Correlation of Subepithelial Haze and
Refractive Regression 1 Month After
Photorefractive Keratectomy for

Dimitrios S. Siganos, MD; Vikentia J. Katsanevaki, MD; Ioannis G. Pallikaris, MD after PRK for myopia is strongly related to regres-
sion of initial refractive effect and increasing
PURPOSE: To relate myopic regression after
myopia. [J Refract Surg 1999;15:338-342]
photorefractive keratectomy (PRK) to subepithe-
lial haze at the first postoperative month.

METHODS: One hundred nineteen eyes of 119
patients underwent excimer laser PRK for treat-
ment of myopia up to -8.00 D. Eyes were examined

Photorefractive keratectomy (PRK) is a wide- spread method for correction ametropias.1 at 1, 3, 6, 9, and 12 months after surgery. All eyes
Although PRK is a relatively safe and efficient received fluorometholone 0.1% for the first 5 post-
method to correct low and moderate myopia, its pre- operative months in a tapered dose.
dictability is dependent on the patients healing Dexamethasone 0.1% qid for 1 month was pre-
scribed to all eyes with a spherical equivalent

refraction less than plano, followed by an augment-
Partial loss of corneal clarity (haze), as judged by ed dose of fluorometholone 0.1%. Eyes with myopia
biomicroscopic observation, is common after PRK.
greater than -0.75 D at 12 months, as well as those
The severity of haze is time dependent, with maxi- that had received dexamethasone at any postoper-
mum haze usually noted in the first 3 months after ative intervalregardless of refractive outcome
were considered to be regressed. Eyes that

surgery, with progressive clearing within approxi- regressed and those that did not regress were com-
pared statistically (Chi-squared statistical criterion
Not uncommonly, haze is accompanied by at least with Yates correction) regarding haze grade.
partial regression of the initial effect, and this resid- RESULTS: Forty-seven percent (56 of 119) of eyes
ual myopia is an indication for reoperation. Durrie regressed. In 89.28% (50 of 56) of eyes, subepithelial
haze grade was 1 to 2, and in 10.71% (6 of 56), subep-

and colleagues2 have described different healing ithelial haze was graded 0 to 0.5 at 1 month. Fifty-
responses, associating increased haze, and myopic three percent of eyes (63 of 119) did not regress and
refractive shift with aggressive healing, in contrast in all, subepithelial haze was graded 0 to 0.5 at the
to inadequate healing associated with clear corneas first month. The correlation between regression
and residual hyperopia. The majority of patients in and haze grade 1 or more at the first postoperative
month was statistically significant (P
their study were classified as normal and had a typ- CONCLUSION: Mild to marked subepithelial
ical healing response after PRK.2 The possibility of haze (grade 1 to 2) at the first postoperative month
modulating the wound healing response after PRKand increasing the predictability of the procedure isimportant.3-9 In order to evaluate the subepithelialhaze at 1 month after surgery as an early predictivefactor of refractive outcome, eyes that had PRK for From the Department of Ophthalmology, University of Crete, Greece myopia up to -8.00 diopters (D) were retrospectively (Siganos, Pallikaris) and the Vardinoyannion Eye Institute of Crete, Greece(all authors) analyzed and the statistical correlation of haze at None of the authors has any proprietary interest in the research or 1 month was compared to late myopic regression.
Correspondence: Dimitrios S. Siganos, MD, Assistant Professor in Ophthalmology, University of Crete School of Medicine, Department of PATIENTS AND METHODS
Ophthalmology, POB 1352, Heraklion, Crete 71110 Greece. Tel: 30 81 One hundred nineteen eyes of 119 patients 394560; Fax: 30 81 312369; Email: [email protected] (60 males) underwent PRK for myopia up to -8.00 D.
Received: April 22, 1998Accepted: December 3, 1998 Patient age ranged from 20 to 37 years, (mean, 28 – Journal of Refractive Surgery Volume 15 May/June 1999
Correlation of Haze and Myopic Regression after PRK/Siganos et al
4.14 yr). Mean preoperative spherical equivalent ated every 2 weeks. If no refractive changes were refraction was -5.20 – -2.20 D (range, -2.50 to apparent 4 weeks after corticosteroids were pre- -8.00 D). In all eyes, attempted correction was aimed scribed, treatment was considered ineffective and at emmetropia. An informed consent was obtained was discontinued. In patients with no refractive change from the first to the third postoperative The preoperative ophthalmic evaluation included month, corticosteroids were also discontinued, refraction (manifest and cycloplegic), videokeratog- under close observation. Intraocular pressure (IOP) raphy (to exclude patients with clinical or subclini- was measured at each examination to monitor corti- cal keratoconus and to provide baseline topographic costeroid response. An IOP over 4 mmHg of the pre- measurements), slit-lamp microscopy, keratometry, operative value or over 21 mmHg, was treated with dilated fundus examination, ultrasound pachyme- simultaneous (during corticosteroid therapy) topical try, biometry, and contrast sensitivity testing in var- ious spatial frequencies. Eyes with known ocular 0.5%,Temserin, Alcon Couvreur, Belgium), one drop surface disorders, previous ocular surgery, kerato- conus, or collagen disorders were excluded.
Apart from refraction, uncorrected and spectacle- All operations were carried out by the same sur- corrected visual acuity, tonometry, and contrast sen- geon according to a standard protocol using the sitivity testing, all the patients underwent slit-lamp Aesculap Meditec Mel 60a argon fluoride excimer microscopy at each examination. Haze density was laser system (Meditec, Heroldsberg, Germany). The graded on a predetermined scale of 0 to 4, according clear zone was 6 mm for spherical corrections and to the following criteria: grade 0, totally clear cornea 5.5 mm for astigmatic corrections. All patients were with no opacity seen by any method of microscopic treated under topical anesthetic instilled before slit-lamp examination; grade 0.5, trace or faint surgery (Alcaine, proparacaine hydrochloride 0.5% corneal haze seen only by indirect, broad tangential W/V, Alcon Couvreur, Belgium). Immediately follow- illumination; grade 1, haze of minimal density seen ing surgery, a bandage contact lens was applied with difficulty with direct and diffuse examination; under sterile conditions on the treated eye and was grade 2, mild haze easily visible with direct focal slit left until re-epithelialization was complete. During illumination; grade 3, moderate opacity that partial- this period, operated eyes received the following reg- ly obscured details of the iris; and grade 4, severe imen: cyclopentolate hydrochloride 1% (Cyclogyl, opacity that completely obscured the details of Alcon Couvreur, Belgium) and diclofenac sodium intraocular structures. According to this grading, corneas with haze grade 0 or 0.5 were considered Germany) eye drops qid for the first 2 postoperative days and tobramycin 3mg/ml/ dexamethasone Patients with a spherical equivalent refraction 1 mg/ml (Tobradex, Alcon Couvreur, Belgium) eye less than plano at the first month examination were drops qid until the day of re-epithelialization. After considered undercorrected (not regressed) and were re-epithelialization was complete, fluorometholone 1mg/ml (FML, Alcon Couvreur, Belgium) was pre- All eyes had complete follow-up for at least scribed to all patients for 5 months in a tapered 1 year. Eyes with a final spherical equivalent refrac- dose, as follows: one drop qid for the first month, one tion less than -0.75 D were considered to be drop tid for the second month, one drop bid for the regressed. Eyes that received dexamethasone at any third month, one drop once a day for the fourth postoperative interval, as well as those where fluo- month, and one drop daily for the fifth month.
rometholone was reinstituted after the fifth month, Patients were examined at 1, 3, 6, 9, and were also considered as regressed, regardless of the 12 months. If myopic regression occurred in the first final refractive outcome. Subsequently, regressed (as 5 months, fluorometholone 0.1% was discontinued determined above) and non-regressed eyes were sta- and dexamethasone 0.1% qid was prescribed for tistically compared to the haze grade of the first 1 month, followed by an augmented dose of fluo- month examination. To estimate the correlation of rometholone 0.1% (four times daily for 1 month, myopic regression at any postoperative interval then tapered and discontinued over a period of with the first month haze grade, the Chi-squared 2 months) and follow-up every 2 weeks). In cases of statistical criterion with Yates correction was used late regression (ie, myopic shift of the patients to correlate qualitative observations. The level of refraction more than 0.50 D after fluorometholone statistical significance of the test was P<.001. The discontinuation), fluorometholone 0.1% qid was eyes were classified according to the presence or reinstituted for 1 month and the patient was evalu- absence of haze or regression in a four-fold table (Table).
Journal of Refractive Surgery Volume 15 May/June 1999
Correlation of Haze and Myopic Regression after PRK/Siganos et al
Fifty-six of the 119 treated eyes (47.05%) Chi-squared Criterion to Classify Eyes
regressed during the first year of follow-up. All After PRK With Respect to Presence or
regressed eyes were treated with an augmented Absence of Corneal Haze
dosage of fluorometholone 0.1% or dexamethasone0.1% according to the above mentioned protocol. The or Refractive Regression
majority of regressed eyes responded to a corticos- Regression
No Regression
teroid therapy and 1 year after treatment, only 5 of Group No.
Group No.
Group No.
119 eyes (4.2%) had a residual myopia (mean spher- ical equivalent refraction, -1.60 – 0.675 D; range, In 50 of the 56 regressed eyes (89.28%), subep- Group a: Eyes with haze and regression at 1 month after surgery ithelial haze grade was graded as 1 or 2 (52 treated Group b: Non-regressed eyes with haze 1 month after surgery eyes had haze grade 1 and eight eyes had haze Group c: Regressed eyes with no haze at 1 month after surgeryGroup d: Eyes with no haze and no regression at 1 month after surgery grade 2) at the first postoperative month. This groupof eyes with regression and haze was defined asgroup a (a=50).
that impair the transparency of the cornea. Haze In six of 56 regressed eyes (10.71%), haze was 0.5 appears after the first postoperative month and at the first month interval. The group of regressed becomes denser up to the third month, as activated eyes with no haze at the first month was defined as keratocytes migrate to repair the wound.10-18 group c (c=6). No eyes from groups a and c had a Epithelial hyperplasia, or the new connective tis- totally clear cornea (haze grade 0) at the first sue growth, apart from haze, was also associated with regression in some studies.1,13,20 Although tis- Sixty-three of 119 treated eyes (52.94%) did not sue regrowth is confirmed by other investigators, regress; 61 (51.26%) were within – 0.75 D of they suggest that corneal thickening accounts for a emmetropia although two eyes (1.28%) were over- small fraction of regressionmostly due to struc- corrected (mean spherical equivalent refraction, tural alterations of the ablated cornea.21 Other fac- tors that may influence refractive outcome are the In all non-regressed eyes, subepithelial haze was concentration of glucosaminoglycans, and especially graded 0 or 0.5; 45 of 63 eyes (71.42%) had trace hyaluronic acid, which can alter corneal hydration haze and 18 eyes (28.57%) were clear. This no haze/no regression group of eyes was defined as d Although not yet clear in terms of cell biology, it seems from clinical studies that there is a direct No non-regressed eyes had a haze grade of 1 or relation between haze, regression, and the depth of more at the first postoperative month (b=0).
photoablation in PRK.6,19 In our study, it was con- Correlation of first month haze to regression at firmed that there was a strong correlation between any postoperative interval after PRK for myopia late regression and haze even at the first month was found to be statistically significant (P<.001) after PRK, when the patient was still hyperopic.
according to the Chi-squared statistical criterion Variation in wound healing response of individual with Yates correction for small groups.
eyes cannot be controlled, but it may be influencedby topical drugs. Various regimens such as non- DISCUSSION
steroidal anti-inflammatory agents22-25, interferon8, Wound healing is of critical importance in cor- plasmin and plasminogen activator inhibitors7,26, recting all corneal refractive errors. Although many collagenase inhibitors27, and antimetabolites28 have studies have been published concerning wound been proposed for the modulation of the healing healing response, fundamental issues regarding response after PRK, all with poor or controversial haze and regression, as well as the pathophysiology of these events, still remain unclear. Studies on The most commonly used regimens for the post- corneal wound healing after PRK have shown operative control of PRK refractive outcome are cor- epithelial hyperplasia and scarring by atypical, newly synthesized collagen. It has been suggested between investigators about whether they should be that haze is due to new collagen and vacuoles used after PRK. Early clinical studies suggest that between intersected collagen lamellae. These vac- corticosteroids play a crucial role in the refractive uoles are filled with atypical glycosaminoglycans outcome of PRK5,29,30; however, after initial hopeful Journal of Refractive Surgery Volume 15 May/June 1999
Correlation of Haze and Myopic Regression after PRK/Siganos et al
reports, efficacy of corticosteroids in this instance is tive, randomized, double masked study. Eye 1993;7:584-590.
7. Lohman CP, Marshall J. Plasmin and plasminogen activator still unclear. Other investigators have claimed that inhibitors after excimer laser photorefractive keratectomy: corticosteroids have no long-term effect on refrac- new concept in prevention of postoperative myopic regres- tion.26,31,32 The latter studies have either short fol- sion and haze. Refract Corneal Surg 1993;9:300-302.
8. Morlet N, Gillies MC, Crouch R, Malloof A. Effect of topical low-up32, high regression in all groups, or unaccept- interferon-a-2b on corneal haze after excimer laser photore- able initial overcorrection.31 Even studies which fractive keratectomy in rabbits. Refract Corneal Surg claim that corticosteroids are of limited value and 9. Bergman RH, Spigelman AV. The role of fibroblast inhibitors are not justified for routine administration after in corneal in corneal healing following photorefractive kera- PRK accept that there may be some individuals who tectomy with 193-nanometer excimer laser in rabbits.
10. Lohman C, Gartry D, Kerr Muir M, Timberlake G, Fitzke F, In our study, all eyes received corticosteroids for Marshall J. Haze in photorefractive keratectomy: its ori- at least 5 months; 40% were treated with augment- gins and consequences. Lasers and Light in Ophthalmology ed doses of corticosteroids because of their tendency 11. Marshall J, Trokel S, Rothery S, Krueger RR. Photoablative toward myopic regression and these eyes finally reprofiling of the cornea using an excimer laser: photore- achieved a satisfactory refractive outcome. The fractive keratectomy. Lasers and Light in Ophthalmology higher incidence of haze and regression or under- 12. Tuft S, Marshall J, Rothery S, Krueger RR. Long term heal- correction in our study may be explained by the rel- ing of the central cornea after photorefractive keratectomy atively young mean age of our patients. Since there using an excimer laser. Ophthalmology 1988;95:1411-1421. was no control group, no conclusions can be made 13. Fantes FE, Hanna KD, Waring GO 3d, Pouliquen Y, Thompson KP, Savoldelli M. Wound healing after excimer about long-term refractive outcome of these eyes as laser keratomileusis (photorefractive keratectomy) in mon- they were not treated aggressively with corticos- keys. Arch Ophthalmol 1990; 108:665-675.
teroids. Haze at 1 month proved to be a reliable pre- 14. Hanna KD, Pouliquen Y, Waring GO 3d, Savoldelli M, Cotter J, Morton K, Menasche M. Corneal stromal wound healing in dictive factor for the refractive outcome. Eyes with rabbits after 193 nm excimer laser surface ablation. Arch mild to moderate haze at the first month are likely to regress at some point during their postoperative 15. SundarRaj N, Geiss MJ 3d, Fantes F, Hanna K, Anderson SC, Thompson KP, Thoft RA, Waring GO 3d. Healing of course and corticosteroid therapy should be excimer laser ablated monkey corneas: an immunohisto- reserved for these eyes. The exact mechanism chemical evaluation. Arch Ophthalmol 1990;108:1604-1610. through which corticosteroids affect regression is 16. Wu WS, Stark WJ, Green WR. Corneal wound healing after 193 nm excimer laser keratectomy. Arch Ophthalmol not yet fully understood, as the entire procedure of regression is still unclear. Whatever the actual 17. Gaster RN, Binder PS, Coalwell K, Berns M, McCord RC, mechanisms, the suppressive effect of corticos- Burstein NL. Corneal surface ablation by 193 nm excimerlaser and corneal healing in rabbits. Invest Ophthalmol Vis teroids on the healing response would be expected during the early postoperative months when there 18. McDonald MB, Frantz JM, Klyce SD, Salmeron B, is maximum keratocyte activity3, however, Gartry Beuerman RW, Munnerlyn CR, Clapham TN, Koons SF,Kaufman HE. One year refractive results of central pho- and colleagues6,31 have shown that topical corticos- torefractive keratectomy for myopia in the nonhumman pri- teroids do not alter the long-term refractive outcome mate cornea. Arch Ophthalmol 1990;108:40-47.
19. Epstein D, Tengroth B, Fagerholm P, Hamberg-Nystrom H.
Excimer retreatment of regression after photorefractive ker-atectomy. Am J Ophthalmol 1994;117:456-461.
20. Hanna KD, Pouliquen YM, Salvodeli M, Fantes F, Thompson 1. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser pho- KP, Waring GO III, Samson J. Corneal wound healing in torefractive keratectomy: 18 months follow-up.
monkeys 18 months after excimer laser photorefractive ker- atectomy. Refract Corneal Surg 1990;6:340-345.
2. Durrie DS, Lesher MP, Cavanaugh TB. Classification of 21. Ramirez-Florez S, Maurice DM. Inflammatory cells, refrac- variable clinical response after photorefractive keratectomy tive regression and haze after excimer laser PRK. J Refract for myopia. J Refract Surg 1995;11:341-347.
3. Marques EF, Leite EB, Cunha-Vaz JG. Corticosteroids for 22. Sher NA, Frantz JM,Talley A, Parker P, Lane SS, Ostrov C, reversal of myopic regression after photorefractive keratec- Carpel E, Doughman D, De Marchi J, Lindstrom R. Topical tomy. J Refract Surg 1995;11(suppl):S302-S308. diclofenac in the treatment of ocular pain after excimer pho- 4. Fitzsimmons TD, Fagerholm P, Tengroth B. Steroid treat- torefractive keratectomy. Refract Corneal Surg 1993;9:425- ment for myopic regression: acute refractive and topograph- ic changes in excimer photorefractive keratectomy patients.
23. David T, Serdarevic O, Salvodelli M, Pouliquen Y. Effects of topical corticosteroids and non steroid inflammatory agents 5. Tengroth B, Epstein D, Fagerholm P, Hamberg-Nystrom H, on corneal wound healing after myopic photorefractive ker- Fitzsimmons TD. Excimer laser photorefractive keratectomy atectomy in rabbits. Refract Corneal Surg 1994; for myopia. Clinical results in sighted eyes. Ophthalmology 24. Ferrari M. Use of topical non steroidal anti-inflammatory 6. Gartry DS, Kerr Muir MG, Marshall J. The effect of topical drugs after photorefractive keratectomy. Refract Corneal corticosteroids on refraction and corneal haze following excimer laser treatment for myopia: an update. A prospec- 25. Brancato R, Carones F, Venturi E, Ventuzzi A.
Journal of Refractive Surgery Volume 15 May/June 1999
Correlation of Haze and Myopic Regression after PRK/Siganos et al
Corticosteroids vs diclofenac in the treatment of the late Eiferman R, Lane SS, Parker P, Ostrov C, Doughman D, recession after myopic photorefractive keratectomy. J Carpel E, Zabel R,Gothard T, Lindstrom RL. The use of 193 Refract Corneal Surg 1993;9:376-378.
nm excimer laser for myopic photorefractive keratectomy in 26. OBrart DPS, Lohman CP, Clonos G, Corbett MC, Pollock sighted eyes. A multicenter study. Arch Ophthalmol WST, Kerr Muir MG, Marshall J. The effects of topical corti- costeroids and plasmin inhibitors on refractive outcome, 30. Seiler T, Wollensak J. Myopic photorefractive keratectomy haze and visual performance after photorefractive keratec- with the excimer laser: 1 year follow-up. Ophthalmology tomy: a prospective randomized observer masked study.
31. Gartry DS, Kerr Muir MG, Lohmann CP, Marshall J. The 27. Corbett MC, O’Brart DPS, Patmore AL, Lohmann CP, Kerr effect of topical corticosteroids on refractive outcome and Muir MG, Marshall J. The effect of collagenase inhibitors on corneal haze after photorefractive keratectomy. Arch corneal transparency after excimer laser photorefractive keratectomy (PRK). Invest Ophthalmol Vis Sci 32. Tengroth B, Fagerholm P, Soderberg P, Hamberg-Nystrom H, Epstein D. Effects of corticosteroids in postoperative care 28. Talamo JH, Collamudi S, Green WR, De la Cruz Z, Filatov V, following photorefractive keratectomies. Refract Corneal Stark WJ. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and 33. Corbett MC, OBrart DPS, Marshall J. Do topical corticos- steroids. Arch Ophthalmol 1991;109:1141-1146.
teroids have a role following excimer laser photorefractive 29. Sher NA, Chen V, Bowen RA, Frantz JM, Brown DC, keratectomy? Refract Surg 1995;11:380-387.
Journal of Refractive Surgery Volume 15 May/June 1999



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