopia, which led to the patients' request for treatment of their residual myopia. Preretreatment assessment included (1) subjective refraction/slit-lamp examination and intraocular pressure measurement; (2) computerized videokeratography Eye-Map system (Alcon, Fort Worth, TX) to exclude significant ablation zone decentration; (3) optical pachymetry; and (4) anterior segment photography. Patients were counseled carefully in a similar fashion to those in other PRK cohorts within the Moorfields excimer laser research programs. In particular, the investigational and, essentially, experimental nature of the retreatment study was emphasized and the possibility of repeated regression and loss of BCVA after retreatment explained fully. It was considered essential that patients undergoing retreatment had entirely realistic expectations in relation to the uncertainty of the refractive outcome. The importance of randomization to one of the two main treatment groups (i.e., overcorrection or exact correction) also was explained in detail, and each patient was required to read and sign a six-page background information and consent form, approved by the Moorfields Eye Hospital Ethics Committee, before surgery. The Procedure A Visx 20/20 laser (Visx Inc.) was used throughout with a fluence of 180 mJ/cm-" at the corneal plane, a pulse repetition
G a r t r y et al •
Retreatment for Regression after Excimer Laser PRK
rate of 5 Hz, and a beam diameter of 6 mm in each case. Manual epithelial debridement was performed and the retreatment carried out as for a standard PRK procedure by one of the two surgeons (DSG, DFPL) responsible for the study.
Postoperative Monitoring and Topical Regimen Patients were seen on days I and 7; months 1, 3, 6, 12, 18; and annually thereafter. A standardized postoperative topical treatment regimen was used for all patients and comprised instillation of diclofenac sodium 0.1%, chloramphenicol 0.5%, and homatropine 2% eyedrops and betamethasone ointment immediately after the procedure and application of a pad. This was removed the next day, and the following regimen was used: dexamethasone 0.1% eyedrops four times daily for 1 week, then twice daily for 3 weeks, and chloramphenicol 0.5% eyedrops four times daily for 1 week.
Resul~ Figures 2A through C show the change in refraction with time after PRK retreatment for (A) the group as a whole (n = 106), (B) those patients with minimal haze after the first PRK (n = 52), and (C) those patients with significant haze after the first PRK procedure (n = 54). When compared with Figure I A, the
E3 LU
0 i ...........
i-
tO U
progress of the whole group after the first PRK retreatment on average resulted in a greater proximity to emmetropia (i.e., - 1 . 7 5 D) after retreatment compared with - 3 . 4 1 D after the first PRK (Tables 1 and 2). It is evident, however, that patients with minimal or no haze after the first procedure achieve the best refractive results (Fig 2B), whereas those in groups B 1 and B2 (i.e., with significant haze) regress as before (Fig 2C). Figure 3 shows the effect of exact treatment versus deliberate 50% overcorrection in terms of (A) the mean refraction versus time for the 2 groups and (B) a scattergram of the 65 patients for whom I-year data are available. When,comparing the patients who received a deliberate 50% overcorrection as a whole (groups A2 and B2 combined) with those receiving an exact correction (groups A1 and B1 combined), the overcorrected groups were statistically significantly closer to emmetropia at all stages of follow-up (P = 0.026 at 6 months, n = 106; P = 0.032 at I year, n = 65). Table 3 provides a summary of the results at 6 months. Figures 4A and B are scattergrams for the four subgroups and show the effect of overcorrection versus exact correction at the 6-month stage (minimum follow-up for all 106 patients enrolled in the study). Those patients with minimal haze before retreatment are shown in Figure 4A (AI and A2), whereas those with a haze grade of 2+ or greater before retreatment are shown in Figure 4B (B 1 and B2). Table 4 summarizes the results from these scattergrams. Table 4 shows that deliberate overcorrection in the minimal haze group resulted in a statistically significantly better outcome at 6 months (i.e.,
uJ
g
0
..........
i ....................
n = 52
(48 @ 1 year +1
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Figure 2. The change in refraction with time after photorefractive keratectomy (PRK) retreatment for (A) the group as a whole (n = 106), (B) those panents with minimal haze after the first PRK (n = 52), and (C) those patients with significant haze after the first PRK procedure (n = 54).
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greater proximity to emmetropia) (P = 0.04). This also was the case for the patients with significant haze after their first PRK procedure (P = 0.027).
Complications Loss of Best-corrected Snellen Visual Acuity. Figures 5A and B show the change in B C V A (A) after the first PRK procedure and (B) after the retreatment procedure. After the first PRK (at
a minimum follow-up period of 1 year), 32% and 10% of patients lost one or two lines of BCVA, respectively, whereas approximately 15% lost one or two lines and 5.6% lost three lines after retreatment. Because the loss of B C V A proved to be cumulative in some of these cases, there were instances of a four-line loss of B C V A compared with that of the original acuity (i.e., the BCVA) before the first PRK procedure. Table 5 documents the eight patients with the worst outcome in our retreatment series in terms of loss of BCVA, anterior stromal
Table 2. Change in Refraction with Time Following Retreatment for the Group as a Whole (n = 106) and According to the Subjective "Haze" Subgrouping (n = 52 with Minimal Haze = I + or Less, and n = 54 with Significant Haze = 2"+ or Greater): Mean _+ SD Mean Spherical Equivalent [D (SD)] Time (mos) Before retreatment 1 3 6 12 18 SD = standard deviation.
134
Whole Group (n = 106) -3.41 +1.31 -0.39 -1.37 -1.69 -1.75
(2.21) (1.78) (2.09) (2.12) (2.06) (2.0I)
Minimal Haze Group (n = 52) -1.89 +0.47 -0.27 -0.28 -0.37 -0.4I
(0.62) (0.97) (0.75) (0.56) (0.47) (0.69)
Significant Haze Group (n = 54) -3.92 +1.72 -0.25 -1.93 -3.97 -4.14
(2.07) (1.97) (2.54) (2.38) (2.10) (2.34)
G a r t r y et al • R e t r e a t m e n t for R e g r e s s i o n after E x c i m e r Laser P R K 5
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haze preretreatment and postretreatment, and original amount of myopia present. The 6-month datapoints for these individuals are highlighted in Figure 4B. Three patients lost a total of four lines of BCVA after retreatment when assessed at the 6-month stage. Significantly; the mean preoperative myopia (i.e., before their first PRK procedure) for these eight patients was -9.53 D (range, - 5 . 5 0 D to -13.625 D), and the mean subjective haze grading after the first procedure was 2.88+. Analysis of variance showed that the presence of significant anterior stromal haze ( > 2 + subjectively) after the first procedure was the most important predictor of a poor outcome after retreatment, being just over four times more influential in contributing to the variance in the data than overtreatment or exact treatment. As shown in Figures 1C and 2C, those patients with significant anterior stromal haze after the first PRK ( ~ 2 + ) have greater variation in refractive outcome, as shown by the larger standard deviations, and more regression after both the first PRK and the retreatment procedure.
Discussion Since the first suggestion that e x c i m e r lasers might be suited to corneal refractive surgery, ] numerous laboratory
Table 3. The Mean Refraction Spherical Equivalent Following the First Photorefractive Keratectomy Compared with the Refraction Following Retreatment at 6 Months of Follow-up (n = 106) for Both Exact Treatment and Deliberate Overcorrection Subgroups: Mean _+ SD Group
Exact (n = 55) Overcorrection (n = 51)
Refraction (SE) after First PRK
Refraction (SE) after Retreatment
-3.12 m 2.04
-1.64 m 2.07
-2.82 --. 1.72
,
-0.15 --. 1.54
SD = standard deviation; PRK = photorefractive keratectomy; SE = spherical equivalent.
and clinical studies have been performed. 2-32 It has been estimated that over the past 7 years since the first clinical exposures,-'- ~ several hundred thousand procedures have been undertaken worldwide, and e x c i m e r laser P R K has b e c o m e an accepted form of treatment for low-to-moderate amounts of myopia. Previous studies have shown, however, that although predictability is reasonable up to approximately - 6 . 0 0 D, it is by no means impossible for patients with lower degrees o f m y o p i a to experience significant regression (loss o f refractive effect) in which their refractive status goes some or all o f the way back to their preoperative level .2-5.24 The problem o f regression is more marked in high myopia, and predictability o f refractive outcome is limited severely in these patients. As seen in Table 6, which provides a s u m m a r y of selected published series with reasonable numbers o f patients and length o f follow-up, 2-6's'932-23 the majority o f centers classify m y o p i a into four grades for the purpose o f description o f results: 1. 2. 3. 4.
Low myopia: up to - 3 . 0 0 D Moderate myopia: from - 3 . 1 0 to - 6 . 0 0 D High myopia: from - 6 . 1 0 to - 9 . 0 0 D Extreme myopia: above - 9 . 1 0 D
In practice, the majority o f patients treated worldwide have been below - 9 . 0 0 D. On averaging the results from these different centers (Table 6), regression is shown to increase with increasing attempted change in refraction. As a guide to counseling prospective patients, Table 7 summarizes the average a c c u r a c y - p r e d i c t a b i l i t y o f the procedure for low, moderate, and high m y o p i a taken from the results in Table 6. It is, o f course, possible that variability in refractive outcome will be reduced and predictability, therefore, improved by the use o f a standard 6m m - d i a m e t e r ablation zone in keeping with the improved results reported when b e a m diameters were increased to 5 m m from the original 3.5 m m or 4 mm. 3° Peer-reviewed
135
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published results of studies with reasonable follow-up and substantial numbers of patients treated with 6-mm zones are awaited. In a questionnaire survey of 182 post-PRK patients from the original United Kingdom trials (treatment range, - 2 . 0 0 D to - 7 . 0 0 D and ablation zone diameter of only 4 mm, with a minimum follow-up of 18 months), 154 (85%) were pleased with the outcome. 2'3'24 Of the remaining ~8 patients, 24 cited regression as the chief cause of their dissatisfaction. Other reasons given much less commonly were the pain of the procedure, lengthy rehabilitation time, reduced BCVA, and night vision problem's. The overall level of satisfaction was therefore surprisingly high and would have been even higher had regression been less and predictability greater. Because there are ever-increasing numbers of patients seeking and
.Table 4. Comparison of Refractive Outcome at 6 Months Following Exact Tt:eatment and Deliberate Overcorrection (as for Table 3) [Groups A1 and A2 (Minimal Haze) and B1 and B2 (Significant Haze)]: Mean + SD
Group
Refraction (SE) after First PRK
Minimal haze exact (A1) Minimal haze overcorrection (A2) Significant haze exact (BI) Significant haze overcorrection (B2)
- 1 . 9 6 -'- 0.72 (n = 25) - 1 . 7 7 + 0.60 (n = 27) - 4 . 1 0 + 1.95 (n = 27) -3.85 + 2.12 (n = 27)
Refraction (SE) after Retreatment at 6-mo Stage -0.72 +- 0.94 +0.04 -+ 0.83 -2.2
+- 1.95
-0.81 + 1.46
SD = standard deviation; PRK = photorefractive keratectomy; SE = spherical equivalent.
136
undergoing PRK, it is inevitable that a significant number will regress partly or, in a minority of cases, totally back toward their original refraction. We have found that subsequent to the commencement of the study reported here, 320 (15%) of our cohort of more than 2000 patients in the Moorfields programs requested retreatment for elimination of residual myopia. If this figure is representative, then centers performing PRK will find that retreatment becomes an important part of their practice. This prospective study was designed, therefore, to determine a logical rationale for excimer laser PRK retreatment. M e c h a n i s m of Regression Regression is caused by the corneal wound-healing response that, as would be expected from first principles, differs from patient to patient and results in variation in refractive outcome and incidence of complications, even among patients with similar or identical errors of refraction. 2-5 In addition, as shown in Tables 6 and 7, regression is a much greater problem when higher degrees of myopia are treated and is the main factor limiting predictability of outcome in these patients. This decreasing predictability with the-treatment of increasing amounts of myopia is likely to be caused by a combination of the increased depth of ablation and, therefore, the volume of tissue removed, the ablation zone edge profile, and the healing characteristics of the more myopic eye. The wound-healing response post-PRK is a combination of epithelial hyperplasia and the deposition of an amorphous material beneath the epithelium. 2'3'25-2s The relative contributions of these two components have been shown to be dependent on technical parameters in laser manufacture, for example, beam diameter, which affects both edge profile and volume of tissue removed. 29'3° Each of these factors is discussed below.
G a r t r y et al • R e t r e a t m e n t for Regression after E x c i m e r Laser P R K [n = 106)
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Epithelial Hyperplasia. Animal studies have shown that epithelial hyperplasia can be considerable after P R K - - a s much as double the normal thickness. ~ Examples have been cited in which loss of epithelium 2 to 3 months after surgery in eyes showing significant regression has resulted in a return to the relatively overcorrected state. 2'3 This then was followed by a similar pattern of exponential regression as seen in the months before the epithelial loss. Anterior Stromal Haze. In animal models, anterior stromal haze was found to be caused by collagen deposition between the epithelium and the photoablated surface. as This layer of material probably contributes to the appearance of anterior stromal haze that c o m m o n l y is seen at slit-lamp examination after surgery. Recent work suggests that this layer consists of new mucopolysaccharides and glycosaminoglycans as well as new, disorganized collagen. Haze is maximal between 3 and 6 months post-PRK and is correlated moderately well with both the amount of myopia treated (depth of ablation, coefficient
of correlation, r = 0.71) and regression (r = 0 . 7 5 ) . 3.4 The greater the amount of anterior stromal haze, in general, the greater the loss of refractive effect or regression. It had been hoped that this wound-healing response could be modified pharmacologically, but to date, the results of prospective, randomized, double-masked studies investigating the role of topical corticosteroids post-PRK have not shown a statistically significant long-term beneficial effect on either refractive outcome or anterior stromal haze. 4`s
In most cases, it is likely that regression is caused by a combination of the two key corneal wound-healing factors (i.e., epithelial hyperplasia and anterior stromal haze). It may be difficult to determine the relative contributions made by each component in an individual patient. When considering a rationale for retreatment, however, these different aspects of corneal wound healing can be taken into account and two basic assumptions made in the design of this study:
Table 5. Preoperative and Postoperative Details of Patients with Marked Total Loss of Bestcorrected Visual Acuity (BCVA) Patient No.
Original Myopia (D)
Haze Before Retreatment
Loss of BCVA
Haze After Retreatment
Final Loss of BCVA
1 2 3 4 5 6 7 8
-6.625 -5.50 -8.00 - 11.00 -11.625' -9.00 -13.625 -10.875
3 3 4 2 2 4 3 2
-1 -2 -1 - 1 -1 0 -1 0
3 2 3 1 2 3 3 2.5
-4 -2 -2 -3 -2.5 -4 -4 -2
137
Ophthalmology Volume 105, Number I, January 1998 T a b l e 6. Excimer Laser Photorefractive Keratectomy for Myopia: Selected Summary of Main Published Refraction mad Visual Acuity Results
Author/Year Seiler et al, 1991 s
Laser Type (Beam Diameter)
No. of Patients
Follow-up
Treatment Range (D)
Gartry et al, 1991: and 19923
Summit (3.5 ram) Summit (4.0 ram)
26 120
1 yr 1 yr to 1 yr, 10 mos
Gartry et al, 19924 and 1993 s
Summit (4.0 mm)
113
I yr rain
Salz et al, 1993 n
Visx (5.0 and 5.5 mm)
12 71 77 133 61 81 total 32 126
2 yrs 1 yr < 1 yr 2 yrs (mean) 1 yrs
- I . 2 5 to - 8 . 3 7 - 1 . 0 0 to - 1 0
6 mos 2 yrs
up to - 6 . 0 0 -1.25 to ?-I0
176
1 yr
Piebenga et al, 199313 Ficker et al, 19936
Visx (5.0 ram) Summit (4.5 and 5.0 mm)
Taylor et al, 199314 Seiler et al, 1994 Is
Visx (6 ram) Summit (4.5 and 5.0 ram)
-1.40 -2.00 -4.00 -6.00 -3.00
to - 9 . 2 5 to - 3 . 0 0 to - 5 . 0 0 to - 7 . 0 0 and - 6 . 0 0 groups
- 1 . 2 5 to - 7 . 5 0
Les Jardinset al, 1994J6't
Meditec (5 ram)
63
> 6 mos
- 1 . 2 5 to - 9 . 0 0
Kim et al, 199417't Rogers et al, 19941s't
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45 14
2 yrs I yr
- 2 . 0 0 to - 6 . 0 0 -10.25 to -20.50
Shimizu et al, 19941~'? •
Summit (4.5 mm)
I yr
-2.00 to-7.50
Orssaud et al, 1994'°'i"
Summit (5.0 ram)
11 low 45 medium 41 high 176
6 mos mean
- 1 . 0 0 to - 8 . 5 0
Maguen et al, 199421 Epstein et aL, 1944 z2 update (see also Tengroth et al 9)
Visx (? 6.0 ram) Summit (4.3 or 4.5 ram)
240 495
1 yr mean 2 yrs min
- 1 . 0 0 to -7.75 -1.25 to - 7 . 5 0
Dutt et al, 1994,3
Summit (5 ram)
35
I yr
- 1 . 5 0 to - 6 . 1 0
(continues)
1. Those patients who have regressed significantly and have minimal anterior stromal haze are likely to have relatively greater epithelial hyperplasia to account for their regression. "2. Those patients exhibiting greater amounts of corneal haze have regressed because of the relatively greater amounts of mucopolysaccharide and glycosaminoglycans _+ collagen deposited.
T a b l e 7. Average Refractive Outcome Following Photorefractive Keratectomy Published Results from T a b l e 1
Preoperative Myopia (D) Range
% of Patients within + 1 D
- 1.00 to - 3 . 0 0 - 3 . 1 0 to - 6 . 1 0 - 6 . 1 0 to - 9 . 0 0
90 72 40
138
of Attempted Correction
Aims of the Study On the basis of the above assumptions, when considering the likely retreatment problems, the following three main questions were addressed: 1. Do those patients with little or no anterior stromal haze behave differently after retreatment compared to "aggressive hazers"? 2. In cases with significant regression, can a more satisfactory result be achieved with a repeat procedure in which only the residual myopia is treated, or is an overcorrection (or "fudge factor") required? It was hypothesized that overcorrection might be needed to offset the tendency of epithelial hyperplasia in the clear corneal group and the generation of new tissue in the significant haze group. The profile of the ablation zone produced during PRK has an influence on corneal wound healing and accounts for the lower incidence of regression when larger ablation diameters are used. 3° A deliberate overcorrection alters
Gartry et al • R e t r e a t m e n t for Regression after Excimer Laser PRK
Table 6 (continued). Refractive Outcome* (%) Within + I D of Intended
92% 83% 45% 30% 56% 20% 88% 73%
overall low medium high low high
Unaided Vision >6 mo
96% 56% low 49% medium 13% high NR
No. of Lines of BCVA Lost (Snellen, %) >2
Comment
Nil 3
Nil Nil
1 corneal graft needed, slow healing in SLE Regression prop to degree of myopia
6
Nil
Steroids of no statistically significant benefit
I
7.7 15 9
2
93% 79% at 1 yr
17
1.4
Nil
75% overall 81% overall
75% overall NR
8 15
Nil Nil
Nil Nil
Role of steroids questioned Regression prop to degree of myopia
88% overall 97.6% low 92% medium 34% high 91% low 62% medium 41% high 91.1% overall
88% ovemll NR
25 6
19 I
Nil Nil
Complications intolerable above -6.00 D
71% overall
NR
100% low 76% medium 44% high 100% low 86% medium 43% high 79% overall 87.5% overall
NR
89% overall 91% overall
80% overall
94% overall
NR
8
14%
NR
NR
4
NR
NR
NR
50% lost a "variable" amount of BCVA and were re-treated Nil Nil Nil
8 18 73
"Quality" of VA reduced in 22% of patients Significant scarring in 50% of patients Predictability better in low myopia
NR 0.4 only
9 38 4 - 7 at 1 yr Nil
NR NR NR Nil
1 potentially serious corneal infection Stabilization between 1.5 and 2 yrs
Nil at 1 yr
Nil
Nil
Loss of BCVA in first 4 mos only
BCVA = best-corrected visual acuity; NR = not reported; VA = visual acuity. * For the purposes of comparison betaveen series, "low" (myopia) is up to -3.00 D, "medium" from -3.10 to -6.00 D, and "high" is greater tb,'m -6.10 D. "t"Proceedings papers (no peer-review process).
the edge profile of the wound, and it was hypothesized that this would be of some benefit in those patients with a proven tendency to regress. 3. Which factors, identifiable after the first PRK, are important predictors of success or failure after a second treatment? As yet, no prospective, controlled studies of retreatment have been reported in the literature. Reports to date relate relatively small numbers of retreatment procedures for regression. 3~-33 In 1 of these studies, 9 (59%) of 17 patients were within + 1.00 D of emmetropia at 6 months, and once again there was marked individual variation after the surgery. 32 To date, no attempt has been made to relate the individual initial wound-healing response after the first PRK in a prospective, randomized, controlled study to either retreatment strategy or identification of predictors of outcome. As can be seen from Tables 1 and 2 anl:l Figures 1 and 2, the initial mean refraction for the 106 patients enrolled into this study was -6.73 D, and the mean refraction (regression) before retreatment was - 3 . 1 4 D. After retreatment, this
figure improved to - 1.75 D. Retreatment could therefore be described as beneficial overall. It also can be seen from Table 2, however, that those patients with minimal haze achieve a result after retreatment, which is relatively close to emmetropia (-0.41 D at 18 months) as compared to the group with significant haze after the first PRK (-4.14 D at 18 months, slightly worse on average than before retreatment). It would seem that the outcome of retreatment closely parallels the outcome of the first PRK in that those patients who generate a large amount of anterior stromal haze tend to do the same after a retreatment with a predicted loss of BCVA and repeat regression. A greater percentage of patients receiving a deliberate overcorrection at retreatment were within __ 1.00 D of the intended refraction (Table 3, Fig 3). The difference was statistically significant when comparing groups A1 and B 1 with A2 and B2 overall (P = 0.026 at 6 months and 0.032 at 1 year). Interestingly, despite the deliberate 50% overcorrection in approximately half of the patients, no patient had significant, sustained overcorrection-hyper-
139
Ophthalmology Volume 105, Number I, January 1998 metropia beyond 1 year (Fig 2A). Table 4 and Figures 4A and B allow comparisons between groups A1 and A2 (minimal haze) and B1 and B2 (significant haze), respectively. In both cases, a statistically significantly better refractive outcome was achieved in the groups undergoing deliberate overcorrection (A2 and B2, P = 0.04 and 0.027, respectively). Eight patients showed a significant loss of BCVA at 6 months (Table 5) after retreatment, which ranged from one to four lines of Snellen. These patients had been in the significant haze group (Fig 4B) and all had moderateto-high myopia before their first PRK ( - 5 . 5 to -13.625 D, mean - 9 . 5 3 D). Analysis of variance showed that anterior stromal haze after the first PRK is highly correlated with refractive outcome after retreatment and is four times more important to the outcome than overtreatment or exact treatment. Those patients with 2+ or more of haze after the first PRK have a high probability of regressing after retreatment and generating a similar amount of haze again with a concomitant loss of BCVA. We concl'ude that in the majority of patients, a retreatment PRK procedure for significant regression will reduce myopia further and that a deliberate 50% overcorrection, or fudge factor, is effective in achieving a better refractive outcome. Patients with relatively little anterior stromal haze after their first PRK procedure can, on average, be expected to generate little haze after retreatment and will, again on average, have regressed by only modest amounts. Overcorrection also is of benefit in those patients with significant haze after their first PRK. However, care must be taken when considering retreatment in these patients. Risk factors that are important predictors of a poor outcome after retreatment are (1) high myopia originally; (2) regression beyond approximately - 3 . 5 0 D; (3) significant anterior stromal haze after the first PRK ( > grade 2+); and (4) loss of BCVA after the first procedure. We consider that patients with these risk factors, especially if including loss of BCVA, should be retreated with great caution (if at all), pending the results of further trials. There is a significant risk of regression, haze, and ppfurther loss of BCVA in this group. Acknowledgment. The authors thank the Excimer Laser Group, Moorfields Eye Hospital, for their contributions to this paper.
References 1. Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol 1983;96:710-5. 2. Gartry DS, Kerr Muir MG, Marshall J. Photorefractive keratectomy with an argon fluoride excimer laser: a clinical study. J Refract Corneal Surg 1991;7:420-35. 3. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser photorefractive keratectomy--18 month follow-up. Ophthalmology 1992;99:1209-19. 4. Gartry DS, Kerr Muir MG, Lohmann CP, Marshall J. The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy. A prospective, randomized, double-blind trial. Arch Ophthalmol 1992; 110:944-52.
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Historical Vignette Richard Liebreich (1830-1917) enjoyed an amazing career in ophthalmology. He was a medical student under Helmholtz when that physician did his early work with the ophthalmoscope. He became the right-hand man of von Graefe at his famous clinic in Berlin. Liebreich next moved to Paris, where he reached the pinnacle of success at the court of Emperor Napoleon III. He operated on the Emperor's mother-in-law and cured her of acute glaucoma in the era prior to the discovery of local anesthesia. After the fall of Napoleon III in 1870, Liebreich became the head of ophthalmology at St. Thomas HoSpital and Medical School in London. Later, he returned to Paris, where he worked as a painter and sculptor. He maintained a limited ophthalmologic practice and treated patients as famous as the Impressionist artist Claude Monet.*
*Historical vignette prepared by James Ravin, MD, of Toledo, Ohio.
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