LASEK, PRK, and Excimer Laser Stromal Surface Ablation (Refractive Surgery)

LASEK, PRK, AND EXCIMER LASER STROMAL SURFACE ABLATION

REFRACTIVE SURGERY Series Editors Dimitri T.Azar, M.D. Massachusetts Eye and Ear Infirmary Schepens Eye Research Institute and Harvard Medical School Boston, Massachusetts Douglas D.Koch, M.D. Cullen Eye Institute Baylor College of Medicine Houston, Texas 1. LASIK: Fundamentals, Surgical Techniques, and Complications, edited by Dimitri T.Azar and Douglas D.Koch 2. Hyperopia and Presbyopia, edited by Kazuo Tsubota, Brian S.Boxer Wachler, Dimitri T.Azar, and Douglas D.Koch 3. LASEK, PRK, and Excimer Laser Stromal Surface Ablation, edited by Dimitri T.Azar, Massimo Camellin, Richard W.Yee ADDITIONAL VOLUMES IN PREPARATION Phakic and Accomodating IOLs, edited by Steve Lane and Jose Guell

LASEK, PRK, AND EXCIMER LASER STROMAL SURFACE ABLATION edited by

Dimitri T.Azar Massachusetts Eye and Ear Infirmary Schepens Eye Research Institute and Harvard Medical School Boston, Massachusetts, U.S.A.

Massimo Camellin SEKAL Rovigo Micro Surgery Rovigo, Italy

Richard W.Yee Hermann Eye Center and University of Texas Health Science Center Houston, Texas, U.S.A. Associate Editors

Robert T.Ang, MD,Sandeep Jain, MD,TakujiKato, MD, PhD Jae-Bum Lee, MD, PhD,Ronald R.Krueger, MD Series Editors

Dimitri T.Azar, MD,Douglas D.Koch, MD

MARCEL DEKKER NEW YORK

This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN 0-203-02591-1 Master e-book ISBN

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Preface Ignotum per ignotius [(To explain) the unknown by the more unknown] How important are the subtle technical details in improving the clinical outcomes of LASEK surgery? Is the reduction of wavefront error greater in LASEK and Epi-LASIK than in LASIK? Does alcohol kill the corneal epithelial cells or does it allow epithelial cell proliferation to occur divorced from the unwanted process of epithelial cell migration over a denuded stroma? These questions, and many others, have fueled the debate regarding LASEK and Epi-LASIK vs. PRK and LASIK. LASEK and Epi-LASIK are not universally employed refractive surgical procedures. They have several advantages over LASIK in patients with relatively thin pachymetry and in patients with borderline corneal topographical changes. However, the advantages of these techniques over PRK are yet to be established. Despite numerous anecdotal reports, clinical observations, and variations of surgical techniques suggesting certain advantages of LASEK and Epi-LASIK over PRK, other studies suggest possible advantages for PRK, at least in the early postoperative period. Clearly, large prospective randomized multi-center studies, carried out by experienced LASEK surgeons, are lacking. New techniques of LASEK also hold great promise to overcome some of its current limitations. Despite the apparent and sometimes unavoidable bias toward LASEK and surface ablation in many chapters of this book, the aim is not to present an argument favoring these techniques, but rather to present a panoramic view of various aspects of these techniques. We focus on the indications, contraindications, and surgical techniques of stromal surface ablation and discuss the postoperative care, wound healing, clinical outcomes, and complications. Also included are several basic chapters discussing wavefront analysis, optical aberration changes after LASEK, the effect of alcohol on corneal cell-cell and cell-matrix interactions, and the pathogenesis and treatment options for postoperative stromal haze. Inclusion of this book in our “Refractive Surgery Series” was initiated with the help of several of the associate editors, who had been postgraduate fellows at the Corneal and Refractive Surgery Service of the Massachusetts Eye and Ear Infirmary. Progress of this project was hindered by the lack of definitive answers to our questions in the peerreviewed literature. Completion of the first draft of the book would not have been possible without the efforts of Drs. Suphi Taneri and Puwat Charukamnoetkanok. Additional manuscripts from Drs. Massimo Camellin, Richard Yee, Ronald Krueger, and several other experienced LASEK surgeons provided more comprehensive coverage of the topic. We acknowledge the support of Dr. Geoff Greenwood and Rosemary Doherty of Taylor and Francis, Inc. and their commitment to this series dedicated to Refractive Surgery. We also thank Leona Greenhill for editorial assistance. Special thanks go to

Rhonda Harris, who has managed this project with utmost dedication, care, and attention to detail. We also thank the contributors for presenting the results of their investigations. Their work will not only help answer many important questions about LASEK and surface ablation, but also underscore the fact that many answers remain unknown. Yes, the field still suffers from explanations of the unknown by even more unknowns, but the observations (and opinions) of the contributors mark a step forward in the path of discovery in this important field. They pave the way for future scientific investigations, which will undoubtedly increase our understanding of LASEK and surface ablation and improve the visual outcomes of future patients undergoing conventional and customized keratorefractive surgery. Dimitri T.Azar Douglas D.Koch

Contents Preface

vi

Contributors

xii

1. Overview of LASEK and Stromal Surface Ablation Suphi Taneri, MD and Dimitri T.Azar, MD 2. Laser Subepithelial Keratomileusis (LASEK): Theoretical Advantages Over LASIK Paolo Vinciguerra, MD and Daniel Epstein, MD, PhD 3. Indications and Contraindications of LASEK Jae Bum Lee, MD, Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD 4. LASEK Preoperative Considerations Robin F.Beran, MD, FACS 5. LASEK Preoperative Evaluation Chun Chen Chen, MD and Dimitri T.Azar, MD 6. LASEK Techniques Chun Chen Chen, MD, Joel Javier, MD, and Dimitri T.Azar, MD 7. Camellin LASEK Technique Massimo Camellin, MD 8. Butterfly LASEK Puwat Charukamnoetkanok, MD and Suphi Taneri, MD 9. Epithelial Flap Hydrodissection and Viscodissection in Advanced Laser Surface Ablation (ALSA) Richard C.Rashid, MD 10. Surface Ablation Without Alcohol: Gel-Assisted LASEK and EpiLASIK using Epilift System Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD 11. Epi-LASIK: Surface Ablation Without Alcohol Ioannis G.Pallikaris, MD, PhD, Vikentia J.Katsanevaki, MD, Maria I. Kalyvianaki, MD, Irini I.Naoumidi, PhD, and Richard W.Yee, MD 12. Postoperative Management of LASEK Ahn Nguyen, MD, Amy Scally, OD, and Dimitri T.Azar, MD 13. LASEK Enhancements Lee Shahinian, Jr, MD

1 15

22

28 36 53 85 95 102

127

133

142 152

14. LASEK in High and Low Myopia Chris P.Lohmann, MD, PhD, David O’Brart, MD, Ann Patmore, BSC, John Marshall, PhD, Christoph Winkler von Mohrenfels, MD, Bernhard Gabler, MD, and Wolfgang Herrmann, MD 15. LASEK vs. PRK: Comparison of Visual Outcomes Minh Hanh Duong, MD and Damien Gatinel, MD 16. LASEK vs. LASIK: Comparison of Visual Outcomes Neal J.Peterson, MD, Alice Z.Chuang, PhD, Rajy M.Rouweyha, MD, and Richard W.Yee, MD 17. Topography-Based Aberration in LASEK vs. PRK and LASIK Michael K.Smolek, PhD, Stephen D.Klyce, PhD, Loan Nguyen, MD, Richard W.Yee, MD, John P.Stokes, MD, Marguerite B.McDonald, MD 18. LASEK Complications Jae Bum Lee, MD, PhD 19. Management of LASEK Complications Massimo Camellin, MD 20. Wavefront Analysis, Principles, and LASEK Application Ronald R.Krueger, MD, Patrick C.Yeh, MD, and Dimitri T.Azar, MD 21. Customized Ablation and LASEK Erin D.Stahl, MD and Daniel S.Durrie, MD 22. Comparison of Wavefront-Guided Photorefractive Keratectomy and LASEK Treatments for Myopia and Myopic Astigmatism Zoltán Z.Nagy, MD 23. Wound Healing After PRK, LASIK, and LASEK Takuji Kato, MD 24. Biochemical Basis of Epithelial Dehiscence and Reattachment After LASEK Eric E.Gabison, MD, Hailton B.Oliveira, MD, Jin-Hong Chang, PhD, and Dimitri T.Azar, MD 25. Refractive Surgical Wound Healing Mechanisms Revisited: A Glimpse at the Future of LASEK James V.Jester, PhD 26. Mitomycin C and Haze: Natural Progression Mujtaba A.Qazi, MD, Jay S.Pepose, MD, PhD, Irwin Y.Cua, MD, Saira A. Choudhri, MD, and M.Azim Mirza, MD 27. Mitomycin C and Surface Ablation Scott D.Barnes, MD and Dimitri T.Azar, MD 28. Use of Autologous Serum to Reduce Haze After LASEK Steven B.Yee, MD, Ning Lin, MD, OD, Alice Z.Chuang, PhD, and Richard W.Yee, MD 29. LASEK After Corneal and Intraocular Procedures Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD

156

170 176

192

211 224 235 259 270

276 289

300

313

343 354

365

30. LASEK After Penetrating Keratoplasty Steven B.Yee, MD, Ning Lin, MD, OD, Corey B.Westerfeld, MD, and Richard W.Yee, MD Index

371

381

Contributors Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Scott D.Barnes, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Robin F.Beran, MD, FACS Columbus Laser and Cataract Center, Columbus, OH Massimo Camellin, MD Sekal Rovigo MicroSurgery, Rovigo, Italy Jin-Hong Chang, PhD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Puwat Charukamnoetkanok, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Chun Chen Chen, MD Department of Ophthalmology, Taipei Municipal Jen-Ai Hospital, National Yang-Ming University, Taipei, Taiwan Saira A.Choudhri, MD Pepose Vision Institute, Chesterfield, MO Alice Z.Chuang, PhD Hermann Eye Center, Department of Ophthalmology and Visual Sciences, University of Texas Health Science Center at Houston, Houston, TX Irwin Y.Cua, MD Pepose Vision Institute, Chesterfield, MO Minh Hanh Duong, MD Service d’ophtalmologie, (Pr Hoang-Xuan), Hôpital Bichat, Fondation Rothschild, Université Paris VII, Paris, France Daniel S.Durrie, MD Durrie Vision Research, Overland Park, KS Daniel Epstein, MD, PhD Department of Ophthalmology, University Hospital, Zurich, Switzerland Eric E.Gabison, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Bernhard Gabler, MD University Eye Clinic, Regensburg, Germany Damien Gatinel, MD Service d’ophtalmologie, (Pr Hoang-Xuan), Hôpital Bichat, Fondation Rothschild, Université Paris VII, Paris, France Wolfgang Herrmann, MD University Eye Clinic, Regensburg, Germany Joel Javier, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA James V.Jester, PhD Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX Maria I.Kaly vianaki, MD Vardinoyannion Eye Institute of Crete, University of Crete, Greece Takuji Kato, MD Juntendo University, Department of Ophthalmology, Tokyo, Japan Vikentia J.Katsanevaki, MD Vardinoyannion Eye Institute of Crete, University of Crete, Greece, University Hospital of Heraklion, Department of Ophthalmology, Crete, Greece Stephen D.Klyce, PhD LSU Eye Center, New Orleans, LA Ronald R.Krueger, MD Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH

Jae Bum Lee, MD, PhD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Ning Lin, MD, OD Hermann Eye Center, Department of Ophthalmology and Visual Sciences, University of Texas Health Science Center at Houston, Houston, TX Chris P.Lohmann, MD, PhD University Eye Clinic Regensburg, Germany, The Rayne Institute, Department of Ophthalmology, St. Thomas Hospital, London, England John Marshall, PhD The Rayne Institute, Department of Ophthalmology, St. Thomas Hospital, London, England Marguerite B.McDonald, MD Southern Vision Institute, New Orleans, LA M.Azim Mirza, MD Pepose Vision Institute, Chesterfield, MO Zoltán Z.Nagy, MD 1st Department of Ophthalmology, Semmelweis University, Budapest, Hungary Irini I.Naoumidi, PhD Vardinoyannion Eye Institute of Crete, University of Crete, Greece Ahn Nguyen, MD Cornea and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA Loan Nguyen, MD LSU Eye Center, New Orleans, LA David O’Brart, MD The Rayne Institute, Department of Ophthalmology, St. Thomas Hospital, London, England Hailton B.Oliveira, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA Ioannis G.Pallikaris, MD, PhD Vardinoyannion Eye Institute of Crete, University of Crete, Greece, University Hospital of Heraklion, Department of Ophthalmology, Crete, Greece Ann Patmore, BSC The Rayne Institute, Department of Ophthalmology, St. Thomas Hospital, London, England Jay S.Pepose, MD, PhD Pepose Vision Institute, Chesterfield, MO; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO Neal J.Peterson, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX Mujtaba A.Qazi, MD Pepose Vision Institute, Chesterfield, MO; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO Richard C.Rashid, MD Clinical Associate Professor of Ophthalmology, West Virginia University School of Medicine, Charleston Division, Charleston, WV Rajy M.Rouweyha, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX Amy Scally, OD Cornea and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA Lee Shahinian, Jr, MD Stanford University, Department of Ophthalmology, Stanford, CA Michael K.Smolek, PhD LSU Eye Center, New Orleans, LA Erin D.Stahl, MD Durrie Vision Research, Overland Park, KS John P.Stokes, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX

Suphi Taneri, MD Zentrum für Refraktive Chirurgie, Munster, Germany Paolo Vinciguerra, MD Istituto Clinico Humanitas, Milan, Italy Corey B.Westerfield, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX Christoph Winkler von Mohrenfels, MD University Eye Clinic, Regensburg, Germany Richard W.Yee, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX Steven B.Yee, MD Hermann Eye Center, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston, Houston, TX Patrick C.Yeh, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School, Boston, MA LASEK, PRK, AND EXCIMER LASER STROMAL SURFACE ABLATION

1 Overview of LASEK and Stromal Surface Ablation Suphi Taneri, MD Zentrum für Refraktive Chirurgie Munster, Germany Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA

HISTORY Laser subepithelial keratomileusis (LASEK) (1–8) is a relatively new laser surgical procedure for the correction of refractive error that combines certain elements of both laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). The LASEK procedure is most commonly performed using dilute alcohol to loosen the epithelial adhesion to the corneal stroma. Laser ablation of the subepithelial stroma is performed before the hinged epithelial sheet is returned to its original position, as with the LASIK flap (Fig. 1). The flap-related LASIK complications and the slow visual recovery and haze risk of PRK may be avoided. The first LASEK procedure was performed at the Massachusetts Eye and Ear Infirmary in 1996 by one of us (DTA) (1). Camellin popularized the procedure and coined the term LASEK for laser epithelial keratomileusis (3,9). The history of LASEK can be traced back to the use of chemical agents to replace manual epithelial debridement in PRK, which was shown to produce scratches and nicking in the Bowman’s layer and to leave variable amounts of epithelium (10,11) (Table 1). Campos used 100% ethanol for 2 minutes on rabbit corneas and noted significant decrease in stromal keratocytes (27) Agrawal used 70% isopropyl alcohol for 2 minutes for epithelium removal in rabbit eyes and observed similar damage to the keratocytes (28). Helena et al. used 50% ethanol for 1 minute and observed increased keratocyte loss (29). A prospective study performed at the Massachusetts Eye and Ear Infirmary by Abad et al. showed that alcohol-assisted epithelial removal was a simple and safe alternative to mechanical epithelial removal before PRK (2). Other investigators using alcohol for epithelial removal included Stein et al., who were able to grasp, lift, pull apart, and split the corneal epithelium using two McPherson forceps (30), and Shah et al., who peeled the epithelium using a dry sponge (31). Carones et al. found significantly better results in terms of haze and corneal regularity in epithelial debridement using a 20% alcohol

LASEK, PRK, and excimer laser stromal surface ablation

2

solution compared to mechanical debridement (32). Other investigators focused on the formulation of ethanol (38.)

Figure 1 Schematic representation of conventional LASEK surgery showing the application of an epithelial trephine to delineate the edge of the epithelial flap (top left), alcohol application (top right), creation of an epithelial flap before laser ablation (bottom left), and replacement of the epithelial sheet over the ablated stroma (bottom right). Table 1. Milestones in LASEK History. 1982 Technique for obtaining sheets of intact rabbit corneal epithelium (Gipson) 1983 Excimer laser application on cadaver bovine corneas (Trokel and Srinivasan) 1984 Photorefractive experiments on animals (McDonald) 1985 PRK on a blind human eye (Seiler) 1987 PRK on a human sighted eye slated for exenteration 11 days after PRK (Seiler) 1988 PRK on a normal sighted eye (McDonald) 1989 Photoablation of fully sighted eyes and treatment on the underside of a free cap (Buratto)

Overview of LASEK and stromal surface ablation

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1990 LASIK (Pallikaris) 1994 Hartmann-Shack wavefront sensing of human eye (Liang and Williams) 1996 Alcohol-assisted epithelial flap reattached over PRK (Azar) 1998 “LASEK” term coined, specialized equipment, and procedure popularized (Camellin) 1999 Customized corneal ablation (Seiler) 1999 Butterfly LASEK (Vinciguerra) 2000 Mitomycin C treatment of corneal haze after PRK in humans (Majmudar and Epstein) 2001 Hydrodissection and viscodissection (Rachid and Langerman) 2001 Gel-assisted LASEK (McDonald) 2002 Human epithelial cell viability in LASEK (Chen and Azar) 2002 Epi-LASIK (Pallikaris)

Camellin advocated the importance of a hypotonic solution obtained by diluting alcohol in distilled water for facilitating epithelial detachment (3), whereas Vinciguerra preferred balanced salt solution for dilution (8). Our group has investigated the mechanisms of epithelial reattachment in LASEK and the functional alterations of the cell membrane integrity and cell metabolism using livecell assays in vitro. Our studies suggested a dose- and time-dependent effect of alcohol on epithelial cells. The 25% concentration of alcohol was the inflection point of epithelial survival. Significant increase in cellular death occurred after 35 seconds of alcohol exposure. Forty seconds of exposure further induced apoptosis after 8 hours of incubation. Our studies on specimens obtained after conventional alcohol-assisted PRK showed that the epithelial cell layer is intact and the epithelial cells are still viable immediately after exposure to alcohol and surgical peeling. The presence of the basement membrane attached to the basal epithelial cell layer in many of our specimens indicates that the point of separation was between the basement membrane and Bowman’s layer (33,34).

TECHNIQUES AND TERMINOLOGY Several techniques of LASEK are described in this book, including the Camellin technique, the Vinciguerra butterfly technique, the McDonald technique, the Pallikaris Epi LASEK technique, and the Azar flap technique (Fig. 2). Additionally, several expressions have been used, including laser subepithelial keratomileusis (1,35,36), subepithelial photorefractive keratectomy (31,37), epithelial flap photorefractive keratectomy (7), laser-assisted subepithelial keratectomy (5,38), excimer laser subepithelial ablation (39), laser epithelial keratomileusis (39–41), and Epi-LASEK (42).

LASEK, PRK, and excimer laser stromal surface ablation

4

ADVANTAGES OF LASEK OVER PRK AND LASIK: EVIDENCEBASED COMPARISONS We have performed a meta-analysis to determine the advantages of LASEK over PRK and LASIK(14) (Table 2). LASEK may avoid several of the inherent complications including free caps, incomplete pass of the microkeratome, flap wrinkles, epithelial ingrowth, flap melt, interface debris, and diffuse lamellar keratitis after LASIK (22,46– 63), and postoperative pain, subepithelial haze, and slow visual rehabilitation after PRK (64–73). Our meta-analysis aimed at evaluating potential benefits and risks of LASEK and investigates the visual outcome in a semi-quantitative fashion showing distinct advantages (14): Safety One eye out of 907 (0.11%) lost two lines of Best Spectacle Corrected Visual Acuity (BSCVA). This was a loss observed in one of our patients on his final visit at 1 month from 20/20 to 20/30. Efficacy Uncorrected Visual Acuity (UCVA) of 20/20 or better at that time was achieved in 76% and of 20/40 or better in 99% (5,14,36,40). Predictability (Spherical Equivalent) The mean spherical equivalent of 152 eyes at 6-month follow-up was calculated to be −0.32 diopter (D)A (7,8,40). At 6-month follow-up, 83% of eyes (5,14,36,40) were within plusmn; 0.50 D and 98.35% of eyes were within ±1.00 D of desired postoperative refractive error (5,14,36). Stability Rouweyha et al. (40) reported a regression of approximately 2 D in 4 eyes of 2 patients (8% of their eyes) with visually significant haze at 6 months, whereas several other authors point out the absence of regression (3). The remarkable aspects of our review are the long-term stable results in complete absence of serious complications, like infections, recurrent erosions, scar, or late-onset corneal haze formation. Second, epithelial closure with recovery of functional vision could

Overview of LASEK and stromal surface ablation

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Figure 2 (A) Overlapping circular marks are preplaced on the cornea. (B) 18% ethanol is released into the marker well. Care is taken to avoid spillage by using a dry sponge to absorb the overflowing ethanol. (C, D) A jeweler’s forceps is used to delineate the flap edges and locate the dissecting plane. (E, F) A dry, nonfragmenting sponge is used to peel the epithelial flap.

LASEK, PRK, and excimer laser stromal surface ablation

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Figure 2 (CONT) (G) Laser ablation is applied to the exposed Bowman’s layer and stroma. (H, I) A 30-gauge Rycroft irrigating cannula is used to hydrate and reposition the epithelial flap. (J) Care is taken to realign the wound edges using the preplaced marks as a guide. (K) Flap edges are aligned, and no epithelial defects are noted after flap repositioning and during the 5-minute waiting period. (L) A bandage soft contact lens is applied at the end of the procedure.

Overview of LASEK and stromal surface ablation

7

be shown to happen at day 4 to day 7 in most cases. Third, we found a tendency toward overcorrection with PRK nomograms. Fourth, we may hypothesize that this tendency may be caused by the decreased wound healing response, which may lead to myopic regression in PRK. Last, postoperative pain and prolonged visual recovery until the epithelium closes remain the biggest disadvantages of LASEK compared to LASIK (14). (See Table 2.) A potential superiority of LASEK to LASIK in wavefront-guided ablations still remains speculative (Fig. 3). LASEK surgery is especially valuable in patients with thin corneas who would not qualify for LASIK surgery. Additionally, LASEK has become a viable option in patients with professions or lifestyles that predispose to flap trauma (contact sports athletes and military personnel) and in patients with low myopia who are at a lower risk for subepithelial haze.

Table 2. Widely Accepted Relative Differences Among PRK, LASIK, and LASEK. PRK

LASEK

LASIK

Range of correction

Low to moderately Low to moderately high Low to moderately high high

Postoperative pain

Moderate 24–48h (25)

Mild to moderate 24– 48h in approximately 50% (16)

Minimal 12h

Postoperative medications

3 wk to several months

3 wk to several mo

1 to 2 wk

Functional vision recovery

3 to 7 d

3 to 7 d

24 h

Refractive stability achieved

3 wk to several mo 3 wk to several mo

1 to 6 wk

Risk of complications

Low

Low to PRK (16)

Low (but higher with use of microkeratome)

Risk of scarring

1% to 2%

Possibly less than PRK

<1%

Dry eye sensitive

1 to 4 wk

1 to 4 wk

Could last up to 12 mo or more

Thin corneas or wide Often not pupils contraindicated

Often not contraindicated

May be contraindicated depending on the amount of intended correction

Special (relative) indications

Thin corneal pachymetry(18) Wide scotopic pupil LASIK complications in fellow eye Predisposition to trauma

Concern about postoperative pain Requirement of rapid recovery Retreatment after incisional surgery or PRK/LASEK

LASEK, PRK, and excimer laser stromal surface ablation

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Keratoconus suspects (irregular astigmatism) Glaucoma suspects Recurrent erosion syndrome Dry eye syndrome Basement membrane disease (18) Special (relative) contraindications

Dry eye syndrome (59) Recurrent erosion syndrome (59) Predisposition to haze formation

Concern about postoperative pain Requirement of rapid visual recovery Contact lens intolerance (15,18)

Thin corneas Wide pupils Dry eye syndrome (59) Recurrent erosion syndrome (59) Glaucoma Scleral buckle Deep-set eye Small palpebral fissure

Additional factors such as surgeon experience, type of laser, age of patient, amount of correction, and administrative regulations of various countries may influence these comparisons.

Overview of LASEK and stromal surface ablation

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Figure 3 Preoperative (A–C) and immediate postoperative (D–F) wavefront maps obtained in a patient undergoing customized LASEK surgery. In this patient, the total aberrations are reduced (A, D) and the higher-order aberrations are increased (B, E), as shown in the color maps and the bar graphs (C, F).

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REFERENCES 1. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad J. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12(4):323–328. 2. Abad JC, An B, Power WJ, Foster CS, Azar DT, Talamo JH. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology; 1997; 104:1566–1575. 3. Camellin M, Cimberle M. LASEK technique promising after 1 year of experience. Ocul Surg News; 2000; 14(1):14–17. 4. Chen CC, Chang JH, Lee JB, Javier JA, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43(8):2593–2602. 5. Claringbold TV. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28(1):18–22. 6. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27(4):565–570. 7. Shah S, Sebai Sarhan AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85(4):393–396. 8. Vinciguerra P, Camesasca FI. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg; 2002; 18(3 Suppl):S371–S373. 9. Cimberle M, Camellin M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News International Edition 1999, Slack Inc, Thorofare, NJ, USA. 10. Campos M, Hertzog L, Wang XW, Fasano AP, McDonnell PJ. Corneal surface after deepithelialization using a sharp and a dull instrument. Ophthalmic Surg; 1992; 23(9):618–621. 11. Griffith M, Jackson WB, LaFontaine MD, Mintsioulis G, Agapitos P, Hodge W. Evaluation of current techniques of corneal epithelial removal in hyperopic photorefractive keratectomy. J Cataract Refract Surg; 1998; 24(8):1070–1078. 12. Hirst LW, Kenyon KR, Fogle JA, Hanninen L, Stark WJ. Comparative studies of corneal surface injury in the monkey and rabbit. Arch Ophthalmol; 1981; 99(6):1066–1073. 13. Campos M, Raman S, Lee M, McDonnell PJ. Keratocyte loss after different methods of deepithelialization. Ophthalmology; 1994; 101(5):890–894. 14. Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol in press. 15. Lans L. Experimentelle Untersuchungen über Entstehung von Astigmatismus durch nichtperforirende Corneawunden. Albrecht Von Graefes Arch Ophthalmol; 1898; 45:117–152. 16. Rapuano CJ, Sugar A, Koch DD, Agapitos PJ, Culbertson WW, de Luise VP, Huang D, Barley GA. Intrastromal corneal ring segments for low myopia: a report by the American Academy of Ophthalmology. Ophthalmology; 2001; 108(10):1922–1928. 17. Braunstein RE, Jain S, McCally RL, Stark WJ, Connolly PJ, Azar DT. Objective measurement of corneal light scattering after excimer laser keratectomy. Ophthalmology; 1996; 103(3): 439– 443. 18. Hovanesian JA, Shah SS, Maloney RK. Symptoms of dry eye and recurrent erosion syndrome after refractive surgery. J Cataract Refract Surg; 2001; 27(4):577–584. 19. Ang RT, Dartt D, Tsubota K. Dry eye after refractive surgery. Curr Opin Ophthalmol; 2001; 12(4):318–322. 20. Lee JB, Ryu CH, Kim J, Kim EK, Kim HB. Comparison of tear secretion and tear film instability after photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 2000; 26(9):1326–1331. 21. Cimberle M, Condon M. LASEK performs better than LASIK in selected cases. Ocul Surg News, May 1, 2002.

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22. Loewenstein A, Goldstein M, Lazar M. Retinal pathology occurring after excimer laser surgery or phakic intraocular lens implantation: evaluation of a possible relationship. Surv Ophthalmol; 2002; 47:125–135. 23. Durairaj VD, Balentine J, Kouyoumdjian G, Tooze JA, Young D, Spivack L, Taravella MJ. The predictability of corneal flap thickness and tissue laser ablation in laser in situ keratomileusis. Ophthalmology; 2000; 107(12):2140–2143. 24. Seiler T, Koufala K, Richter G. Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg; 1998; 14(3):312–317. 25. Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg; 2001; 27(11):1796–1802. 26. Magallanes R, Shah S, Zadok D, Chayet AS, Assil KK, Montes M, Robledo N. Stability after laser in situ keratomileusis in moderately and extremely myopic eyes. J Cataract Refract Surg; 2001; 27(7):1007–1012. 27. Wilson SE. LASIK: management of common complications. Laser in situ keratomileusis. Cornea; 1998; 17(5):459–467. 28. Melki SA, Talamo JH, Demetriades AM, Jabbur NS, Essepian JP, O’Brien TP, Azar DT. Late traumatic dislocation of laser in situ keratomileusis corneal flaps. Ophthalmology; 2000; 107(12):2136–2139. 29. Agrawal VB, Hanuch OE, Bassage S, Aquavella JV. Alcohol versus mechanical epithelial debridement: effect on underlying cornea before excimer laser surgery. J Cataract Refract Surg; 1997; 23(8):1153–1159. 30. Helena MC, Filatov VV, Johnston WT, Vidaurri-Leal J, Wilson SE, Talamo JH. Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy. Cornea; 1997; 16(5):571–579. 31. Stein HA, Stein RM, Price C, Salim GA. Alcohol removal of the epithelium for excimer laser ablation: Outcomes analysis. J Cataract Refract Surg; 1997; 23:1160–1163. 32. Shah S, Doyle SJ, Chatterjee A, Williams BE, Llango B. Comparison of 18% ethanol and mechanical debridement for epithelial removal before photorefractive keratectomy. J Refract Surg; 1998; 14:8212–8214. 33. Carones F, Fiore T, Brancato R.Mechanical vs. alcohol epithelial removal during photorefractive keratectomy. J Refract Surg; 1999; 15(5):556–562. 34. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK. Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol; 1992; 110(4):537–540. 35. Spurr SJ, Gipson IK. Isolation of corneal epithelium with Dispase II or EDTA. Effects on the basement membrane zone. Invest Ophthalmol Vis Sci; 1985; 26(6):818–827. 36. Lee JB, Choe CM, Kim HS, Seo KY, Kim EK. Comparison of TGF-beta1 in tears following laser subepithelial keratomileusis and photorefractive keratectomy. J Refract Surg; 2002; 18(2): 130–134. 37. Lee JB, Choe CM, Seong GL, Gong HY, Kim EK. Laser Subepithelial Keratomileusis for Low to Moderate Myopia. 6-Month Follow-up. Jpn J Ophthalmol; 2002; 46(3):299–304. 38. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(2 Suppl):S222–S223. 39. Shahinian L. Laser-assisted subepithelial keratectomy for low to high myopia and astigmatism. J Cataract Refract Surg; 2002; 28(8):1334–1342. 40. Lohmann CP, Winkler von Mohrenfels C, Gabler B, Hermann W, Muller M. [Excimer laser subepithelial ablation (ELSA) or laser epithelial keratomileusis (LASEK)-a new keratorefractive procedure for myopia. Surgical technique and first clinical results on 24 eyes and 3 months follow-up]. Klin Monatsbl Augenheilkd; 2002; 219(1–2):26–32. 41. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18(3):217–224. 42. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK) . J Refract Surg; 2001; 17(2 Suppl):S219–S221.

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43. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK for the correction of myopia and myopic astigmatism. J Cataract Refract Surg; 2002; 28(8):1343–1347. 44. Azar DT, Ang RT. Laser Subepithelial Keratomileusis: evolution of alcohol assisted flap surface ablation. Int Ophthalmol Clin; 2002; 42:89–97. 45. Azar DT, Taneri S, Chen CC. Laser sub-epithelial keratomileusis (LASEK) review and clinicopathological correlations. Middle East J Ophthalmol; 2002; 10:54–59. 46. Piechocki M. Alcohol-free LASEK procedure proves to effective in pilot study. Ocul Surg News June 1, 2002; Waikoloa, Hawaii. 47. Agarwal A, Agarwal A, Agarwal T, Bagmar A, Agarwal S. Laser in situ keratomileusis for residual myopia after primary LASIK. J Cataract Refract Surg; 2001; 27(7):1013–1017. 48. Azar DT, Farah SG. Laser in situ keratomileusis versus photorefractive keratectomy: an update on indications and safety. Ophthalmology; 1998; 105(8):1357–1358. 49. Bianchi C. LASIK and corneal ectasia. Ophthalmology; 2002; 109(4):619–622. 50. Cochener B, Savary-Le Floch G, Colin J. [Excimer surface photoablation versus Lasik for correction of mild myopia]. J Fr Ophtalmol; 2001; 24(4):349–359. 51. Dada T, Sharma N, Vajpayee RB, Dada VK. Sterile central disciform keratopathy after LASIK. Cornea; 2000; 19(6):851–852. 52. Farah SG, Azar DT, Gurdal C, Wong J. Laser in situ keratomileusis: literature review of a developing technique. J Cataract Refract Surg; 1998; 24(7):989–1006. 53. Frisch L, Dick HB. [Bilateral simultaneous LASIK. Pro and contra]. Ophthalmologe; 2000; 97(12):881–884. 54. Guell JL, Griss O, deMuller A, Corcostegui B. LASIK for the correction of residual refractive errors from previous surgical procedures. Ophthalmic Surg Lasers; 1999; 30(5):341–349. 55. Helena MC, Meisler D, Wilson SE. Epithelial growth within the lamellar interface after laser in situ keratomileusis (LASIK). Cornea; 1997; 16(3):300–305. 56. Knorz MC, Jendritza B, Liermann A, Hugger P, Liesenhoff H. [LASIK for myopia correction. 2-year follow-up]. Ophthalmologe; 1998; 95(7):494–498. 57. Melki SA, Azar DT. LASIK complications: etiology, management, and prevention. Surv Ophthalmol; 2001; 46(2):95–116. 58. Petersen H, Seiler T. [Laser in situ keratomileusis (LASIK). Intraoperative and postoperative complications]. Ophthalmologe; 1999; 96(4):240–247. 59. Spigelman AV. Complications of LASIK. J Refract Surg; 2001; 17(4):475. 60. Velou SM, Colin J. Photo essay: disastrous complications following a bilateral, same-day laser in situ keratomileusis (LASIK) procedure. Arch Ophthalmol; 2002; 120(2):226–227. 61. Waring GO, Carr JD, Stulting RD, Thompson KP, Wiley W. Prospective, randomized comparison of simultaneous and sequential bilateral LASIK for the correction of myopia. Trans Am Ophthalmol Soc; 1997; 95:271–284. 62. Webber SK, Lawless MA, Sutton GL, Rogers CM. Staphylococcal infection under a LASIK flap. Cornea; 1999; 18(3):361–365. 63. Webber SK, Lawless MA, Sutton GL, Rogers CM. LASIK for post penetrating keratoplasty astigmatism and myopia. Br J Ophthalmol; 1999; 83(9):1013–1018. 64. Yavitz EQ. Diffuse lamellar keratitis caused by mechanical disruption of epithelium 60 days after LASIK. J Refract Surg; 2001; 17(5):621. 65. Van Gelder RN, Steger-May K, Yang SH, Rattanatam T, Pepose JS. Comparison of photorefractive keratectomy, astigmatic PRK, laser in situ keratomileusis, and astigmatic LASIK in the treatment of myopia. J Cataract Refract Surg; 2002; 28(3):462–476. 66. Winkler von Mohrenfels C, Hermann W, Gabler B, Muller M, Marshall J, Lohmann CP. [Topical Mitomycin C for the prophylaxis of recurrent haze after excimer laser photorefractive keratectomy (PRK)-a pilotstudy of 5 patients]. Klin Monatsbl Augenheilkd; 2001; 218(12): 763–767. 67. Wu G, Xie L, Yao Z. Post-PRK muscular asthenopia and eccentric ablation. Chin Med J (Engl); 2001; 114(2):167–169.

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68. Cochener B, Le Floch-Savary G, Colin J. [Excimer photorefractive keratectomy (PRK) versus intrastromal corneal ring segments (ICRS) for correction of low myopia]. J Fr Ophtalmol; 2000; 23(7):663–678. 69. Sakarya Y, Ozatep V, Ermip SS. Drift index to explain patient complaints after PRK. J Cataract Refract Surg; 2000; 26(2):161. 70. Steinert RF, Hersh PS. Spherical and aspherical photorefractive keratectomy and laser in-situ keratomileusis for moderate to high myopia: two prospective, randomized clinical trials. Summit technology PRK-LASIK study group. Trans Am Ophthalmol Soc; 1998; 96:197–227. 71. Katlun T, Wiegand W. [Change in twilight vision and glare sensitivity after PRK]. Ophthalmologe; 1998; 95(6):420–426. 72. Abad JC. Posterior corneal protrusion after PRK. Cornea; 1998; 17(4):456–457. 73. Damji KF, Munger R, Herndon LW, Allingham RR. Reduction of IOP after PRK. Ophthalmology; 1997; 104(10):1525–1526. 74. Rozakis GW. Halos after PRK. J Refract Surg; 1997; 13(4):340. 75. Feit R, Taneri S, Ang RT, Chen CC, Azar DT. LASEK techniques and outcomes. Ophth Clin North Am; 2003; 16:127–135. 76. Walker MB, Wilson SE. Recovery of uncorrected visual acuity after laser in situ keratomileusis or photorefractive keratectomy for low myopia. Cornea; 2001; 20(2):153–155. 77. Zhou X, Wu L, Dai J, Zhu R. [The epithelial-flap abnormality of laser epithelial keratomileusis]. Chung Hua Yen Ko Tsa Chih; 2002; 38(2):69–71. 78. Li DQ, Tseng SC. Three patterns of cytokine expression potentially involved in epithelialfibroblast interactions of human ocular surface. J Cell Physiol; 1995; 163(1):61–79. 79. Helena MC, Baerveldt F, Kim WJ, Wilson SE. Keratocyte apoptosis after corneal surgery... Invest Ophthalmol Vis Sci; 1998; 39(2):276–283. 80. Choi YS, Kim JY, Wee WR, Lee JH. Effect of the application of human amniotic membrane on rabbit corneal wound healing after excimer laser photorefractive keratectomy. Cornea; 1998; 17(4):389–395. 81. Park CK, Kim JH. Comparison of wound healing after photorefractive keratectomy and laser in situ keratomileusis in rabbits. J Cataract Refract Surg; 1999; 25(6):842–850.

2 Laser Subepithelial Keratomileusis (LASEK): Theoretical Advantages Over LASIK Paolo Vinciguerra, MD Istituto Clinico Humanitas Milan, Italy Daniel Epstein, MD, PhD University Hospital Zurich, Switzerland

INTRODUCTION Although laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are now accepted refractive procedures that have been performed on millions of eyes, both surgical modalities are associated with problems and complications that can make them less than optimal in specific cases. Aside from microkeratome and flap complications, LASIK is limited in scope by the thickness of the preoperative cornea and the associated inability to treat high refractive errors with a reasonably-sized optical zone. In addition, there may be a risk for ectasia if too much stromal tissue is removed during the procedure (1). PRK is burdened by the triple onus of postoperative pain, slow rehabilitation of best spectacle corrected visual acuity (BSCVA), and the often unpredictable development of subepithelial haze (2). In many countries, LASIK has overtaken PRK as the primary refractive procedure for those very reasons. Laser subepithelial keratomileusis (LASEK) expands the armamentarium of the refractive surgeon and specifically addresses some of the shortcomings of LASIK and PRK.

THE PROCEDURE LASEK is based on the principle of creating an epithelial flap, which is used to cover the stroma after the laser ablation.The procedure is performed as follows: A specially-designed 9.0-mm trephine is centered on the entrance pupil and pressed down, making a 70 µm-deep circular cut through the epithelium, except at the 12 o’clock position, where an 80 degree hinge is left. A 9.5-mm marker is then centered on the circular trephination, and two to three drops of a 20% ethanol-distilled water solution are instilled inside the marker. The alcohol is carefully dried after 30 to 40 seconds with a

LASEK, PRK, and excimer laser stromal surface ablation

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microsponge. Special care must be taken that no alcohol leaks onto the peripheral cornea or the conjunctiva. After the marker is removed, a spatula is used to lift the edge of the circular epithelial incision. Once the edge has been lifted along the 280 degrees, which had been cut, a specially designed hoe-like spatula is used to carefully free the epithelium and roll it up like a scroll toward the 12 o’clock position. The laser ablation is then performed in the standard manner, after which the epithelial flap is rolled back to cover the ablated stroma. A therapeutic contact lens is then applied for 3 to 4 days. The eye is treated with antibiotics/ steroid drops for approximately 1 week.

PATIENTS STUDIED Five hundred twenty-six eyes of 268 patients (mean age 35±12 years) were treated with LASEK. A Nidek EC−5000 excimer laser was used. The mean (±standard deviation [SD]) preoperative spherical equivalent (SE) was −5.51 diopter (D) ±3.48 D (range, −15.88 D to +5.50 D), the mean sphere −4.98 D ±3.43 D (range, −15.00 D to +4.25 D), and the mean cylinder −1.08 D ±1.44 D (range, −8.00 D to +6.00 D). Mean preoperative uncorrected visual acuity (UCVA) was 20/60. Minimum follow-up was 12 months. At 12 months postoperatively, the mean SE was −0.10 D ±0.70 D, the mean sphere +0.20 D ±0.60 D, and the mean cylinder −0.42 D ±0.90 D. Eighty-six percent of the eyes were within 0.50 D of aim (Fig. 1), and 53% had an UCVA of 20/20 or better (Fig. 2). Eighty-one percent of the eyes has a postoperative BSCVA of 20/20 or better at 1 year. On the first postoperative day, 74% of the patients reported that they had experienced only mild discomfort after the procedure. Twenty percent had noted marked discomfort, but only 6% had perceived pain.

Figure 1 Scattergram of attempted refractive change vs. achieved refractive change 1 year postoperatively.

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Figure 2 Histogram illustrating the distribution of UCVA 1 year after surgery. Three days postoperatively, 38% of the eyes had regained their preoperative BSCVA. By 2 weeks after LASEK, that figure had increased to 44%. At 1 month postoperatively, all eyes had recovered their preoperative BSCVA (Fig. 3). Gains of one line or more of BSCVA were noted up to the fourth month after LASEK. Mean postoperative refraction showed stability over time, with a value of +0.04 D at 1 month, −0.27 D at 6 months, and −0.07 D at 1 year (Fig. 4). At 1 year, no eye had lost two or more lines of BSCVA. In fact, none had lost one line, whereas 32% had gained one line and 12% gained two lines of BSCVA (Fig. 5). Subepithelial haze never exceeded trace, and in 80% of the eyes no haze was detectable at all 6 months postoperatively.

Figure 3 Stability of BSCVA over time, with 1 standard deviation.

LASEK, PRK, and excimer laser stromal surface ablation

Figure 4 Stability of refraction over time depicted with the spherical equivalent refraction and 1 standard deviation.

Figure 5 Histogram of gained/lost BSCVA lines at 1 year postoperatively.

18

Laser subepithelial keratomileusis (LASEK)

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Flap management (the preablation rolling and postablation unrolling of the epithelium) was deemed easy in 62% of the cases, required some extra effort in 33%, and was difficult in 5%. Only seven flaps were “lost,” and in those cases a straightforward PRK was performed. Vector analysis of the cylinder component showed significant angle deviation in only 2.5% of the cases and significant undercorrection of the astigmatism in only 1.9%.

DISCUSSION LASIK and PRK have revolutionized corneal refractive surgery, but despite impressive achievements, neither can be regarded as ideal for every case. Accordingly, there is room for an alternate procedure that can deliver its own set of advantages. LASIK is limited by the thickness of the preoperative cornea. A thin cornea imposes bounds on the correction range with LASIK if optical zone size is not sacrificed. Although the minimum required residual stroma under the flap is not known, most surgeons assume that a bed of at least 250 µm is needed to prevent the development of ectasia. If a 180-µm flap is planned, and if the preoperative corneal thickness is less than 500 µm, less than 70 µm would be available for ablation. In fact, even that may be an overoptimistic estimate, because the calculation does not take into account the observation that flap thickness may actually vary by as much as ±30 µm, a factor that should be considered because the majority of surgeons do not perform intraoperative pachymetry. In the presence of a relatively thin cornea, and if PRK is not acceptable because of the postoperative pain and the slow visual recovery, we suggest that it is now possible for a refractive surgeon to consider LASEK as a reasonable alternative. Using LASEK on a thin cornea widens the range of correction (compared to LASIK) and increases the potential for retreatment, an option often not available in LASIK when the procedure is used in a borderline-thickness cornea. Because there is more stroma to treat, LASEK may in some eyes make possible the use of a larger optical zone than would be feasible if LASIK were performed. The larger the optical zone, the lower the risk for the visual problems in mesopic illumination, which trouble many patients after excimer refractive surgery (3–5). LASEK may also be appropriate in patients who do not want to be treated with a microkeratome. By definition, LASEK eliminates all potential keratome complications. Monocularly treated LASIK patients who have had a difficult bout of diffuse lamellar keratitis or who have scars after such an episode may feel more comfortable if the second eye undergoes a LASEK procedure. The same applies to LASIK patients with persistent epithelial ingrowth who may have had their flaps lifted two or three times to remove the epithelial cells (6). Again, by definition, all potential lamellar and interface complications are eliminated by LASEK. Proposing LASEK to a patient who has had LASIK in the first eye in not unreasonable because, as shown by our results, pain after LASEK is rare, making the procedure much more attractive than PRK from the patient’s point of view. A further argument for LASEK is the impressively rapid recovery of BSCVA, as compared to standard PRK. Admittedly, recovery is not as fast as in LASIK, but considerably faster than after PRK,

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with almost 40% of the eyes regaining their preoperative BSCVA on the third postoperative day. In terms of safety, efficacy, and accuracy, our observations suggest that LASEK results are comparable to long-term outcomes after LASIK and PRK. At 1 year postoperatively, no eye had lost any line of BSCVA, 53% of the eyes had an UCVA of 20/20 or better, and 86% of the eyes were within 0.50 D of aim. It is noteworthy that subepithelial haze is unusually discreet or absent in LASEK eyes, in contrast to what is seen after PRK. Although purely speculative, one explanation for this observation may be that the epithelial flap acts to protect the stroma by decreasing the magnitude of keratocyte apoptosis, thus making for less haze formation. It has been shown that as soon as the corneal epithelium is damaged (whether in PRK or LASIK), a cytokine-mediated cascade is initiated, leading to apoptosis (7). Yet, it is well-established that only rarely is there haze after LASIK, a procedure that causes much less epithelial damage than the pre-PRK epithelial scraping. Creating an epithelial flap (as in LASEK) may also be less of a trauma than the epithelial debridement used in PRK, possibly leading to a more subdued apoptosis response. LASEK is predicated on the use of ethanol to facilitate the creation of the epithelial flap. In excimer refractive surgery, ethanol has previously been applied to remove the epithelium before PRK. Published reports on the use of ethanol in PRK have not shown any detrimental effect on the refractive outcome or on the postoperative visual acuity (8,9). We conclude that in eyes in which LASIK is not advisable, in eyes in which retreatment may be necessary, in patients in whom serious post-LASIK sequelae developed in the first eye, and for surgeons or patients who prefer a refractive procedure without a microkeratome, LASEK represents a reasonable alternative. As illustrated by our results, LASEK has fewer complications than PRK (less pain, faster visual rehabilitation, less haze) and, by virtue of not using a keratome and not producing a stromal flap, fewer complications than LASIK.

REFERENCES 1. Gimbel HV, Penno EE, van Westenbrugge JA. Incidence and management of intraoperative and early postoperative complications in 1000 consecutive laser in situ keratomileusis cases. Ophthalmology; 1998; 105:1839–1848. 2. Seiler T, Holschbach A, Derse M. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology; 1994; 101:153–160. 3. Hersh PS, Stulting RD, Steinert RF. Results of phase III excimer laser photorefractive keratectomy for myopia. Ophthalmology; 1997; 104:1535–1553. 4. Ben-Sira A, Loewenstein A, Lipshiz I. Patient satisfaction after 5.0-mm photorefractive keratectomy for myopia. J Refract Surg; 1997; 13:129–134. 5. Brunette I, Gresset J, Boivin JF. Functional outcome and satisfaction after photorefractive keratectomy. Part 2: survey of 690 patients. Ophthalmology; 2000; 107:1790–1796. 6. Wang MY, Maloney RK. Epithelial ingrowth after laser in situ keratomileusis. Am J Ophthalmol; 2000; 129:746–751. 7. Wilson SE, Kim WJ. Keratocyte apoptosis: implications for corneal wound healing, tissue organization and disease. Invest Ophthalmol Vis Sci; 1998; 39:220–226.

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8. Abad JC, Talamo JH, Vidurrai-Leal J. Dilute ethanol versus mechanical debridement before photorefractive keratectomy. J Cataract Refract Surg; 1996; 22:1427–1433. 9. Carones F, Fiore T, Brancato R. Mechanical vs. alcohol epithelial removal during photorefractive keratectomy. J Refract Surg; 1999; 15:55–62.

3 Indications and Contraindications of LASEK Jae Bum Lee, MD, PhD, Puwat Charukamnoetkanok, MD, and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA The advantages of photorefractive keratectomy (PRK) are its precise predictability and reliable safety as a corrective procedure for low to moderate myopia (1,2). However, its predictability decreases in cases of high myopia, and its effects are limited by postoperative pain, corneal haze, and myopic regression (3). Laser in situ keratomileusis (LASIK) offers fast visual recovery with minimal postoperative discomfort. However, flap-wrinkling, epithelial ingrowth, diffuse lamellar keratitis, and iatrogenic keratoectasia may develop after surgery (4). Laser epithelial keratomileusis (LASEK) involves creation of an epithelial flap after the application of an alcohol solution and then the repositioning of this flap after laser ablation (5). In theory, LASEK combines the beneficial aspects of both PRK and LASIK. It does not need any flap in the stroma like LASIK, thus eliminating inherent flap complications. This chapter discusses indication and contraindications for LASEK. The goal is to offer patients the most optimal refractive surgical procedures for their ocular conditions.

INDICATIONS FOR LASEK LASEK-treated eyes were shown to have lower postoperative pain and less postoperative corneal haze than PRK-treated eyes in mild to moderate myopia (Table 1) (Fig. 1) (6). Patients with low to moderate myopia who are at a low risk for subepithelial haze also may benefit from LASEK. The most ideal candidates for LASEK are those with mild to moderate myopia up to −7.00 diopter (D). Gabler et al. (7), however, reported that LASEK has been effective in treating up to −14.50 diopters of myopia. At these pathological ranges, the risk of wound healing abnormalities manifesting as haze and regression might be expected. A high degree of corneal haze was observed in cases with more than −10 diopters of myopia. The excimer laser we used was a broad-beam laser. Scanning spot

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Table 1. Corneal Haze and Pain Scores After PRK or LASEK. PRK

LASEK

P

2.36±0.67

1.63±0.81

0.047

1 mo

0.86±0.45

0.46±0.24

0.02

3 mo

0.45±0.27

0.29±0.26

0.22

Pain score Haze score

PRK, photorefractive keratectomy; LASEK, laser epithelial keratomileusis.

lasers might reduce severe corneal haze because of lower energy used during LASEK. Candidates should be older than age 20 years and have a stable prescription, with less than 0.25 to 0.50 D change within the past 1 year. Surgeons should consider LASEK for patients whose corneal characteristics render them at greater risk for LASIK or whose professions or lifestyles, such as athletes involved in contact sports and military personnel, predispose them to flap trauma. LASEK might also play a role in refractive surgery when patients are reluctant to undergo incisional surgery, when ophthalmologists have a preference for LASEK, or when small amounts of refractive error may make the risk of flap complication unacceptably high. Patients with redundant conjunctiva that might cause pseudo-suction when the suction ring is applied may avoid this potential complication by undergoing LASEK. The characteristics that may make LASEK a better choice for the patient include: (1) corneal thinning, in which less than 200 to 250 µm of tissue would be left in the bed should LASIK be performed instead; (2) very small cornea that might cut the limbus when one use the microkeratome; (3) difficulty achieving satisfactory suction for the microkeratome cut; (4) narrow palpebral fissure, in which case the microkeratome cannot be well-applied; (5) epithelial anterior basement membrane dystrophy, because of the risk of epithelial ingrowth; (6) superficial corneal lesion such as anterior stromal dystrophy or granular dystrophy; (7) severe neovascularized cornea caused by long-term contact lens use; (8) presence of tears in the peripheral retina wherein if suction is applied, postoperative complications such as retinal detachment and retinal hemorrhage may occur (9) when the microkeratome is not available. Additional Advantages of LASEK Over PRK Kornilovsky (8) reported that the main advantages of LASEK over PRK are the absence of pain and corneal opacities. Other potential advantages of LASEK are as follows. First, if making of epithelial flap is unsuccessful, one can easily convert to PRK. Second, the risk of infection is reduced because the epithelial flap acts as an effective protective barrier. Third, if re-treatment for PRK is needed, LASEK can be used to reduce the risks of corneal haze. Fourth, although the immediate postoperative visual acuity is not as good as LASIK, patients have relatively good visual acuity during the

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Figure 1 Left (A) shows +2 grade corneal haze in the center of the cornea with 20/30 uncorrected visual acuity 3 months after PRK. Right (B) also shows grade 1 corneal haze with 20/20 uncorrected visual acuity 3 months after LASEK. early postoperative days, enabling simultaneous bilateral surgery to be performed. However, most patients may prefer to undergo sequential treatment because of postoperative discomfort. Additional Advantages for LASEK Over LASIK LASEK avoids the corneal lamellar cut. Therefore, flap-related complications in LASIK such as flap displacement, flap striae, and epithelial ingrowth, are essentially eliminated (Fig. 2). Because LASEK does not require microkeratome, there is no need for wide exposure of the eyeball using a speculum. This minimizes pain during surgery and the risk of ptosis after surgery (9). LASEK After Other Surgical Procedures LASEK can be performed to improve the refractive error in patients who underwent previous eye surgeries. Postkeratoplasty corneas tend to be very steep, leading to increased risk of flap complication such as buttonhole. LASEK offers an attractive alternative to treat postkeratoplasty astigmatism. Surface ablation procedures such as LASEK may also be useful after radial keratotomy (RK). By avoiding the flap, the risk of further weakening the corneal biomechanics is minimized. LASEK also circumvents the “pizza effect” occasionally observed when making LASIK flaps after RK.

PREOPERATIVE CONSIDERATIONS Careful patient selection and review of the risks and benefits of LASEK are important considerations. Patients’ information and education are essential for LASEK. The patient

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Figure 2 Epithelial ingrowth can be seen 4 weeks after LASIK procedure. should thoroughly understand the LASEK procedure and nature of postoperative recovery by viewing information sheets and obtaining additional information from patient counselors, the surgeon, and other patients. Patients need to realize that they will experience greater postoperative discomfort after LASEK compared to LASIK. They must also be informed that the visual recovery will be delayed, but the long-term visual results are comparable to those of LASIK.

CONTRAINDICATIONS Contraindications for LASEK are similar to PRK. Retinal, optic nerve, and hereditary conditions should be inquired and excluded before surgery. Careful slit-lamp examination is essential to rule out any significant corneal abnormalities. Vascularization that involves the optical zone can result in bleeding during the procedure and lead to irregular ablation. Absolute ocular contraindications are clinical keratoconus, monocular patients, exposure keratopathy, and herpes zoster. The relative contraindications are history of herpes simplex keratitis, previous ocular surgery, any active/residual/recurrent ocular disease, unstable/ progressive myopia, irregular astigmatism, corneal scar, and forme fruste keratoconus (topographic changes) (Table 2). Other contraindications for LASEK include uveitis, cataract, retinopathies, and significant lagophthalmos. Because patients are given topical steroids postoperatively, it is important to rule out the presence of glaucoma or a suspected glaucoma that may make the eye vulnerable to raised intraocular pressures (11). Funduscopy is an important examination in myopic patients because of the possibility of a retinal hole or degenerative retina (12). It also rules out any optic disc or macular disease. One should refrain from operating on individuals with large pupils (>7

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mm) in dim light because of the increased risk of night glare and halos (13). Advanced keratitis sicca with diffuse superficial punctate keratopathy or corneal filaments are a possible contraindication for LASEK. In LASEK, two essential components are the making of an epithelial flap and the use of contact lens. The production of tear film decreases with age. Older patients may find the postoperative contact lens uncomfortable. To maintain good adhesion of epithelial flap to stroma, patients should be instructed to avoid rubbing or blinking excessively, particularly during the first postoperative day.

GENERAL HEALTH Like all other refractive surgery procedures, the success of LASEK depends on proper wound healing. Any systemic conditions that may potentially be detrimental to the healing process of eyes should be actively uncovered during preoperative examination. Relative general contraindications are diabetes mellitus (type I and II), clinically significant atopy,

Table 2. Absolute Ocular Contraindications for LASEK. Keratoconus Monocular patients Severe dry eye (Sjögren syndrome) Active infection of cornea and conjunctiva Herpes zoster ophthalmicus

and pregnancy or lactation. During pregnancy or nursing, there may be hormonal changes that could alter the refractive errors and corneal haze (14). A recent study (15) has demonstrated a chance of regression 13.5 times higher in women using oral contraceptives. Patients should be warned of this apparent increased risk. Patients with active systemic connective tissue diseases (e.g., systemic lupus, rheumatoid arthritis) are considered poor LASEK candidates because of the potential for poor epithelial healing and the risk of a corneal melt. A history of keloid formation of the skin is no longer considered a contraindication to LASEK. History of keloid does not appear to increase risk of corneal haze. In our experience (6), contact lens intolerance after surgery occurred in 4% eyes, and most of these had folds in Decemet’s layer. Most patients were older than age 40 years. Although the reason for the contact lens intolerance is not clear, patients older than 40 should be informed of this increased risk. LASEK offers patients another choice of refractive surgery in mild to moderate myopia. It reduces the incidence of postoperative significant pain and corneal haze and could avoid various flap and interface-related problems after LASIK. However, careful patient selection is essential for successful outcome.

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REFERENCES 1. Seiler T, Holschbach A, Derse M, Jean B, Genth U. Complications of myopic photorefractive keratectomy with the excimer laser.. Ophthalmology; 1994; 101:153–160. 2. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser photorefractive keratectomy: 18 months follow-up.. Ophthalmology; 1992; 99:1209–1219. 3. Wang Z, Chen J, Yang B. Comparison of laser in situ keratomileusis and photorefractive keratectomy to correct myopia from −1.25 to −6.00 diopters.. J Refract Surg; 1997; 13:528–534. 4. Hersh P, Brint S, Maloney RK. Photorefractive keratectomy versus laser in situ keratomileusis for moderate to high myopia.. Ophthalmology; 1998; 105:1513–1523. 5. Camellin M. LASEK may offer the advantages of both LASIK and PRK.. Ocular surgery news international 1999; March. 6. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia.. J Cataract Refract Surg; 2001; 27:565–570. 7. Gabler B, vonMohrenfels W, Lohmann CP. LASEK: A histological study to investigate the vitality of corneal epithelial cells after alcohol exposure.. Invest Ophthalmol Vis Sci; 2001; 42:S560 [abstract 3222]. 8. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK).. J Refract Surg; 2001; 17(2Suppl):S222–S223. 9. Hori-Komai Y, Toda I, Tsubota K. Laser in situ keratomileusis: association with increased width of palpebral fissure.. Am J Ophthalmol; 2001; 131(2):254–255. 10. Farris RL. Contact lenses and the dry eye.. Int Ophthalmol Clin; 1994; 34(1):129–136. 11. Gimno JA, Munoz LA, Valenzuela LA, Molto FJ, Rahhal MS. Influence of refraction on tonometric readings after photorefractive keratectomy and laser assisted in situ keratomileusis.. Cornea; 2000; 19(4):512–516. 12. Arevalo JF, Ramirez E, Suarez E, Antzoulatos G, Morales-Stopello J, Ramirez G, Torres F, Gonzalez-Vivas R. Rhegmatogenous retinal detachment in myopic eyes after laser in situ keratomileusis. Frequency, characteristics, and mechanism.. J Cataract Refract Surg; 2001; 27(5):674–680. 13. Hersh PS, Steinnert RF, Brint SF. Photorefractive keratectomy versus laser in situ keratomileusis: comparison of optical side effects. Summit PRK-LASIK Study Group.. Ophthalmology; 2000; 107(5):925–933. 14. Sharif K. Regression of myopia induced by pregnancy after photorefractive keratectomy. J Refract Surg; 1997; 13(5Suppl):S445–S446. 15. McCarty CA, Ng I, Waldon B, Garrett SK, Downie JA, Aldred GF, Wolfe RJ, Taylor HR. Relation of hormone and menopausal status to outcomes following excimer laser photorefractive keratectomy in women. Melbourne Excimer Laser Group. Aust N Z J Ophthalmol; 1996; 24(3):215–222.

4 LASEK Preoperative Considerations Robin F.Beran, MD, FACS Columbus Laser and Cataract Center Columbus, OH

INTRODUCTION All refractive surgical procedures demand appropriate preoperative patient selection and patient preparation to achieve optimal postoperative results. This principle is extremely important when performing laser subepithelial keratomileusis (LASEK), because the characteristics of this technique are considerably different than the more popular procedure, laser in situ keratomileusis (LASIK). Patient selection includes consideration of candidate age, personality characteristics, occupational and recreational activities, as well as a number of specific ocular considerations. Preoperative patient preparation focuses on patient education and optimizing the ocular status for surgery. Failure to address these issues may reduce one’s chances for the best and safest outcome.

PATIENT CHARACTERISTICS The patient selection and evaluation process should begin with the initial patient contact. This contact is usually via phone, although there will be visitors and walk-ins. In addition to obtaining the vital personal information to permit continued contact, the staff member should record any comments regarding the encounter with the candidate that they believe to be pertinent. The candidate’s personality is important in determining which procedure is preferred, or even if one is a good refractive surgery candidate. An experienced and sharp staff member may pick up on personality characteristics that may be helpful. This awareness by the staff to access the patient’s interest and demeanor should persist throughout all aspects of the testing and evaluation process. The amount of contact time with the patient is limited and, thus, every minute is valuable. Table 1 summarizes certain personality traits that may favor LASEK vs. LASIK. Patient preference for the choice of procedure should never be overlooked. Many refractive surgeons are surprised at the number of patients who are uncomfortable and concerned about the idea of cutting a flap in their cornea. A significant portion of refractive surgery candidates has refrained from having laser vision correction because of safety concerns and lack of confidence. LASEK does satisfy some of these candidates’ fears regarding potential flap complications and potential for ectasia. Thus, providing LASEK as an option for patients can definitely increase the number of individuals electing to have surgery.

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Table 1. Patient Personality Characteristics. LASEK

LASIK

Well educated/informed

Obsessive/particular

Actively involved in process

Inpatient

Tolerant of pain

Poor pain tolerance

Eye rubber

Familiar with LASIK (friends/family)

Willing to accept slow visual recovery

There is nothing difficult about considering the lifestyle, occupational, and recreational characteristics with regard to the choice of a refractive surgical procedure. One simply needs to use common sense and weigh the overall advantages vs. the disadvantages for each procedure in that individual patient choosing the optimal for safety and visual improvement. Table 2 summarizes the lifestyle and occupational characteristics that may favor LASEK vs. LASIK. For younger patients, especially in their early 20s, it has been my belief that surface ablation offers the advantage of greater flexibility for future treatments if needed. The chance of a significant change in the refractive error of a 20-year-old over a lifetime is certainly much greater than that for a 40-year-old. Although we know that the LASIK flap can be successfully elevated after several years for an enhancement, there is most likely a time at which this cannot be accomplished. If an enhancement is desired in this situation, then one will be faced with the decision as to whether to re-cut a second flap or to perform surface ablation. The true consequences for each of these choices are not known at this time. Many photorefractive keratectomy (PRK) patients have had subsequent treatments after 6 or more years without any apparent complications. The considerations with regard to corneal instability and ectasia appear more important in LASIK enhancements and are not well-understood. For the younger patient with a life expectancy of 50 or 60 years, providing the greatest flexibility for the future does desire merit.

CLINICAL FINDINGS THAT MAY INFLUENCE THE CHOICE OF LASEK VS. LASIK The most common problems faced are deep-set eyes and small palpebral fissure width. In these situations, safe application of the vacuum ring and maintenance of adequate suction are often difficult with our present microkeratome systems. Therefore, with LASEK, one can safely eliminate the potential flap complication that might arise. The most common reason for choosing LASEK is the presence of an ocular characteristic not favorable for LASIK. Refractive surgeons have their own criteria for these ocular characteristics and for performing LASIK. Surgeon comfort levels for residual stromal bed range from 200 microns to 300 microns. Controversy exists over the degree of myopia (potential for stromal haze) safely treated with surface ablation. Others

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exist, and the following are those that seem important to use in accessing one’s candidacy for the procedures.

Table 2. Lifestyle and Occupational Characteristics. LASEK High risk for trauma

LASIK Minimal risk for trauma

Law enforcement

Golf

Firefighters

Swimming

Martial arts

Business professional

Basketball

Aerobics

Flexible schedule

Need for short recovery time

Easy access for follow-up

Long distance for follow-up Need to minimize risk of infection

Corneal Thickness Corneal thickness considerations are mandatory in the choice of laser vision correction procedure. The presence of inadequate corneal thickness in performing LASIK has the potential to lead to corneal instability and corneal ectasia. This has been documented in the literature over the past 3 years. There is still not a concrete understanding of the absolute limits and, as mentioned, surgeon comfort levels range from 200 microns to 300 microns of residual intact posterior stroma. Skeptics and those using lower amounts of tissue raise issues regarding the reported cases of ectasia and claim inaccurate microkeratome cuts, improper patient selection (early keratoconus), and incorrect measurements as reasons for this complication. At this time, it appears that the majority of surgeons feel comfortable with 250 microns of stroma as their limit. More conservative surgeons lean toward 300 microns as their limit. Another issue is the potential structural changes caused by the construction of a lamellar flap in a thin cornea. With lamellar keratoplasty for hyperopia, “controlled steepening (ectasia)” was achieved with a single, deep cut. A 160-micron flap in a 460micron cornea may possibly in and of itself create a degree of structural weakening. The best guideline at present seems to be using 500-micron total corneal thickness as the minimal limit for LASIK. To enable candidates who do not meet the aforementioned criteria to still undergo LASIK, surgeons will consider the use of a thinner corneal flap. Again, a number of questions arise, including the actual achieved flap thickness, the flap consistency of the microkeratome, potential for increased flap complications during construction, and a potential increase in striae or folds.

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Corneal Tissue Integrity and Quality Corneal tissue integrity and quality are important with respect to maintaining the strength of the cornea postoperatively. The only gauge available to access the quality or “normality” of the corneal tissue is topography. The presence of either the anterior or the posterior surface abnormalities suggestive of keratoconus can alert one to the likelihood of an abnormality of the stromal tissue. Unfortunately, the ability to routinely and simply obtain and analyze corneal tissue to identify abnormalities in the collagen structure is not available. Surface ablation is a better consideration for suspicious cases, because most would agree it is less likely than a lamellar procedure to induce weakening. Excessive Corneal Curvatures Excessive corneal curvatures can increase the risk of an intraoperative flap complication in LASIK. Either extremely steep (>48) or extremely flat (<40) radii of curvature can alter the tissue delivery into the microkeratome and result in free, thin, incomplete, or buttonholed flaps. Some microkeratomes have improved their suction rings to address this, but surface ablation does definitely eliminate this concern. Depending on the microkeratome, flatter corneal curvatures may reduce the ability to achieve larger diameter LASIK flaps necessary for hyperopic ablation. Again, LASEK is a valuable alternative in these cases. Small Corneal Diameters Small corneal diameters can predispose to free caps as well as insufficient flap diameter to permit a complete hyperopic ablation. It is helpful to check this preoperatively with the reticule of the laser microscope. Identification of the inability to construct a large enough flap centered on the pupil enables one to choose LASEK. This will reduce the chance of irregular astigmatism developing, which is seen in LASIK with incomplete and asymmetrical ablations. Miscellaneous Corneal Pathology Miscellaneous corneal pathology such as neovascularization, scars, and guttata must not be ignored. LASEK is frequently the best option in these instances. Anterior basement membrane dystrophy may be treated and then LASIK considered; however, in most cases it is probably best not to take a chance on an epithelial defect. PRK is my preference over LASEK because the abnormal epithelium and basement membrane is being removed in the same way that one would treat the problem with a superficial keratectomy. Pupil Size and Centration Pupil size and centration are important determining factors in the choice of procedure. A large scotopic pupil size (7–9 mm) may increase the risk for significant glare and halos, especially if a 6.0-mm ablation is used. The effective optic zone size is reduced in LASIK

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as compared to that with surface ablation because of the thickness of the flap tissue. Dr. Mia Pop’s study several years ago demonstrated that in comparable degrees of myopia, the PRK patients related less glare and halo effects than the LASIK patients. It is helpful to be able to offer LASEK to these patients to improve their confidence in proceeding with laser vision correction. As mentioned, any decentration of the pupil in a small diameter cornea can compromise the completeness of the ablation pattern. This is more frequent with hyperopic treatments. It is a good practice to preoperatively check the proposed ablation zone with the reticule of the laser microscope to confirm adequate flap coverage if planning LASIK. Dry Eye patients Dry eye patients undergoing LASIK are at risk for a neurotrophic keratitis. This is believed to be caused by transection of the corneal nerves. A superior hinge position seems to increase the incidence of this complication as more of the corneal nerves are transected as they enter from the horizontal limbus. Using a nasal hinge does appear to reduce the frequency. Fortunately, this complication tends to be temporary, but may last 6 months or more despite treatment. Possibly because surface ablation only exposes the nerve endings, this condition does not occur, at least not in the same presentation. Despite this advantage, caution still must be exercised when considering laser vision correction in extremely dry eye patients. The Posterior Segment The posterior segment is frequently forgotten when performing refractive surgery. The dramatic increase in intraocular pressure occurring with the application of the fixation ring does have implications with respect to posterior ocular structures. The effects on the vitreous, retina, vessels, and optic nerve must all be considered. Retinal Vascular Changes Retinal vascular changes of several types have been reported. Both central retinal vein and branch venous occlusions have been identified. One would expect that there were predisposing and pre-existing factors that made these vessels susceptible to closure with increased intraocular pressure. Superficial and intraretinal hemorrhages have also been seen after LASIK. At least one report of a macular hemorrhage has been described. Lattice Degeneration Lattice degeneration of the retina raises questions as to the chances of developing a rhegmatogenous retinal detachment caused by the rapid increase and decrease in intraocular pressure causing a shift in the vitreous. Vitreo-retinal traction might then result in a retinal tear. Certainly, this could possibly happen in eyes without lattice degeneration, but the lattice would seem to increase the odds. So far there is no good data to help with this issue.

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The Optic Nerve The optic nerve may be impacted by the application of the fixation ring and subsequent increased intraocular pressure. Although at least one study reported a damage to the optic nerve fiber layer after LASIK, it seems most would now agree that this was caused by the testing method and not actual loss of nerve fibers. Nonarteritic anterior ischemic optic neuropathy has been reported after LASIK. High-risk eyes may be better-served with surface ablation to minimize alterations in blood flow. For the same reason, if an eye with glaucomatous optic atrophy requires laser vision correction, might not surface ablation be preferred? Previous Ocular Surgery Previous ocular surgery can make it difficult to obtain adequate suction with the fixation ring. In eyes having had a scleral buckling procedure, one may not achieve good vacuum. The same is true for an eye that has undergone a trabeculectomy. Aborted LASIK procedures may be better served with surface ablation. Consecutive hyperopia in previous radial keratotomy eyes may have less chance of developing irregular astigmatism with LASEK than with LASIK. Concerns regarding the development of corneal haze seen with myopic surface ablation after PRK should be lessened for hyperopic surface ablation because the treatment zone is peripheral to the visual axis. The Degree of Refractive Error The degree of refractive error has played a role in the choice of procedure. The preferred treatment for higher degrees of myopia has been LASIK to reduce the incidence of haze and regression. LASEK results have shown similar success to LASIK patients even for the higher ranges of myopia. Thus, it is an acceptable option for those patients or eyes having any characteristic best treated with surface ablation. Everyone is familiar with the general contraindications for laser vision correction: unstable refraction, younger than age 18 years, autoimmune/connective tissue disease, as well as neurotrophic/herpetic keratitis. Patient preference for LASIK with its quicker visual recovery and minimal postoperative discomfort is definitely a contraindication for LASEK. A relative contraindication for LASEK is anterior basement membrane dystrophy. It is prudent to remove the diseased epithelium and basement membrane rather than to replace it. My personal experience has been that LASEK in anterior basement dystrophy significantly prolongs the postoperative visual recovery.

PATIENT EDUCATION The importance of education cannot be overemphasized! Patient education can only begin after the surgeon, staff, and co-managing physicians understand the LASEK procedure and the education process. It may seem ridiculously obvious; however, the surgeon must be the first to be educated, not only about the LASEK technique but also about the importance of the office process to provide a quality experience for the patients. It is imperative that the

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surgeon has a total commitment and confidence in the results of surface ablation. Only then will the staff be able support the patients during their evaluation and treatment. During the initial contact, it is helpful if the staff member conveys the concept that there is not just one refractive surgical procedure that is best for all candidates. One should not go into great detail, but should simply in the appropriate circumstance plant the seed that LASIK is not the only available procedure. This prepares the patient to begin the thought process required in selecting their procedure. This is not an easy transition for those practices in which LASIK has been the only procedure offered or used. In these cases, when you do try to explain to patients that they are good LASIK candidates, they will always be hesitant to have surface ablation because they perceive it as an inferior procedure. By using this concept of multiple procedures, one will not get into this predicament, thereby reducing patient confusion. It is inevitable that all LASEK patients will come into contact with patients having undergone LASIK. If the LASEK patient does not understand why LASEK was chosen, doubt will arise as to the surgeon’s competence and reasons for performing a procedure with a longer visual recovery and more postoperative discomfort. The patient must be able to easily explain the reason for LASEK to the individuals having had LASIK. This ensures satisfied patients who will refer friends, to their LASEK surgeon. The greatest problem with performing LASEK is communicating the nature of the postoperative course to the patient. Most patients are saturated with the rapid, painless, dramatic visual recovery after LASIK. Therefore, it is necessary to emphasize to all patients that the postoperative visual recovery may be 1 or 2 weeks and also that there is the potential for significant discomfort for the first 3 to 4 days. I explain that by 1 week after surgery, approximately 80% of eyes will be 20/40 or better, and by 1 month 98% to 99% will be there. Adequate preparation by the patient for this delayed recovery will spare both you and them the distress created if they become compromised during this time. Preoperative ocular findings such as increased intraocular pressure, lattice retinal degeneration, blepharitis, and dry eye syndrome are all addressed and treated appropriately before proceeding with surgery. A topical fluoroquinolone is initiated four times per day beginning 24 hours before surgery. Finally, patients are instructed not to wear cosmetics or perfumes to surgery.

5 LASEK Preoperative Evaluation Chun Chen Chen, MD Taipei Municipal Jen-Ai Hospital, National Yang-Ming University Taipei, Taiwan Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA

GENERAL MEDICAL HISTORY The general history of the patient is helpful in identifying systemic pathologies that may be a contraindication to the laser subepithelial keratomileusis (LASEK) procedure. Relative systemic contraindications that theoretically might affect healing and influence the refractive outcome include: pregnancy, diabetes mellitus, immunocompromise, collagen disorders, e.g., systemic lupus erythematosus (SLE) and rheumatoid arthritis, allergies or atopia, systemic infections (HIV or tuberculosis), and systemic medication of certain drugs, such as steroids and hormone replacement therapy.

OCULAR HISTORY This should include previous ocular surgery, orthoptic treatment, and refractive surgery. In particular, an accurate contact lens history should be ascertained when the lenses were last worn, the type of contact lens, the ongoing wearing success or not, and the reasons of discontinuation of contact lens wear, which are all equally essential points. Ocular surface abnormalities resulting from Sjögren’s disease, alkali burn, or ocular cicatricial pemphigoid are absolute contraindications of LASEK. Moderate to severe dry eye syndromes resulting in surface abnormalities are relative contraindications to refractive surgery (1,2). Punctum occlusion and tear replacement therapy are often necessary to stabilize the dry eye condition before surgery. A history of neurotrophic corneal ulcers, herpes zoster ophthalmicus, or nonhealing epithelial defects makes the patients ineligible for refractive surgery. A history of herpes simplex virus (HSV) keratitis represents another relative contraindication to refractive surgery. Photorefractive keratectomy (PRK) and phototherapeutic keratectomy (PTK) performed on patients with a history of HSV have resulted in cases of reactivation of latent virus (3). Oral acyclovir given in the peri-operative period may be beneficial in preventing recurrence of the disease.

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SOCIAL AND OCCUPATIONAL HISTORY Evaluating the patient’s vocational and recreational refractive needs is important for surgical goals and planning. Patients should be informed of the possible complication of refractive surgery and the best-corrected visual acuity may be compromised. Those whose careers have strict requirement of visual acuity should check with their employers before undergoing keratorefractive surgery. Patients of presbyopic age may benefit from monovision (4,5), whereas younger patients (<35–40 years of age) are usually not tolerant of this approach.

VISUAL ACUITY Visual acuity (VA) is usually recorded by Snellen notation, i.e., 6/12 or 20/40, depending on the testing distance of 6 meters in the UK or Australia and 20 feet in the United States, respectively (6). Early Treatment Diabetic Retinopathy Study (ETDRS) charts are valuable for conducting LASEK studies (Fig. 1). Documentation of uncorrected and best spectacle corrected visual acuity at near and distance is useful for evaluating the efficacy and predictability of the refractive surgery. Severe and extreme myopia is associated with reduced best spectacle corrected visual acuity, which may be different between spectacle correction and contact lens correction. High diopters of myopia and astigmatism may enjoy a level of visual acuity in rigid gas permeable contact lens that may be impossible to reach by refractive surgery. Myopic patients, who are 45 to 50 years of age, need to understand the implications of opting for full distance. It is important to document and discuss these details with the patients in assessing postoperative outcomes, and in achieving high levels of patient’s satisfaction. Refraction A definite, accurate refraction is obviously essential and is the most critical assessment in respect to outcome, because the most accurate laser system cannot improve on a poor refraction. A cycloplegic refraction is important to ensure a significant accommodative component is not evident (7). Cycloplegia is conducted by instilling one drop of cyclopentolate three times (at 10-minute intervals). A cycloplegic refraction is performed 30 minutes after the last drop is instilled. Alternatively, 1% tropicamide can be instilled at least three times (again, at 10-minute intervals) and refraction performed 15 minutes after the last dose. The cycloplegic refraction is mandatory to prevent overcorrecting the patient, and it should be performed with retinoscopy and then subjective refinement. In some cases, severe ametropia associated with alterations of the posterior pole (myopic staphyloma) makes retinoscopy difficult.

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Figure 1 ETDRS visual acuity chart. This chart is valuable for LASEK studies, although it may be less convenient than the Snellen chart for routine measurements of visual acuity. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.) Objective Refraction In most cases, the manifest refraction is the one selected for the refractive surgery correction. It must therefore be carefully performed so that it provides the best visual acuity with the least amount of minus correction. One must be extremely careful not to

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over-minus the patient. The refraction should be doubly checked in the trial frame, which should be well positioned with careful vertex distance measurement, especially as the amount of myopia increases. The first measurement to be taken is the interpupillary distance (PD), and then the trial frame or the phoropter PD needs to be adjusted accordingly (6). Ensure that the trial frame fits properly or that the patient always keeps the head against the phoropter. The horizontal orientation between both trial frame or phoropter head and the patient’s eye is important for astigmatic axis assessment. The back vertex distance (BVD), the distance between the eye and the back of the trial lens in situ, needs to be measured in a trial frame for spherical equivalent over minus 4.0 DS. Streak retinoscopy and autorefractors (Fig. 2) are objective methods of determination of refractive error. During the refraction, to avoid unwanted accommodation, the patient should be instructed to look at a fixation light in the distance (6 meters/20 feet equivalent), and the room illumination should be low. In aphasia or strabismus, the fellow eye is occluded; otherwise, the fellow eye is fogged until the visual acuity is 6/12 (20/40) or poorer. For the eye undergoing retinoscopy, it is desirable to neutralize any “with movement” with positive spheres before neutralizing the “against movement” with negative cylinders to prevent stimulation of accommodation. The refinement of axis of the corrective cylinder is accomplished through the observation of the break, skew, or straddling phenomena. After the refinement of the axis of the cylinder, the power of the cylinder is refined by adding a small amount of minus sphere to obtain the “with movement.” The cylinder power is then adjust so that the “with movement” has the same quality in all meridians. Occlude one eye at the end of the objective assessment and adjust the spherical component within the trial frame to compensate for the working (refraction) distance. Subjective Refraction Jackson Cross-Cylinder Technique To refine the cylinder component there are two widely used and well-described methods using either the Jackson cross-cylinder or the fan and block technique. A cross-cylinder incorporates two lens of equal power with opposite signs; therefore, the mean sphere power is zero. It is used for subjective refinement of axis and power of the cylinder. The axis of the cylinder is refined by rotating the cross cylinder, as led by the flip choices, with the axes of the Jackson cross-cylinder straddling the axis of the corrective cylinder (8). After the determination of the axis, the cross-cylinder is turned 45 degrees, and the power of the cylinder is refined. When the power of cylinder is changed, then adjustment of the spherical component is also needed. The cross-cylinder technique requires for the circle of least confusion to be focused on the retina.

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Figure 2 Automated refractors are helpful in obtaining an approximate idea of the patient’s refractive error. They should not be used as the sole basis of LASEK treatments. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.) The spherical component of the objective refraction needs to be confirmed. This power is adjusted by requesting the patient to look at a letter on the last line of distinct vision and to reply if the letter improves in clarity or reduces with the addition of a powered lens. To ensure that accommodation is not stimulated, add the positive lens in +0.25 diopter (D) step. If a reduction of visual acuity occurred, then remove the plus lens. To avoid the over-correction of myopia, the examiner can ask the patient whether the image is becoming smaller or sharper or perform the duochrome (bichromatic) test. Red-Green (Duochrome, Bichromatic) Test The red-green (duochrome, bichromatic) test may be used to study the optimal spherical correction that has already been refined to within 1 D of emmetropia (8). It is based on the chromatic aberration; when a pencil of light is rendered convergent by a plus lens, the red light is focused behind green light because of longer wavelength. While fogged with the plus lens, the patient is asked to gaze at letters or circles on a half-red, half-green

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background. The letters on the red side should become clearer. Plus lenses are removed in 0.25 D step until the letters on two backgrounds become equal. At the endpoint of subjective refraction, place a +1.00 DS lens into the trial frame and record the VA obtained. This is called “fogging” and the +1.0 DS lens is the “fogging lens.” The VA should “blur back,” i.e., be reduced to approximately 6/12 (20/40) if the patient’s correctable VA was approximately 6/5 (20/15). If the patient can still see the original line or that above with “fogging,” the patient has too much negative sphere incorporated into the subjective prescription and, therefore, the letters on the green background will be clear while the letters on the red will be blurred. Binocular Balancing The final step of subjective refraction is the achievement of equal and minimal accommodative tone in both eyes. The tests of binocular balancing require that correctable visual acuity of both eyes is essentially equal. The most sensitive test of binocular balance is the prism dissociation method. Four or five prism diopters of vertical prism are placed before one eye. After fogging of both eyes with +1.0 D sphere, the sharpness of the fogged images (6/12 or 20/40 line) is compared. Plus sphere is added in +0.25 D step in one eye and then in the other eye. If the eyes are balanced, the patient will report that the eye with the additional +0.25 D sphere will be more blurred. After a balance of the binocular images is established, remove the prism and unfog the binocular until the maximal visual acuity is obtained. The other commonly used test of binocular balance is fogging method. With the +2.0 D sphere placed before each eye, the patient is asked to look at the letter on the 6/20 (20/100) or 6/20 (20/70) line. While a −0.25 D sphere is placed in front of one eye and then the other, the patient will be able to identify the image of the eye with the −0.25 D sphere more clearly. If the eyes are not in balance, the sphere should be added or subtracted in 0.25 D step until balance is achieved. Refinement of Cylindrical Correction Frequently, the magnitude and axis of astigmatism documented by the aforementioned technique are different from the data obtained by computerized videokeratography (CVK), keratometry, and autorefraction. In such a situation, it is helpful to repeat the subjective refraction according to the axis and power suggested by the topographic power. Lenticular astigmatism should be suspected if there are significant disparities between the topography and subjective findings. Lenticular astigmatism accounts for the difference between corneal astigmatism and total astigmatism. It can be produced by lens surface or by tilting or decentration of the spectacle lens with respect to cornea. If the resultant ocular astigmatism axis is different to the corneal axis, then the former axis direction will have been created in accordance with the theory of obliquely crossed cylinders. External Eye Examination External examination should focus on the globe position, eyelid, eyelash, and lacrimal apparati. In eyes with prominent brow, narrow palpebral fissure, or deep-set eyes, the

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surgeon should be prepared to alter technique and perform instrumentation to obtain sufficient exposure of the eyeball. The patient should be informed in advance if these procedures (e.g., lateral canthotomy) are possible. Any lid abnormalities, such as lagophthalmos, entropin, ectropin, and trichiasis, can cause problems with corneal exposure and ocular surface instability. Blepharitis, canaliculitis, and dacryocystitis can predispose patients to infection in the peri-operative period. Secretions of the meibomian gland may be responsible for sands of Sahara syndrome. An excessively oily tear film can interfere with the uniformity of the ablation. Those problems should be recognized and treated before planning surgery. Biomicroscopic Examination The slit lamp examination allows detailed examination of conjunctiva, corneal scars, corneal neovascularization, kerato-conjunctivitis sicca, superficial corneal dystrophy, keratoconus, pterygium, pterygoid, irregular epithelium, evidence of recurrent corneal erosion, filtering bleb, redundant conjunctiva, anterior uveitis, keratitis, and lenticular clarity. Examination of the conjunctiva should detect any scarring from previous trauma, surgery, inflammatory disease, or infection, or any conjunctival lesions. The presence of conjunctival pathology can potentially interfere with proper lid closure and create corneal dellen and other ocular surface abnormalities. The cornea should be examined for evidence of any epithelial, stroma, or endothelial pathology. Corneal neovascularization is frequently observed in long-term contact lens wearers and is commonly seen at the superior limbus. History of recurrent corneal erosion, basement membrane dystrophy, and dry eye syndrome can create epithelial defect intraoperatively and postoperatively, which increase the incidence of epithelial ingrowth, postoperative infection, and prolong recovery. The tear film should be observed and tear break-up time recorded. If tear film or tear break-up time decreases, further evaluation, including Schirmer testing, is indicated. Corneal sensitivity should be tested, and if decreased, potential causes of neurotrophic corneal disease should be searched. The corneal stroma should be examined for thickness and clarity. An increase in corneal thickness should prompt the examiner to evaluate endothelial cell function. Corneal thinning may be caused by keratoconus, pellucid degeneration, previous infection with loss of stroma, inflammatory disease, or trauma. Stromal opacity with neovascularization may indicate previous herpetic infection or other chronic ocular surface inflammatory processes. The corneal endothelium should be assessed for the presence of any endothelial changes such as endothelial dystrophies, guttata, and ruptures in the Descemets membrane, which is contraindicated to perform intrastromal laser ablation. Anterior chamber depth and inflammation should be evaluated. The presence of any iris abnormality may indicate previous herpes zoster infection, trauma, anterior segment dysgenesis syndrome, or uveitis. The lens should be checked for any evidence of cataract formation. With the exception of very small, visually insignificant congenital cataracts, lens opacities represent an absolute contraindication to refractive surgery.

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Corneal Aesthesiometry Corneal aesthesiometry measures sensitivity of the cornea. An empirical measurement can be made by placing a thread of cotton in contact with the cornea, causing bleparospasm. The absence or slowness of the reflex indicates corneal aesthesia or hypoesthesia. There are specific instruments (keratoesthesiometers) for the quantitative measurement of corneal anesthesia (e.g., Cochet-Bonnet model or Frey’s model). The center of the cornea is more sensitive than the peripheral areas. The filament of the keratoesthesiometer is perceived by the central cornea when it exerts a pressure of 10 to 12 mg/mm2, and by the peripheral cornea when it exerts pressure of 16 to 18 mg/ mm2. Contact lens will reduce the corneal sensitivity. Besides, corneal hypoesthesia is subject to all the complications associated with dry eyes. Fundus Examination A detailed fundoscopic examination should be performed to detect any evidence of macular or retinal pathology that could potentially affect visual acuity. Myopic macular degenera-tion, posterior staphyloma, peripheral retinal lesions (e.g., holes, tears), optic nerve pathology, chorioretinopathy, and posterior vitreous detachment should be documented by chart, photography, or angiography and then discussed with the patient. Any retinal or macular pathology that requires further treatment should be referred preoperatively for management. All patients should be informed that the risk of myopic retinal detachment still exists after refractive surgery and annual retinal examination is required (11,12). Tonometry Intraocular pressure should be measured to detect ocular hypertension or pressure status in glaucoma patients (Fig. 3). Patients with ocular hypertension who plan to undergo LASEK should be aware of the risk or steroid response in the postoperative period that may necessitate anti-glaucoma medication. In glaucoma patients, better control of intraocular pressure should be attained before LASEK. Pupil Size Pupil size is theoretically important in the optical quality of the retinal image and therefore visual performance (13–16). Optical aberrations generally increase with increasing pupil size (17). Aberrations can misdirect light into the eye and can result in symptoms such as glare and haze (18). After refractive surgery, visual quality can be significantly influenced in those patients with large pupil when the pupil diameter is larger than the ablation zone or the level of treatment is higher (19,20). Pupil size should be evaluated under photopic and mesopic lighting conditions. The pupil diameter can be measured by several methods. The Colvard pupillometer (Fig. 4), developed with Matthew Colvard by Oasis Medical, uses light-amplification technology (21). The levels of illumination are controlled to be 250 to 300 lux and 3 lux, which simulate the daytime (photopic) and nighttime (scotopic) conditions, respectively. The

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examinations should be performed after keeping the patient in the room for at least 30 seconds and the fellow eye open. The pupillometer was placed in front of one eye and adjusted before and after until the pupil was in sharp focus through the viewing screen. The other options include the Rosenbaum pupil caliper, some auto-refractometers, and infrared television camera connected to a monitor (10). Ocular Dominance Ocular dominance can be established by history or distance fixation test. Examiners can ask the patients about their preferred or shooting eye when looking through the lens or camera. The dominant eye generally is identified by use of sighting dominance tests. One of the more common tests is the “hole test,” for which the patient is asked to frame an object through a hole formed by the patient’s outstretched hands (22). When the patient constricted the size of the hole by hand, the eye that continued to align with the object and the hole was considered the dominant eye.

Figure 3 A pheumatonometer is used to check the intraocular pressure after application of the suction ring. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.)

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Figure 4 Colvard pupillometer. Measurement can be optimized by controlling ambient illumination during pupil measurements. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.) Understanding the dominance of the eye helps decide the priority of treatment. The basis for treating the nondominant eye first is that the unexpected visual problems (fluctuations, glare, and halo) will be less problematic for the patient if the dominant eye is still functioning normally in the early postoperative period. This also allows the surgeon to assess the effects of wound healing and the predictability in the nondominant eye, which may provide important information for planning the surgery on the dominant eye. Many patients feel more comfortable with having their nondominant eye treated first when no contraindications are evident. In those patients who wish to achieve monovision, dominant eyes will be conventionally corrected for distance (22). Orthoptic Examination Motility testing includes examination of ductions, versions, and measurement of any tropias or phorias. This is useful for evaluating binocular vision and potential postoperative diplopia. Any history or finding that suggests amblyopia should also be carefully documented.

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Corneal Topography Corneal topography is now considered an integral component of preoperative evaluation of the refractive patient. Corneal topography can be used to detect regular and irregular astigmatism, corneal warpage from contact lens wear, or compressive lid lesions, clinical and preclinical or forme fruste keratoconus, pellucid marginal degeneration, and postoperative refractive effects of refractive surgery. Corneal topography is also helpful in determining refractive stability when used as an adjunct to manifest and cycloplegic refraction. Methods of measuring corneal topography fall into two broad categories: reflectionbased methods and projection-based methods. Examples of reflection-based topography include keratometry (Fig. 5) and videokeratoscopes (Fig. 6). The computer-assisted video-keratoscopy uses a collimating cone to reflect 25 or 30 rings off the corneal surface (23). These reflected rings yield as many as 8,000 data points for computer analysis. This technique detects curvature and refractive power of the anterior corneal surface. However, corneal elevation cannot be calculated from measurement of slope alone. New topography systems based on the principle of projection are becoming more widely used in clinical practice. These devices include slit photography, rasterstereography, moiré interference, and laser interferometry. The Orbscan corneal topography system measures anterior and posterior corneal elevation (relative to best-fit sphere), surface curvature, and corneal thickness by a scanning optical slit device (Fig. 7). The optical acquisition head scans the eye using light slits that are projected at a 45-degree angle (24). Twenty slits are projected sequentially on the eye from the left and twenty slits from the right side for a total of forty slits. The instrument’s software analyses up to 240 data points per slit and calculates the axial curvature (mm or D) of the anterior and posterior corneal surfaces. It also calculates the elevation of the anterior and posterior surface of the cornea as well as the corneal thickness of the entire cornea. Thirty-three percent of patients presenting for the surgical correction of myopia have abnormal corneal topographic patterns (25). This has been found to be caused by keratoconus in 6% of patients and corneal warpage in 38% of contact lens wearers (25). Topography maps in both clinical and preclinical (forme fruste) keratoconus demonstrate cone-like or asymmetric bowtie-like steepening, usually inferiorly. There is a subgroup of patients who present the typical topographic pattern of keratoconus but good spectaclecorrected acuity and a normal biomicroscopic appearance, so-called keratoconus suspects. It is uncertain whether this represents a forme-fruste or keratoconus or a normal variant. Many topographic patterns can result from contact lens-induced corneal warpage, but they tend to comprise flattening in the area of lens bearing, with possible adjacent steepening. After the cessation of lens wearing, the cornea tends to return to its former shape, with the greatest changes occurring early. In contact lens wearers, it is advisable to perform the topography only after the lens has been discontinued for at least 2 weeks (soft lenses) or 4 weeks (hard or semi-rigid lenses). If abnormalities persist after the cessation of lens wearing, topographic examinations should be repeated at intervals until the corneal shape has normalized or stabilized.

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Figure 5 Manual keratometer. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.)

Figure 6 Compact placido-based corneal topographical unit. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.)

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Figure 7 An elevation-based topographical unit is useful in detecting substantial changes in the posterior corneal surface and in measuring corneal pachymetry. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.) Pachymetry Pachymetry is an invaluable tool in the measurement of corneal thickness (Fig. 8). It is very helpful to understand the corneal thickness preoperatively and assess the amount of correction attainable. Care should be taken in disinfection of pachymetry probe if pachyme-try is applied intraoperatively. Types of pachymetry include optical, ultrasound, and scanning laser. The most common method of pachymetry is ultrasound. Ultrasonic pachymeters provide highly repeatable results with minimal variations between observers. However, if there is any opacity or pathologic change of the cornea, optical pachymetry is recommended, because it will generate further indication of the thickness of the central, paracentral, and peripheral corneal regions. This measurement is essential in patients with keratoconus. There are some factors that may influence the predictability of pachymetry, such as chronic contact lens wearer, excessive wet cornea, and topical anesthesia.

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Contrast Sensitivity Halo, glare, and visual disturbances at night can happen even though the patients have good visual acuity after refractive surgery (26,27). The daily activity confronts the individ-

Figure 8 Ultrasonic pachymetry. To be able to measure intraoperative corneal pachymetry, the machine may require standardization in the range of 200 µm. (From Ang RT, Azar DT. Adjunctive Instrumentation in LASIK. In: Azar DT, Koch DD, eds. LASIK: Fundamentals, Surgical Techniques, and Complications. New York, NY: Marcel Dekker, 2003.) ual with an ever-changing set of visual targets, luminances, and contrast that require rapid visual interpretation. Snellen testing of visual acuity is performed only at high contrast. Contrast sensitivity testing evaluates the patient’s ability to perceive a variety of coarse, intermediate, or fine details at differing contrast relative to the background. Therefore, contrast sensitivity seeks to objectively assess the equivalent of the patient’s visual function in the real world.

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Contrast sensitivity testing could be performed by two different optotypes: gradings (sinusoidal and square wave) and standard Snellen letters. Currently, the letter optotype contrast charts designed by Terry, Pelli-Robson, and Regan are more reproducible, sensitive, and specific and have become clinical alternatives to sine wave gratings. The Regan charts present letter targets of different sizes at varied contrast sensitivity, which can be used to establish a true contrast sensitivity function (CSF) curve in the eye. In contrast, Terry and Pelli-Robson charts offer only one size of letter targets with decreased contrast on each successive line. Furthermore, glare disability could reduce the contrast sensitivity of the visual system. More recently, the combinations of brightness acuity tester (BAT), as a glare source, with Regan or Pelli-Robson contrast sensitivity charts have been required by the U.S. Food and Drug Administration as part of the investigational clinical studies of refractive devices. Impairment of contrast sensitivity function could be found in cataract, glaucoma, optic neuritis, and amblyopia patients. Recent studies have demonstrated the decrease in lowcontrast sensitivity in the patients after PRK and laser in situ keratomileusis (LASIK). Persistent impairment of contrast sensitivity under low-contrast conditions may be found in myopic patients when the level of the treatment is greater than 6.0 D or the ablation zone is smaller (19,20,28). The loss of contrast sensitivity in darkness may be caused by optical aberration, the change in the anterior curvature or posterior surface, and the light scattering of proliferating cells, activated keratocytes, and extracellular matrix (29–33). The measurement of contrast sensitivity function can not only provide the adjunctive information of visual function but also offer a preoperative baseline. All patients should be informed of the possibility of decreased contrast sensitivity after refractive surgery. Informed Consent Informed consent should include apprising the patient of surgical and nonsurgical refractive options, the risks, benefits, side effects, and expected outcome of the procedure, and a discussion of enhancement procedure. It is important to address the patient expectations and provide a realistic probability of outcome after surgery. The aim of the refractive surgery is achieving the best vision possible in the safest most conservative way. It is possible to wear spectacles for demanding fine visual tasks, including night driving. The patient is required to read and sign the consent to acknowledge comprehension. There should be ample opportunity during the discussion for the patient to ask questions. All the discussed information should be accurately documented in the patient file. The necessity for close and long-term follow-up and continued dilated retinal examinations, especially for those with high myopia, should be emphasized in the consent.

CONCLUSIONS The evaluation of LASEK includes recording a thorough history, performing a complete clinical ophthalmologic examination, using appropriate preoperative tests, and obtaining informed consent for the surgical procedure. The patients should be aware of the expected level of success, the timescale of visual recovery, and possible complications

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that may occur. A stringent preoperative assessment is likely to pay considerable dividends to both the patient and surgeon in the long-run.

REFERENCES 1. Hovanesian JA, Shah SS, Maloney RK. Symptoms of dry eye and recurrent erosion syndrome after refractive surgery.. J Cataract Refract Surg 2001; 27:577–584. 2. Lee JB, Ryu CH, Kim J, Kim EK, Kim HB. Comparison of tear secretion and tear film instability after photorefractive keratectomy and laser in situ keratomileusis.. J Cataract Refract Surg 2000; 26:1326–1331. 3. Asbell PA. Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy.. Trans Am Ophthalmol Soc 2000; 98:285–303. 4. Wright KW, Guemes A, Kapadia MS, Wilson SE. Binocular function and patient satisfaction after monovision induced by myopic photorefractive keratectomy.. J Cataract Refract Surg 1999; 25:177–182. 5. Hom MM. Monovision and LASIK.. J Am Optom Assoc 1999; 70:117–122. 6. Charles NJM, Taylor HR, Gartry DS, Trokel SL. Excimer lasers in ophthalmology: principles and practice,. 1st ed.. Patient assessment in photorefractive surgery.. Boston: ButterworthHeinemann, 1997:131–136. 7. Machat JJ. Excimer laser refractive surgery,. 1st ed.. Preoperative PRK patient evaluation.. Thorofare. NJ: SLACK Incorporated, 1996:63. 8. Albert DM, Jakobiec FA. Principles and practice of ophthalmology: clinical practice,. 1st ed.. Principles of applied clinical optics. Philadelphia: W.B.Saunders, 1994: 3613–3615. 9. Holzer MP, Solomon KD, Vroman DT, Vargas ZG, Sandoval HP, Kasper TJ, Apple DJ. Diffuse lamellar keratitis: evaluation of etiology, histopathologic findings and clinical implication in an experimental animal model.. J Cataract Refract Surg 2003; 29:542–549. 10. Buratto L, Brint SF, Ferrari M. LASIK: surgical techniques and complications. In:. 1st ed.. Preparation for surgery.. Thorofare. NJ: SLACK Incorporated, 1998:23–24. 11. Arevalo JF, Ramirez E, Suarez E, Cortez R, Ramirez G, Yepez JB. Retinal detachment in myopic eyes after laser in situ keratomileusis.. J Refract Surg 2002; 18:708–714. 12. Mackool RJ. Causes of post-LASIK retinal detachment. J Cataract Refract Surg 2001; 27: 1708–1709. 13. Applegate RA. Limits to vision: can we do better than nature?. J Refract Surg 2000; 16: S547– S551. 14. Walsh G, Charman WN. The effect of pupil centration and diameter on ocular performance.. Vision Res 1988; 28:659–665. 15. Schwiegerling J. Theoretical limits to visual performance.. Surv Ophthalmol 2000; 45: 139– 146. 16. Applegate RA, Thibos LN, Hilmantel G. Optics of aberroscopy and super vision.. J Cataract Refract Surg 2001; 27:1093–1107. 17. Schallhorn SC, Kaupp SE, Tanzer DJ, Tidwell J, Laurent J, Bourque LB. Pupil size and quality of vision after LASIK.. Ophthalmology 2003; 110:1606–1614. 18. Hong X, Thibos LN. Longitudinal evaluation of optical aberrations following laser in situ keratomileusis surgery.. J Refract Surg 2000; 16:S647–S650. 19. Nagy ZZ, Munkacsy G, Krueger RR. Changes in mesopic vision after photorefractive keratectomy for myopia.. J Refract Surg 2002; 18:249–252. 20. Rani A, Balasubramanya R, Sharma N, Tandon R, Vajpayee RB, Dada VK, Singh R. Outcomes after laser in situ keratomileusis re-treatment in high myopes.. J Refract Surg 2003; 19: 159– 164.

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21. Colvard M. Preoperative measurement of scotopic pupil dilation using an office pupillometer .. J Cataract Refract Surg 1998; 24:1594–1597. 22. Jain S, Ou R, Azar DT. Monovision outcomes in presbyopic individuals after refractive surgery.. Ophthalmology 2001; 108:1430–1433. 23. Bogan SJ, Waring GO, Ibrahim O. Classification of normal corneal topography based on computer-assisted videokeratography.. Arch Ophthalmol 1990; 108:945–949. 24. Liu Z, Huang AJ, Pflugfelder SC. Evaluation of corneal thickness and topography in normal eyes using Orbscan corneal topography system.. Br J Ophthalmol 1999; 83:774–778. 25. Wilson SE, Klyce SD. Screening for corneal topographic abnormalities before refractive surgery.. Ophthalmology 1994; 101:147–152. 26. Holladay JT, Dudeja DR, Chang J. Functional vision and corneal changes after laser in situ keratomileusis determined by contrast sensitivity, glare testing, and corneal topography.. J Cataract Refract Surg 1999; 25:663–669. 27. Holladay JT. Optical quality and refractive surgery.. Int Ophthalmol Clin 2003; 43:119–136. 28. Chan JW, Edwards MH, Woo GC, Woo VC. Contrast sensitivity after laser in situ keratomileusis. One-year follow-up.. J Cataract Refract Surg 2002; 28:1774–1779. 29. Chang SW, Benson A, Azar DT. Corneal light scattering with stromal reformation after laser in situ keratomileusis and photorefractive keratectomy.. J Cataract Refract Surg 1998; 24: 1064– 1069. 30. Kaji Y, Obata H, Usui T, Soya K, Machinami R, Tsuru T, Yamashita H. Three-dimensional organization of collagen fibrils during corneal stromal wound healing after excimer laser keratectomy.. J Cataract Refract Surg 1998; 24:1441–1446. 31. Wachtlin J, Langenbeck K, Schründer S, Zhang EP, Hoffmann F. Immunohistology of corneal wound healing after photorefractive keratectomy and laser in situ keratomileusis.. J Refract Surg 1999; 15:451–458. 32. Baek T, Lee K, Kagaya F, Tomidokoro A, Oshika T. Factors affecting the forward shifting of posterior corneal surface after laser in situ keratomileusis.. Ophthalmology 2001; 108: 317–320. 33. Seitz B, Torres F, Langenbucher A, Behrens A, Suarez E. Posterior corneal curvature changes after myopic laser in situ keratomileusis.. Ophthalmology 2001; 108:666–672.

6 LASEK Techniques Chun Chen Chen, MD Taipei Municipal Jen-Ai Hospital, National Yang-Ming University Taipei, Taiwan Joel Javier, MD, and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA In this chapter, we will review the LASEK techniques that are commonly used at the time of writing. We also compare the Azar technique, illustrated in Figure 1, with other LASEK techniques, described in chapters 7 through 11. We also review the preoperative medications, patient preparation, effect of alcohol on corneal epithelial sheet preparation, and repositioning of the epithelium on the stromal bed after excimer laser surface ablation.

PREOPERATIVE MEDICATION Topical Anesthetics There are several kinds of topical anesthetics that can be used, including tetracaine 0.5%, proparacaine 0.5%, and xylocaine 2% to 4%. Tetracaine is more epitheliotoxic, which may aid epithelial debridement. Xylocaine has slower onset but may have prolonged action. Proparacaine is less painful than teracaine on instillation. Topical NSAIDS Topical NSAIDs could be used both preoperatively and postoperatively for relief of pain. Diclofenac sodium 0.1% (Volteran, CIBA) and ketorolac tromethamine 0.5% (Acular, Allergan) are two common topical NSAIDs. However, there are some adverse effects of excessive use of topical NSAIDs, including toxicity and delayed epithelial healing. Topical Antibiotics The broad-spectrum antibiotics are used for prophylaxis of infection. A combination of antibiotic-steroid preparation such as TobraDex (Alcon) is commonly used. The disadvan-

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Figure 1 Azar LASEK technique. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. NovemberDecember 2004 In press) tage of tobramycin is the reduced effectiveness against streptococcal bacteria, although there is excellent staphylococcal and pseudomonal coverage. The introduction of fluoroquinolones offers the increased broad-spectrum coverage and low toxicity. Fluoroquinolones could be used in combination with aminoglycosides or steroids. Application of Topical Medication Preoperatively, drops are instilled at 5-to 10-minutes intervals starting proximately 15 to 30 minutes before the procedure. Topical anesthetic drops will be applied to both upper and lower fornix. It is helpful to achieve the even distribution of the anesthetic medication by asking the patient to look to the left and right directions. Topical anesthesia can also be applied by means of an anesthetic-soaked surgical spear to the upper fornix or conjunctival limbus to avoid excessive medication over epithelium. It is

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also useful to instill a few drops of topical anesthetic into the fellow eye to reduce blepharospasm and further improve the cooperation and fixation of patients.

PREPARATION OF THE EYELIDS The periocular skin is cleaned with a solution of betadine, being careful not to allow it into the eye, because it is toxic to the epithelium. The skin is then dried with sterile gauze. Trimming the lashes is almost never necessary because of the use of adhesive plastic drapes.

PATIENT POSITIONING AND PREPARATION Once the laser is programmed, the patient can be brought into the laser suite. Minimizing the actual time the patient is underneath the laser helps alleviate anxiety; thus, all preparation of the laser should be performed before the arrival of each patient. The name and operative eye should be confirmed. In presbyopic patients, the question of targeting monovision should be verified. The patient should be positioned on the operating chair/table in a comfortable position that will ensure a stable, immobile, and appropriate position for the entire procedure. The patient should be advised to assume a comfortable and quiet position and not to move the arms or legs during the operation. The patient’s head should be positioned so that the invisible line that connects the forehead and chin through the center of the nose is perpendicular to the operating microscope and laser beam. The fellow eye should be covered, ideally with a solid eye shield instead of a pressure patch. This allows the patient to keep both eyes open during the procedure to avoid a bell’s phenomenon in the operative eye. Application of the Drape To cover the eyelashes and skin, a drape with a central fenestration is preferred. The patient is asked to open the eyes wide. The drape is applied to the lower eyelid, including the eyelashes. The same procedure is performed on the upper eyelids. Placement of the Speculum The ideal speculum should provide maximal access to the globe, allow for temporal and superior surgical approaches, and provide maximal patient comfort when fully opened. The Liebermann adjustable wire speculum is a popular design that provides constant exposure and is quite resistant to squeezing of the patient. The unique 45-degree angle contours to the facial angle on the temporal side, permitting accessibility for temporal and superior techniques. The Machat adjustable wire speculum is a variation of the Liebermann design with increased angle of the arms to maximize the exposure of the globe.

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The surgeon frees and opens the two arms of the speculum using the adjustment screw to adapt it to the eyelid opening of the patients. The arms of the speculum are introduced individually under the edges of the eyelids, assisted by lid retraction, and avoiding contact with the corneal surface. The instrument is centered within the inter-palpebral space, and then the screw is turned until the arms sufficiently open the eyelids. The speculum must provide perfect tension to maintain centration and balance.

FLAP MARKING The marking of the cornea allows the surgeon to have the precise reference points to realign the flap in the corneal beds. The cornea could be marked peripherally with pararadial lines or circles. The marking instruments that are frequently used are Ruiz paracentral, Buratto, Machat, and Slade markers. They are wiped with gentian violet marking pad, such as Preinked Marking Pad (Visitec), and then placed on the peripheral cornea. Excessive use of gentian violet should be avoided, because this has been associated with corneal toxicity. During the LASEK procedure, the flap adhesion to the corneal stromal bed is crucial for rapid epithelial healing and visual recovery. Meticulously marking of the cornea is important to facilitate perfect realignments of LASEK flap. A floral pattern by overlapping 3-mm circles around the corneal periphery is demonstrated by Azar et al. (Fig. 2A and Fig. 2B) (1).

CHEMICAL AGENTS FOR EPITHELIAL REMOVAL Chemical agents have long been used to remove the corneal epithelium (2). Citron et al. found n-heptanol to be superior to scraping in terms of preservation and smoothness of the basement membrane after removal of the corneal epithelium in rabbit (3). Hirst et al. evaluated chemical versus mechanical removal of the epithelium in the monkey and rabbit and found iodine-cocaine and n-heptanol to be equivalent to mechanical scraping (4). For centuries, the alcohols have been appreciated for their antimicrobial properties (5). They are fast-acting, barely toxic with topical application, nonstaining, nonallergenic, and readily evaporate. For infection control purposes, ethyl alcohol (ethanol) and isopropyl alcohol (isopropanol) are alcoholic solutions most often used. Their antimicrobial efficacies are enhanced in the presence of water, with optimal concentrations being from 60% to 90% (7). The exact mechanism by which alcohols destroy microorganisms is not fully understood. The most plausible explanations for the antimicrobial action are coagulation (de-naturation) of proteins, e.g., of enzymatic proteins, and lipid dissolution, leading to the loss of specific cellular functions. Because the outer cellular structures are quite different between the eukaryotic and prokaryotic cells (cell membrane and cell wall, respectively), human cells are more resistant to alcohol as compared with microbial ones (8).

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Figure 2 Marking the paracentral corneal portion (A) with an overlapping floral pattern (B). Several studies have been performed in rabbits comparing alcohol vs. mechanical debridement (9). Campos et al reported increased keratocyte loss and inflammation when

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using a sponge soaked in 100% ethanol for 2 minutes and warned against its use (10). Agrawal et al. found increased anterior keratocyte loss and inflammation when using 70% isopropyl alcohol applied for 2 minutes (11). Helena et al. described increased keratocyte loss but decreased inflammation using 50% ethanol for 60 seconds (12).

EPITHELIAL SURVIVAL AFTER ALCOHOL APPLICATION Concentrations of ethanol ranging from 10% to 30% are widely used to remove the corneal epithelium before PRK (9). Stein et al. reported that using dilute alcohol (25%) in 91 cases of PRK was a safe, effective, and predictive method of removing the epithelium (13). Abad et al. found that chemical de-epithelialization with dilute ethanol (18%) appears to be safe and effective and might promote faster rehabilitation (14). Managing the corneal epithelium as a hinge flap with 20% ethanol is a safe technique with faster visual rehabilitation and reduced haze compared with debridement of epithelium with alcohol (15). Gaber et al. used 0.1% tryphan blue to test the viability of the epithelial flap of human cadaver eyes after alcohol treatment. They observed the epithelial cells were vital up to 45 seconds of 20% ethanol exposure (16). We have detected a dose- and time-dependent effect of dilute alcohol on cultured corneal epithelial cells (5). The 25% concentration of dilute alcohol was the inflection point of epithelial survival (Fig. 3). Significant increase in cellular death occurred after 35 seconds of 20% alcohol exposure (Fig. 4). Forty seconds of exposure further increased apoptosis after 8 hours of incubation (Fig. 5). These findings are consistent with the clinical observations of varied epithelial attachment to the stromal bed after LASEK surgery. Preparation of Ethanol The ethanol could be diluted in distilled water (1,5,9,14,15,17–19) and balanced salt solution (BSS) (13,20,22). Theoretically, the ethanol would be more effective in water solution. However, the epithelial protection may be greater in BSS. At this time, it is not clear whether modification of the preparation of dilute alcohol would allow for better cell survival and adhesion in vivo (5).

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Figure 3 Fluorescein viability stain with calcein acetoxymethyl ester (AM)/ethidium homodimer of the cells after (A) 10%, (B) 20%, (C) 24%, (D) 25%, (E) 26%, and (F) 40% EtOHH2O treatment for 20 seconds. Metabolically active cells convert nonfluorescent calcein-AM into green fluorescent polyanionic calcein and exclude ethidium homodimer (A). Damaged cell membranes allow permeation of ethidium homodimer

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and its binding to nucleic acids resulting in red fluorescence (F). Bar=50 µm. (G) Cellular survival after different concentrations of alcohol treatment for 20 seconds. The percentage of viable cells (with exclusive green fluorescence) was calculated by counting cells per 10 fields at 400× magnification. (From Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Published courtesy of Invest Ophthalmol Vis Sci 2002; 43(8):2593–2602.) The method of preparing 18% ethanol is drawing 2 mL of dehydrated alcohol (American Reagent Laboratories, Shirley, NY) from ampules into a 12-mL syringe. Add the sterile water for injection to 11 mL and mix well (1). Although it has been advocated that plastic syringes should be avoided for storage of alcohol because of the risk of contaminations by toxic monomers (17), we have used them successfully for the installation of alcohol through an irrigation and aspiration (I & A) trephine instead of the hollow metal handle of Carones LASEK pump (Fig. 6).

TREPHINATION Purpose The purposes of trephination are: 1. Delineation of the epithelium 2. Pre-incision of corneal epithelium 3. Reservoir of alcohol

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Figure 4 Fluorescein viability stain with calcein-AM/ethidium homodimer of cells exposed to 20% EtOH-H2O for (A) 20, (B) 25, (C) 30, (D) 35, (E) 40, or (F) 45 seconds. Calcein-positivegreen fluorescence indicates metabolically active cell, and ethidium homodimer positive-red fluorescence indicates damage to the cell membrane and binding to nucleic acids. Bar=50 µm. (G) Cellular survival with different exposure times. The percentage of viable cells was

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calculated from the number of green, red, and bicolored cells counter per 10 fields at 400× magnification. Control group was treated with 100% KSFM (0% ethanol). (From Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Published courtesy of Invest Ophthalmol Vis Sci 2002; 43(8):2593– 2602.) Sizing The size of the epithelial trephines should correspond to the optic zone of laser ablation. The various sizes of the trephines are presented in Table 1 Success Carones LASEK Pump OZ Chambers (Fig. 6) Optic zone (OZ) chambers have semi-sharp edges to delineate the epithelium. By centering the OZ chamber on the cornea, the epithelium is delineated on the edges by moving the chamber clockwise and counterclockwise. The pump dispenses premeasured amount of fluid into an optic zone chamber. After the push of a button, the pump dispenses a premeasured amount of dilute alcohol into the OZ chamber.

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Figure 5 TUNEL labeling of cultured corneal epithelial cells exposed to 20% EtOH-H2O for 20 seconds (A-C) and 40 seconds (D-F) and to EtOH-KSFM for 40 seconds (G-I) The TUNEL positivity was evaluated after 8 (A, D, G), 12 (B, E, H), and 24 (C, F, I) hours of incubation. Maximal TUNEL positivity after 20 seconds of EtOH-

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H2O exposure was detected at 24 hours of incubation (C) (58.05±33.10) and after 40 seconds of EtOH-H2O exposure at 8 hours of incubation (D) (94.12% ±1.21 %). Substantially lower TUNEL positivity was seen after 8,12, and 24 hours of incubation with EtOHKSFM for 40-seconds (G: 0.65±0.02%, H: 7.11±1.49%, I: 4.52±1.05%). (J) TUNEL positivity after 8, 12, and 24 hours of incubation of 20% EtOH-H2O for 20 and 40 seconds and 2% EtOH-KSFM for 20 and 40 seconds compared to controls. Control groups were treated with 100% KSFM for 20 seconds. (From Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Published courtesy of Invest Ophthalmol Vis Sci 2002; 43(8):2593–2602.) Table 1. Sizing Profile of the Trephines. Diameter (mm) Carones LASEK pump OZ chambers (ASICO, Westmont, IL)

7.0, 9.0, 9.5, 10, 10.5

Carones LASEK pump (ASICO, Westmont, IL)

7.0, 9.0, 9.5, 10

Azar-Carones LASEK I & A trephine (ASICO, Westmont, IL) Janach epithelial trephine* (Janach)

8.0, 9.0

Janach alcohol solution cone* (Janach)

8.5, 9.5

Shahinian epithelial trephine† (Janach)

8.0, 9.0

Shahinian alcohol wells† (Janach)

9.0, 10.0

*Janach combination system; †Shahinian combination system.

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Figure 6 (A) Carones LASEK pump (ASICO AE–2910). (B) Carones LASEK OZ chambers (ASICO AE– 2912). Azar-Carones LASEK I & A Trephine (Fig. 7) The Carones alcohol dispenser consists of a customized diameter semi-sharp marker attached to a hollow metal handle served as a reservoir for the alcohol. Irrigation and aspiration of the alcohol is feasible after application of firm pressure on the central cornea. Janach Globe Fixation Ring (Fig. 8) The Janach globe fixation ring is designed to help the stability of the globe during the trephination and alcohol application. Janach Microtrephine and Alcohol Well (17–19) The trephine is designed to perform a preincision of corneal epithelium and leave a hinge of approximately 90 degrees at the 12-o’clock position and allow the alcohol solution to

Figure 7 Azar-Carones LASEK I & A trephine (ASICO AE–2918).

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Figure 8 Janach globe fixation ring (JANACH 2296). penetrate under the flap. The depth of the trephine is designed to be 70 µm, 80 µm in 8mm trephines, and 90 µm in 9-mm trephine. A blunt portion of the blade, of approximately 100 degrees at the 12-o’clock position, protects the area of the hinge. The Janach trephine cuts the proper depth and is sharp only for only 270 degrees of its circumference. The remaining 90 degrees is blunt in order to leave a hinge-like piece. The trephine could effectively perform approximately 100 incisions. A saw-toothed version also is available for very thick epithelia. There is another epithelial trephine which is barrel-shaped, of 8.0, and 9.0 diameter (Fig. 9). It could be incorporated into a combination system (Janach combination system, Shahinian combination system) with alcoholic wells. An alcohol solution cone, which is approximately 0.5 mm or 1 mm larger than the trephine, will be placed on the eye after trephination. Two to three drops of alcoholic solution will be instilled inside the well and is left for 25 to 30 seconds (17–19).

Figure 9 Janach epithelial trephine (new combination system) (JANACH 2940).

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Figure 10 Our current LASEK technique. (A) Multiple marks are applied around the corneal periphery, simulating a floral pattern. (B) An alcohol dispenser consisting of a customized 7-or 9-mm semi-sharp marker attached to a hollow metal handle serves as a reservoir for 18% alcohol. Firm pressure is exerted on the cornea and alcohol is released into the well of the marker. (C) After 25 to 30 seconds, the ethanol is absorbed using a dry cellulose sponge. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. NovemberDecember 2004 In press.) ALCOHOL CIRCULATION Alcohol will stay in the barrel of the trephine for 20 to 40 seconds (Fig. 10A and Fig. 11). Young patients or contact lens wearer may require longer time for the dilute ethanol to detach the epithelium. Firm pressure will be applied firmly to avoid alcohol leakage. After certain exposure periods (for example, 25 seconds), the ethanol is

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Figure 11 Alcohol circulation.

Figure 12 Alcohol absorption. absorbed using a dry cellulose sponge (Weck cell or Merocel; Xomed, Jacksonville, FL) on the alcohol reservoir (Fig. 10B and 12). The corneal and conjunctival surface could then be rinsed thoroughly with balanced salt solution to prevent alcohol spillage onto the epithelium outside the barrel. Camellin et al. introduced a method of irrigation with

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antihistamine to reduce any initial release of histamine (18). The cornea will be dried with a Merocel sponge to reveal the trephination edge (Fig. 13).

FLAP ELEVATION The LASEK technique is evolved from PRK (1,20). Abad et al. showed that alcohol assisted epithelial removal was a simple and safe alternative to mechanical epithelial removal (9,14). By applying 25% ethanol for 3 minutes, Stein et al. were able to grasp, lift, pull apart, and split the corneal epithelium using two McPherson forceps (13). Similarly, Shah et al. exposed the epithelium to 18% ethanol for 30 to 40 seconds and performed epitheliorrhexis of the loosened epithelium by use of a dry sponge (15). D’ecollement of the flap was successfully performed with a scalpel by doctor Scerratia after 40 seconds of exposure to 20% ethanol (21). LASEK Spatulas Spatulas are required to lift, protect, and replace the corneal flap during LASEK procedure. Because the preservation of the integrity is paramount, LASEK spatulas would allow flap manipulation with minimal trauma.

Figure 13 Epithelial flap edge revelation. The Carones LASEK spatula is a double-ended instrument with a curve representing a 30-degree section of the 7 mm and 9 mm of each side (Fig. 14A). The spatula engages in the delineated edge of the epithelium to create an epithelial flap.

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The Vinciguerra-Carones LASEK spatula is specially designed to engage the edge of epithelial flap for easy lifting of the epithelial flap (Fig. 14B). The vaulted curve of the spatula matches the curve of the cornea. This curved spatula allows for easy placement of the flap after laser ablation and removes any wrinkle formation as the flap is placed. The epithelium is detached with the hockey spatula or epithelial microhoe (Fig. 14C, D). The Janach epithelial micro-hoe is used to complete the incision. The epithelium is detached by making tiny movement almost perpendicular to the margin. Personal Experience (Azar’s Technique) (1,5) After anesthesia and application of a lid speculum, the cornea is marked with overlapping 3.0- mm circles around the corneal periphery. An alcohol dispenser consisting of a customized 9.5- mm semi-sharp marker, attached to a hollow metal handle, with a reservoir for the 18% alcohol, allows irrigation/aspiration of the alcohol after applying firm pressure on the central cornea. After 25 to 30 seconds, the solution is absorbed using the suction port and a dry cellulose sponge. One arm of a jeweler’s forceps (Fig. 15) or the Azar LASEK scissors (ASICO, right and left, Fig. 15), is inserted under the epithelium and traced around the delineated margin of the epithelium, leaving 2 to 3 clock hours of intact margin (Fig. 1 and Fig. 10A–C). The loosened epithelium can also be peeled as a single sheet using a Merocel sponge (Fig. 17), leaving a flap with the hinge still attached (Fig. 18). A hydrodissection cannula can be used to assist with lifting the epithelium (Fig. 16C). Alternative Techniques In Camellin’s technique, the precut margin is lifted with a hockey spatula to detach the epithelium, and the epithelial flap is gently detached, gathered, and folded up at the 12o’clock position. Because the preincision is not always perfect, an epithelial microhoe is used to complete it. The hoe is pressed firmly downward and pulled approximately 1 millimeter toward the pupil center. Alternatively, the epithelium is detached with the short side of a hockey spatula, making tiny movements almost perpendicular to the margin. The flap is generated and completed along the entire arc of trephination up to the hinge (17–19).

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Figure 14 (A) Carones LASEK spatula (ASICO AE-2920). (B) Vinciguerra Carones LASEK spatula (ASICO AE-2922). (C) Janach epithelial detaching spatula (JANACH 2910A). (D) Janach epithelial microhoe (JANACH 2915A).

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Figure 15 Flap elevation by the jeweler’s forcep (A) or the Azar LASEK scissor (B) (ASICO AE-5489, AE-5499).

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Figure 16 Our current LASEK technique. (A) One arm of a modified Vannas scissors (note the knob at the tip of the lower arm) is then inserted under the epithelium and traced around the delineated margin of the epithelium, leaving a hinge of 2 to 3 clock hours of intact margin, preferably at the 12 o’clock position. (B) The loosened epithelium is peeled as a single sheet using a Merocel sponge or the edge of a jeweler’s forceps, leaving it attached at its hinge. (C) After laser ablation is performed, an anterior chamber cannula is used to hydrate the stroma and epithelial flap with balanced salt solution. (D) The epithelial flap is replaced on the stroma using the cannula under intermittent irrigation. (E) Care is taken to realign the epithelial flap using the previous marks and to avoid epithelial defects. The flap is allowed to dry for 2 to 5 minutes. Topical steroids and

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antibiotic medications are applied. (F) A bandage contact lens is placed. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. NovemberDecember 2004 In press.) To maintain the viability of epithelial cells, Dr. Vinciquerra proposed a modification of the LASEK technique that preserves the connection between the corneal flap and limbus

Figure 17 Former variant of our technique using a Merocel sponge to fashion the epithelial flap. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. NovemberDecember 2004 In press.) (22). The butterfly technique requires the use of the Vinciguerra PRK/LASEK spatula (Fig. 20) to impart a thin abrasion to the paracentral corneal epithelium, from 8 to 11 o’clock, to spare the optic zone. After positioning the LASEK OZ chamber that is connected to the LASEK pump, apply 20% alcohol for approximately several seconds. The length of time depends on the firmness of the epithelial adhesion noted during the initial abrasion, with a firmer adhesion requiring a slightly longer time. With the Vinciguerra-Carones LASEK spatula, cautiously dissect the epithelium from Bowman’s membrane up to the limbus. It is mandatory to keep the cornea well hydrated in order to preserve the

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Figure 18 Generation of corneal epithelial flap.

Figure 19 Transmission electron micrographs of freed epithelial sheets after 20% alcohol application for 25 seconds (specimen I: A; II: B; III: C; and IV: D). Variable separation of the

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basement membrane zone was seen. (A) Specimen I showing a localized area of irregular basement membrane zone (arrow) and basal cell membrane disruption (arrowheads) (original magnification ×17,750). (B) Discontinuous basement membrane zone beneath the basal epithelial cells (arrows), evident at higher magnification, was associated with decreased number of electron-dense hemidesmosomes (arrowheads) (original magnification ×30,000). (C) The basal cell membranes and the basement membrane (arrows) were disrupted in specimen III. Autographic vacuoles formation (arrowheads) was extensive in the cytoplasm (original magnification ×1650). (D) Specimen IV: the freed epithelial sheet retained a duplicated basement membrane zone. Pockets of cross-banded anchoring fibrils were arranged in a network between the layers of basal lamina (arrows). Electron-dense hemidesmosomes (arrowheads) were present along the basal cell membrane (original magnification ×17,750). Bar=1 µm. (From Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Published courtesy of Invest Ophthalmol Vis Sci 2002; 43(8):2593– 2602.) obtained loosening effect otherwise the second half of the flap will be dehydrated after the completeness of dissection of the first half of the flap.

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Dr. McDonald used viscous gel (hydroxypropyl cellulose 0.3%) to aid in the separation of the epithelial sheet. The syringe filled with the gel was connected to the cannula (23). After epithelial trephination, a 2.25 round knife scored down to Bowman’s layer for a distance of 1 to 2 mm. Ten drops of sodium chloride 5% were administered to slightly stiffen the cells and then removed. By sawing back and forth, the epithelial sheet could be lifted. Gel was injected under the epithelium before the cutting in the middle by scissors. The flap was pushed away after application of gel. Epithelial flap hydrodissection was possible to be performed by balanced salt solution, GenTeal, and GenTeal-Gel (24). Dr. Rashid found that epithelial flap hydrodissection was easier with GenTeal than GenTeal--Gel.

Figure 20 Inverted phase contrast photographs of the tissue culture from one of the three freed epithelial sheets generated after 20% ethanol treatment for 25 seconds. (A) Epithelial outgrowth was observed at day 1

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extending from original sheet border (arrowheads) to the 1-day outer border (arrows). (B) The cell attachment and epithelial outgrowth were persistent until day 15. Bar=50 µm. (From Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Published courtesy of Invest Ophthalmol Vis Sci 2002; 43(8):2593–2602.) Flap Edges and Electron Microscopy The basal epithelial cell layer maintained a compact and regular arrangement. The basement membrane layer showed discontinuous and irregular extracellular matrix fragments. These fragments, however, were still attached to the basal epithelial cell layer, indicating that the point of separation was likely to be within the basement membrane or between the basement membrane and Bowman’s layer. The adherence of the basement membrane to the basal layer of the epithelium is significant because it is believed that the basement membrane provides the stability and support that keeps the epithelium intact even with manipulation, thereby preserving the integrity and viability of the entire epithelium. The presence of desmosomes provides anchoring mechanisms for the epithelium to adhere to the ablated stroma. Electron Microscopy The epithelial sheet specimens were obtained from patients undergoing PRK. The epithelial sheets were fixed in half-strength Karnovsky fixative (2% paraformaldehyde and 2.5% glutaraldehyde) in 0.2 M sodium cacodylate buffer (pH 7.4) overnight and postfixed in 1% osmium tetroxide in 0.2 M sodium cacodylate for 1.5 hour. After dehydration in graded alcohol, the eyes were embedded in epoxy resin (Epon-Araldite). Thick sections (1 µm) were stained with toluidine blue, and a suitable area containing basal layers was chosen. The blocks were trimmed accordingly, thin- sectioned (80–90 Ǻ), stained with 2% uranyl acetate-Reynold’s lead nitrate, and examined with a transmission electron microscope (model 410; Philips, Eindhoven, The Netherlands). Electron Microscopic Analysis of Epithelial Sheets Removed Using 20 % Alcohol Normal corneal epithelia are nonkeratinizing, stratified, squamous epithelia five to seven layers thick. Desmosomes are present along all cell membranes abutting other cell membranes. The cells of the basal layer are columnar, and hemidesmosomes are present along their basal plasma membrane adjacent to the basement membrane. Beneath the

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epithelium is a unilamellar basement membrane that overlies a thick collagen stroma through which anchoring fibers extend from the lamina densa (25,26). Azar et al. studied the electron micrograph of four freed epithelial sheets, which were obtained from 20% alcohol exposure (Fig. 19). The freed epithelial sheet displayed normal stratification. The basal epithelial surface of isolated epithelial sheets showed blebbing of the basal cell membrane and autophagic vacuoles within the cytoplasm of the epithelial basal cells of the freed sheet in two of the four specimens. They also observed variable basement membrane complex configurations beneath the epithelial basal cells: unilamellar basement membrane with focal disruptions, irregular and discontinuous basement membrane with intact hemidesmosome, disruptions of basal cell membranes with absent basement membrane, and duplicated basement membrane containing dense bundles of anchoring fibrils. Gabeler et al. also demonstrated that the plane of separation after ethanol exposure in human cadaver eyes was between the lamina densa and the Bowman’s layer (16). The viability of the ethanol-treated epithelial sheet was further studied in tissue culture for cell migration and attachment (5). One of the three specimens showed outgrowth and attachment of epithelial cells from the epithelial sheet at days 1 to 15 (Fig. 20). These findings were reinforced by the electron microscopic evaluations of the epithelial tissue specimen in vivo. The basal epithelial cell layer maintained a compact and regular arrangement. The basement membrane layer showed discontinuous and irregular extracellualr matrix fragments. These fragments, however, were still attached to the basal epithelial cell layer, indicating that the point of separation was likely to be within the basement membrane or between the basement membrane and Bowman layer. The adherence of the basement membrane to the basal layer of the epithelium is significant because it is believed that the basement membrane provides the stability and support that keeps the epithelium intact even with manipulation, thus preserving the integrity and viability of the entire corneal epithelium. The presence of desmosomes provides a possible anchoring mechanism for the epithelium to adhere to the ablated stroma (1). Irrigation and Reapproximation After excimer laser ablation, a 30-gauge Rycroft anterior chamber cannula (Becton Dickinson, Franklin Lakes, NJ) is used to wash the ablation site and epithelial flap with balanced salt solution to remove debris or remaining loose epithelial cells (Fig. 21). Washing the ablated surface and epithelial flap also facilitates the ease of repositioning of the flap by lubricating the stromal and epithelial surfaces. The folded epithelial sheet is then gently manipulated and repositioned onto the ablated stromal bed using the straight part of the Rycroft cannula and gentle intermittent irrigation. Exposure of the flap to unnecessarily large amounts of fluid may cause the epithelium to swell resulting in poor coaptation of the wound edges. The flap is allowed to float into position and is then meticulously realigned using the previously placed corneal markings to minimize epithelial defects. After LASEK, there is usually a clear visual axis, slight flap edema and minimal to moderate conjunctival injections similar to LASIK. Flap-related complications of LASIK procedures such as striae are reported to occur in 1% to 3% of cases (Stark 1999). The incidence of striae causing a decrease in best corrected visual acuity (BCVA) is difficult

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to ascertain using current literature although Gimbel et al. reported a 0.6% decrease in BCVA in 1,000 cases caused by microwrinkling. Flap desiccation and contraction during laser ablation, wrinkling caused by stretching or drying, tenting, misalignments, irregular flap thickness, freecaps, epithelial defects, and even movements during eye drape and speculum removal may cause striae in LASIK. Biomicroscopy after the procedures is a good technique used by surgeons to detect striae and other complications which may not be properly visible under the operating microscope. Epithelial flap and contact lens displacement in LASEK may also be detected early with biomicroscopy. Prevention of these flap complications in LASEK can easily be avoided by careful manipulation during the reflection and repositioning of the hinged flap and prevention of flap dehydration.

Figure 21 Laser treatment shown (A) is followed by gentle irrigation with BSS (B). The epithelial flap is then gently reflected back onto the stromal bed (C) and the margins realigned (D). In LASEK, epithelial flaps are of a more resilient nature. Epithelial flaps may be folded towards the hinge. Hydration of the epithelial tissue and careful realignment of the tissue after laser ablation produces minimal striae detectable by biomicroscopy, which do not seem to affect BCVA. Epithelial flaps in this respect are easier to manage as compared to LASIK flaps. Minimizing flap striae in both LASIK and LASEK procedures is necessary in achieving good postoperative visual acuity. There have been no published advantages or drawbacks associated with either meticulous realignment and coaptation of wound edges against poor flap repositioning in LASEK.

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Drying Time and Instrumentation After the flap is properly reapproximated, it is then allowed to air dry for 5 minutes to allow adhesion of the epithelial flap to the underlying stroma. Previous electron microscopic studies of central epithelial tissue in vivo showed that the bonds between the basement membrane is responsible for providing support and stability to the epithelium that allows it to withstand manipulation. Desmosomes present are believed to facilitate the adherence of the epithelium to the treated stromal bed (A1). The time allotted for proper adhesion of the flap to the ablated stroma varies fro different authors; Lee et al. have suggested that a minute is adequate drying time for proper adhesion of epithelium and stroma. Excessive drying may cause dehydration, resulting in flap shrinkage or retraction. Drying times may be titrated according to the surgeon’s technique. The flap may be kept moist by careful placement of a drop of balanced salt solution on the central part of the cornea. There are different techniques used for the creation and repositioning of the LASEK flap. Janach describes the repositioning of the flap using a spatula (Janach, J2920A, Como, Italy). Lee also describes the use of the same repositioning spatula to flatten and smooth the central portion of the epithelial flap during reapproximation. The epithelial flap may also be repositioned with ease using an irrigating cannula. Repositioning of the flap may be performed without specialized instruments depending on the surgeons’ preference. Contact Lens Application Bandage contact lenses are placed on the epithelial flap after it has sufficiently adhered to the stroma to prevent external factors such as the blink reflex to dislodge the flap (Fig. 22).

Figure 22 Contact lens application after flap repositioning (A). Moving the contact lens around (B) will test if the epithelium is adherent to the stromal bed (note the change in contact lens position made evident by the change in contact lens markings).

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Although contact lenses prevent the displacement of the epithelial flap by eyelidmediated sheering forces, the epithelial cell adhesion may occur within 1 to 3 days after surgery. Theoretically, contact lenses with a flat base curve (8.6 to 8.7 mm) will be advantageous to flap adhesion because it will facilitate a slight pressure effect to prevent flap displacement. Steep base curve contact lenses may have an advantage in preventing flap movements and improving patient comfort. These lenses, however, must be fitted well because tight lenses may produce stromal edema, ciliary flush, and chemosis. The contact lens will also aid in the healing of the epithelium and minimize postoperative pain. The epithelial flap is observed immediately after surgery with the contact lens in place. The adhesion of epithelium to the stromal bed is deemed sufficient if rotating the contact lens does not produce movement of the flap (negative contact lens spinning test). In the event that the epithelium is not adequately adhered to the underlying stroma, the contact lens should be removed, the epithelial flap positioned properly, and replacement of the contact lens performed with application of pressure in appropriate locations. The process of migration, mitosis, and differentiation govern regeneration of the disrupted corneal epithelium. After corneal epithelial injury, plasma membranes of the cuboidal basal epithelial cells surrounding the site of injury start to flatten and extend pseudopodia into the injured area. During the migration of these epithelial cells, there is constant simultaneous creation and dissolution of attachments between proteins in the epithelial cells’ plasma membrane and the extracellular matrix components. The dynamic changes in cellular interactions extend to the adjacent cells allowing the mass of epithelial cells to migrate towards the injury site without losing contact with its anchors. Polymorphonuclear cells from the tear film remove remnants of damaged cells from the injury site and a monolayer of migrating basal cells begins to migrate onto the wound area at a rate of 0.75 µm/minute. (Schultz 1997). Production of migratory cells occurs in a mitotic zone 3 to 5 millimeters peripheral to the injury site. The cells overlying the cuboidal basal cells also move into the injury site after the migration of the basal cells. The migration of cells into the defect halts once contact inhibition is established. The complete covering of the injury site induces epithelial cell mass regeneration to its original thickness. Basal epithelial cells reform adhesion complexes and differentiate into intermediate wing and superficial squamous cells which differentiate by secreting keratin proteins that found the barrier proteins of the epithelium.

REFERENCES 1. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol 2001; 12:323–329. 2. Gundersen T. Herpes cornea with special reference to its treatment with strong solution of iodine. Arch Ophthalmol 1936; 15:525–549. 3. Cintron C, Hassinger L, Kublin CL, Friend J. A simple method for the removal of rabbit corneal epithelium utilizing n-haptanol. Ophthalmic Res 1979; 11:90–96. 4. Hirst LW, Kenyon KR, Fogle JA, Hanninen L, Stark WJ. Comparative studies of corneal surface in the monkey and rabbit. Arch Opthalmol 1981; 99:1066–1073.

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5. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci 2002(8):2593–2602. 6. Tortora GJ, Funke BR, Case CL. Microbiology: An Introduction,. In: . 3rd ed.. Decontamination, Disinfection, and Sterilization. Redwood City: Benjamin & Cummings, 1989:149–149. 7. Larson EL. Alcohols. In: Block SS, Ed. ed.. Disinfection, Sterilization and Preservation. Philadelphia: Lea & Febiger, 1991: 191–203. 8. Berne RM, Levy MN. Principles of Physiology. 2nd ed.. Functional anatomy of prokaryotic and eukaryotic cells. St. Louis: Mosby, 1996:85–90. 9. Abad JC, Bonnie A, Power WJ, Foster CS, Azar DT, Talamo JH. A prospective evaluation of Alcohol-assisted versus mechanical epithelial removal before photo-refractive keratectomy. Ophthalmology 1997; 104:1566–1574. 10. Campos M, Raman S, Lee M, McDonnell PJ. Keratocytes loss after different methods of deepithelialization. Ophthalmology 1994; 101:890–894. 11. Agrawal VB, Hanach OE, Bassage S, Aquavella JV. Alcohol versus mechanical epithelial debridement: effect on underlying cornea before excimer laser surgery. J Cataract Refract Surg 1997; 23(8):1153–1159. 12. Helena MC, Filatov VV, Johnson WT. Effect of 50% ethanol versus mechanical epithelial debridement on keratocyte loss and inflammatory response after excimer photorefractive keratectomy (Abstr). Invest Ophthalmol Vis Sci 1995; 36(suppl):24. 13. Stein HA, Stein RM, Price C, Salim GA. Alcohol removal of the epithelium for excimer laser ablation: outcome analysis. J Cataract Refract Surg 1997; 23:1160–1163. 14. Abad JC, Bonnie A, Talamo JH, Visaurri-Leal J, Cantu-Charles C, Helena MC. Dilute alcohol versus mechanical debridement before photorefractive keratectomy. J Cataract Refract Surg 1996; 22:1427–1433. 15. Shah S, Sebai Sarhan AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol 2001; 85:393–396. 16. Gabler B, Von Monhrenfels W, Lohmann CP. LASEK: a histological study to investigate the vitality of corneal epithelial cells after alcohol exposure. Invest Ophthalmol Vis Sci 2001; 42: S680. 17. Camellin M, Cimberle M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surg News 1999:28–29. 18. Camellin M, Cimberle M. LASEK has more than 1 year of successful experience. Ocular Surg News 2000; 18(14):1, 14–17. 19. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low and moderate myopia. J Cataract Refract Surg 2001; 27:565–570. 20. Carones F, Fiore T, Brancato R. Mechanical vs. alcohol epithelial removal during photorefractive keratectomy. J Refract Surg 1999; 15:556–562. 21. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg 2001; 17(suppl):S219–S221. 22. Vinciguerra P, Camesasca FI. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg 2002; 18(suppl):S371–S373. 23. McDonald MB. Refractive surgery, the next generation. New Orleans: American Academy of Ophthalmology, 2001. 24. Rashid RC. LASEK: review of complications, epithelial flap hydrodissection and mitomycin C, American Society of Cataract and Refractive Surgery, American Academy of Ophthalmology, 2002. 25. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK. Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol 1992; 110:537–540. 26. Spurr SJ, Gipson IK. Isolation of corneal epithelium with Dispase II or EDTA: effects on the basement membrane zone.. 1985; 26:818–827.

7 Camellin LASEK Technique Massimo Camellin, MD Sekal Rovigo Microsurgery Rovigo, Italy

INTRODUCTION After a period of using photorefractive keratectomy (PRK) plus alcoholic disepithelization, the Camellin laser subepithelial keratomileusis (LASEK) technique was born in 1998 (1–8). Observing how easy it was to detach an epithelium while leaving it intact, repositioning it over the treated stroma was attempted, and after that first encouraging experience, the technique was consolidated with the use of instruments that have the purpose of preserving flap integrity despite its adherence. In this chapter, we will explain the main steps of the procedure and include a brief description of the necessary instruments. Epithelial Precut This first step, initially proposed only to delineate the area to be detached, showed greater importance over time as the precut allowed alcohol to flow under the epithelium more easily. The instrument used is a microtrephine. The sharp edge of the blade is from 80 to 90 microns deep and occupies 270 degrees of the entire circumference, leaving an un-cut hinge of 90 degrees at the 12 o’clock position. (Fig. 1) (E.Janach Sr., L.Via Borgo Vico 35 Como, Italy). The blade can be smooth or sawlike, with the latter being more efficient in thick epithelium. The instrument must be pressed strongly to avoid too much superficial trephination. To ensure that the cut is as deep as possible, the trephine must be rotated for 10 degrees two or three times. It is important to remember to hold the handle always with the right hand and position it at 9 o’clock, even in left eyes (Fig. 2). Alcohol Solution The detaching solution can be composed of balanced salt solution (BSS) (80%) plus pure alcohol (20%) or distilled water (80%) plus pure alcohol (20%). Distilled solution plus alcohol showed a more powerful effect but had more toxic consequences for epithelial viability. We suggest, however, that one should continue to use this latter solution at least until practice improves one’s flap construction technique. The solution has to be prepared

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Figure 1 Microtrephine for LASEK.

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Figure 2 Microtrephine rotation whilst cutting. every hour using a glass syringe because the rubber in a plastic one could react with the alcohol leaving toxic monomers. The solution is shaken before every treatment. We throw away the first drops, spilling them before injecting the solution into a well to be sure the solution has the right concentration of alcohol. The solution can be heated to 32 degrees Celsius. Doing so can reduce the time that it must be left in the well. We usually leave the solution inside the well for 20 seconds. The Well This instrument looks like a round radial keratotomy marker but the significant difference is that it consists of a double edge for increasing eye stability during alcohol exposure (Fig. 3). Additionally, the double edge allows better control over leakage of the solution. The leakage of the alcohol solution is thought to be responsible for the pain in the early post-operative period. To avoid this problem, it is useful to accurately dry the well with a cotton sponge before taking away the instrument. The well can be filled with diclofenac and left for 5 seconds before drying. This procedure greatly reduces the possibility of alcohol contamination over the conjuntiva and minimize postoperative pain. Edge Detachment The maneuver for detaching the edge has two functions; the first is to enhance the precut and the second is to check the mobility of the flap. In the case of a strongly adherent flap, additional drops may be placed for 10 seconds after having created a gap in the epithelium. The gap allows the new solution to flow more easily under the epithelium.

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Almost all flaps become easy to detach afterwards. The instrument called the micro-hoe has three sides that allow easy detachment in the right and the left sides by only tilting the handle (Fig. 4).

Figure 3 Well for containing alcohol solution (Janach).

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Figure 4 Micro-hoe for detaching epithelium (Janach). Flap Sliding An easy flap (usually found in 60% of eyes) can be separated by simply dragging it towards the 12 o’clock position (Fig. 5). We believe the technique has to be performed in all cases even in those flaps that are more difficult to detach. If the flap is slightly adherent to the stroma, a bow dissector can be used. This is performed by leveling the cornea like a microkeratome while sliding with gently oscillatory movements (Fig. 6). The degree of difficulty increases when the epithelium is strongly attached as in reoperations or in particular patients (more frequent in dark eyes and long term soft lens

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wearers). If, despite new alcohol application, resistance seems strong, we have to use the hockey spatula, which is held vertically and moved with small but precise movements.

Figure 5 Dragging epithelium in LASEK (easy flap).

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Figure 6 Bow dissector in medium adherent epithelium (Janach). The more attached the flap, the stronger the pressure needed to detach it without tearing. A limbal double-edged ring helps keep the eye firm during these maneuvers (Fig. 7).

PRK This phase only needs a check for the right diameter of the flap compared to the treatment that is going to be performed. Attention must be paid to any suction ring device that some types of laser have because these can vacuum the flap. Flap Re-positioning A drop of BSS has to be instilled over the stroma to make re-positioning easy. Two rounded spatulas are useful for gently moving the epithelium. A soft contact lens is fitted and compressed with a flap applanator allowing water under epithelium to get out (Fig. 8). The choice of the lens must take into account the preoperative curvature and the flap integrity. The recommendation is to use a steeper lens in case of a small hinge, torn flap, and in a hyperopic treatment. Lens Removal The lens must be left in place for at least 4 days. In our opinion, if the lens does not cause discomfort it should be left for 6 to 7 days to allow the epithelium to become thicker and

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more attached. A possible reason why the lens may be removed early is if it causes discomfort because of debris or tightness.

Figure 7 (A-D) How the flap has to be managed to have an intact hinge at the end of the dissection. The sequence demonstrated and direction of movements with a hockey spatula in hard attached epithelia is demonstrated using arrows.

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Figure 8 Johnston applanator (Rhein medical) used to compress the flap (always to be used over a soft lens). CONCLUSIONS LASEK is a relatively simple, safe, and effective surgical technique. Attention to surgical detail may allow for a rapid learning curve. Almost 60% of the flaps are easy to detach and in these cases using all the aforementioned steps may not be imperative. For the cases in which flap elevation is more difficult, the full feasibility of the technique needs little effort to follow, and in so doing, 90% of the flaps become well- managed.

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REFERENCES 1. Camellin M. LASEK: nuova tecnica di chirurgia refrattiva mediante laser ad eccimeri. Viscochirurgia 1998(3); Vol XIII:39–43. 2. Camellin M. LASEK. CDROM, Editore Fabiano, 0, 1999. 3. Cimberle M, Camellin M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News International; 1999(3):14–15. 4. Camellin M. LASEK. Operative techniques in cataract and refractive surgery. In: Elander R, Ed. Vol. 3, 2000:98–108. 5. Cimerle M, Camellin M. LASEK technique promising after 1 year of experience. Ocular Surgery News 2000(14):14–17. 6. Camellin M. La LASEK Chrirurgia Refrattiva Principi e Tecniche. Fabiano Editore 2000: 403– 411. 7. Angelucci C, Camellin M. LASEK vs. LASIK: New procedure may offer fewer risks. Eye World 2001; 6:13–41. 8. Cimerle M, Camellin M. LASEK is easier than LASIK, it is less painful than PRK and it allows for wider range of correction than both. It also prevents haze more effectively. Ocular Surgery News 2001; 19:46–47.

8 Butterfly LASEK Puwat Charukamnoetkanok, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA Suphi Taneri, MD Zentrum für Refraktive Chirurgie Munster, Germany In 1999, Vinciguerra developed a butterfly laser subepithelial keratomileusis (LASEK) to preserve the limbal connection of epithelial stem cells and limbal vascular connections (1). He postulates that these connections enhance epithelial viability and are essential for re-establishing corneal epithelial adhesion and stratification (2). To date, he has treated more than 1,000 patients using this technique.

SURGICAL TECHNIQUE (FIG. 1) Preoperative preparation: topical anesthetics, nonsteroidals, and/or antibiotics are applied before surgery. This is followed by preparation of the eyelids and positioning of the eye under the operating microscope. An eyelid drape is applied and a speculum is placed as described in Chapter 6. Corneal marks, used in the Azar LASEK technique, may assist in replacement of the flap, but most surgeons do not use them when performing the Vinciguerra butterfly LASEK. A corneal alcohol well is used to apply the alcohol on the corneal epithelium (Fig. 2). There is no need to create a trephine mark to maximize the continuity between the epithelial flaps and the peripheral epithelium. Sharp-edged trephines can be used to apply to the alcohol but they should not be rotated, so as to avoid cutting the epithelium (Fig. 3). The butterfly LASEK involves making a narrow paracentral epithelial incision from 8 to 11 o’clock. The 20% alcohol solution was applied to the corneal epithelial for 5 to 30 seconds (3). A specially designed spatula is used to separate epithelium from Bowman’s layer starting from the center and proceeding to the periphery on both sides (Fig. 4). A special retractor facilitates moving of the two epithelial flaps toward the limbus. Excimer laser photoablation proceeds after drying the stromal surface. The flaps are repositioned to cover the central cornea in an overlapping fashion (See Fig. 5.). Vinciguerra et al. (2) compared conventional LASEK in one eye with the butterfly LASEK in the fellow eye of 35 patients. Preoperative mean spherical equivalent

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refraction was −5.30±3.7 diopters (D). At 12 months postoperatively, mean spherical equivalent

Figure 1 Schematic illustration of the Vinciguerra butterfly technique. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. NovemberDecember 2004 In press.)

Figure 2 Janach alcohol well (JANACH 2941).

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Figure 3 Janach epithelial trephine (JANACH 2900).

Figure 4 Vinciguerra PRK/LASEK spatula (ASICO AE-2766). refraction was within −1.0±0.4. There was no loss of best-corrected visual acuity (BCVA). At 12 months, 96.2% of the corneas were completely clear. The rest of the corneas had no more than trace of haze. Furthermore, 97% of the patients reportedly preferred butterfly LASEK to conventional LASEK because of increased comfort. The authors observed a more rapid return to epithelial transparency and visual recovery, which he attributed to a better flap viability in the butterfly LASEK.

CRUCIFORM LASEK S. Percy Amoils developed the cruciform LASEK using a rotating microbrush to cut the cross (1). The surgeon created thin cruciate microgrooves using specially designed microbrush. The diluted alcohol solution is applied for 30 seconds. After removal of excess alcohol solution with sponge spear, the four flaps are then dissected back. The excimer laser is applied and the flaps are repositioned. Postoperatively, a bandage contact lens is placed for 3 days. Advocates for this techniques reason that because all four flaps are left attached to the limbus, they are more viable because of better nutrition. Also, thinner epithelial incisions may result in faster healing.

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Figure 5 (A) Star-shaped incision of epithelium as another variant of our technique. (B) Z-shaped incision of epithelium as another variant of our technique.

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Figure 5 (CONT) (C) Ying-yang or Sshaped cut of epithelium as a variant of our technique. (D) Variant of Vinciguerra butterfly technique (without epithelial abrasion prior to alcohol application). (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol. November-December 2004 In press.)

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REFERENCES 1. Samalonis LB. LASEK techniques. EyeWorld; 2002; 7:31–32. 2. Vinciguerra P, Camesasca FI. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg; 2002; 18:S371–S373. 3. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43:2593–2602.

9 Epithelial Flap Hydrodissection and Viscodissection in Advanced Laser Surface Ablation (ALSA) Richard C.Rashid, MD West Virginia University School of Medicine, Charleston Division Charleston, WV

INTRODUCTION Laser in situ keratomileusis (LASIK), currently the most common refractive surgery world-wide, is performed by 50% of The American Society of Cataract and Refractive Surgery (ASCRS) members, and of those performing more than 5 procedures per month, approximately 2% performed laser subepithelial keratomileusis (LASEK), yet 45% of ASCRS members plan to perform LASEK in the future, according to Duffey (1), who analyzed the 2002 ASCRS survey for refractive surgery trends. The evolution of LASEK began in 1949 when Dr. Jose Barraquer began his refractive keratoplasty techniques, followed in 1961 by the keratomileusis freeze-lathing procedures, then Dr. Luis Ruiz automated Barraquer’s microkeratome and automated lamellar keratoplasty (ALK) gained mild acceptance in the late 1980s to mid 1990s. The next evolutionary stages began in the mid 1980s with Dr. Theo Seiler using a metal masking template and the excimer laser to create corneal arcuate incisions, followed by Dr. Marguerite McDonald’s photorefractive keratectomy (PRK), and Dr. Lucio Buratto substituted the excimer for the cryolathe by ablating the corneal cap posterior surface. Dr. Ioannis G. Pallikaris combined the ALK concept of a hinged corneal flap and ablation of the corneal stromal bed, which he labeled LASIK, followed by the introduction of LASEK. LASIK rapidly became the procedure of choice over PRK surface ablation, even though it was more costly, complicated, and added the risks of microkeratome complications, because surgeons were looking for ways to reduce the patient’s postsurgical pain and a more rapid improvement in vision, the so-called “wow phenomena”. It also became clinically evident that LASIK decreased the use of topical steroids, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDS), haze formation, and postoperative care. The LASIK advantages were obvious, but it became apparent that many patients were not good LASIK candidates. LASIK contraindications included a multitude of factors, such as too steep or too flat corneas, very low or high refractive errors, thin corneas, epithelial dystrophies, and the fear of some surgeons and patients concerning the use of the microkeratome to “cut the cornea.”

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Thus, new evolution stages occurred as surgeons wanted a less invasive surgery than LASIK, but more comfortable procedure than PRK, which led to the development of LASEK. As is common, when a new ophthalmic procedure goes through the normal transitional phases, terminology changes can occur, with several different terms applied to basically the same procedure, causing some confusion. Laser subepithelial keratomileusis is no exception. The LASEK term has been used by Condon (2) and Vinciguerra (3). Pallikaris (4) described his “epi-LASIK technique”. Durrie (5) recommends advanced surface ablation for alcohol-assisted PRK and LASEK, and it is important to note the program title of the second international LASEK meeting in Cleveland, Ohio, May 2003, was “Second International Congress on LASEK and Advanced Surface Ablation.” In our office we now use advanced laser surface ablation (ALS A) for LASEK and transepithelial or alcohol-assisted PRK (6). In this chapter, LASEK is used for the current specific procedure but we recommend ALSA, to avoid confusion with LASIK, for the general designation of the several surface ablation techniques. Azar’s and Camellin’s LASEK procedure which combine the retention of an epithelial flap after surface ablation with the potential advantages of less pain with more rapid visual recovery than PRK and decreased potential LASIK flap complications, make it a reasonable alternative, especially for non-LASIK candidates. Because of these potential advantages we began LASEK in 2001, when it was just on the horizon, and in the past 600 laser vision correction cases performed, approximately 50% were LASEK and 50% LASIK. Several ophthalmologists, e.g., Camellin (7), Yee (7), Claringbold (8), and Gayton (9) perform only LASEK. Currently, LASEK may be approaching “high noon,” but we cannot predict where the sun will set. It became obvious after a few LASEK cases that alcohol application time varied significantly, as did epithelial devitalization, flap shredding, post-operation inflammation, patient discomfort, and visual recovery. Therefore, we began looking for techniques that would facilitate the formation of better epithelial flaps with or, hopefully, without alcohol application. The first idea was a form of “fluidic dissection” such as hydrodissection of the lens with balanced salt solution (BSS) during cataract extraction. A more earnest pursuit of a hydrodissection technique came after conversations with Dr. Patrick Condon of Ireland, who presented at the European Cataract and Refractive Surgery Congress 2000 his procedure of replacing the epithelial flap followed by irrigation with BSS under the flap, which we, with his approval, have applied the terms “subepithelial hydrofloatation and cleaning.” At the time we were developing the fluidic epithelial dissection techniques, a literature search revealed no articles or reports of any similar techniques. The original LASEK epithelial flap (LEF) hydrodissection (HD) technique was performed, after the epithelium was scored and alcohol applied, by injecting BSS subepithelially through a Slade LASIK cannula with the tip placed under the loosened epithelial edge. The technique was successful with the very first case and since has been used in a variety of methods in more than 1000 LASEK procedures. This is the first published formal report on hydroviscodissection, but we first introduced LASEK epithelial flap hydrodissection (10) (LEFHD) at the International

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Society of Refractive Surgery, 2001. Later, McDonald introduced gel-assisted LASIK (11) using GenTeal Gel (Hydroxypropyl methylcellulose 0.3% plus Carbopol 980; Ciba Vision) at the American Academy of Ophthalmology, 2001, and Langerman (12) introduced viscodissection (VD) with Celluvisc (carboxymethyl cellulose 1%; Allergan) at the First International LASEK Congress 2002. Hydroviscodissection Mediae and Terminology As a result of the successful hydrodissection technique with BSS, we evaluated several mediae, specifically BSS, air, GenTeal, and GenTeal Gel, as dissection mediae and later reported on the safety and efficacy of all of these mediae for hydrodissection and viscodissection (10,13–17). We originally designated BSS and GenTeal (hydroxypropyl methylcellusose 0.2%; Ciba Vision) as hydrodissection (HD) mediae and GenTeal Gel as a viscodissecting (VD) mediae (13–16). After the introduction of Celluvisc by Langerman, GenTeal and GenTeal Gel by Rashid, and Laservisc (0.25% hyaluronate; Laservisc, Germany) by Rau (18) as viscodissecting media, we now recommend the use of the terminology hydrodissection when BSS is used and viscodissection with more viscous fluidic mediae, including Gen-Teal, Celluvisc, GenTeal Gel, and Laservisc (20–22). Hydroviscodissection indicates the general surgical manuevers, not the media. BSS is available, cost-effective, and easy to handle. BSS hydrodissection characteristically causes slight to considerable epithelial ballooning and drains quickly, yet makes flap retraction easier and less traumatic (Fig. 1) (10,13). Air proved to be a poor dissecting media, although air bubbles that occur and remain under the flap after hydroviscodissection do give a “ball-bearing effect,” prevent epithelial settling, and make flap retraction very easy (13–19). GenTeal proved to be an excellent fluidic dissecting media, characteristically causing significant epithelial stretching and ballooning, with longer retention keeping the epithelium elevated, and greatly facilitates flap retraction and replacement while decreasing flap shredding (Fig. 2) (14–17,19–22). GenTeal Gel is very effective in dissecting and maintaining epithelial ballooning, making epithelial retraction the easiest, as the flap literally floats over the retained Gel, but it costs more, is not as easy to use, plus it requires more surgical time and preablation cleanup (Fig. 3) (15–17,19–22). Overall, BSS hydrodissection and GenTeal or GenTeal Gel viscodissection all proved to be safe (10,11,13–17,19–22), efficacious mediae techniques for fluidic epithelial dissection, as are Celluvisc (12) and Laservisc (18), with the latter being more expensive. Originally, BSS hydrodissection was rated as the best epithelial detachment modality (13–15) because of cost, availability, ease of handling characteristics at surgery, and other criteria. We now rate GenTeal Viscodissection as the best overall epithelial dissection media technique, offering the advantages of both BSS hydrodissection and GenTeal Gel viscodissection with minimal disadvantages (Table 1) (17–20,22).

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Figure 1 BSS hydrodissection characteristics with and without alcohol. Epithelial ballooning is common but drains quickly, yet makes flap retraction easier and less traumatic.

Figure 2 GenTeal viscodissection characteristics with and without alcohol. Epithelial stretching and ballooning is common, with better retention and easier flap retraction, combining advantages of hydrodissection and viscodissection with few disadvantages. Rau (18) basically used the same viscodissection techniques but substituted Laservisc for GenTeal as the viscodissection media and reported that flap retraction and

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repositioning were easier, more stable, and “the excellent transparence of the flap is cause for the faster optical recovery in comparison to the classical technique” of Camellin.

Figure 3 GenTeal Gel viscodissection characteristics with and without alcohol. Epithelial stretching and ballooning with long retention greatly facilitates flap retraction but requires more surgery and preablation clean-up time. Table 1. Fluidic Dissecting Media Comparison for Hydrodissection (HD) vs. Viscodissection (VD). LASEK Epithelial Flap HD vs. VD BSS/HD

GenTeal/VD

GenTeal Gel-VD

Safety

Equal

Equal

Equal

Effectiveness

Good

Excellent

Best

Efficiency

Moderate

Most

Least

Surgical difficulty

Moderate

Moderate

Most

Surgery time

Moderate

Least

Most

Preablation clean-up

Least

Moderate

Most

Alcohol

Easier

Easier

Easier

No alcohol

Difficult

Difficult

Difficult

Cost

Least

Moderate

Most

Availability

Equal

Equal

Equal

Visual results

Equal

Equal

Equal

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Conclusion: Fluidic Dissection Medial Technique Overall rank

#2

#1

#3

Hydroviscodissection Technique Our original LASEK hydrodissection technique was to use a disposal corneal trephine over a piece of drape placed superiorly under the trephine to protect the hinge area, followed by scoring of the epithelial edge with a bent needle or scissors, which allows alcohol, if used, to seep down between and loosen the epithelial incision edges. The Brown LASIK hoe (RHEIN) was then used to gently elevate the edge of the flap and using a 3-mL syringe filled with BSS, the tip of a Slade LASIK cannula (Fig. 4) was placed under the flap edge, and the BSS delivered in a controlled fashion with care not to abrade Bowman’s membrane or puncture the epithelium. We now use the Rashid LASEK cannula (Fig. 5) or a variation of it and GenTeal viscodissection (17,19–21) technique for all cases. Although some flap shredding occurs, especially at the edge where retraction is initiated, the epithelial flap is usually more intact, plus easier to retract and replace when hydroviscodissection is used. Hydroviscodissection can be performed in many cases without the use of alcohol. Initially, this was especially obvious in patients with basement membrane disease and in a specific group of individuals in whom Bashour (23) confirmed the clinical observations of the author and others that there is a “significant correlation with age, Northern European ethnicity, fair skin type, blue eyes, blonde hair,

Figure 4 Slade LASIK cannula (RHEIN).

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Figure 5 Rashid LASEK hydrodissection and viscodissection cannula (RHEIN). and facial skin wrinkling” as increased risk factors for epithelial defects with LASIK. This inherent “epithelial defect risk” makes hydroviscodissection easier, with or without alcohol, in these patients, making them excellent LASEK candidates, thus avoiding the multiple complications caused by LASIK induced epithelial defects (10,13,15–17,21). A clinical observation is that many of these individuals have rosacea and/or dry eye syndrome, plus often a history of hives. We closely examine the facial skin before surgery and perform punctal occlusion on these patients. We now occlude all four puncta, either with four Herrick collagen implants (Lacrimedics, Inc.) or soft PLUG-SA (Oasis Medical Inc.) or two permanent plugs and two collagen implants, on all laser vision correction patients. LASEK Cannula Initially, there were no specific LASEK cannula available, so the Slade LASIK cannula was the first to be evaluated and although successful, had the disadvantage of the epithelium catching on the cannula anterior to the port and the fluid initially goes over rather than under the epithelium if the flap edge is not loosened and elevated properly. Realizing a specific LASEK cannula with a flat smooth bottom, a tapered anterior lip with a curved superior aspect, and the port located very near the tip was needed, we collaborated with Rhien Medical and designed the Rashid-LASEK cannula (19,20,22) incorporating the aforementioned specifications plus a rectangular horizontal port near the tip. The author has no financial interest in this product.

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Figure 6 Seibel LASIK cannula: one direction, multiple side ports (left shown) (RHEIN). Currently, this LASEK cannula and similar variations with a round front port nearer the tip proved to be the most successful to initiate and complete hydro or viscodissection. It also is very effective in flushing out debris adherent to a LASIK flap. Several other cannula were evaluated, including one directional, multiple side port cannulae, e.g., the Seibel (Fig. 6), and McDonald McLASEK (Fig. 7), the two directional Güell (Fig. 8), and the three directional Burratto cannula (Fig. 9), and all proved ineffective in initiating hydro or viscodissection (19,20,22) because of the shape of the tip and the location of the ports. A two-cannulae technique using a front port cannula, e.g., the Slade LASIK or Rashid LASEK cannula, to initiate hydro or viscodissection, followed by a one-directional multiple port, e.g., Seibel, or a multi-directional cannula, e.g., Guell or Burrato, can be effective in detaching the epithelial flap (19,20,22). The advantage of the multiple one directional side port cannulae is that once hydro or viscodissection has been initiated, they can be passed into the created channel and with gentle downward pressure along the entire curved cannula shaft plus a slight sweeping motion, like a water broom, to complete the hydroviscodissection procedure (19,20,22).

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Figure 7 McDonald McLasek cannula: one direction, multiple side ports (left shown. (MASTEL).

Figure 8 Güell LASIK cannula: two direction, multiple ports (RHEIN).

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Figure 9 Burrato LASIK cannula: multi-directional ports (RHEIN). Keys to Successful Fluidic Dissection The keys to successful fluidic dissection, whether hydro or viscodissection, are a loosened epithelium, especially at the edge where it is more adherent; placing the cannula port under the flap edge before fluid delivery; and using a fluidic dissection media that is cost-effective, available, and easy for the assistants and surgeons to use during surgery. Techniques for Loosening Epithelium Techniques to loosen the epithelium and decrease or eliminate alcohol application before fluidic dissection are: 1. The use of xylocaine gel 2% for 15 to 30 minutes preoperatively, which initiates anesthesia, lubricates, and loosens the epithelium. A moist Merocel sponge is used to gently massage and remove the excess gel and further loosen the epithelium before scoring the epithelium (13–17,19–22). Berstein (24) uses a similar concept, painting the conjunctiva and cornea for 30 seconds with a proparacaine-soaked Merocel sponge to enhance anesthesia and mechanically loosen the epithelium. 2. Enhance the epithelial incision with scissors or a bent needle which allows alcohol, if used, to seep under the edges, further loosening the epithelial edge attachments, but may give a ragged edge. A disposable trephine gives a more defined edge and is easier to enhance.

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3. Alcohol application: 18% to 25% ethanol and application time are surgeons’ choices. We use 20% alcohol with BSS, prepared as follows. Two milliliters of medical alcohol (98%) and 8 milliliters of BSS are aspirated into a glass syringe along with an air bubble and shaken for 30 seconds. Remove the needle and cap the syringe. When alcohol is needed, place a cannula on the syringe, clear the air and deposit alcohol in the well or on the sponge. It is important to note that the mixture be fresh or changed every 3 hours. General Alcohol Application 3A. General application on a soaked Merocel sponge placed over the entire flap area. This can be performed for the total or partial time and is much more efficacious if the sponge is moved around with a forcep or other instrument with some pressure (Fig. 10). This is very effective in loosening the epithelium and, in fact, worked very nicely before the use of alcohol wells. 3B. The use of an alcohol well, which must be large enough to be peripheral to the edge of the incisions. A combination of the alcohol well and sponge application with pressure and movement is also effective (10,12). 3C. The special MELKI (25) alcohol well (ASICO), which has a peripheral section going from 3 to 9 mm and a smaller central area for decreased application time centrally if necessary, can be used for this M-LASEK technique, e.g., minimum alcohol maximizes epithelial viability (Fig. 11).

Figure 10 General alcohol application on Merocel sponge with instrument pressure.

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Local Alcohol Application 3D. Local application using a soaked long strip of Merocel placed just over the epithelial incision (Fig. 12) (20,22,25). 3E. Merocel spear placed just over the epithelial area where hydroviscodissection is to be initiated, greatly limiting the alcohol applied area.

Figure 11 Melki M-LASEK alcohol well (ASICO). Peripheral well confines alcohol over epithellal incision. Central well used for minimal application if needed.

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Figure 12 Local alcohol application on merocel sponge strip over epithelial incision, sparing central area. Alcohol application time varies from 20 to 60 seconds, depending on the surgeon and patient’s epithelial response, especially of the fellow eye. 4. Suction epithelial detachment (SED) performed by applying a contact lens suction removal device with a rotating motion (Fig. 13) (19–22). Suction epithelial detachment can be attempted before and/or after alcohol application. If the epithelial edge is lifted and folded on itself, it is possible to tear the flap so one should make sure the flap edges are flat before applying the device and initiating the rotating movements. A central flap tear is rare, and we have only seen a few. It is important to also perform SED over the hinge site, making epithelial dissection in this area easier and preventing shredding of the hinge. 5. Lifting the flap edge with an instrument, e.g., the Machat spatula (ASICO), Brown hoe (Rhein), or bent needle, makes it easier to slip the cannula tip, including the port, under the flap before initiating hydroviscodissection. 6. We have occasionally used the Easy-Freeze (16) cryo-applicator (Eurocrystal, Italy). The concept is to enhance anesthesia and prevent haze. This is a heavy stainless steel instrument, shaped like a top hat with a large curved bottom and a small top end. The instrument is frozen, removed from freezer, and placed immediately on the intact cornea for 30 to 60 seconds. An ice ball is often seen and may also help to loosen the epithelium. The small end is placed on the stromal bed after ablation. No specific clinical studies have been performed and further evaluation would be interesting. One disadvantage is it takes a long time to freeze and multiple instruments might be required if used routinely.

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7. McDonald (11) applies sodium chloride 5 % o ver the entire cornea for 10 seconds “which stiffens and loosens the epithelial cells without killing them.” All of these techniques may be tried before application of alcohol, especially general application, to ascertain whether alcohol is necessary to further loosen the epithelium. Many epithelial flaps can be dissected without alcohol, although it may take a lot of

Figure 13 Figure 13. Suction epithelial detachment (SED) with contact lens suction device. (Note detached epithelium at arrow) (Rashid). patience and increased time. There is no question that alcohol application makes flap retraction with or without hydroviscodissection easier and faster. McDonald (11) has investigated incorporating ultrasound and sonic energy to evaluate their efficacy in loosening the epithelium. Epithelial Flap Manipulation Techniques Even with all of these techniques, some flaps are initially difficult to retract and often shredding occurs at the edge and the hinge. It is more effective to detach, loosen, and retract the flap edges in a U-shaped fashion along the incision rather than going straight across during flap retraction. We stress taking care at the hinge area, because one can make a beautiful, perfect flap only to have it shred or torn from the hinge where the epithelium is more adherent. If the flap hinge should completely tear, just fold the flap

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back gently in the superior fornix, cover it with GenTeal Gel, and when irrigating the cornea be careful not to float it away, then replace it as a free flap. Replacing the flap is performed using either a wet technique with a one-direction irrigating cannula, e.g., Seibel, or a very moist Merocel sponge, or a dry technique with a spatula. Replacement is easier if the hinge is totally intact. The flap will adhere quicker with the dry replacement technique. Air can be used to dry the flap. If the flap is irregular, too adherent to position properly, or has subepithelial debris, one can use Condon’s (2) “subepithelial hydrofloatation and cleaning” irrigation technique with any appropriate cannula and BSS and reposition the flap. The epithelial flap is usually stretched and larger than the defect and some surgeons will trim the edges with scissors, removing the shredded edges, and try to place the epithelial edges edge to edge. There may be large defects and particularly if central, one can place the central edges together and leave the peripheral edges unopposed. At this point, one drop of proparacaine followed by several drops of sodium chloride 5% solution is used to increase epithelial flap adherence and reduce stromal edema before placing a nonionic low water content bandage soft contact lens (BSCL), usually a B&L S of 66, Optima FW, or 2-Week Lens. Petelin et al. (26) and Durrie (27) have reported that a nonionic low water (BSCL) content avoids the “tight lens syndrome” seen at 2 to 3 days postoperatively. McDonald previously used a Protek BSCL (28), which is no longer available, but the CSI lens, also by CIBA, has therapeutic Food and Drug Administration (FDA) approval and can be used as a BSCL. If the BSCL comes out, it will usually, but not always, remove the epithelial flap. Patients are given a new contact lens kit and advised to clean and, if possible, replace the BSCL. Epithelial Sanctity: Perfect vs. Partial vs. No Flap; Viable vs. Nonviable Flap Several important factors causing a resurgence of ALSA are that surface ablation avoids flap complications, is less costly, gives better wavefront custom results, induces less aberrations associated with LASIK, and now there are better methods of controlling postoperative pain and dryness. The first question is will LASEK or PRK, alcohol-assisted or not, be the best ALSA procedure? Thus, the sanctity of the flap becomes more important. Durrie et al. (29) and others have reported the fact that ALSA induces less aberrations, and MacRae (30) reported increased spherical aberrations with LASIK myopic corrections. Schallhorn (31) reported “distinctly different” and greater higher order aberrations with LASIK over “conventional PRK.” Most past presentations, e.g., Durrie (29), Rau (32), Rashid (10), and others have reported less patient discomfort, faster visual recovery, and equal longterm visual results with LASEK vs. PRK. However, Litwak et al. (33), and earlier, Garcia de-Quevedo (34) presented data “that PRK eyes felt less discomfort and had better vision than LASEK eyes” and “healed faster.” The next question, “Should we save the epithelium or scrape it off?” was literally the topic of the round table discussion at the Second International Congress on LASEK and Advanced Surface Ablation, Cleveland, Ohio, May 2003. There were diverse opinions, e.g., Yee (35) advocated salvaging as much of the epithelial flap as possible while others felt any flap that is “not perfect” should be removed to promote faster healing. Moore

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(22) personally advised the author that some reported up to a 50% removal rate of imperfect flaps. In more than 900 LASEK procedures, we have removed less than 15 epithelial flaps, and always try to retain as much epithelium as possible (36). If a perfect LASEK epithelial flap could be made without alcohol or with minimal use of alcohol, it would be advantageous. Alcohol is a known contributing cause of epithelial cell death, toxicity, plus conjunctival and general inflammation post-operative. If the corneal flap was more viable would patient comfort, epithelial healing, and visual restoration be improved? Durrie et al. (5) reported that epithelial healing is as good in alcohol-assisted advanced laser surface ablation with removal of the flap and has basically little difference with LASEK in healing, visual recovery, and patient comfort. So, there is still some controversy whether a perfect vs. nonperfect vs. no flap, or a viable flap vs. a nonviable flap makes a difference in patient comfort, faster epithelial healing, and visual recovery, but most surgeons agree there is minimal difference in longterm vision. Is it possible that applying alcohol for 60 to 90 seconds to create a more uniform epithelial flap easier and using the devitalized epithelial flap only as a protective “patch” might promote more even healing, increased comfort, and be as effective as a 25% or more viable flap? These questions will continue to be debated, and rightly so! LASEK With Mitomycin-C: Haze Prevention and Treatment: The use of mitomycin-C remains variable. There are many earlier reports, e.g., by Carones (37), Majmudar, Epstein et al (38) and Rashid (39) all at ASCRS 2000, and Azar (40), of excellent results in treating, reducing, or preventing postoperative corneal haze without major complications with the use of mitomycin, especially in complicated and high ablation cases. Some, e.g., Aldave (41), Hashemi (42), Rashid (16,17,19–22,43), and others, use mitomycin-C prophylactically with surface ablation to prevent corneal haze and all reported good results and no specific related complications. This is probably because of the fact that the mitomycin is placed on the avascular cornea. Most ophthalmologists are aware of the potential scleral melting syndrome seen postoperatively with pterygium or glaucoma filtering procedures in which mitomycin is placed over vascularized sclera. As more people are using mitomycin C 0.02% with an application time ranging from 30 seconds to 2 minutes to prevent corneal haze after surface ablation, it is important to protect the peripheral limbal vessels, epithelium, and stem cells. We recommend the use of a GenTeal Gel Barrier, which is placed 360 degrees over the limbal epithelium, to confine mitomycin only over the ablated stroma while protecting vessels and lubricating the limbal epithelium and stem cells (Fig. 14 and Fig. 15) (17,19–22). Our primary LASEK hydroviscodissection protocol is depicted in Figure 16: (steps 1– 12), although a bladeless microkeratome technique is currently being evaluated.

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Figure 14 GenTeal Gel Barrier (Rashid) placed 360 degrees over peripheral epithelium and limbus to confine mitomycin-C over ablated stroma while protecting and lubricating limbal vessels, epithelium, and stem cells.

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Figure 15 Merocel sponge with mitomycin-C (0.02%) contained within a GenTeal Gel Barrier. Bladeless Microkeratome Flap Retraction Technique A “perfect” epithelial flap dissection is not always possible. Some downward pressure must be exerted by the instrument on the cornea anterior to the epithelial edge during dissection. Hoes dissect a small narrow area and spatulae require more downward pressure to flatten the cornea for the one sweep technique. Both techniques can cause flap button-holes or shredding, especially if hydroviscodissection is not performed, or the epithelium is more adherent. In ALSA cases, we recently began using a bladeless microkeratome to retract the epithelial flap after hydroviscodissection, which is necessary, has been completed. In this method, the flap is prepared by trephination, alcohol application if necessary, GenTeal viscodissection followed by application of the Möria (−1) vacuum ring, and the manual Carriazo-Barraquer microkeratome without a blade is passed until the front edge of the

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head reaches the inside ring edge, retracting the flap to the superior hinge (6). Usually and depending on the extent of hydroviscodissection, two types of flaps are produced: a one-sheet flap with a superior hinge (Fig. 17A−17C), or a central epithelial opening over

Figure 16 (LASEK) ALSA with hydrodissection or viscodissection protocol: Step 1. Score epithelium with Sloan trephine (KATENA). Step 2. Enhance incision with scissors or needle. Step 3. Apply 20% alcohol 30 to 60 seconds *optional. Step 4. Remove alcohol with Merocel sponge. Step 5. Suction epithelial detachment (SED). Rashid. Step 6. HD or VD with BSS, GenTeal, or GenTeal Gel.

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Figure 16 (CONT) Step 7. Retract flap with hoe or spatula. Step 8. Laser ablation performed. Step 9. GenTeal Gel barrier (Rashid) for mitomycin-C. Step 10. Mitomycin-C on Merocel sponge inside GenTeal Gel barrier. Step 11. Replace and dry epithelium; apply BSCL. Step 12. Johnston Applanator (optional).

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Figure 17 (A) Bladeless moria manual C-B microkeratome in place after GenTeal viscodissection and preadvancement. (B) Flap retraction after MK pass and return (Note flap at hinge superiorly at white arrow and mk return at yellow arrow) (C) Epithelial flap retracted superiorly, preablation. the epithelium most elevated by retained GenTeal, creating a superior and inferior flap. When a central opening occurs, two opposite linear relaxing incisions may be necessary in the more peripheral points of the opening, thus converting it to a “butterfly” type of flap. Flap shredding can occur and is usually at the peripheral lower flap edge or at the hinge. There is usually enough residual superior flap to cover all or most of the stromal bed. Hinge shredding can be prevented by not pushing the front edge of the microkeratome head past the suction ring inside edge. The disadvantage to this technique is suction application and the resultant subconjunctival hemorrhages. Naphcon-A (naphazoline-0.025%; pheniramine-0.3%, ALCON is used as is in LASIK cases, to decrease these hemorrhages. In two attempted cases without GenTeal viscodissection the microkeratome passed over the epithelium, but both were successfully completely with viscodissection.

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Further refinement and evaluation of this technique has been curtailed as moria has developed an epithelial microkeratome but it is not yet FDA approved.

SUMMARY LASEK epithelial flap hydrodissection and viscodissection are safe, effective, and efficient LASEK maneuvers but require increased time, cost, and surgical skills. BSS for hydrodis-section and GenTeal, GenTeal Gel, Celluvisc, or Laservisc for viscodissection are all effective and safe laser epithelial flap dissecting media techniques. Currently, we rate GenTeal viscodissection as the number one choice of fluidic dissecting techniques because it combines the advantages of both BSS hydrodissection and GenTeal Gel viscodissection with minimal disadvantages. Hydrodissection or viscodissection make flap retraction easier, less traumatic, decreases corneal and conjunctival drying, decreases alcohol application time, and may be performed without alcohol in many cases. Hydrodissection or viscodissection techniques are adaptable to any surgeon’s LASEK protocol requiring only the media of choice, a syringe, and a front port cannula, e.g., the Rashid LASEK or Slade LASIK cannula, to initiate and complete epithelial detachment. A two cannula technique using an appropriate front port cannula to initiate hydroviscodissection followed by a cannula with multiple one-directional side ports, e.g., the Seibel, for completion, can be very effective. Enhancing the epithelial incision before or even without alcohol application makes hydroviscodissection easier. Alcohol, although not necessary in every case, makes hydroviscodissection easier. Alcohol application with a Merocel sponge applied with pressure and movement may be more effective than using an alcohol well to loosen epithelium, may decrease alcohol time, and may be used in combination with the alcohol well (6). Epithelial flap detachment with a contact lens suction cup or a Rashid LASEK Merocel Sponge (Ultracell Medical Technologies, Inc.) allows direct observation and identification of the loosened area. Easy-Freeze cryothermy may enhance epithelial detachment, as may sodium chloride 5%. Complications seen are the same as LASEK in general, e.g., dry eyes, persistent epithelial defects, e.g., those lasting more than 14 days postoperative, which are most likely neurotrophic, and haze (10,16). The only specific hydroviscodissection complications seen have been flap puncture, tear, loss or iatrogenic removal, and conversion to PRK, and an occasional Bowman’s membrane abrasion, which cause no major complications (10,15,17). Visual results are comparable with all three media and no specific alterations in one’s nomogram appears necessary but these should be monitored. It is interesting to note that alcohol is a drying agent and the fluidic dissecting media are wetting agents; yet, we have not altered our nomogram and feel this is because Bowman’s membrane is intact before the ablation and the different effects negate each other, although we have not seen a difference using fluidic dissecting media without alcohol. One must be careful when using hydroviscodissection especially with BSS, because the fluid can potentially hit the laser optics and if so, can cause hot spots. One must be

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very careful and protect the optics. We recommend looking at the mirrors each day before initiating surgery. If mitomycin-C is used, we recommend the use of the GenTeal Gel Barrier to contain the mitomycin and protect limbal vessels, epithelium, and stem cells. Some surgeons decrease their nomograms from 4% to 12%, depending on age and amount of ablation, when using mitomycin, because it may prevent normal healing regression. Lastly, Pallikaris (44) has developed his subepithelial separator, Caniazo (45) has reported his pendular LASIK microkeratome is capable of creating a subepithelial flap, plus Moria (France) and Gebauer (Germany) companies have developed subepithelial microkeratome, all of which eliminate the use of alcohol. If in the long term, these instruments are proven efficient, effective and are available, they may make these hydro viscodis-section techniques outdated. All the techniques described are not FDA approved and the author has no financial conflicts but may still be more cost-effective for lowvolume surgeons who cannot justify the investment in another microkeratome.

REFERENCES 1. Talsma J, Duffey RJ. ASCRS survey LASIK continues to be dominant. Ophth Times 2002; 28(9):1, 50–51. 2. Condon PI. LASEK-Laser Epithelial Keratomileusis. ASCRS, San Diego, CA, Apr 28–May 2, 2001; Paper: Abstract 10; p. 3. 3. Vinciguerra P. Laser Epithelial Keratomileusis Made Easy: Patient Selection Technique, Results. ASCRS. Philadelphia, PA, June 1–5, 2002; Course 1108; Abstract: Program p. 80. 4. Pallikaris I. Epi-Keratome. International Society of Refractive Surgery. Orlando, FL, Oct 18–19, 2002; Paper: Abstract: p. 44. 5. Durrie DS, Petelin PM Jr. LASEK using the LADAR Vision platform. ASCRS, Philadelphia, PA, June 1–5, 2002: Paper: Abstract 311:p. 79. 6. Rashid RC. New LASEK Techniques: Rashid LASEK Sticksponge and Bladeless Microkeratome Flap Retraction. Third International Congress on LASIK and Epi-LASIK and Advanced Surface Ablation. Houston, TX, March 19–20, 2004: Paper. 7. Personal communication with Camellin M and Yee R. 8. Claringbold TV II. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 9. Gayton JL. Reasons for switching from LASIK to LASEK. ASCRS, Philadelphia, PA, June 1–5, 2002; paper: abstract 473:p. 120. 10. Rashid RC.LASEK: Why, How, Advantages and Complications. International Society of Refractive Surgery Fall Symposium. New Orleans, LA, Nov 8–10, 2001; paper: abstract: p. 52. 11. Burrill A. Gel-assisted LASEK. Cataract Refract Surg Today 2002:57–58. 12. Langerman DW. LASEK A Visco-dissection Technique. First International LASEK Congress, Houston, TX, March 22–23, 2002: Paper. 13. Rashid RC. Hydrodissection of LASEK Epithelial Flap: A new surgical maneuver. First International LASEK Congress Houston, TX, Mar 22–23, 2002: Paper. 14. Rashid RC. LASEK Enhancement Challenges. International Society of Refractive Surgery, Fall Refract Cat Symp, 2002: Paper: Abstract: p. 43. 15. Rashid RC, Moore GS. LASEK Epithelial Flap Hydrodissection vs. Viscodissection: A media technique comparison. International Society of Refractive Surgery, 2002: Poster Abstracts: p. 78. 16. Rashid RC. LASEK: Review of Complications, Epithelial Flap Hydrodissection and Mitomycin-C. ASCRS, Philadelphia, PA, June 1–5, 2002: Paper: Abstract 313:p. 79.

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17. Rashid RC, Moore GS. LASEK Epithelial Flap Hydrodissection vs. Viscodissection: A media technique comparison. XXIV Pan-Am Congress of Ophthalmology, San Juan, Puerto Rico, Mar 28–Apr 1, 2003:Poster: pp. 1089: Abstract: Program p. 92. 18. Rau M. First results of a LASEK viscodissection technique. ASCRS, San Francisco, CA, Apr 12–16, 2003; Paper: Abstract 289:p. 75. 19. Rashid RC. New LASEK Surgical Techniques. XXIV Pan-Am Congress of Ophthalmology, San Juan, Puerto Rico, Mar 28–Apr 1, 2003; Paper: Abstract: Program p. 92. 20. Rashid RC. LASEK Epithelial Flap Hydro-viscodissection Instruments: Comparison of cannulae. ASCRS, 2003; Paper: Abstract 290:p. 75. 21. Rashid RC, Moore GS. New LASEK techniques: Suction Epithelial Detachment; HydroViscodissection; and Mitomycin—GenTeal Gel Barrier. ASCRS, San Francisco, CA, Apr 12– 16, 2003; Poster: 151: Abstract: ASCRS Program p. 135. 22. Moore GS, Rashid RC. New LASEK techniques and instruments. Second International Congress LASEK, 2003; Paper. 23. Bashour M. Risk factors for epithelial defictin LASEK. ASCRS, San Diego, CA, Apr 28–May 2, 2001; Paper: Abstract 90:p. 23. 24. Berstein RM. Proparacaine “Painting” to facilitate LASEK flap epithelial peeling. ASCRS, San Francisco, CA, Apr 12–16, 2003; Paper: Abstract 85:p. 23. 25. Melki S. M-LASEK: Minimize alcohol, Maximize survival. ASCRS, San Francisco, CA, Apr 28–May 2, 2003; Paper: Abstract 284:p. 74. 26. Petelin P, Durrie DS, Husiman EE. Laser Assisted Subepithelial Keratectomy (LASEK). International Society Refractive Surgeons Fall Refractive Symposium, New Orleans, LA, Nov 8–10, 2001; Paper: Abstract: p. 52. 27. Durrie DS. Selecting a Contact Lens for LASIK. Refractive Eyecare For Ophthalmologist; 2002; 6(4). 28. Bourque L, McDonald M, Salib G, Planchard L, Culotta T, Smolek M, Klyce S.. ASCRS, San Francisco, CA, Apr 12–16, 2003; Paper: Abstract 291:p. 75. 29. Durrie DS, Stahl JE, Collins MJ. Comparison of LASIK and LASEK for 1 to 7D of Myopia with up to 3D of Astigmatism. ASCRS, San Diego, CA, Apr 28–May 2, 2001: Paper: Abstract 9:p. 3. 30. MacRae S, Cox I. Effect of Customized Pupil Size, Optical Zone Size, and Refractive Error on the magnitude of Spherical Aberration Induced by LASIK. ASCRS, San Francisco, CA, April 12–16, 2003; Paper: Abstract 192:p. 50. 31. Schallhorn SC. Differences in Aberrations Induced by PRK and LASIK. ASCRS, San Francisco, CA, April 12–16, 2003; Paper: Abstract 194:p. 51. 32. Rau M. First Results of LASEK for the Correction of Myopia. International Society of Refractive Surgery Fall Symposium, New Orleans, LA, Nov 8–10, 2001; Paper: Abstract: p. 52. 33. Litwak S, Chayet A, Missiroli F, Garcia-de-Quevedo V, Robledo N. . International Society of Refractive Surgery Fall Symposium, New Orleans, LA, Nov 8–10, 2001; Paper: Abstract p. 51. 34. Garcia-de-Quevedo V. Clinical Comparison of LASEK and PRK. First International LASEK Congress, Houston, TX, March 22–23, 2002; Paper. 35. Yee R. “Should we save the epithelial or scrape it off?”. Second International Congress LASEK, Cleveland, OH, May 30–31, 2003; Round table discussion. 36. Rashid RC. LASEK conversions to PRK of surgery. Third International Congress on LASEK and EPI-LASIK, and Advanced Surface Ablation. Houston, TX, March 19–20, 2004; Paper. 37. Carones F. Treating Haze and Regression by Scraping and Mitomycin-C. ASCRS, Boston, Mass, May 20–24, 2000; Paper: Abstract: 720:p. 182. 38. Majmudar PA, Epstein RJ, et al. Topical Mitomycin-C for Corneal Haze after Refractive Surgery. ASCRS, Boston, Mass, May 20–24, 2000; Paper: Abstract 721:p. 182. 39. Rashid RC. Mitomycin-C uses in PRK. ASCRS, Boston, Mass, May 20–24, 2000; Paper: Abstract: 723:p. 182.

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40. Shahinian L, Claringbold TV, Azar DT, Camellin M, Vinciguerra P. LASEK (Laser-assisted Subepithelial Keratectomy). ASCRS, Philadelphia, PA, June 1–5, 2002. Course 2 207: Abstract Program p. 86. 41. Piantoni G, McLeod SD, Abbott RL, Aldave AJ. LASIK Complications: Prevention and Management. XXIV Pan-Am Congress of Ophthalmology, San Juan, Puerto Rico, March 28– Apr 1, 2003; Course TW0432: Abstract: p. 53. 42. Hashemi H, Takeri MR, Gotouhi A. Effect of Prophylactic Application of Mitomycin-C in PRK for High Myopic. ASCRS, San Francisco, CA, Apr 12–16, 2003; Paper: Abstract 13: p. 4 and personal communication. 43. Rashid RC. Mitomycin-C uses in PRK. ASCRS, Boston, MA, May 20–24, 2000; Paper: Abstract: 723:p. 182. 44. Pallikaris I. Epi-Keratome. International Society of Refractive Surgery, Orlando, FL, Oct 18– 19, 2002; Paper: Abstract: p. 44. 45. Carriazo CC. LASIK and LASEK pendular microkeratome. ASCRS, San Francisco, CA, Apr 12–16, 2003; Paper: Abstract 293:p. 76.

10 Surface Ablation Without Alcohol: GelAssisted LASEK and Epi-LASIK using Epilift System Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute Harvard Medical School Boston, MA Manual epithelial debridement was found to produce scratches and nicking in the Bowman’s layer and to leave variable amounts of epithelium (1,2). Chemical agents like 0.5% proparacaine iodine, cocaine, alkali n-heptanol, and ethanol have been used to remove the corneal epithelium in experimental studies (3,4). Currently, 18% to 20% ethanol is commonly used in laser subepithelial keratomileusis (LASEK). However, it is potentially toxic to the corneal tissue. The use of 100% ethanol for 2 minutes on rabbit corneas lead to a significant decrease in stromal keratocytes after 24 hours (4). Similarly, when using 70% isopropyl alcohol for 2 minutes for epithelium removal in rabbit eyes, Agrawal et al. found an increased inflammatory response and damaging effect on keratocytes (5). Helena et al. observed increased keratocyte loss but decreased inflammation after using 50% ethanol for 1 minute compared to mechanical debridement (6). Indeed, the toxic effect of alcohol on epithelial cells has been used for therapeutic purposes. For example, 50% ethanol was reported in the treatment of progressive or recurrent epithelial in-growth after laser in situ keratomileusis (LASIK) (7). Despite superior results to those using mechanical scraping, the reliability on alcohol for the manipulation of the corneal epithelial in LASEK is one of its major drawbacks. The search for nontoxic alternatives to alcohol is ongoing to improve the safety, efficacy, and reproducibility of the methods to separate the corneal epithelium from the stroma. Promising candidates include less toxic substances such as methylcellulose gel or water and mechanical devices similar to LASIK microkeratomes (the Epilift system for EpiLASIK surgery described below and the Pallikaris separator described in chapter 12).

GEL-ASSISTED LASEK The alcohol-free McDonald technique uses LASIK-microkeratome suction and a methylcellulose gel to create the epithelial sheet (Fig. 1). A curved cannula (Mastel Precision, Rapid City, SD) with fine holes along the side through which GenTeal Gel (hydroxypropyl methylcellulose 0.3%; Novartis Ophthalmics, Duluth, GA) can simultaneously emanate is used. Because methylcellulose gel unlike alcohol does not

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stiffen the epithelial cells, metallic instruments should never touch the epithelium. Instead, the cells are stripped using suction and manipulated on a cloud of gel.

Figure 1 McDonald alcohol-less technique. (From Taneri S, Zieske JD, Azar DT. Evolution, Techniques, Clinical Outcomes, and Pathophysiology of LASEK: Review of the Literature. Surv Ophthalmol November-December 2004 in press.) In the procedure, generous amounts of GenTeal Gel are applied to the corneal surface to keep the epithelium in good condition. A rounded cataract blade is used to make a small linear abrasion in the far periphery of the cornea. Ten drops of NaCl 5% are added for 10 seconds to slightly stiffen the epithelium. The suction ring is positioned on the cornea. While the suction is on, a LASEK spatula is slipped through the 1-mm or 2-mm linear abrasion. Using that hole as a fulcrum, a spatulating motion is made and the epithelium stripped off. After a maximum of 30 seconds suction time the dedicated curved cannula is slipped under the epithelium and GenTeal Gel is blown out to dome-up the epithelium. Finally, the raised epithelium is bisected with Vannas scissors, creating two halves. After parting the two sides, the surgeon uses a wet Weck-cel sponge to remove the gel from Bowman’s layer and performs the ablation. After ablation, the surgeon again applies GenTeal Gel, reposts the epithelial sheet to its original position, and places a bandage contact lens (8).

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A recent study of gel-assisted performed on 39 eyes of 23 patients demonstrated favorable result of this technique. The preoperative mean spherical equivalent was −5.53 diopters (D) and mean cylinder was +1.05 D. All patients tolerated the procedure well. There was minimal haze that resolved soon after surgery. At 3 months, 100% had a BCVA of 20/40 or better, 64% had a best-corrected visual acuity (BCVA) of 20/25 or better, and 50% had a BCVA of 20/20 or better (9).

EPI-LASIK USING THE EPILIFT SYSTEM LASEK has proven to be safe, effective, and predictable; however, postoperative pain and prolonged visual recovery until the epithelium closes remain the biggest disadvantages of LASEK compared to Epi-LASIK, in which the epithelium and its basement membrane (lamina densa) are consistently seperated from Bowman’s layer prior to laser surgery (Figure 2). This approach, using the epilift system, results from the shape and angle of the blade separating the epithelium from the stroma (Figure 3).

Figure 2 Light microscopy of the central cornea after EpiLift surgery (A) and the peripheral cornea at the junction of cut and uncut epithelium (B). Electron microscopy of the epithelium after being separated shows

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the cleavage plane to be above Bowman’s layer (C). External photography of the cornea 1 day (D) and 2 days (E) after surgery illustrate the rapid readhesion of the epithelial flap to the ablated stromal bed. (Modified from VisiJet with permission). Surface Ablation without Alcohol The success of the surgical technique using the EpiLift system depends on 4 factors: the applanator, the EpiLift, parameter control, and the relatively short learning curve. The applanator flattens the epithelium at a fixed distance from the point of separation and provides tissue alignment for cleaving. The radius of curvature of the EpiLift allows for atraumatic cleaving. The epithelial flap provides a natural contact bandage lens and acts as a barrier to help prevent haze. Use of a low vacuum suction ring and controlled transition

Figure 3 Prior to surgery, the microkeratome head is attached to the suction ring (A, green arrow) outside the eye. Diagramatic illustration of the mechanism of EpiLift showing the applanator and separator with the angled blade design (B) as the epithelium is lifted. The cleavage plane occurs between the lamina densa and Bowman’s layer. (Modified from VisiJet with permission).

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speed and low oscillation rate across the path of separation allow for gentle tissue cleavage. The learning curve is relatively short because the separator system operates similar to existing mechanical microkeratomes and is set up prior to placement on the cornea. Potential advantages of Epi-LASIK in wavefront-guided ablations still remain speculative. Achieving the optimal treatment dose can be hampered by patient subjectivity in establishing an accurate refraction. New wavefront technology will be able to obtain objective refractive data and may decrease the need for re-treatment in all types of laser corrective surgery (10). Many investigators express their belief that LASEK may become the procedure of choice in wavefront-guided customized ablations because the benefit of these complex ablations may not be negated by variable iatrogenic aberrations because of a microkeratome-created stromal flap (11–14). However, the greater wound healing response in LASEK patients compared to Epi-LASIK patients may also mask the fine contours provided by wavefront-guided ablations and cause significant aberrations itself. Additional study of the biochemical and histopathological causes of the healing response may lead to the development of a flap-making solution superior to the ethyl alcohol used mainly. A separation below the lamina densa would be desirable to further minimize haze formation and quicken visual recovery. Perhaps a better understanding of how the epithelium adheres to the ablated stroma would lead us to better techniques and ultimately outcomes.

REFERENCES 1. Campos M, Hertzog L, Wang XW, Fasano AP, McDonnell PJ. Corneal surface after deepithelialization using a sharp and a dull instrument. Ophthalmic Surg; 1992; 23:618–621. 2. Griffith M, Jackson WB, Lafontaine MD. Evaluation of current techniques of corneal epithelial removal in hyperopic photorefractive keratectomy. J Cataract Refract Surg; 1998; 24:1070– 1078. 3. Hirst LW, Kenyon KR, Fogle JA, Hanninen L, Stark WJ. Comparative studies of corneal surface injury in the monkey and rabbit. Arch Ophthalmol; 1981;99:1066–1073. 4. Campos M, Raman S, Lee M, McDonnell PJ. Keratocyte loss after different methods of deepithelialization. Ophthalmology; 1994; 101:890–894. 5. Agrawal VB, Hanuch OE, Bassage S, Aquavella JV. Alcohol versus mechanical epithelial debridement: effect on underlying cornea before excimer laser surgery. J Cataract Refract Surg; 1997; 23:1153–1159. 6. Helena MC, Filatov VV, Johnston WT. Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy. Cornea; 1997; 16:571–579. 7. Kim SY, Sah WJ, Lim YW, Hahn TW. Twenty percent alcohol toxicity on rabbit corneal epithelial cells: electron microscopic study. Cornea; 2002; 21:388–392. 8. Piechocki. T W. Alcohol-free LASEK procedure proves to effective in pilot study. Ocular Surgery News, Waikoloa, Hawaii, 2002. 9. Samalonis LB. LASEK techniques. EyeWorld; 2002; 7:31–32. 10. Sugar A, Rapuano CJ, Culbertson WW. Laser in situ keratomileusis for myopia and astigmatism: safety and efficacy: a report by the American Academy of Ophthalmology. Ophthalmology; 2002; 109:175–187.

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11. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18:217–224. 12. Vinciguerra P, Camesasca FI. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg; 2002; 18:S371–S373. 13. Claringbold TV, 2nd. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 14. Azar DT AR. Laser Subepithelial Keratomileusis (LASEK). International Ophthalmological Clinics; 2002; 42:89–97.

11 Epi-LASIK: Surface Ablation Without Alcohol Ioannis G.Pallikaris, MD, PhD Vikentia J.Katsanevaki, MD and Maria I. Kalyvianaki, MD Vardinoyannion Eye Institute of Crete, University of Crete, Greece, University Hospital of Heraklion Crete, Greece Irini I.Naoumidi, PhD Vardinoyannion Eye Institute of Crete, University of Crete Greece Richard W.Yee, MD Hermann Eye Center, University of Texas Health Science Center at Houston Houston, TX

INTRODUCTION Despite the encouraging clinical results of laser epithelial keratomileusis (LASEK), numerous authors agree that the creation of the epithelial flap without the use of alcohol could add to the safety of advanced surface ablation (ASA) (1–4). To avoid the use of alcohol, McDonald has recently proposed a modified mechanical epithelial separation, with injection of viscoelastic under a small epithelial incision (M.B.Mc Donald, Binkhorst lecture, New Orleans 105th annual meeting of the American Academy of Ophthalmology). Epi-LASIK refers to an alternative surgical approach for the mechanical epithelial separation by a motorized mechanical epi-separation device. With this technique, the epithelial separation is performed using an instrument that was initially designed in the University of Crete to operate similarly to a microkeratome and was developed by a specialized surgical instruments manufacturer (Duckworth and Kent, Baldock, England). This motor-driven device (Norwood Abbey Eyecare, Australia) features a proprietary blade that separates the epithelial layer without dissecting corneal stroma. Suction pressure and blade’s oscillation frequency and head advance speed was optimized based on tests performed on *

Financial disclosure: Author Ioannis G Pallikaris is a patent holder of the device of epithelial mechanical separation presented. The rest of the authors have no financial interest in any device or instrument reported herein.

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Figure 1 Subepithelial separator produced and distributed by Norwood Abbey Eyecare. porcine eyes (Fig. 1). The particular characteristics of the device under patent are currently undergoing clinical trials in Europe and awaiting appropriate Food and Drug Administration (FDA) device approval in the United States. Initial trials on porcine eyes have shown that the epithelial separation could be repeatedly achieved with the use of a proprietary oscillating blade without requiring any use of alcohol. Epithelial separation is achieved in a totally controlled way and most importantly, as shown by optical microscopy of the specimens, the separation is complete so that the reflection of the separated tissue require minimal surgical manipulations (Fig. 2). Epi-LASIK: Surgical Procedure The operative eye is anesthetized with topical tetracaine hydrochloride 0.5% eye drops, a sterile drape is applied, and a lid speculum is inserted. After copious irrigation with balanced salt solution using an anterior chamber cannula, the corneal epithelium is dried

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Figure 2 Light microscopy. Gross specimen of a porcine eye after the epithelial separation with the use of the subepithelial separator. with the use of a merocel sponge, and the cornea is marked with a standard LASIK marker. The subepithelial separator is applied onto the operative eye and the suction is activated through a foot pedal. The advance of the oscillating blade separates the epithelium leaving a 2- to 3-mm nasal hinge, the suction is released, and the device is removed from the eye. The epithelial sheet is reflected nasally with the use of a moistened merocel sponge to reveal the corneal stroma to be ablated. After the application of the excimer laser ablation, the cornea is irrigated with balanced salt solution, and the epithelial sheet is positioned back in place using the straight part of the cannula under intermittent irrigation. The epithelial sheet is floated back in place using the previous corneal marks and is left to dry for 2 to 3 minutes. After that time, the epithelial sheet is well-adhered onto the corneal stroma. Anti-inflammatory and antibiotic eye drops are instilled and a therapeutic contact lens is applied onto the operative eye. Postoperative treatment includes anti-inflammatory eye drops (diclofenac sodium 0.1%; CIBA Vision Ophthalmics, Duluth, GA) for 2 days and combined eye drops of tobramycin dexamethasone (Tobradex, Alcon, Fort Worth, TX) until the removal of the lens on the day of reepithelization. After the removal of the lens fluorometholone (FML, Allergan, Irvine, CA), eye drops are prescribed in a tapered dose for 2 months. Epi-LASIK: Initial Histopathological and Clinical Results In an initial clinical study, we have used the final version of the sub epithelial separator in 21 eyes of 18 patients. All epithelial sheets were totally separated with regular borders and a diameter of approximately 8 to 9 mm. Ten patients received Epi-LASIK treatment in one eye and LASEK treatment in the fellow eye using two different alcohol solutions (15% and 20%, for 20 seconds). All epithelial sheets obtained either mechanically or after the use of alcohol were removed and the treatments were converted to photorefractive keratectomy (PRK). The specimens underwent transmission electron microscopy. We found basement membrane discontinuities and basal cell fragmentation in specimens obtained with alcohol-assisted separation and confirmed that the alcoholassisted cleavage plane was within the basement membrane. In contrast, the basement membrane of the mechanically separated epithelial disks was mostly intact and showed

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minimal cellular fragmentation indicating that in these cases the separation was not within but underneath the basement membrane (5) (Figs. 3 and 4). In 11 additional eyes of eight patients, the epithelial sheet was left in place and the patients were followed-up for up to 3 months. Three of these patients received EpiLASIK treatment in both eyes whereas the rest received conventional PRK in the fellow eye (five patients). The mean re-epithelization time of the eyes that underwent EpiLASIK was 4.7 ±0.8 days. Biomicroscopy showed a transparent epithelial sheet on the first postoperative day (Fig. 5). During the postoperative course, the epithelial sheet showed some focal opacity at the borders of newly synthesized epithelium. On the day of re-epithelization, which was verified by negative fluorescein staining, the majority of Epi-LASIK-treated eyes showed a central epithelial raphe (Fig. 6). One patient who was treated with Epi-LASIK in both eyes reported mild photophobia and tearing on the first 2 postoperative days; otherwise, no other patients reported any pain or other subjective symptom after Epi-LASIK. Table 1 summarizes the subjective pain on the first postoperative day, the visual acuity on the day of re-epithelization, the time of re-epithelization, and the recorded haze 1 month after the treatment of the five myopic patients who underwent simultaneous PRK and Epi-LASIK treatments in each eye, respectively.

Figure 3 Transmission electron microscopy micrograph. Epithelial sheet obtained with the Epi-LASIK technique. Basal layer of the epithelial flap consisting of lamina lucida and lamina densa with occasional focal disruptions. We recorded subjective pain in two PRK eyes and perhaps some haze results in the first month that could favor Epi-LASIK. There were no striking differences between the two modalities regarding the re-epithelization time and the visual acuity on the day of reepithelization.

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Because of the small number of eyes reported, we could not provide any conclusive results of comparing Epi-LASIK to conventional PRK. A larger series with adequate

Figure 4 Transmission electron microscopy micrograph. Epithelial sheet obtained with LASEK. Basal layer of epithelial flap. Epithelial cells of the flap with minimal trauma and edema. Cellular blebbing (formation of cytoplasmic fragments) was typical for this technique. follow-up could provide some answers regarding the probable beneficial effect of the remaining epithelial sheet in terms of postoperative pain and the incidence of haze after the treatment. Nomenclature The term Epi-LASIK is based on the Greek word epipolis, which means superficial. Based on the use of a mechanical device to separate the epithelium and the entire basal lamina from Bowman’s and the underlying stroma, Epi-LASIK is a reasonable term. The term LASEK should be reserved for the use of alcohol-assisted epithelial separation. Both Epi-LASIK and LASEK, however, can be categorized as advanced surface ablations (ASA).

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Figure 5 Slit lamp photograph on the first postoperative day after EpiLASIK for myopia. Table 1. Clinical Results of 5 Myopic Patients That Were Treated with Epi-LASIK (1 Eye) and PRK (Fellow Eye). Patient

1 Epi

*

Pain

Re-epi

**

***

2 PRK

Epi

3 PRK

Epi

4 PRK

Epi

5 PRK

Epi

PRK

−

−

−

−

−

+

−

+

−

+

5

4

5

6

5

5

5

6

6

6

VA

20/25

20/25

20/25

20/32

20/25

20/32

20/40

20/40

20/32

20/32

Haze****

Clear

Trace

Trace

Mild

Clear

Trace

Trace

Trace

Clear

Trace

*

Reported pain on the first postoperative day. Day of re-epithelization (negative fluorescein staining). *** Visual acuity on the day of re-epithelization. **** Recorded haze on the first postoperative month. **

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Figure 6 Slit lamp photograph of an eye that underwent myopic correction with Epi-LASIK. Notice the central raphe of newly synthesized epithelium (postoperative day 4). DISCUSSION It is believed that the basement membrane provides the stability and support that keeps the epithelium intact, thus preserving the integrity of the entire corneal epithelium (6). Under this consideration, the adherence of the basement membrane to the basal layer of the epithelium must be significant for the viability of the epithelial disks, so we could assume that although alcohol dilutions are not reported toxic in the used concentrations, the cleavage plane of the mechanical epithelial disk separation may be considered superior. It will be important to determine if the epi-flap becomes adherent to the ablation surface or if the epi-flap acts only as a bandage until epithelial migration is complete. Studies by Fini et al. suggest the important role of the basal lamina in preventing activation of abnormal wound healing and haze (7). The basal lamina is variably present in LASEK and may account for the variability of clinical efficacy when compared to PRK (8,9). The wound healing time reported in this study suggests no difference in the time to complete healing between Epi-LASIK and LASEK (Table 1). In fact, the time to heal may actually be longer when compared to PRK. Future results of clinical studies

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may elucidate the probable beneficial effect of the remaining epithelial/basal lamina sheet on the corneal healing response after subepithelial treatments and perhaps the clinical importance of avoiding the use of alcohol for surface ablations. Additional use of woundhealing modulators, growth factors, or autologous serum may be adjunctive in EpiLASIK (10,11).

REFERENCES 1. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18(3):217–224. 2. Claringbold VT. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 3. Shahinian L. Laser-assisted subepithelial keratectomy for low to high myopia and astigmatism. J Cataract Refract Surg; 2002; 28:1334–1342. 4. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK for the correction of myopia and myopic astigmatism. J Cataract Refract Surg; 2002; 28:1343–1347. 5. Pallikaris JG, Naoumidi II, Kalyvianaki MI, Katsanevaki VJ. Epi-LASIK: Comparative histological evaluation of mechanical and alcohol-assisted epithelial separation. J Cataract Refract Surg; 2003; 29:1496–1501. 6. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43(8):2593–2602. 7. Stramer BM, Zieske JD, Jung JC, Austin JS, Fini ME. Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest Ophthalmol Vis Sci; 2003; 44(10):4237–4246. 8. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12(4):323–328. 9. Espana EM, Grueterich M, Mateo A, Romano AC, Yee SB, Yee RW, Tseng SC. Cleavage of corneal basement membrane components by ethanol exposure in laser-assisted subepithelial keratectomy. J Cataract Refract Surg; 2003; 29(6):1192–1197. 10. Lin N, Yee RW. Autologous Serum in LASEK.Philadelphia, PA: ASCRS, June 2002. 11. Yee SB, Lin N, Yee RW. Use of Autologous Serum to Reduce Haze after LASEK. Chapter 30.

12 Postoperative Management of LASEK Ahn Nguyen, MD and Amy Scally, OD Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, MA Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA Alcohol-assisted photorefractive keratectomy (PRK) and laser subepithelial keratomileusis (LASEK) are very similar procedures with a major difference being the preservation of the epithelial flap in LASEK. The postoperative management of LASEK patients is, therefore, not very different from PRK patients. Early on, the goal is to preserve the integrity of the epithelial flap, promote healing, reduce postoperative pain, and minimize complications. In later stages, the focus is on visual recovery, stabilization, and monitoring for development of haze. It is essential that the managing physician recognize the earliest signs of tight lens syndrome, anesthetic abuse, and infectious keratitis throughout the follow-up period to prevent the visually significant sequelae of these complications.

MEDICATIONS Postoperative eye drops start in the laser room after repositioning of the epithelial flap. The usual combination includes diclofenac sodium 0.1% (Voltaren Ophthalmic; Ciba Vision Ophthalmics, Duluth, GA), ciprofloxacin 0.3% (Ciloxan; Alcon Laboratories, Inc.), and prednisolone acetate 1% (Pred Forte 1%; Allergan America). A bandage contact is then placed on the eye. The Soflens 66 (Bausch & Lomb, Rochester, NY) is commonly used. It is a hydrophilic lens with 66% water and two different base curves, a steep/medium and a flat/medium, able to fit most corneal curvatures thereby minimizing the incidence of epithelial flap loss and contact lens loss in the early postoperative period. Its nonionic material has the potential advantage of not entrapping corneal debris and loose epithelium. Other contact lens choices include the Precision UV (Bausch & Lomb), Sequence (Bausch & Lomb), and Acuvue (Vistakon) lenses. The bandage lenses should remain in place for several days until complete reepithelialization of the corneal surface. Frequent lubrication with preservative-free artificial tears is advised to avoid over-drying of the cornea.

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Table 1. Target Organisms Covered by Prophylactic Treatment. Organisms

Aminoglycoside

Fluoroquinolone

Gram-negative organisms* Staphylococcus aureus (29,34–37,45) Staphylococcus epidermis (43,45)

+

+

Streptococcus viridans (32,37,46)

−

−

Streptococcus pneumonae (30,39)

−

−

Mycobacterium chelonae (33,38,40,44)

−

+

Mycobacterium fortuitum (38)

−

+

Nocardia asteroids (27,28)

+

*

No reported cases.

The usual postoperative regimen includes topical fluoroquinolone (ciprofloxacin, ofloxacin, or levofloxacin) and steroid (prednisolone acetate 1%) drops 4 times per day for 1 week. The fluoroquinolone is chosen because of its broad spectrum of activity against both Gram-negative and Gram-positive organisms (Tables 1 and 2). The fluoroquinolone is stopped after the first week and the topical steroid is continued twice per day for another week. Observation Schedule The follow-up schedule for LASEK patients is similar to PRK patients. The parameters monitored at each visit are the same as those with PRK. Patients are seen on day 1 and day 3 or until complete epithelialization of the surface. They are seen again at 1 week, 1 month, 3 months, 6 months, and 1 year after the procedure. This schedule allows the managing physicians to address any flap-related issues presenting early in the postoperative course as well as any potential late complications. On the first postoperative day, the visual acuity is assessed and the eye examined. Vision is usually suboptimal from the early surface irregularities. The contact lens should be comfortable, move normally, and be free of deposits. Early recognition of tight lens syndrome may eliminate an unwarranted source of discomfort for patients (Table 3). The overnight wear of contact lenses may cause drying of the corneal surface. This results in

Table 2. Organisms Not Covered by Fluoroquinolone or Aminoglycoside. Organisms Fungus Curvularia (47)

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Aspergillus flavus (42) Fusarium solani (46) Acremonium astrogriseum (48) Scedosporium apiospermum (49) Herpes simplex (31) Enterovirus (41,46)

Table 3. Potential Contact Lens-Related Complications. Poor lens fit Lens loss Tight lens syndrome Deposits on contact lens Hypoxic edema Sterile subepithelial infiltrates Toxic keratopathy Sterile hypopyon Infectious keratitis Epithelial abrasion after lens removal Dry eyes

the contact lens adhering to the corneal surface, limiting lens movement. Patients with decreased endothelial cell counts are especially prone to hypoxia and resulting corneal decompensation when contact lenses are worn overnight. Discontinuing contact lens wear can solve these contact lens-related problems. Under the protective lens, the epithelial surface is usually smooth with only minor disturbances. While many investigators have demonstrated epithelial cells survival after alcohol-assisted debridement (1,2), epithelial cells devitalization may occur after the 20% alcohol exposure. While the cells may appear swollen, gray, and opaque, they will often recover. The presence of folds in the epithelium indicates inadequate adherence, which warrants early lens removal. Identification of any early sign of infection is especially important at this time, because the disturbed epithelium is most prone to colonization by bacteria. The focus of the second postoperative visit on day 3 is to ascertain complete healing of the epithelium. The contact lens can be removed at this time. Minor irregularities on the surface can be seen after contact lens removal but they are usually inconsequential. By 1 week, most patients will have recovered relatively good vision because of healing of the ocular surface. Comparative studies of LASEK and PRK have shown that visual recovery in LASEK is faster than PRK. Lee et al. found that 59% of their LASEK patients had recovered an uncorrected vision of 20/25 or better at 1 week and 63% at 1

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month when compared to 37% of their PRK patients achieving 20/25 or better at 1 week and 56% at 1 month (3,4). Shah et al. observed that their LASEK patients presented with significantly better vision than their PRK patients at all visits during their 62.6 weeks of follow-up (5). In a noncomparative study, Azar et al. showed that 64% of their LASEK patients achieved an uncorrected visual acuity of 20/25 or better at 1 week and 92% at 1 month. Postoperative spherical equivalent of ±0.50 diopter (D) was achieved in 58% of eyes at 1 month and 100% of eyes at 12 months (1). In separate reports, Camellin, Claring-bold, Vinciguerra, and Rouweyha observed the same trend of early visual recovery (6–10). In Rouweyha’s nonrandomized comparative study of LASIK vs. LASEK, it was observed that after the initial slower recovery, LASEK patients do as well as LASIK patients with regard to refractive outcome and stability beyond 1 week. Rouweyha did not demonstrate any overcorrection or undercorrection in either group at 6 months, and 68% of LASEK patients and 72% of LASIK patients were within ±0.50 D of emmetropia at 6 months (10). At 1 month, almost complete visual recovery is expected. From this stage on, parameters to be followed are vision rehabilitation and haze development. Lee et al. reported lower haze scores in LASEK eyes as compared to PRK at 1 month (3,4). The amount of haze in LASEK eyes peaked at 1 month. By 3 months, the difference in haze scores between the two groups was not statistically significant (3,4). Claringbold and Vinciguerra found that haze was not prevalent after LASEK (8,10). Rouweyha et al. showed visually significant haze accompanied by regression in four of the 46 LASEKtreated eyes (8%) at 6 months (10). This is much lower than the previously reported incidence of haze 6 months after PRK (27). In the eyes with haze, Rouweyha et al. reported difficulty with flap lifting during the procedure (10). It has been speculated that the preserved epithelium protects the ablated surface from the influx of inflammatory mediators theorized to induce haze. Perhaps the flap also minimizes activation of stromal keratocytes and their production of collagen and extracellular matrix (11). Whether the reduced haze is caused by the LASEK procedure itself or by the difference in the laser delivery system (small spot vs. broad beam) remains to be determined. The suggested advantages of LASEK since its development focus on earlier visual recovery, less pain, and less haze formation as compared with PRK (6,7). Most authorities share this experience (1–5,8,10). However, more recently, a retrospective comparative study between LASEK and PRK by Litwat questioned these potential benefits. The epithelial healing time was longer, pain more prominent, and visual recovery slower in patients who underwent LASEK. The incidence of haze was equal in both groups (12). To date, most LASEK studies have been small and follow-up has been limited; long-term studies are still needed to determine the value of LASEK. Nevertheless, LASEK has been accepted as an alternative to LASIK when the thickness of the cornea is marginal, an alternative that appears to be as good as the more-studied PRK procedure. Contact Lens Removal The use of a soft bandage lens is an important feature in post-LASEK patients to minimize pain and promote healing. The protective lens is usually maintained until the epithelium has completely healed and is removed at day 3 to 5 (1,3,4,8). If the lens is lost

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after the first day, it is usually not replaced. While protective lenses can be of help, they can also be the source of problems for many patients. Prompt recognition of contact lensrelated complications is therefore of utmost importance. Patients need to be closely monitored while their contact lens is in place. Lenses need to be removed at an earlier date if there is evidence of wrinkles and folds in the epithelial flap, which is indicative of irregular epithelial settlement, presence of an infiltrate, or tight lens syndrome in the early postoperative period. Bandage lenses used in refractive surgery have been shown to harbor bacteria leading to postoperative infection (26). Several events can combine to cause tight lens syndrome in refractive patients. Postoperative conjunctival chemosis especially in the presence of alcohol leakage during the procedure, tear stagnation, and lens drying. With the preceding events, the eye is acutely red and painful, the cornea is edematous from hypoxia, and an inflammatory reaction in the anterior chamber may occur. In this setting, an early infectious process must be ruled out. The contact lens is removed and after infectious causes are ruled out, topical steroids may be started (13–15). Epithelial Defect Management One of the potential advantages of LASEK over PRK is preservation of the epithelial flap and the resultant faster recovery. If care is taken not to tear the epithelial flap during the procedure, most loose epithelium will settle and adhere by day 3. In Azar’s series, 63% of patients had an epithelial defect on day 1, only 9% on day 3, and no defect observed at 1 week (1). Most authors have also reported a similar time range for epithelial healing (1,3,4,8). While some authors have reported faster epithelial healing time with LASEK as compared to PRK, others have failed to demonstrate this difference. Lee et al. showed no significant differences in epithelial healing time between the two groups (3,4), while Litwat showed a slower healing time in his LASEK patients as compared to his PRK patients (12). Claringbold reported small epithelial defects at the time of contact lens removal on day 4. If the bandage contact lens is lost on the first operative day, it is not usually replaced even in the presence of an epithelial defect. Even in patients in whom there was epithelial damage from a dislodged contact lens, the epithelial flap usually heals without any complication (8). Frequent lubrication with preservative free tears and ointment as needed is advised to promote healing. Punctual occlusion can be added if the other measures fail to keep the surface lubricated. Recurrent erosion syndromes after LASEK have only been reported in one study (12). Pain Management Pain is still a major issue in the early postoperative period, although it has been suggested that LASEK causes less pain than alcohol-assisted PRK. In a prospective, randomized, comparative study between LASEK and PRK, Lee et al. found that LASEK eyes have statistically significant less pain than PRK eyes. However, they also reported that pain can be quite severe if alcohol leakage occurs during the LASEK procedure (3,4). In Azar’s series of LASEK patients, 47% had no pain in the first postoperative day, only 18% reported pain at day 3, and no reports of pain at 1 week (1). In Camellin’s series, no

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pain was reported in 44% of patients in the first 24 hours after surgery (6,7). Similarly, only 16.7% of patients in Kornikovsky’s series reported significant pain (16). It is speculated that the preserved epithelial surface acts as an additional protective barrier to an otherwise bare stroma, thus decreasing the incidence of post-LASEK pain. In his study of time course and intensity of pain after PRK, Verma et al. observed that the intensity of pain is maximal at 8 to 10 hours after surgery and usually subsides by 24 hours even in the presence of an epithelial defect (17). The previous studies suggested that most of the pain control is only needed during the first day after the procedure. Some authors feel that dilute solutions of topical anesthetic can be safely dispensed for a short period of time without potential for abuse. Tutton et al. used topical diclofenac 2 to 5 hours while awake for the first 24 hours to effectively reduce pain without hindering the healing process (18). Topical NSAIDS work through reduction in prostaglandin synthesis that may be increased after excimer laser (18). NSAIDS have also been shown to carry some anesthetic properties (19). Shahinian et al. demonstrated that dilute topical proparacaine 0.05% could be safely used as needed for at least 1 week after surgery to provide pain control (20). Verma et al. used topical tetracaine 1% every half-hour for 24 hours. However, many of his patients reported break-through pain likely caused by the short half-life of tetracaine (17). Cherry found that topical anesthetic, topical diclofenac, and the use of a bandage contact lens have an additive effect in the management of pain after LASEK (21,22). Several patients have been reported at informal meetings whereby dilute topical anesthetic led to anesthetic abuse after LASEK with devastating corneal complications. Accordingly, we feel that although the limited and supervised use of topical anesthetic is probably safe, the risk for corneal toxicity from potential abuse is inherently present. We routinely give oral percocet 5/325 mg to be taken every 4 hours as needed for pain. In most cases, this regimen was adequate, although patients occasionally reported drowsiness and gastrointestinal upset. We do not use topical nonsteroidal antiinflammatory drugs (NSAIDS) or topical anesthetic. Infection Prophylaxis and Management Microbial keratitis after refractive surgery is relatively rare but its sequelae may be devastating. A recent review article on the subject found 41 cases of infectious keratitis after LASIK reported in the literature (23). Estimated incidence varies from 0.1% to 1.2 % (23). Infection rate after PRK is higher because of the lack of epithelium protecting the bare stroma from invasive pathogens. There is no reported incidence of infection after LASEK. In theory, LASEK carries less potential for infection because the epithelial flap is preserved and acts as an effective barrier to infections. Infections after refractive procedures are usually acquired intraoperatively but may also result from postoperative contamination. The most common causative organisms after refractive surgery are the Gram-positive cocci from the ocular adnexa, (i.e., Staphylococcus aureus, Staphylococcus epidermitis, Streptococcus viridans, Streptococcus pneumoniae) (23). Studies of early infectious keratitis after LASIK showed that the mean onset was 5.3±6 days after surgery (25). Patients present with acute onset of pain and with decreased vision. Late-onset infections have been shown to occur

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up to 3 months after surgery (25). Onset of PRK-associated infection is also early because most of the inoculation occurs while the epithelium is still healing. The best treatment is prevention. Measures can be taken during the preoperative, intraoperative, and postoperative period. Preoperative predisposing factors should be identified and addressed, including blepharitis, meibomitis, dry eye conditions, and immunosuppressive states. Intraoperative measures include sterile techniques, a good lid scrub with betadine, careful draping of the lid margin and lashes, and avoiding excessive manipulation of the epithelial flap. Epithelial defects, delayed epithelialization, and topical corticosteroid use are additional risk factors in the postoperative period. The protective lens used also carries the potential risk of contamination. Staphylococcus epidermitis has been cultured from soft contact lenses used in patients after refractive procedures (26). Patients are routinely given a prophylactic fluoroquinilone four times per day for 1 week or until epithelial healing is complete. Fluoroquinolone has a broadspectrum activity covering most Gram-negative and some Gram-positive organisms. Management of infectious keratitis after refractive procedures is similar to that for bacterial keratitis not related to refractive procedures. Corneal infiltrates after LASEK usually start in the epithelium and may be easier to manage than an infiltrate located under a LASIK flap. The size of the infiltrate and the epithelial defect should be recorded to allow comparison on follow-up examinations. Scraping of the infiltrate is done before starting empiric treatment. Scraping samples are inoculated on chocolate, blood, and Sabouraud’s agar, along with thioglycolate broth. Plates are also sent for Gram and Giemsa stain. Empiric treatment is started with a broad-spectrum antibiotic, either a combination of fortified cefazolin (133 mg/mL) and fortified tobramycin (14 mg/mL) or monotherapy with a fluoroquinolone on an hourly basis. Adjustment is made according to clinical response and culture sensitivity. Topical cyclopentolate 1% or atropine 1% can be used twice per day to prevent posterior synechiae formation. The use of topical corticosteroids is controversial and probably should not be started until the pathogen is identified and a clinical response to treatment is documented. Prevention is still much better than having to manage the complications after surgery. Early detection and treatment may improve the final outcome.

REFERENCES 1. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad J. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12(4):323–328. 2. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell vitality and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43(8):2593–2602. 3. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 4. Lee JB, Choe CM, Seong GJ, Gong HY, Kim EK. Laser subepithelial keratomileusis for low to moderate myopia. 6 months follow-up. Jpn J Ophthalmol; 2002; 46(3):299–304. 5. Shah S, Sebai Sarhan AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85:393–396. 6. Camellin M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News International editions, 1999.

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7. Camellin M. Laser technique promising after 1 year of experience. Ocul Surg News; 2001; 14(1):14–17. 8. Claringbold TV II. Laser-assisted subepithelial keratectomy for correction of myopia. J Cataract Refract Surg; 2002; 28(1):18–22. 9. Vinciguerra P, Camesasca FL. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg; 2002; 18(3 Suppl):S371–S373. 10. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18(3):217–224. 11. Li D, Tseng SCG. Three patterns of cytokine expression potentially involved in epithelialfibroblast interaction in human ocular surface. J Cell Physiol; 1995; 163:61–79. 12. Litwak S, Zadok D, Garcia-de Quevedo V, Robledo N, Chayet AS. Laser-assisted subepithelial keratectomy versus photorefractive keratectomy for the correction of myopia. A prospective comparative study. J Cataract Refract Surg; 2002; 28:1330–1333. 13. Wilson MS, Millis EAW. Daily Wear Soft Contact Lenses. In: Millis EAW,, Ed. Contact Lenses in Ophthalmology.: Butterworth & Co. Ltd, 1998:61–79. 14. Hamano H, Kaufman H. Selection of Contact Lenses: Clinical applications. In: Hamano H, Kaufman H,, Eds. The Physiology of the Cornea and Contact Lens Applications. New York: Churchill Livingstone Inc,, 1987:61–86. 15. Rao GN, Saini JS. Complications of Contact Lenses. In: Aquavella JV, Rao GN, Eds. Contact Lenses. Philadelphia: JB Lippincott Company, 1987:195–225. 16. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(2):S222–S223. 17. Verma S, Corbett MC, Patmore A, Heacock G, Marshall J. A comparative study of the duration and efficacy of tetracaine 1% and bupivacaine 0.75% in controlling pain following photorefractive keratectomy (PRK). Eur J Ophthalmol; 1997; 7:327–333. 18. Tutton MK, Cherry PM, Sunder Raj PS, Fsadni MG. Efficacy and safety of topical diclofenac in reducing ocular pain after excimer photorefractive keratectomy. J Cataract Refract Surg; 1996; 22:536–541. 19. Zaidman GW, Amsur K. Diclofenac and its effect on corneal sensation. Arch Ophthalmol; 1995; 113:262. 20. Shahinian L Jr, Jain S, Jager RD, Lin DT, Sanislo SS, Miller JF. Dilute topical proparacaine for pain relief after photorefractive keratectomy. Ophthalmology 1997; 104:1327–1332. 21. Cherry PM, Tutton MK, Adhikary H. The treatment of pain following photorefractive keratectomy. J Refract Corneal Surg; 1994; 10:S222–S225. 22. Cherry PM. The treatment of pain following excimer laser photorefractive keratectomy: Additive effect of local anesthetic drops, topical diclofenac, and bandage soft contact. Ophthalmic Surg Lasers; 1996; 27:S477–S480. 23. Pushker N, Dada T, Sony P, Ray M, Agarwal T, Vajpayee RB. Microbial Keratitis after Laser in situ Keratomileusis. J Refract Surg; 2002; 18(3):280–286. 24. Alio JL, Perez-Santonja JJ, Tervo T, Tabbara KF, Vesaluoma M, Smith RJ, Maddox B, Maloney RK. Postoperative Inflammation, microbial complications, and wound healing following laser in situ keratomileusis. Review article. J Refract Surg; 2000; 16:523–538. 25. Detorakis T, Siganos DS, Houlakis VM, Kozobolis VP, Pallikaris IG. Microbial examination of bandage soft contact lenses used in laser refractive surgery. J Refract Surg; 1998; 14: 631–635. 26. Buratto L, Ferrari M. Photorefractive keratectomy for myopia from 6D–10D. Refract Corneal Surg; 1993; 9(28):S34–S36. 27. Nascimento EG, Carvalho MJ, de Freitas D, Campos M. Nocardial keratitis following myopic keratomileusis. J Refract Surg; 1995; 11:210–211. 28. Perez-Santonja JJ, Sakla HF, Abad JL, Zorraquino A, Esteban J, Alio JL. Nocardia keratitis after laser in situ keratomileusis. J Refract Surg; 1997; 13:314–317. 29. Watanabe H, Sato S, Maeda N, Inoue Y, Shimomura Y, Tano Y. Bilateral corneal infection as a complication of laser in situ keratomileusis. Arch Ophthalmol; 1997; 115:1593–1594.

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30. Mulhern MG, Condon PI, O’Keefe M. Endophthalmitis after astigmatic myopic laser in situ keratomileusis. J Cataract Refract Surg; 1997; 23:948–950. 31. Davidorf JM. Herpes simplex keratitis after LASIK (letter). J Refract Surg; 1998; 14:667. 32. Kim HM, Song JS, Han HS, Jung HR. Streptococcal keratitis after myopic laser in situ keratomileusis. Korean J Ophthalmol; 1998; 12:108–111. 33. Reviglio V, Rodriguez ML, Picotti GS, Paradello M, Luna JD, Juarez CP. Mycobacterium Chelonae keratitis following laser in situ keratomileusis. J Refract Surg; 1998; 14:357–360. 34. Webber SK, Lawless MA, Sutton GL, Rogers CM. Staphylococcal infection under a LASIK flap. Cornea; 1999; 18:361–365. 35. Hovanesian JA, Faktorovitch EG, Hoffbauer JD, Shah SS, Maloney RK. Bilateral bacterial keratitis after laser in situ keratomileusis in a patient with human immunodeficiency virus infection. Arch Ophthalmol; 1999; 117:968–970. 36. Al-Reefy M. Bacterial keratitis following laser in situ keratomileusis for hyperopia. J Refract Surg; 1999; 15(suppl):S216–217. 37. Quiros PA, Chuck RS, Smith RE, Irvine JA, McDonnell JP, Chao LC, McDonnell PJ. Infectious ulcerative keratitis after laser in situ keratomileusis. Arch Ophthalmol; 1999; 117:1423–1427. 38. Gelender H, Carter HL, Bowman B, Beebe WE, Walters GR. Mycobacterium keratitis after laser in situ keratomileusis. J Refract Surg; 2000; 16:191–195. 39. Dada T, Sharma N, Dada VK, Vajpayee RB. Pneumococcal keratitis after laser in situ keratomileusis. J Cataract Refract Surg; 2000; 26:460–461. 40. Chung MS, Goldstein MH, Driebe WT Jr, Schwartz BH. Mycobacterium chelonae keratitis after laser in situ keratomileusis successfully treated with medical therapy and flap removal. Am J Ophthalmol; 2000; 129:382–384. 41. Sharma N, Dada T, Dada VK, Vajpayee RB. Acute hemorrhagic keratoconjunctivitis following laser in situ keratomileusis. Clin Exp Ophthalmol; 2000; 28:431–433. 42. Sridhar MS, Garg P, Bansal AK, Gopinathan U. Aspergillus flavus keratitis after laser in situ keratomileusis. Am J Ophthalmol; 2000; 219:802–804. 43. Karp KO, Hersh PS, Epstein RJ. Delayed keratitis after laser in situ keratomileusis. J Cataract Refract Surg; 2000; 26:925–928. 44. Garg P, Bansal AK, Sharma S, Vemuganti GK. Bilateral infectious keratitis after laser in situ keratomileusis: A case report and review of the literature. Ophthalmology; 2001; 108:121–125. 45. Levartovsky S, Rosenwasser G, Goodman D. Bacterial keratitis following laser in situ keratomileusis. Ophthalmology; 2001; 108:321–325. 46. Gupta V, Dada T, Vajpayee RB, Sharma N, Dada VK. Polymicrobial keratitis after laser in situ keratomileusis. J Refract Surg; 2001; 17:147–148. 47. Chung MS, Goldstein MH, Driebe WT Jr, Schwartz B. Fungal keratitis after laser in situ keratomileusis: A case report. Cornea; 2000; 19:236–237. 48. Read RW, Chuck RS, Rao NA, Smith RE. Traumatic acremonium atrogriseum keratitis following laser in situ keratomileusis. Arch Ophthalmol; 2000; 28:418–421. 49. Sridhar MS, Garg P, Bansal AK, Sharma S. Fungal keratitis after laser in situ keratomileusis. J Cataract Refract Surg; 2000; 26:613–615.

13 LASEK Enhancements Lee Shahinian, Jr, MD Stanford University Stanford, CA

LASEK ENHANCEMENTS With the increasing use of laser-assisted subepithelial keratectomy (LASEK) to correct a wide range of refractive errors (1–6), it is important to determine the technique, safety, and efficacy of enhancements. Study Design Six surgeons contributed data to this study: Thomas Claringbold, Daniel Durrie, Jorge Muravchik, Woo Jin Sah, Steven Schaller, and Lee Shahinian. Twenty-one eyes of 16 patients were included in this retrospective survey analysis. The primary procedure was LASEK in all cases. Average age was 41 years (range 24–58). Before enhancement, 16 eyes were myopic and four eyes were hyperopic. The average time from primary procedure to enhancement was 10 months (3–26 months). Average follow-up after enhancement was 5.6 months (1–12 months). The six surgeons used a variety of excimer lasers. Nine eyes were treated with the Visx S2, five with the B&L, three with the Visx S3, three with the Lasersight, and one with the Nidek EC5000. Surgical Technique The surgical technique was identical to the primary procedure. A 20% alcohol solution was applied for an average of 37 seconds (10–50) for the enhancement vs. 36 seconds (25–45) for the primary procedure. In eight of 21 eyes, it was more difficult to lift the central portion of the epithelial flap in the area of previously ablated stroma. Results For the hyperopic eyes, mean preoperative spherical equivalent (SE) was +1.44 diopters (D), and mean postoperative SE was −0.12 D. For the myopic eyes, mean preoperative SE was −1.09 D, and mean postoperative SE was +0.07 D. *

Presented at the First International LASEK Congress, Houston, Texas, March 22, 2002.

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Table 1. Postoperative Uncorrected Visual Acuity After LASEK Enhancement. UCVA

n

%

20/15

2

9.5

≥20/20

12

57

≥20/25

18

86

≥20/30

20

95

≥20/40

21

100

Figure 1 After LASEK enhancement, the uncorrected visual acuity (UCVA) showed a shift to the left, indicating improved visual acuity after surgery. Table 2. Gain and Loss of BSCVA After LASEK and LASEK Enhancements. Overall Change After LASEK and Enhancement n (%)

Post-LASEK Change After Enhancement n (%)

Loss of 1 line

3 (14)

3 (14)

No change

15 (72)

14 (67)

Gain of 1

3 (14)

3 (14)

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line Gain of 2 lines Total eyes

0

1 (5)

21

21

Postoperatively, 57% of eyes had uncorrected visual acuity (UCVA) of 20/20 or better, 95% were 20/30 or better, and 100% were 20/40 or better (Table 1). Figure 1 shows the dramatic improvement in UCVA after enhancement. Table 2 demonstrates that there was no significant gain or loss of best-corrected visual acuity (BCVA). One eye developed 2+ haze 1 month after enhancement. UCVA and BCVA were 20/25 at that time. In the eight eyes (38%) in which the surgeon reported difficulty in lifting the central portion of the epithelial flap, the average interval between enhancement and primary procedure was 9.6 months. This was not significantly different than the corresponding interval (9.1 months) for the remaining eyes.

CONCLUSIONS With the exception of postoperative haze in one eye, LASEK enhancement after primary LASEK appears to be safe and effective in a small pooled series. The epithelium is often more adherent over the area of previous stromal ablation. Longer follow-up on more eyes is needed to determine the incidence and severity of stromal haze after LASEK enhancement.

REFERENCES 1. Camellin M, Cimberle M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News, 1999; March: 28. 2. Shah S, Sebai Sarhan AR, Doyle SJ. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85:393–396. 3. Claringbold T. Laser assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 4. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad J. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12(4):323–328. 5. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27(4):565–570. 6. Shahinian L. Laser-assisted subepithelial keratectomy for low to high myopia and astigmatism. J Cataract Refract Surg; 2002; 28(8):1334–1342.

14 LASEK in High and Low Myopia Chris P.Lohmann, MD, PhD University Eye Clinic Regensburg, Germany, The Rayne Institute, St Thomas Hospital London, England David O’Brart, MD, Ann Patmore, BSC, and John Marshall, PhD The Rayne Institute, St. Thomas Hospital London, England Christoph Winkler von Mohrenfels, MD, Bernhard Gabler, MD, and Wolfgang Herrmann, MD University Eye Clinic Regensburg, Germany Refractive surgery is a constantly changing field with new technologies being developed and introduced routinely. Currently, excimer laser photorefractive keratectomy (PRK) and excimer laser in situ keratomileusis (LASIK) are the surgical procedures most commonly being used to treat myopia (1,2). PRK changes the corneal curvature by ablating part of Bowman’s layer and anterior corneal stromal tissue after removing the epithelium. In contrast, LASIK does not remove the epithelium, Bowman’s layer, or anterior stromal tissue but does remove deep stromal tissue after making a cut into the corneal stroma at 160 µm using a microkeratome. Over the past 15 years, PRK has been the subject of intensive scientific and clinical research. Based on numerous clinical trials, which have shown PRK to be safe and effective for the correction of low to moderate degrees of myopia, approval of the procedure was granted by the Food and Drug Administration (FDA) in the United States in 1995. However, PRK requires corneal epithelial debridement before laser ablation. This is a major disadvantage of the procedure, because it leaves the patient with a significant amount of pain for 3 to 4 days postoperatively, and increases healing time with a loss of corneal transparency (1). Recently, interest has grown in the technique of LASIK. This technique is based on the concept of lamellar corneal surgery postulated by Barraquer in 1949 (3). Since then, various modifications have been undertaken, but it met with limited success because of its complexity, poor predictability, and sight-threatening complications (4). With the introduction of both microkeratomes and the excimer laser, in-situ reshaping of the corneal surface with submicron accuracy became reality. Initially, it was postulated that by creating an intrastromal ablation, it might be possible to improve the outcome of higher degrees of myopia by avoiding the influence of the healing epithelium on stromal wound healing as seen in PRK. However, in clinical practices, LASIK can safely correct up to −10.0 D because of decreased predictability and stability at greater refractive errors

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(2). The advantages of the intrastromal excimer laser ablation over the surface are cited principally as minimal postoperative discomfort, a rapid recovery of visual function, and minimal disturbances in corneal transparency. There has been rapid uptake of LASIK by corneal surgeons and the perceived short-term advantages have raised the demand for this procedure by patients. Although very limited data on the long-term effects of LASIK were available, LASIK obtained FDA approval in 1999. It is of concern that both early and long-term complications of LASIK are not yet fully elucidated and certainly not held in appropriate regard by some ophthalmologists and patients. LASIK is technically more demanding, more invasive of a greater portion of the cornea, and, although very rare, the intraoperative and early postoperative complications have the potential to cause significant loss of visual function (5). The long-term effects of LASIK on the biomechanical properties of the cornea have not been investigated so far. Histological evidence and simple mathematical models suggest that the tensile strength and stability of the cornea may be considerably compromised in years after surgery (6). The first signs of this may be the clinical reports of iatrogenic keratectasias after LASIK (2). This is in contrast to the well-documented long-term safety and stability of PRK. Laser epithelial keratomileusis (LASEK), first popularized by Camellin, is a new surgical procedure to correct refractive errors (7). This technique may combine the advantages and eliminate the disadvantages of both PRK and LASIK. LASEK is based on detachment of the corneal epithelium using an alcohol solution, creating an epithelial flap that is then repositioned after the laser ablation. The epithelium regenerates itself within a few days and, in the meantime, the existing flap protects the ablated corneal surface. In this chapter, we report our results of LASEK for the treatment of myopia on 314 eyes with a maximum follow-up of 18 months.

PATIENTS AND METHODS Patients Three hundred fourteen myopic eyes (187 patients) with a mean age of 28.7 years (range 19 to 42 years) were enrolled in this study between August 2000 and February 2002. Patients with pre-existing ocular pathology, sicca syndrome, diabetes, or connective tissue disorders were excluded from this study. Preoperative spherical refraction was between −2.00 and −10.00 diopters (D). All eyes had less than 1.0 D of refractive cylinder. A detailed ocular examination was performed on each patient preoperatively, including subjective and objective refraction, corneal topography, measurements of pupil diameter under mesopic conditions, Goldmann applanation tonometry, slit-lamp biomicroscopy, and funduscopy. Patients were asked to remove hard contact lenses at a minimum of 4 weeks before surgery and soft contact lenses at a minimum of 4 days. Patients were examined postoperatively on day 3, day 7, and thereafter at 1, 3, 6, 12, and 18 months.

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LASEK Surgical Procedure The LASEK procedure is illustrated in Figure 1a to 1e and was performed under topical anesthesia. After a lid speculum was applied to the patient’s eye, the surgery consisted of the following steps: 1. A 8.5-mm in diameter incision of the corneal epithelium was performed using a LASEK corneal epithelial trephine with a 70-µm depth calibrated blade (Geuder,

Figure 1 LASEK surgical technique. (a) Incision of the epithelium. (b) 20second exposition to ethanol. (c) Mobilization of the epithelium. (d) Excimer laser ablation. (e) Repositioning of the epithelium.

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Heidelberg, Germany) (Fig. 1a). The trephine is designed to create a 280-degree epithelial incision, leaving a blunt section of 80 degrees at the 12-o’clock position for the formation of a hinge. The trephine was placed centrally on the pupillary axis and downward pressure of the trephine was evenly applied to the blade and slight rotation of the blade (approximately 5 degrees in both directions) was used to create the incision. 2. A 9.0-mm alcohol solution cone (Geuder, Heidelberg, Germany) was placed on the corneal surface encircling the epithelial incision (Fig. 1b). This cone was filled with 20% ethanol (in distilled water) and left for 20 seconds. The cornea was then dried and thoroughly washed with balanced salt solution (BSS) to remove all remaining alcohol. 3. To create the epithelial flap, the precut margin of the epithelium was lifted using the sharp side of the epi-peeler (Geuder, Heidelberg, Germany) and the epithelial flap was gently detached and folded up at its hinge at the 12-o’clock position using the blunt, large side of the epi-peeler (Fig. 1c). 4. A Chiron Technolas 117 excimer laser (221 eyes) or the Summit Apex excimer laser (93 eyes) were used to perform the laser ablation (Fig. 1d). The maximum diameter of the laser beam was 7.0 mm for the Chiron Technolas laser and 6.5 mm for the Summit laser. In all eyes, we have aimed for emmetropia. 5. After the laser ablation the entire cornea was flooded with BSS and the epithelial flap was repositioned using the blunt side of the epi-peeler (Geuder, Heidelberg, Germany) (Fig. 1e). 6. The cornea was covered with a Bausch & Lomb PureVision soft contact lens for 3 days to secure the epithelial flap. Postoperative Management Ofloxacine and dexamethasone eyedrops were used five times daily for 3 days postoperatively. After the removal of the bandage contact lens on day 3 after surgery, patients were switched to dexamethasone eyedrops three times daily for 3 weeks and daily for 1 week. Artificial tears (carbomer 2.0 g) were administered immediately after the surgery and were used five times daily for 4 weeks. Assessment of Postoperative Pain The first 50 patients were asked to complete a “visual analogue pain chart,” which consisted of a series of horizontal lines 10 cm in length with “no pain” written at one end and “worst pain imaginable” at the other. At each assessment period patients were asked to make a vertical mark across the given line in a position that best represents the severity of pain they were experiencing. Time “0” hours was taken as the time of surgery. Over the next 3 days, patients recorded their pain score initially at 30-minute intervals for 6 hours, then, when awake, every hour for 3 days. Assessment of Corneal Haze Corneal haze was graded clinically at each visit based on the following scale:

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0: no haze 0.5: trace, just perceptible 1: easily seen on slit-lamp biomicroscopy 2: moderate haze 3: pronounced haze; iris details still visible 4: severe haze, iris details obscured Assessment of Halos and Glare Because postoperative halos and glare are reported by many patients as a problem of night vision after PRK and LASIK, we have measured the size of halos and glare preoperatively and at 3 months postoperatively in 20 patients (20 eyes) with a preoperative myopia between −5.0 and −6.0 D using objective tests described previously (8,9). The halo test (8) was performed using a computer and a high-resolution monitor under mesopic conditions. The patient fixated on a bright white light source, 40 minutes of arc in diameter, located in the center of the otherwise dark monitor screen. A small white spot acted as a cursor and was moved centripetally until it coincided with the perceived edge of the halo. The movement of this cursor was restricted to 12 radii at 30-degree intervals, passing through the center of the halo source. When the patient determined that the cursor location was coincident with the halo edge, the cursor’s location was recorded by pressing the mouse button. The cursor then moved to the next meridian. The position of the halo edge was recorded at all 12 meridia, and the area within these points was calculated in square millimeters. Glare caused by forward light scatter was measured using a two-part test in which visual contrast was measured first with a central test stimulus generated on a highresolution monitor (9). This stimulus flickered at 7.5 Hz between the background level and the match level. The patient adjusted the contrast between the match luminance and the background to minimize flicker by means of buttons on the computer keyboard. Then the test was repeated with a bright, annular light source flickering in counterphase and surrounding the central test stimulus. This “straylight” provided an additional luminance for the forward scatter of light.

RESULTS Surgical Experience With the exception of three eyes, the preparation of the epithelial flap was easy and without any complications. In one eye, a central buttonhole was created during the preparation of the epithelial flap. In the other two eyes, the epithelium was very adherent and the preparation required additional exposure to the ethanol for 10 seconds.

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Clinical Examination Some dead superficial epithelial cells were seen underneath the bandage contact lens; however, no erosion of the epithelium was noted using fluoresceine dye at the third postoperative day. In most eyes, a slight epithelial edema was noted at day 3 before removing the contact lens. Throughout the postoperative period, we have not seen any instability of the epithelium and patients did not report any signs of epithelial breakdown. However, one patient (one eye) lost the contact lens on day 1 after the surgery. This led to a loss of the epithelial flap. Postoperative Pain None of the patients reported severe postoperative pain that is usually experienced after PRK. During the time the bandage contact lens was placed, most patients reported slight ocular discomfort. On the Visual Analogue Pain Chart, the maximum level of pain was 3.6. This maximum was reached between 3 and 5 hours after the surgery. The pain intensity declined thereafter to a level of 2 until removal of the contact lens. After removal of the contact lens, no pain was reported by all patients. Postoperative Refraction In all eyes, we aimed for emmetropia. Postoperative refraction was measured for the first time at the 1-week follow-up. At this stage, all eyes were between plano and +1.25 D. In the next few months, the refraction changed slightly. All eyes were within +0.50 and −0.75 after 3 months. For analysis, we divided the eyes into two groups: the first group included all eyes with a correction of up to −6.00 D. The second group consisted of all eyes with preop refraction (SE) between −6.25 and −10.00 D. A total of 189 eyes underwent corrections up to −6.00 D (SE). Fourteen (14) eyes had 18 months of follow-up and all were within +0.50 and −0.75 D. Fifty-eight eyes reached the 12-month follow-up (±0.50 D=84% and ±1.00 D=97%), and 117 eyes reached the 6month follow-up (±0.50 D=81% and ±1.00 D=98%) (Fig. 2a and 2b). We started to treat myopia over −6.00 D (SE) 10 months after we began treating lower myopes, follow-up data for corrections between −6.25 D and −10.00 D are therefore available for only up to 12 months. Out of a total of 87 eyes in this group, seven eyes reached the 12-month follow-up and these eyes were within +0.50 and −0.50 D. Twentynine eyes have reached the 6-month follow-up (±0.50 D=86% and ±1.00 D=90%), and 51 eyes have reached the 3-month follow-up (±0.50 D=90% and ±1.00 D = 98%) (Fig. 3a and 3b).

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Figure 2 Postoperative refraction (SE) after LASEK in myopic eyes between −2.00 and −6.00 D. (a) 6-months follow-up. (b) 12-month follow-up.

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Figure 3 Postoperative refraction (SE) after LASEK in myopic eyes between −6.25 and −10.00 D. (a) 3-month follow-up. (b) 6-month follow-up.

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Figure 4 Stability of postoperative refraction. (a) For corrections between −2.00 and −6.00 D. (b) For corrections between −6.25 and −10.00 D. Both high and low myopia groups demonstrated excellent stability of postoperative refraction (Fig. 4a and 4b).

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Postoperative Visual Acuity Immediately after surgery, uncorrected visual acuity (UCVA) was 20/40 in all treated eyes. At day 7, all eyes had a UCVA of 20/40 or better. At 6 months, UCVA was 20/40 or better in 97% and 20/20 or better in 67%. Postoperative best corrected visual acuity (BC V A) was equal to or better than preoperative BCVA in 73% for corrections up to −6.00 D and 50% for corrections between −6.00 and −10.00 D; 24% (for corrections up to −6.00 D) and 37% (for corrections between −6.00 and −10.00 D) of the eyes improved by one Snellen line. In contrast 9% (for corrections up to −6.00 D) and 13% (for corrections between −6.00 and −10.00 D) of the eyes decreased by one line. No eye lost more than one line of BCVA (Fig. 5a and 5b). Postoperative Corneal Haze None of the eyes showed any significant subepithelial haze usually seen after PRK at any postoperative stage (Fig. 6a and 6b). Mean corneal haze was 0.16 (SD 0.18) for corrections up to −6.00 D and 0.19 (SD 0.17) for corrections between −6.00 and −10.0 D. Only a single eye, which lost the epithelial flap caused by the loss of the contact lens developed significant haze of +1. Postoperative Halos and Glare On direct questioning, only two patients (two eyes) noted halos around bright light sources at night. In all treated eyes the magnitude computerized measurements of halo was postoperatively greater than before the surgery. Objective halo measurements showed that there was an increase in size postoperatively compared to preoperatively from 430 mm2 (mean, SD ±238 mm2) to 1900 mm2 (SD ±563 mm2). No correlation was observed between halo size and degree of preoperative refractive error, but a significant correlation was found with preop size of the pupil under mesopic conditions.

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Figure 5 Safety of myopic LASEK. (a) For correction between −2.00 and −6.00 D. (b) For corrections between −6.25 and −10.00.

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Figure 6 Corneal transparency after LASEK. (a) Most corneas showed no haze after LASEK. (b) In a very few cases slight haze was seen at 3 months. Five patients (five eyes) reported glare at night but only one patient (one eye) mentioned that this glare interfered with night vision. The preoperative and postoperative

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measurements of glare caused by forward light scatter expressed as percentage contrast between the luminance of the background and match stimuli showed that without stray light, only marginal differences existed between the preoperative and postoperative readings. However, in the presence of the glare source, we noted an increase in postoperative glare compared to preoperative levels. Objective glare measurements confirmed that there was an increase in glare postoperatively caused by forward light scatter compared to preoperatively. In the presence of the glare, source the preoperative mean value was 7.8% (SD ±2.8%) compared to 11.8% (SD ±6.9%) at 3 months postoperatively.

CONCLUSIONS LASEK results in very good refractive outcomes for the treatment of myopia between −2.00 and −10.00 D. The postoperative refraction remains stable during the 12-month follow-up. Visual recovery after LASEK is relatively fast with the usual immediate postoperative uncorrected visual acuity of 20/40. After 1 week, most eyes have uncorrected visual acuity of 20/25 or better. No eye lost more than one line of Snellen acuity. There was no or minor postoperative corneal haze. Compared to PRK, ocular discomfort after LASEK was tolerated much better. Both subjective and objective tests of glare and halos after LASEK are comparable to PRK and LASIK. Because LASEK does not require stromal cut, problems in the long-term biomechanical instability of the cornea are avoided.

REFERENCES 1. American Academy of Ophthalmology. Ophthalmic procedure preliminary assessment: excimer laser photorefractive keratectomy (PRK) for myopia and astigmatism. Ophthalmology 1999; 106:422–437. 2. Sugar A, Rapuano CJ, Culbertson WW, Huang D, Varley GA, Agapitos PJ, de Luise VP, Koch DD. Ophthalmic procedure preliminary assessment: Laser in situ keratomileusis for myopia and astigmatism: safety and efficacy. Ophthalmology; 2002; 109:175–187. 3. Barraquer JI. Queratoplasty refractive. Estudios Inform Oftal Inst Barraquer; 1949; 10:2. 4. Nordan LT. Keratomileusis. Int Ophthalmol Clin; 1991; 31:7. 5. Ambosio Jr R, Wilson SE. Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surg; 2001; 17:350–379. 6. Roberts C. The cornea is not a piece of plastic. J Refract Surg; 2000; 16:407–413. 7. Camellin M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News International Edition; 1999; 3:14–15. 8. Lohmann CP, Fitzke FW, O’Brart DPS, Kerr Muir M, Marshall J. Halos: a problem for all myopes? A comparison between spectacles, contact lenses, and excimer laser photorefractive keratectomy. Refract Corneal Surg; 1993; 9:S72–S75. 9. Lohmann CP, Fitzke FW, O’Brart DPS, Kerr Muir M, Timberlake GT, Marshall J. Corneal light scattering and visual performance in myopes: a comparison between spectacles, contact lenses, and excimer laser photorefractive keratectomy. Am J Ophthalmol; 1993; 115:444–453.

15 LASEK vs. PRK: Comparison of Visual Outcomes Minh Hanh Duong, MD and Damien Gatinel, MD Service d’ophtalmologie, (Pr Hoang-Xuan), Hôpital Bichat, Fondation Rothschild, Université Paris VII Paris, France Laser subepithelial keratomileusis (LASEK) combines the advantages of photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) (1,2). Corneal haze seems reduced in LASEK compared to PRK. Several factors that could explain the reduction of the intensity of the corneal haze in LASEK technique include corneal epithelium replacement, alcohol epithelial debridement, and corneal stromal patching. This chapter reports the result of an investigation of the role of corneal epithelial replacement on postoperative pain, immediate visual recovery, and corneal haze by a comparative single masked study using the technique of LASEK or PRK with alcohol epithelial debridement. Myopic patients whose spherical equivalent was less than –5 diopters (D), and whose cylinder was less than or equal to 2 D were included in the study.

TECHNIQUE In LASEK, epithelial debridement was initiated using an 8-mm blade of Hanna’s trephine to trephine corneal epithelium. Twenty percent diluted ethanol in salt balanced solution was placed inside the blade for 30 seconds. We were careful to avoid spillage on the untreated area. The ethanol was absorbed by a merocel sponge afterwards. The epithelium was then irrigated with a balanced salt solution. Creation of the epithelial flap began at the edge of the epithelial trephination using a Troutman forceps. The epithelium was raised as a flap, leaving a hinge in the cornea at the 3 or 9 o’clock position. During the creation of the epithelial flap, we had the option of irrigating the cornea to avoid corneal desiccation. After drying the surface with a merocel sponge, the laser was applied on the exposed bed. We used a Nidek EC 5000 excimer laser as the delivery system. Our nomogram was 10% under correction to the spherical equivalent of the intended treatment. The stroma was rinsed and the epithelial flap was replaced with the same Troutman forceps. At the end of the procedure, soft bandage contact lens was placed to secure the flap and topical antibiotic was applied. In PRK, epithelial debridement and photorefractive keratectomy were performed similar to the LASEK technique. At the end of the procedure, the epithelial flap was removed, a soft bandage contact lens was placed, and topical antibiotic was applied.

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The patients were masked in terms of what procedure they underwent. However, our study design determined the first eye undergo LASEK and the second eye to undergo PRK. If the creation of the epithelial flap was unsuccessful in the first eye we converted to a PRK and treated the second eye with LASEK. Postoperative treatment included antibiotic drops (ciprofloxacin) four times daily, and a combination steroidal anti-inflammatory and antibiotic drops (dexamethasone and neomycin) twice daily for the first 4 days. The soft contact lens bandage was removed at the fifth postoperative day. The patient received the combined steroidal antiinflammatory and antibiotic drops four times daily for the next 7 days. To relieve postoperative pain, the patients were prescribed a combination of paracetamol (2,400 mg per day) and dextropopoxyphène (180 mg per day). The patients were examined at the first, fifth, and fifteenth postoperative day and then monthly thereafter. We analysed maximal postoperative pain, refractive outcomes, and corneal haze. Maximal pain was graded according to an analogical visual scale from 0 to 10. At each examination, we measured manifest refraction and corneal haze levels by slit-lamp examination and graded the haze according to the Food and Drug Administration (FDA) guideline protocol. Analysis of visual acuity was performed after converting decimal visual acuity to LogMAR equivalent. Statistical analyses were performed with the paired Student t test.

RESULTS We included 26 eyes of 13 patients, eight females and five males. Patients’ mean age was 30.4±5 (range 22–41) years. In the LASEK group, preoperative mean spherical equivalent was −2.6±1.1 diopters (D) (range −1.25 to −4.75), whereas in the PRK group it was −2.9±1.1 D (range −1.25 to −4.62). There was no statistical difference between the two groups. Mean preoperative astigmatism was 0.5±0.7 (range 0–2) D and 0.5±0.6 (range 0–1.75) in the LASEK and the PRK groups, respectively (non-statistically significant). Epithelial flap creation was unsuccessful in three cases (18.7%). Time spent to create the epithelial flap was approximately 8 minutes. We excluded one patient from our follow-up because the bandage contact lens and epithelium were removed on the first postoperative day. Mean postoperative pain grading was available in 11 patients. It was 5.7±2.37 (range 1–9) and 5.3±2.3 (range 1–8) in the LASEK group and the PRK group, respectively. In one case in which the postoperative pain was not graded, the patient reported much more pain in the PRK operated eye than in the LASEK operated eye. There was no statistical difference in mean postoperative pain between the two groups. The mean difference in pain level between PRK eye and LASEK eye for each patient was 0.8± 1.5 (range −1 to 3). Mean visual acuity recovery at the first postoperative examination was 0.63 ±0.16 (range 0.4–1.2) in the LASEK group and 0.70±0.36 (range 0.1–1.2) in the PRK group. There was no statistical significant difference between the two groups in terms of immediate visual recovery.

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Mean follow-up was 73.5±30.5 days (range 30–107) in the LASEK group and 73.9±46.6 days (range 71–197) in the PRK group. There was no statistical difference in follow-up duration between the two groups. Mean postoperative spherical equivalent was 0.33±0.68 D (range −1 to +1.5) in the LASEK group and 0.36±0.75 D (range −1.25 to +1.5). There was no statistical difference between the two groups concerning spherical equivalent outcomes. Mean postoperative astigmatism was 0.21±0.51 D (range 0–1.75) in the LASEK group and 0.23±0.36 D (range 0–1) in the PRK group. There was no statistical significant difference in postoperative astigmatism between the two groups. Best-corrected visual acuity (BCVA) postoperatively was 1.0±0.10 (range 0.7–1.2) in the LASEK group and 1.1±0.06 (range 0.8–1.2) in the PRK group. In the LASEK group, one patient lost 0.1 of BCVA, in the PRK group 2 patients lost 0.1 and 0.2 of BCVA. There was no statistical significant difference in postoperative BCVA between the two groups. Mean postoperative corneal haze at the last examination was 0.5±0.3 (range 0–1) in the LASEK group and 0.5±0.5 (range 0–2) in the PRK group. There was no statistical significant difference in mean postoperative corneal haze between the two groups.

DISCUSSION Mechanical epithelial debridement in traditional PRK for correction of low to moderate myopia induces moderate to severe pain, corneal haze, and delayed visual acuity recovery. By using the corneal epithelium to cover stroma after photoablation, the LASEK technique could theoretically maintain the safety of PRK while reducing pain, allowing for rapid corneal epithelium healing, and minimizing corneal haze. The role of the epithelium in the healing mechanism is unclear. Other factors in LASEK technique, including the use of alcohol debridement or soft contact lens patch, could explain pain relief and minimal corneal haze. In our single masked comparative study, we did not find any significant difference between LASEK and PRK with alcohol epithelial debridement concerning postoperative pain, refractive outcomes, and corneal haze. Corneal epithelial replacement in our study does not seem to play a role in postoperative pain and corneal haze intensity. In our study, both LASEK and PRK with alcohol epithelial debridement and soft contact lens patch induced little haze. There were three other studies (3–5) comparing the effectiveness and safety of LASEK with those of PRK. Lee et al. and Autrata et al. showed that LASEK reduced the incidence of significant postoperative pain and corneal haze, while Litwak et al. (6) reported that PRK resulted in better outcome. In both studies, the surgeons used mechanical scraping as a method for de-epithelialization in PRK. Lee et al. (3) performed a prospective study of 27 patients (54 eyes) with a manifest refraction of −3.00 to −6.50 D. PRK was performed in one eye and LASEK in the fellow eye. The choice of first eye to be treated and the surgical method were randomized. There was a 2-week interval between the procedures in all patients. Postoperative pain, epithelial healing time, uncorrected visual acuity (UCVA), manifest refraction, corneal haze, and surgical preference were examined. The patients were followed-up for 3

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months postoperatively. They reported that there were no significant between-eye differences in UCVA, refractive error, or epithelium healing time. However, LASEKtreated eyes had significantly lower postoperative pain scores and corneal haze than PRK-treated eyes. Further-more, at 3-month visit, 63% of the patients preferred the LASEK procedure. Litwak et al. (6) also performed a prospective study on 50 eyes of 25 patients with mild to moderate myopia (mean preoperative spherical equivalent [MSE]) −3.00, range −0.75 to −7.75). At 1 month, the UCVA was similar in both groups. No eye lost lines of BCVA or developed haze. At 1 day, 72% of the patients reported more discomfort in the LASEK-treated eye compared to 24% who reported more about the PRK-treated eye. At 3 days, 80% reported problems with the LASEK-treated eye and 4% reported problems with the PRK eye. More recently, Autrata et al. (5) reported results of a single-blinded, prospective, and comparative study between LASEK and PRK performed in 184 eyes of 92 patients with low to moderate myopia (MSE −4.65 D, range −1.75 to −7.50 D. At 1 week, the mean UCVA of the LASEK group was significantly better than the PRK group (0.64± 0.21 vs. 0.87±0.23, p=0.34). The difference in UCVA was not statistically significant after the 1month visit. The mean pain level was significantly lower on days 1 and 3 in the LASEK eyes (p<0.05). The mean corneal haze level was lower in the LASEK group (0.21) compared to the PRK group (0.43) −p<0.05). Eighty six percent of the patients preferred LASEK to PRK. There were several differences between these studies that may explain their different conclusions regarding postoperative discomfort. In Litwak et al. (6) the procedures were performed simultaneously in both eyes, whereas in Lee et al. (3) and Autrata et al. (5), there was a 2-week interval between procedures. The patients in these two studies were asked about discomfort immediately after the surgery and after 1 week, respectively. Furthermore, Litwak et al. found that it takes longer to loosen the corneal epithelium using diluted alcohol in Hispanic patients (minimal time to create a complete epithelial flap was 40 seconds). Abad et al. (7,8) found that chemical de-epithelialization using 18% to 20% alcohol applied for 30 seconds could be associated with a quicker visual rehabilitation as compared to mechanical scraping. The authors also noted a trend toward less subjective haze in patients who had alcohol debridement. Stein et al. (9) used 25% diluted alcohol and reported similar results. Carones et al. (10) also found that using alcohol epithelial debridement is associated with less haze compared to mechanical epithelial debridement. During wound healing after excimer laser photoablation, the keratocytes could be influenced by the regenerating epithelium (11). Covering the denuded surface of the cornea after PRK with the corneal epithelial flap may modify responses of the stromal keratocytes and the production of extracellular matrix and collagen, thereby reducing haze formation. In our study, we did not notice any difference in corneal haze with or without the epithelial flap. In a study with a follow-up of more than 1 year, Shah et al. (12) noticed that the haze was reduced when protecting the photoablated stroma with an epithelial flap without a soft bandage contact lens. We postulate that the second factor in corneal haze reduction after alcohol de-epithelialization could be the protection of the denuded stroma either by a soft bandage contact lens or by an epithelial flap. Further histological and large double-masked studies are necessary to confirm this hypothesis.

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ACKNOWLEDGMENT The authors acknowledge the assistance of Dr. Puwat Charukamnoetkanok in the preparation and review of the manuscript.

REFERENCES 1. Cimberle M, Camellin M. LASEK may offer the advantages of both LASIK and PRK.. Ocular Surgery News International; 1999; 10:28. 2. Camellin M. LASEK. Operative Techniques in Cataract and Refractive Surgery;, 2000. 3. Lee JB, Seong GJ, Lee JH. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 4. Lee JB, Kim JS, Choe C, Seong GJ, Kim EK. Comparison of two procedures: photorefractive keratectomy versus laser in situ keratomileusis for low to moderate myopia. Jpn J Ophthalmol; 2001; 45:487–491. 5. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy for myopia: two-year follow-up (1). J Cataract Refract Surg; 2003; 29:661–668. 6. Litwak S, Zadok D, Garcia-de Quevedo V, Robledo N, Chayet AS. Laser-assisted subepithelial keratectomy versus photorefractive keratectomy for the correction of myopia. A prospective comparative study. J Cataract Refract Surg; 2002; 28:1330–1333. 7. Abad JC, Talamo JH, Vidaurri-Leal J, Cantu-Charles C, Helena MC. Dilute ethanol versus mechanical debridement before photorefractive keratectomy. J Cataract Refract Surg; 1996; 22:1427–1433. 8. Abad JC, An B, Power WJ, Foster CS, Azar DT, Talamo JH. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology; 1997; 104:1566–1574. 9. Stein HA, Stein RM, Price C, Salim GA. Alcohol removal of the epithelium for excimer laser ablation: outcomes analysis. J Cataract Refract Surg; 1997; 23:1160–1163. 10. Carones F, Fiore T, Brancato R. Mechanical vs. Alcohol epithelial removal during photorefractive keratectomy. J Refract Surg; 1999; 15:556–562. 11. Li D, Tseng SCG. Three patterns of cytokine expression potentially involved in epithelialfibroblast interactions of human ocular surface. J Cell Physiol; 1995; 163:61–79. 12. Shah H, Sebai Sahran AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85:393–396.

16 LASEK vs. LASIK: Comparison of Visual Outcomes Neal J.Peterson, MD, Alice Z.Chuang, PhD, Rajy M.Rouweyha, MD, and Richard W.Yee, MD Hermann Eye Center, University of Texas Health Science Center at Houston Houston, TX

INTRODUCTION Photorefractive keratectomy (PRK) has been demonstrated to be a safe and effective treatment of low to moderate myopia (1,2). Since the introduction and advancement of the excimer laser, increasingly excellent results are being achieved with PRK. Despite these excellent results, postoperative pain, a relatively long recovery period, and the development of stromal haze limit the role of PRK in the current refractive surgery arena (3). Laser in situ keratomileusis (LASIK) has largely replaced PRK. LASIK offers the advantages of minimal postoperative pain or discomfort, rapid visual recovery, good refractive stabilization, and absence of stromal haze development. These advantages, especially the rapid visual recovery and minimal discomfort, led to the rapid popularization of LASIK. This popularization continues to guide additional patients to select refractive surgery for the correction of their myopia. Unfortunately, LASIK is not the perfect refractive surgery. Several studies comparing long-term outcomes of LASIK to PRK have failed to demonstrate any superiority of LASIK (4,5). Additionally, the creation of the lamellar flap in LASIK is associated with many well-described complications (6–11). These complications may potentially cause significant visual impairment and thus limit the usefulness of LASIK. The risks associated with flap formation have influenced some refractive surgeons to select PRK as their procedure of choice over LASIK. Recent advancements in wavefront-guided ablation technology have additionally increased the current interest in refractive techniques that do not require a lamellar flap (12,13). The ideal refractive surgery would combine the safety of PRK with the comfort and rapid visual recovery of LASIK. In 1996, Azar (14) first performed a refractive surgery that had the potential to combine the advantages of these two refractive surgery techniques. The technique was called the “alcohol-assisted flap PRK.” Later, a slightly modified technique called laser epithelial keratomileusis (LASEK) was described and popularized by Massimo Camellin, MD in 1999 (15). Camellin proposed that this hybrid of PRK and LASIK eliminates the shortcoming while still maintaining the advantages of each individual procedure. In LASEK, the

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central corneal epithelium viability is maintained. Thus LASEK has the potential of providing a quick visual recovery with minimal discomfort while eliminating the need for a microkeratome and possible flap-related complications. Since Camellin first coined the acronym LASEK, several alternate names have been used to describe this technique. Among these alternate names are laser-assisted subepithelial keratectomy (16), subepithelial PRK (17), laser subepithelial keratomileusis (18), and epi-LASEK (19). In this chapter, we present the data from our own cohort of LASEK-treated and LASIK-treated eyes and review the current literature comparing the long-term outcomes of LASEK and LASIK performed in patients with low to high myopia.

PATIENTS AND METHODS We retrospectively reviewed the records of 63 consecutive eyes (35 patients) treated with LASEK for myopia ranging between −1.50 to −14.75 diopters (D) (mean −7.40± 2.71 D) with and without astigmatism. Fourteen LASEK-treated eyes were corrected for monovision and were thus eliminated from refractive outcomes analysis. The remaining 49 emmetropia-targeted LASEK-treated eyes were evaluated for refractive outcomes analysis. A similar cohort of 84 consecutive eyes (43 patients) treated with LASIK for myopia ranging between −2.75 to −11.25 D (mean −6.10±2.17 D) with and without astigmatism was also analyzed. Twelve LASIK-treated eyes were corrected for monovision and were eliminated from refractive outcomes analysis. The remaining 72 emmetropia-targeted LASIK-treated eyes were evaluated for refractive outcomes analysis. All LASEK-treated eyes were assessed for corneal haze development. All LASEK-treated and LASIK-treated eyes were assessed for the number and type of enhancement procedures required over 12 months of follow-up. A single surgeon (R.W.Y.) performed all refractive surgeries during a 14-month period using the Alcon Summit Autonomous LADAR Vision excimer laser (Orlando, FL). Ablation diameters ranged from 6 to 8 mm based on scotopic Colvard pupillometry measurements. Ablation depths varied from 18 to 174 µm based on preoperative myopia. Both spherical myopia and myopia with astigmatism were treated. Uncorrected visual acuity, manifest refraction, best-spectacle Snellen visual acuity, stability of refraction, enhancement procedures performed, development of haze, and development of other complications were assessed before and up to 12 months after surgery. LASEK-treated and LASIK-treated eyes were examined on day 1, at 1 and 2 weeks, and at 1, 3, 6, and 12 months. Comparisons of the two techniques were made at these time points. Twelve-month data were available for 33 LASEK-treated and 36 LASIK-treated eyes. LASEK Technique A lid speculum is applied to ensure adequate exposure, and the cornea is marked inferiorly. This is followed by epithelial micro-rephination. Using a 60-to 80-µm deep calibrated blade, the trephine is centered on the pupil, pressed down, and rotated slightly. The 270-degree trephine is specially designed to leave a hinge of 60 to 80 degrees at the

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12-o’clock position. We used two ring sizes for our epithelial micro-trephinations: 8.0 mm and 9.0 mm. The larger 9.0-mm trephine was used for larger treatment zones. A cylindrical well with a diameter 0.5 mm wider than the incision is then centered on the pupil encircling the previous incision. Several drops of 20% ethanol solution (created by diluting nonpreserved absolute ethanol in balanced salt solution) are instilled into the well. This 20% ethanol solution is left in contact with the corneal epithelium for approximately 45 seconds. The ethanol solution is then removed using a dry weck cell sponge, followed by a thorough rinsing of the cornea epithelium with balanced salt solution. The inferior margin of the epithelium is lifted using a blunt end of a number 69 Beaver blade and gently peeled toward the 12-o’clock position. As the epithelium is gathered toward the 12-o’clock position, the hinge left on micro-trephination maintains epithelial attachment. Once the epithelial flap is completely gathered at the 12-o’clock position, a standard small-spot PRK ablation is performed. Once ablation is complete, the epithelial flap is repositioned using a fine canula or small spatula. Extra care is taken to smooth the epithelial surface without creating tears in the epithelium. Finally, a soft contact lens (B&L Purevision) is placed on the eye and left in position for 3 to 4 days to protect the epithelial flap. The lid speculum is removed, and epithelium and contact lens position are examined by slit-lamp microscopy. Several specially designed surgical tools have been designed for use in LASEK. These tools include a micro-trephine with an 80-degree hinge (Janach J2900S) and the alcohol solution well (Janach J2905), which may be used in the initial steps of microtrephination and ethanol-assisted epithelial debridement. In addition, the epithelial microhoe (Janach J2915A) and repositioning spatula (Janach J2920A) may make flap removal and repositioning easier.

RESULTS Baseline demographic and refractive characteristics of the LASEK and LASIK-treated groups are presented in Table 1. There was no difference in the age or sex ratio of the two groups, but a statistically significant difference in the degree of preoperative myopia was noted. LASEK-treated eyes were significantly more myopic than LASIK-treated eyes. The preoperative mean spherical equivalent (MSE) of the LASEK-treated eyes was −7.40±2.71 D, compared to −6.10±2.17 D in LASIK-treated eyes (p=0.002). This difference was caused by selection criteria used to determine good candidates for LASIK. Patients with insufficient corneal thickness for LASIK were given the option of LASEK for correction of their myopia. After the initial healing period, LASEK-treated eyes obtained refractive outcomes comparable with that of LASIK-treated eyes. Figure 1 shows the cumulative percent of eyes with uncorrected visual acuity (UCVA) better than 20/40 for each treatment group at consecutive time intervals. After the first 2 weeks, there was no statistically significant

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Table 1. Baseline Demographic and Refractive Data. Eyes

Sex (M/F)

Mean Age, y (range)

Preoperative MSE* (D)

LASEK

63

12/14

40.29±7.94 (27–62)

−7.40±2.71

LASIK

84

23/20

39.63±10.43 (20 to 60)

−6.10±2.17

0.65

0.76

0.002†

P value

*Mean spherical equivalent. †Statistically significant P < 0.05.

Figure 1 Cumulative percent of all LASEK and LASIK eyes with UCVA better than 20/40 at consecutive time intervals. difference observed between the two groups and the percent of eyes that achieved UCVA better than 20/40 (p < 0.0001 at day 1, p < 0.005 at weeks 1 and 2, p > 0.05 at all other time points). The difference in refractive outcomes seen during the first 2 weeks of recovery was most likely caused by epithelial flap irregularity (20). Figure 2 shows the cumulative percent of LASEK-treated eyes that obtained UCVA of 20/20, 20/25, and 20/40 at time points 1, 3, 6, and 12 months. The percent of eyes obtaining UCVA of 20/20 continued to increase from 52% (n=46) at 1 month to 67% (n=33) at 12 months. In contrast, the cumulative percent of eyes maintaining UCVA of at least 20/40 displayed a slight regressive trend from 93% (n=44) of eyes at 3 months to 88% (n=33) of eyes at 12 months.

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Figure 2 Cumulative uncorrected visual acuity in LASEK-treated eyes.

Figure 3 Cumulative uncorrected visual acuity in LASIK-treated eyes. Distribution of UCVA obtained in LASIK-treated eyes is portrayed in Figure 3. The percent of LASIK-treated eyes obtaining UCVA of 20/20 was 54% (n=70) at 1 month, and increased to 75% (n=36) by 12 months. Unlike the slight regressive pattern seen by 12 months in LASEK-treated eyes, the 87% (n=70) of LASIK-treated eyes with UCVA of at least 20/40 at 1 month increased to 97% (n=36) by 12 months.

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Figure 4 is a scattergram of attempted vs. achieved refraction of the LASEK-treated and LASIK-treated eyes at 12 months. At 12 months, 58% (n=33) of LASEK-treated eyes and 75% (n=36) of LASIK-treated eyes were within 0.5 D of emmetropia. This difference observed at 12 months did not reach statistical significance (p=0.14). Figure 5 shows the percent of eyes within 0.5 D at time points 1, 3, 6, and 12 months for LASEK and LASIK groups. The defocus equivalent more accurately measures residual refractive errors after refractive surgery than does the spherical equivalent (21). In contrast to the spherical

Figure 4 Scattergram of attempted vs. achieved refraction at 12 months.

Figure 5 Percent of eyes within 0.5 D of emmetropia at consecutive time points.

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equivalent, which may mask refractive errors through offsetting spherical and cylindrical components, the defocus equivalent takes into account only the absolute value of refractive errors. The defocus equivalent is calculated in the following equation: defocus equivalent = |sphere| + |½ cylinder|. Figures 6 and 7 depict the defocus equivalent of LASEK-treated and LASIK-treated eyes at 1 month and 12 months, respectively. In general, LASEK-treated eyes trended toward a slightly increased defocus equivalent from month 1 to month 12, whereas LASIK-treated eyes retained a stable defocus equivalent over the 12–month period. Refractive stability was obtained within 1 month and was maintained for the entire year for LASIK-treated eyes. LASEK-treated eyes rapidly progressed to near emmetropia within the first month, but then proceeded to follow a gradual trend of regression over the next 12 months. The trend of refractive stability of both procedures is portrayed in Figure 8. Mean spherical equivalent for LASEK-treated eyes at 1 month was 0.10±0.73 D, and −0.24±0.67 D for LASIK-treated eyes (p=0.01). By 12 months, the mean

Figure 6 Percent eyes at consecutive defocus equivalents at 1 month.

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Figure 7 Percent eyes at consecutive defocus equivalents at 12 months. spherical equivalent was −0.68±1.08 D and −0.27±0.56 D for LASEK-treated and LASIK-treated eyes, respectively (p=0.06). The safety of both procedures was exceptional. No eye treated with LASEK or LASIK had lost two or more lines of best-corrected visual acuity (BCVA) at 12 months. The distribution of eyes and lines of BCVA gained or lost at 12 months is depicted in Figure 9. Complications Overcorrections of greater than 0.5 D occurred in seven LASEK-treated eyes (n=45) and in four LASIK-treated eyes (n=70) at 1 month. No clinically significant difference was

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Figure 8 Plot graph of mean spherical equivalent from pre-op to 12 months.

Figure 9 Change in BCVA at 12 months from baseline. noted between the rates of overcorrection in the two groups (p=0.10). Overcorrection was more likely to occur in LASEK-treated eye with a higher degree of myopia. By 12 months, 1 LASEK (n=33) and 1 LASIK-treated eye (n=36) remained overcorrected. Haze development is a concern in PRK-like procedures and is more common with deeper ablation depths. It has been proposed that the incidence of haze is decreased in

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LASEK as compared to PRK (22–24). Our LASEK-treated eyes were followed-up and examined for signs of haze development during the 12-month follow-up period. The presence of haze was recorded as follows: 0=no haze, clear cornea; trace (grade 0.5)= haze barely discernable by slit-lamp microscopy; grade 1=haze easily seen with slit-lamp microscopy but does not affect vision; grade 2=dense haze that affects vision; grade 3=dense haze that obscures some iris details; and grade 4=dense haze that completely obscures iris details. The incidence of haze developing at any point during the 12-month follow-up period in LASEK-treated eyes was 51% (n=63). Figure 10 shows the distribution of maximum

Figure 10 Maximum haze grade in LASEK-treated eyes by 12 months. haze development during the 12-month follow-up period. The mean grade of maximum haze development over 12 months was 0.50±0.63. Six eyes in five patients had clinically significant haze (grade 2+) develop. Clinically significant haze was more likely to develop in eyes with a higher degree of myopia, thus requiring deeper ablation depths. The mean degree of preoperative myopia in eyes with clinically significant haze developing was −9.75±2.44 D (range −7.88 to −14.50 D). By 12 months, 11 eyes in eight LASEK patients had undergone regression for a rate of 17% (n=63). Four of the regressed eyes developed 2+ corneal haze during the regression process. At 12 months, all 11 eyes had BCVA of 20/25 or better. One additional patient had a posterior subcapsular cataract develop, along with late-onset 2+ corneal haze in one LASEK-treated eye at 12 months. Eleven eyes in eight LASIK patients also underwent regression, for a rate of 13% (n=84). At 12 months, all 11 eyes had BCVA of 20/25 or better. One LASIK-treated eye developed epithelial in-growth that did not require retreatment. Additionally, one LASIKtreated eye incurred a vitreous detachment at 10 months. No intra-operative flap related complications were encountered. Enhancement procedures were performed on LASEK-treated and LASIK-treated eyes that had undergone regression, had residual astigmatism, or that remained overcorrected. Enhancement procedures included second LASEK and LASIK procedures, along with

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astigmatic keratotomy. Through the 12 months, 19 LASEK-treated eyes and 27 LASIKtreated eyes required enhancement procedures, for a rate of 30% (n=63) and 32% (n=84), respectively. Of the eyes that required enhancement, 11 (17%) of the LASEK-treated eyes, compared to 14 (17%) of the LASIK-treated eyes, had a second LASEK or LASIK procedure for enhancement. No statistical difference was noted between the rates of enhancement procedures, the type of enhancement procedures performed (AK vs. reLASIK/LASEK), or the number of enhancement procedures performed on a single eye.

DISCUSSION We add our cohort of LASEK-treated eyes to the growing body of studies demonstrating LASEK to be a safe and effective treatment for a wide range of myopia with and without astigmatism. Our LASEK-treated eyes maintained uncorrected visual acuity comparable to their LASIK-treated counterparts in this study. Even though good visual acuity was maintained, LASEK-treated eyes followed a slight regressive pattern. Approximately −0.75 D of myopic regression was seen when mean spherical equivalents were followed from month 1 to month 12. This regressive trend may be due to the high degree of preoperative myopia treated with LASEK. This myopic regression in LASEK has not been previously reported. Many studies report excellent long-term refractive outcomes for LASEK-treated eyes. Shahinian (16) followed a cohort of 146 LASEK-treated eyes for a 12-month period. He found that after 12 months, 56% of his LASEK-treated eyes had an UCVA of 20/20 whereas 96% maintained UCVA of 20/40 or better (n=55). In addition, the mean refraction of his cohort was stable and close to zero from month 1 to month 12, indicating no myopic regression. Claringbold (25) reports similar refractive outcomes in his cohort of 222 myopic eyes treated with LASEK. At 12 months, 82% of LASEK-treated eyes had an UCVA of 20/20, and 100% had UCVA 20/25 or better (n=84); 96.4% of eyes were within ±0.5 D of intended correction, and all eyes were within ±0.75 D. Anderson et al. (19) conducted the largest study of LASEK-treated eyes to date. They treated and followed-up 343 eyes for up to 6 months. In this study, the authors found that 85% of LASEK-treated eyes were within ±0.5 D and 94% were within ±1.0 D of the intended correction at 6 months (n=115); 98% of eyes maintained UCVA of at least 20/40 through 6 months (n=122). Autrata et al. (26) performed the LASEK study with the longest follow-up period. Their cohort consists of 92 patients with low to moderate myopia who underwent LASEK in one eye and PRK in the other. All eyes were followed-up for a 24-month period, without any patients lost to follow-up. At 24 months, 91% of LASEK-treated eyes had UCVA better than 20/40, with 62% of eyes within ±0.5 D and 92% within ±1.0 D of the intended refraction (n=92). Although not discussed in the study, their PRK and LASEK-treated eyes followed a myopic regression pattern similar to that seen in our cohort. Their mean spherical equivalent at 1 month was 0.81±0.95 D, which slowly regressed to −0.21±0.43 D by 12 months. From month 12 to 24, refraction stabilized. This 1.0 D of myopic regression is very similar to the 0.75 D of regression observed in our LASEK-treated eyes with low to high myopia.

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Because of its enormous popularity, an increasing number of patients seek out refractive surgeons to perform LASIK for correction of myopia. As was seen in our cohort of patients, many potential refractive surgery candidates are prevented from having LASIK because of inadequate corneal thickness. In this situation, LASEK should be offered as the refractive surgery of choice. Several additional clinical situations are encountered when LASEK has been proposed as the primary refractive surgery modality. These situations include: patients with steep or flat corneas; patients involved in activities or occupations that predispose them to eye trauma and possible flap dehiscence; large pupils that require a wider and therefore deeper ablation; high myopia; keratoconus suspect; deep-set eyes; narrow palpebral fissure; glaucoma; filtering blebs; anterior scleral buckle; previous vitrectomy; optic nerve drusen; dry eye disease; and cases of patient apprehension caused by microkeratome use (14,16,19). Elimination of the microkeratome is the major advantage of LASEK over LASIK. Avoiding use of the microkeratome prevents flap-related complications such as complete flap removal, flap slippage, diffuse lamellar keratitis (DLK), epithelial ingrowth, peripheral flap melt, flap dehiscence, buttonhole, incomplete flap, deep infectious keratitis, corneal perforation, and corneal ectasia (6–11,27,28). The epithelial flap created in LASEK is not known to be associated with the same complications seen with the lamellar flap of LASIK. Even in the worst-case scenario, if the epithelial flap is completely removed during LASEK, the procedure simply becomes a standard PRK, which has been repeatedly shown to be a safe and effective treatment for myopia with excellent and predictable refractive outcomes. Scerrati (29) describes two additional advantages of LASEK over LASIK. He found that his group of 30 LASEK-treated eyes had fewer aberrations as compared to 30 LASIK-treated eyes when comparing corneal topographic meridian values. This LASEK group also had better contrast sensitivity at 3 months and substantially increased contrast sensitivity at 6 months compared to the LASIK-treated eyes. When Camellin first described LASEK, he proposed that it had the advantages of less postoperative pain and haze than is seen in PRK. Several studies have investigated these claims by conducting prospective, comparative, paired eye trials in which one eye is treated with PRK and the other with LASEK in the same patient (23,24,26,30). All three studies designed to investigate corneal haze found that mean corneal haze was significantly less in LASEK-treated eyes as compared to their PRK-treated counterparts. Lee et al. (23) found that haze was significantly reduced at 1 month, but that there was no difference in the amount of haze at 3 months. Shah et al. (24) found LASEKtreated eyes had a statistically significant reduction in haze at 12 months as compared to their PRK paired eye. Autrata et al. (26) found a statistically significant reduction in mean corneal haze score at all time points investigated (1, 3, 6, 12, and 24 months). Reported maximal mean corneal haze scores range from 0.46 (24) to 0.73 (26). Our maximal mean corneal haze score was 0.50±0.63 for the 12 months that LASEK-treated eyes were followed-up. This haze score is akin to previously reported scores, despite the high degree of preoperative myopia treated in our LASEK group. Anderson et al. (19) reported clinically significant haze developing in 1.6% of LASEK-treated eyes (n=295). We observed clinically significant haze developing at a rate of 9.5% in our cohort of LASEK-treated eyes. The difference seen may be attributable to the high degree of preoperative myopia treated in our cohort. Shahinian

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(16) reports that haze development was more common in eyes with higher preoperative myopia. In our cohort, eyes that developed clinically significant haze likewise had a higher degree of myopia than did eyes that remained haze-free. Mild discomfort and foreign body sensation are seen in LASEK during the first few days postoperatively. Several studies have demonstrated less pain associated with LASEK than with PRK. Lee et al. (24) found that patients rated pain levels on a subjective pain scale significantly less in LASEK-treated than in PRK-treated eyes. Autrata et al. (26) also found that LASEK resulted in an overall decreased pain score on days 1 through 3, as reported by patients on a questionnaire of subjective pain levels. Anderson et al. (19) reported that 87% of LASE K-treated eyes experienced no postoperative pain (n=342). One study contradicts these results and claims that LASEK results in more postoperative pain than PRK. Litwak et al. (30) found that 72% of their patients reported more discomfort on day 1 in LASEK-treated than PRK-treated eyes (n=25). This increased to 80% of patients reporting more discomfort in the LASEK eye by day 3. It is postulated that the epithelial flap is responsible for the decreased incidence of haze and pain seen in LASEK by conferring mechanical and immunochemical protection. As such, much research has gone into determining the factors involved in this protection and the extent of cell viability maintained by the epithelial flap. Corneal epithelial cell viability has been demonstrated in cells exposed to 20% alcohol for up to 30 seconds (31–33). The viability of these cells fell off markedly when exposed to higher concentrations of alcohol, or duration exceeding 45 seconds. After exposing the corneal epithelial cell to alcohol for 60 seconds, the majority of cells had died (31). Removal of the corneal epithelium causes damage to the underlying stromal keratocytes. Decreases in keratocyte density are known to lead to increased keratocyte density and increased collagen and extracellular matrix synthesis (24). This activation of stromal keratocytes is believed to play a role in the subepithelial haze seen in PRK. Various cytokines are also known to function in stromal wound healing after excimer laser keratectomy. Among these cytokines are transforming growth factor β (TGF-β) and keratinocyte growth factor. TGF-β expression is increased in tears after PRK (34). Increased TGF-β expression and TGF-β receptor expression play a key role in the activation and proliferation of stromal keratocytes. Activation of stromal keratocytes leads to the deposition of extracellular matrix and the formation of corneal fibrosis, scarring, and haze (35). Lee et al. (36) demonstrated that levels of TGF-β1 and other cytokines released in the tears are decreased in eyes treated with LASEK than in eyes treated with PRK. This decreased cytokine production may be one of the reasons for less haze formation after LASEK. In addition, a viable epithelial flap further decreases stromal exposure to these cytokines by acting as a mechanical barrier blocking tears from reaching freshly ablated and healing stroma. Lastly, this epithelial flap acts as a biological therapeutic lens that protects the ablated stroma and may reduce pain levels. In conclusion, LASEK offers a safe and effective treatment for low to high myopia. LASEK may be offered in many situations in which LASIK is not an option. Refractive outcomes for LASEK are excellent and comparable to refractive outcomes achieved with LASIK. By eliminating the use of a microkeratome, LASEK avoids any of the flaprelated complications seen in LASIK. The rate of haze formation in LASIK is low but may be more likely with deeper ablation depths. LASEK-treated eyes have less haze

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formation and pain than do PRK-treated eyes. Finally, lower residual aberrations that are achieved in LASEK may maximize the advantages of wavefront-guided ablations.

REFERENCES 1. Gartry DS, Kerr Muir M, Marshall J. Excimer laser photorefractive keratectomy: 18-month follow-up. Ophthalmology; 1992; 99:1209–1219. 2. Salz JJ, Maguen E, Nesburn AB. A two-year experience with excimer laser photorefrative keratectomy for myopia. Ophthalmology; 1993; 100:873–882. 3. Alio JL, Artola A, Claramonte PJ. Complications of photorefractive keratectomy for myopia: two-year follow-up of 3000 cases. J Cataract Refract Surg; 1998; 24:619–626. 4. Hersh PS, Brint SF, Maloney RK. Photorefractive keratectomy versus laser in situ keratomileusis for moderate to high myopia. A randomized prospective study. Ophthalmology; 1998; 105:1513–1523. 5. Pop M, Payette Y. Photorefractive keratectomy versus laser in situ keratomileusis. A controlmatched study. Ophthalmology; 2000; 107:251–257. 6. Melki SA, Azar DT. LASIK complications: etiology, management, and prevention. Survey of Ophthalmology; 2001; 46:95–116. 7. Jacobs JM, Taravella MJ. Incidence of intraoperative flap complications in laser in situ keratomileusis. J Cataract Refract Surg; 2002; 28:23–28. 8. Lin RT, Maloney RK. Flap complications associated with lamellar refractive surgery. Am J Ophthalmol; 1999; 127:129–136. 9. Stulting RD, Carr JD, Thompson KP. Complications of laser in situ keratomileusis for the correction of myopia. Ophthalmology; 1999; 106:13–20. 10. Knorz MC. Flap and interface complications in LASIK. Curr Opin Ophthalmol; 2002; 13: 242– 245. 11. Ambrosio R Jr, Wilson SE. Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surg; 2001; 17:350–379. 12. Panagopoolou SI, Pallikaris IG. Wavefront customized ablations with the WASCA Asclepion Workstation. J Refract Surg; 2001; 17:S608–S612. 13. Wilson SE, Mohan RR, Hong J-W. The wound healing response after laser in situ keratomileusis and photorefractive keratectomy: elusive control of biological variability and effect on custom laser vision correction. Arch Ophthalmol; 2001; 119:889–896. 14. Azar DT, Ang RT, Lee JB. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12:323–328. 15. Cimberle U, Camellin M. LASEK may offer advantages of both LASIK and PRK. Ocular Surg News Int; 1999; 10:14–15. 16. Shahinian L Jr. Laser-assisted subepithelial keratectomy for low to high myopia and astigmatism. J Refract Surg; 2002; 28:1334–1342. 17. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(supplement):S222–S223. 18. Dastjerdi MH, Soong HK. LASEK (laser subepithelial keratomileusis). Curr Opin Ophthalmol; 2002; 13:261–263. 19. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK for the correction of myopia and myopic astigmatism. J Cataract Refract Surg; 2002; 28:1343–1347. 20. Rouweyha RM, Chuang AZ, Mitra S. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18:217–224. 21. Waring GO. Standard graphs for reporting refractive surgery. J Refract Surg; 2000; 16: 459– 466.

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22. Lee JB, Choe C-M, Seong GJ. Laser subepithelial keratomileusis for low to moderate myopia: 6-month follow-up. Jpn J Ophthalmol; 2002; 46:299–304. 23. Lee JB, Seong GJ, Lee JH. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 24. Shah S, Sebai Sarhan AR, Dole SJ. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85:393–396. 25. Claringbold TV. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 26. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy for myopia: two-year follow-up. J Cataract Refract Surg; 2003; 29:661–668. 27. Mifflin M, Kim M. Laser in situ keratomileusis flap dehiscence 3 years postoperatively. J Cataract Refract Surg; 2002; 28:733–735. 28. Sridhar MS, Rapuano CJ, Cohen EJ. Accidental self-removal of a flap—a rare complication of laser in situ keratomileusis surgery. Am J Ophthalmoly; 2001; 132:780–782. 29. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg; 2001; 17(supplement):S219–S221. 30. Litwak S, Zadok D, Garcia-de Quevedo V. Laser-assisted subepithelial keratectomy versus photorefractive keratectomy for correction of myopia. A prospective comparative study. J Cataract Refract Surg; 2002; 28:1330–1333. 31. Gabler B, Winkler Von Mohrenfels C, Dreiss AK. Vitality of epithelial cells after alcohol exposure during laser-assisted subepithelial keratectomy flap preparation. J Cataract Refract Surg; 2002; 28:1841–1846. 32. Chen CC, Chang JH, Lee JB. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43:2593–2602. 33. Dreiss AK, Winkler Von Mohrenfels C, Gabler B. Laser epithelial keratomileusis (LASEK): histological investigation for vitality of corneal epithelial cells after alcohol. Klin Monatsbl Augenheilkd; 2002; 219:365–369. 34. Vesaluoma M, Teppo AM. Gronjagen-Riska C, Tervo T. Release of TGF-beta 1 and VEGF in tears following photorefractive keratectomy. Curr Eye Res; 1997; 16:19–25. 35. Kaji Y, Mita T, Obata H. Expression of transforming growth factor β superfamily and their receptors in the corneal stromal wound healing process after excimer laser keratectomy (letter). Br J Ophthalmol; 1998; 82:462–463. 36. Lee JB, Choe CM, Kim HS. Comparison of TGF- β1 in tears following laser subepithelial keratomileusis and photorefractive keratectomy. J Refract Surg; 2002; 18:130–134.

17 Topography-Based Aberration in LASEK vs. PRK and LASIK Michael K.Smolek, PhD, Stephen D.Klyce, PhD, and Loan Nguyen, MD LSU Eye Center New Orleans, LA Richard W.Yee, MD and John P.Stokes, MD Hermann Eye Center, University of Texas Health Science Center at Houston Houston, TX Marguerite B.McDonald, MD Southern Vision Institute New Orleans, LA

INTRODUCTION The current state of the art of excimer laser vision correction encompasses three basic types of surgical procedures: photorefractive keratectomy (PRK), laser in-situ keratomileusis (LASIK), and laser epithelial keratomileusis (LASEK). Given the recently acquired ability to extract detailed optical aberration information from ocular and corneal topography wavefronts, interest has turned to how these three procedures compare in terms of their average optical performance. Does the LASEK procedure generate fewer aberrations than PRK or LASIK, or does it produce a similar outcome? Although all three procedures use excimer laser ablation to reshape the cornea, the methods differ in complexity and in the complications that may arise during and after surgery. Some of these complications directly affect optical aberrations and visual performance. The PRK procedure was first described by Trokel in 1983 (1), and there soon followed a number of studies on the mechanisms and efficacy of the ablation process (2–4). PRK in blind-eye human studies was reported soon after Trokel’s description (5,6), and the first sighted-eye case report was presented by McDonald in 1989 (7). The PRK procedure requires the surgical removal of a circular patch of epithelium over the central cornea (typically by debridement), followed by precisely controlled reshaping of the stroma through tissue ablation with the excimer laser (8). After ablation, epithelial cells must proliferate and migrate over the ablated stromal surface from the intact peripheral epithelium, a process that usually takes 3 to 5 days. PRK complications can include corneal haze, halos, glare, postoperative pain, and a regression from the desired refractive correction (9,10).

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The LASIK procedure was patented by Peyman in the mid 1980s (11,12), later clinically introduced by Pallikaris in 1989 (13), and subsequently described by Burrato (14,15). The LASIK procedure requires the temporary lifting of a thinly cut flap of anterior stromal tissue under which the stromal bed is reshaped by the excimer laser. Creation of the flap by a microkeratome requires surgical expertise and sets it apart from ordinary PRK. LASIK has a number of clinically significant advantages over PRK, including reduced likelihood of haze and pain because of the retention of an intact central epithelium. In addition, LASIK shows less regression of the desired refractive effect. However, LASIK does have unique complications that include problems associated with the creation or replacement of the flap, epithelial ingrowth or other infiltrates occurring beneath the flap, and the possibility of corneal distension resulting from a stromal bed that is too thin to support the tensile forces arising from intraocular pressure (16,17). LASEK was introduced by Camellin in 1999 (M. Camellin, MD. “LASEK May Offer the Advantages of Both LASIK and PRK.” Ocular Surgery News, International Edition, March 1999). Only a few reports on LASEK have been published to date (18–20). In a simplistic sense, LASEK is an attempt to use the best aspects of PRK and LASIK while avoiding the worst complications of either procedure. The typical LASEK procedure begins with the controlled application of diluted alcohol to initiate the release of epithelium from the stroma. The epithelial cells remain attached to one another in a sheet through retention of intercellular junctions, but the basement epithelial cells release their binding to the basement membrane. The intact epithelial sheet (typically circular) is carefully scraped from the central cornea, but an attachment to the cornea along a hinge of epithelium is retained. The bare stroma is then ablated by the excimer laser just as in PRK, and the sheet of epithelium is repositioned over the cornea. The LASEK procedure has been shown to significantly increase postoperative comfort for the patient as compared to PRK (19). In the current study, we evaluated the corneal topography of LASEK, PRK, and LASIK for corneal wavefront aberrations preoperatively and at specific times in the early postoperative period. Data were compared to determine whether significant differences exist between LASEK and PRK or LASIK in terms of aberrations caused by corneal shape.

MATERIALS AND METHODS This study was conducted in accordance with the Declaration of Helsinki for human research. All data were acquired retrospectively from historical examination records for two surgeons at two different clinics: Dr. McDonald for the Southern Vision Institute in New Orleans, Louisiana and Dr. Yee for the Hermann Eye Center at the University of Texas in Houston, Texas. All eyes in the study were treated for low to moderate amounts of myopic astigmatism. Although all of the corrections included astigmatism, in this report we use the generic acronyms of LASEK, PRK, and LASIK when referring to the three cohorts. All LASEK data came exclusively from the Hermann Eye Center, where the corneal topography was recorded with an EyeSys 2000 corneal topographer. All PRK and LASIK data were provided by the Southern Vision Institute and recorded with the Tomey TMS corneal topographer. Records were reviewed for quality of the topographic

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examinations, and topographic maps suitable for analysis were collected for preoperative examinations and at follow-up examinations at 1 week, 1 month, 3 months, and 6 months, postoperatively. Different lasers were known to be used among the three cohorts, but no information was recorded to specify whether different laser software or nomograms were used within each cohort. Details about the LASEK, PRK, and LASIK patient cohorts are shown in Table 1. All corneal topography was identically analyzed for corneal wavefront aberrations using CTView version 3.18 (Sarver and Associates, Merritt Island, FL). CTView is a

Table 1. Cohort Information. Procedure

Number of Eyes

Number of Patients

Laser System

LASEK

31

18

Autonomous LadarVision

PRK

21

14

Nidek ED-5000

LASIK

31

23

Autonomous LadarVision

software application that provides identical topographic and wavefront analysis to be performed with data from different commercial topography systems. CTView was set to its default settings using a 10-mm corneal diameter topographic fit to determine the focal point of the cornea and a 4-mm “entrance pupil” diameter for determination of the wavefront errors. Wavefront error was specified as the sum of the RMS (root mean square) error of Zernike polynomial coefficients describing wavefront shape, which avoided dealing with sign differences for terms in left and right eyes when raw Zernike coefficients are used (21). Only specific aberration types were collected for this study: total aberrations for the second to sixth order, low aberrations of the second order, highorder aberrations of the third to sixth order, second-order astigmatism, second-order defocus, third-order coma, and fourth-order spherical aberration.

RESULTS Table 2 shows the mean manifest refraction data for the cohorts for the preoperative and 6-month periods. Note that the cohorts were not identical in that spherical error of the LASEK cohort was greater than that of the PRK and LASIK groups. Table 3 shows the mean spherical equivalent of the manifest refraction for preoperative and 6-month periods. The residual error indicates that the achieved LASIK correction was less than either LASEK or PRK. Table 4 indicates the mean attempted correction programmed into the laser algorithm for the corneal plane. Corneal aberrations measured in microns of mean RMS error were extracted from topography maps and plotted as a function of time in months. Results indicated that LASEK topography had significantly less total corneal aberration (Fig.1) and significantly less second-order low-order corneal aberration than for the PRK or LASIK cohorts at 1 week and beyond. The low-order aberrations are virtually identical to total aberrations in terms of magnitude and trend and are not shown here. There was a large

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spike in total and low aberrations at 1 week for the PRK and LASIK cohorts, followed by a decline to aberration

Table 2. Mean Manifest Refraction. Procedure

Preoperative* Sphere

6 Months* Cylinder

Sphere

Cylinder

LASEK

−7.40

−1.46

−0.15

−0.38

PRK

−3.84

−1.21

−0.28

−0.67

LASIK

−4.92

−1.35

−0.86

−0.54

*Values are in diopters at the spectacle plane.

Table 3. Mean Manifest Refraction Spherical Equivalent. Procedure

Preoperative*

6 Months*

Percent Error Corrected

LASEK

−8.13

−0.34

95.8

PRK

−4.44

−0.62

96.0

LASIK

−5.60

−1.13

79.8

*Values are in diopters at the spectacle plane.

error levels that were not significantly different from the preoperative state at 6 months. Meanwhile, LASEK exhibited a response that was completely reversed to that of PRK and LASIK. In LASEK, the total and low-order aberrations initially declined at 1 week and then returned to a level that was not significantly different from the preoperative level. Both PRK and LASIK showed an immediate increase in defocus at 1 week and beyond (Fig. 2), whereas LASEK showed a rise only at 1 month and beyond. Curiously, the preoperative defocus aberrations were significantly greater for PRK and LASIK compared to LASEK. The cause for this result is not known. The astigmatism aberration (Fig. 3) showed an immediate and significant decline at 1 week and beyond for LASEK, but the PRK and LASIK cohorts showed no significant decline. At 6 months, LASEK astigmatism was significantly less than LASIK. With slightly larger sample sizes to reduce variance, the 6-month difference between LASEK and PRK might become significant as well. As expected, all three procedures exhibited an increase in their high-order corneal aberrations after surgery (Fig. 4). In particular, LASEK had significantly less high-order aberrations than PRK from 1 week to 3 months. This effect was caused primarily by the immediate and large postoperative increase in high-order aberrations seen with PRK, which gradually declined over time. In contrast, the LASEK cohort showed no immediate peak in postoperative high-order aberration, but the error increased at 1 month and plateaued thereafter. LASIK high-order aberration response showed an increase at 1 week, followed by a stabilization at 1 month and beyond. Postoperative LASEK and

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LASIK results for high-order aberrations were therefore not significantly different except at 1 week. Curiously, the preoperative PRK group was significantly higher than both the LASEK and LASIK cohorts, which complicated the analysis. With respect to individual high-order aberrations, fourth-order spherical aberration showed a large and significant increase for all three cohorts at the 6-month period compared

Table 4. Mean Attempted Correction. Procedure

Sphere*

Cylinder*

Spherical Equivalent*

LASEK

−5.92

−1.61

−6.22

PRK

−3.44

−0.80

−3.66

LASIK

−3.54

−1.37

−4.02

*Values are in diopters at the corneal plane.

Figure 1 Total aberrations of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition from the second to sixth radial order. Error bars indicate ± standard error of the mean. Asterisks indicate time periods in when the LASEK cohort was significantly different from both the PRK and LASIK cohorts (p<0.05).

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Figure 2 Defocus aberration of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition of the second radial order defocus term. Error bars indicate ± standard error of the mean. Asterisks indicate time periods when the LASEK cohort was significantly different from both the PRK and LASIK cohorts (p<0.05). The doublebarred cross indicates the time period when the LASEK cohort was significantly different from the PRK cohort only.

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Figure 3 Astigmatism aberration of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition of mean. Asterisks indicate time periods when the LASEK cohort was significantly different the two second radial order astigmatism terms. Error bars indicate±standard error of the from both the PRK and LASIK cohorts (p<0.05). The single-barred cross indicates the time period when the LASEK cohort was significantly different from the LASIK cohort only. to their preoperative values (Fig. 5). As seen with other aberrations, LASEK had a spherical aberration value at 1 week that was not different than the preoperative value. This lagging effect was not seen in the PRK or LASIK cohorts. Both the preoperative PRK and LASIK cohorts were significantly elevated in error compared to the LASEK group. With respect to third-order coma (Fig. 6), both PRK and LASIK showed a spike at 1 week, whereas the LASEK value again exhibited a lagging effect and did not significantly change from the preoperative value. At 1 month and beyond, all three cohorts exhibited elevated coma. However, we found that the postoperative coma values

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for PRK did not significantly differ from the preoperative value, which was already significantly elevated when compared to the LASIK and LASEK cohorts.

Figure 4 High-order aberration of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition of the third through sixth radial order terms. Error bars indicate ± standard error of the mean. Asterisks indicate time periods when the LASEK cohort was significantly different from both the PRK and LASIK cohorts (p0.05). The double-barred cross indicates the time period when the LASEK cohort was significantly different from the PRK cohort only.

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Figure 5 Spherical aberration of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition of the fourth radial order spherical aberration term. Error bars indicate±standard error of the mean. Asterisks indicate time periods when the LASEK cohort was significantly different from both the PRK and LASIK cohorts (p<0.05). The mean best spectacle corrected visual acuity (BSCVA) results as a function of time are shown in Figure 7. Figure 8 shows the acuity data for preoperative (top) and 6–month data (bottom) expressed in terms of the frequency of eyes whose BSCVA is specified by the ability to read Snellen chart lines. Note that PRK and LASIK tended to have more cases of poor visual acuity for the preoperative period, which suggests that the preoperative corneal topographies for PRK and LASIK may have been more aberrated than that of LASEK. The graphical data for the high-order aberrations of coma for PRK (Fig. 6) and spherical aberration for both PRK and LASIK (Figure 5) tend to support the idea that the preoperative PRK and LASIK cohorts were more aberrated to begin with, and this seems to be reflected in the preoperative BSCVA data.

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Figure 6 Coma aberration of the cornea as a function of time in months. Aberration is defined by the mean of the sum of RMS error in microns for Zernike decomposition of the two third radial order coma terms. Error bars indicate ± standard error of the mean. Asterisks indicate time periods when the LASEK cohort was significantly different from both the PRK and LASIK cohorts (p<0.05). The doublebarred cross indicates the time period when the LASEK cohort was significantly different from the PRK cohort only.

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Figure 7 BSCVA plotted as a function of time in months. Acuity measurement is provided in both LogMAR and Snellen fractions. A 0.02-interval in LogMAR acuity is indicative of a one-letter difference on an ETDRS visual acuity chart. The single-barred cross indicates the time period when the LASEK cohort was significantly different from the LASIK cohort only (p<0.05).

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Figure 8 Histograms of frequency of eyes in percent plotted with respect to BSCVA specified in Snellen fractions. The top bar graph indicates the preoperative distribution, whereas the bottom graph indicates the distribution at 6 months after surgery.

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Figure 9 Average preoperative corneal wavefront map (top) and the corresponding simulation (bottom) of visual performance through the averaged wavefront. The wavefront map is an average of 21 individual maps and is presented in the orientation of the right eye (nasal to

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the right; superior to the top). Medium green indicates zero aberration. Negative error is indicated by hot colors. Note the strong prevalence of astigmatism aberration in the averaged wavefront. The image simulation is of an 8.5-inch letter chart seen at 20 feet. The dark bar indicates the 20/20 Snellen acuity line and the bottom line indicates 20/10. Note that the 20/20 letters are barely legible because of the aberrations present in the preoperative state. The map at the top of Figure 9 shows the average wavefront before LASEK surgery (n=20), and the map at the top of Figure 10 illustrates the aberration at 6 months after LASEK surgery (n=10). These wavefronts are presented using a right eye orientation, with a medium green contour indicating zero RMS error. The images at the bottoms of Figures 9 and 10 show the corresponding ray-traced simulations for distance eye charts (at 20 feet) imaged through the averaged corneal wavefronts at the top of the two figures. These simulations are in a sense estimations of the potential acuity with these averaged wavefront errors. In the preoperative condition shown in Figure 9, the 20/20 Snellen acuity line is barely legible (fifth line from top demarcated by horizontal bars), whereas the corresponding postoperative image in Figure 10 shows the relative lack of aberrations at 6 months and the potential ability to see 20/10 Snellen letters. Of course, the simulation does not take into account many other factors involved in seeing and is only indicative of the averaged wavefront data for many corneas and not a specific result for a single patient.

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Figure 10 Average postoperative (6 months) corneal wavefront map (top) and the corresponding simulation (bottom) of visual performance through the averaged wavefront. The wavefront map is an average of 16

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individual maps and is presented in the orientation of the right eye (nasal to the right; superior to the top). Medium green indicates zero aberration. Negative error is indicated by hot colors. Note the strong prevalence of coma and spherical aberration in the averaged wavefront. The image simulation is of an 8.5-inch letter chart seen at 20 feet. The dark bar indicates the 20/20 Snellen acuity line and the bottom line indicates 20/10. Note that even the 20/10 letters are clearly legible, although all letters are surrounded by a fuzziness because of the high-order aberrations present at 6 months. DISCUSSION There are several interesting results from this study. First, it was shown that the LASEK procedure apparently produced fewer total and low-order aberrations despite the fact that the attempted refractive correction was larger. In particular, the LASEK procedure appeared to be more efficient in producing an astigmatic correction; however, this interpretation should be made with caution because both the PRK and LASIK procedures attempted smaller cylinder error corrections. The study did not look at the efficiency of correcting individual eyes; therefore, these average results do not take into account cylinder axis and vectorial changes in cylinder error. A second finding is that all three procedures end up producing essentially similar levels of high-order aberration at 6 months. An increase in high-order aberration is expected with any refractive surgical procedure now in use, because of our limited understanding in controlling aberrations, such as spherical aberration and coma, even with customized corneal ablation procedures. This study suggests that in terms of all high-order aberrations combined, the LASEK method showed no particular advantage over PRK or LASIK by 6 months, but this result should be confirmed by a larger and better-controlled study. A third finding is the distinctly different response among the three procedures at 1 week. The LASEK cohort tended to show no change at 1 week from the preoperative levels for most individual or grouped aberrations (except astigmatism). However, PRK and, to a lesser extent, LASIK tended to show a large increase in aberrations at 1 week. It is difficult to resolve the cause of this difference. It is known that apoptosis is present immediately after surgery and particularly documented in the case of PRK. Corneal

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edema caused by apoptosis perhaps results in unusual topographic changes to the cornea, which elicit increased aberration. In LASEK, the epithelium is kept largely intact, and perhaps apoptosis may be reduced because of this. It is not known if bandage lens-fitting differences in the cohorts could cause corneal molding effects to reduce aberrations in the LASEK group at 1 week, which then is resolved by 1 month. Either theory is speculative until the 1-week LASEK data are replicated under more controlled conditions. The early postoperative topographic and aberration increases that were measured are not demonstrated in the visual acuity of the patients. LASEK corneas tend to have slightly worse BSCVA at 1 month from the preoperative levels, whereas there is very little change in the PRK or LASIK acuities, and perhaps even a suggestion of an improvement. This tends to run contrary to the aberration findings that indicate that total and low-order aberrations are reduced in LASEK and high-order aberrations are approximately the same in all three cohorts. So, why should BSCVA be worse in LASEK at 1 month despite topographical results suggesting it should be improved in comparison to PRK or LASIK? The answer may lie in optical effects that cannot be measured by shape alone, namely in the transmission quality of light. It is possible that there is some form of forward-scattering or haze in the LASEK corneas at 1 month, and this effect has been noted in the literature. We did not look at the effects of haze in this study. It is clear, however, that whatever caused the diminished acuity in the LASEK group was transient, and by 6 months, LASEK acuity was significantly improved compared to 1 month. In fact, LASEK acuity at 6 months is better than that of the LASIK cohort, nearly significantly better than that of PRK, and appears to be on a trend toward continued improvement. There are limitations in this study, which must be taken into account when assessing the clinical significance of the data. First, two different surgeons were used and, consequently, surgical techniques and environments may play a role in the reported differences in patient outcomes. It is also possible that the surgeons selected patients differently, and this might account for slightly worse preoperative BSCVA in the PRK and LASIK groups (Fig. 7) and with certain high-order aberrations, such as coma and spherical aberration, being elevated in preoperative PRK as compared to LASEK (Figs. 5 and 6). LASIK showed a preoperative elevation in error with spherical aberration but not coma. The study also did not look specifically for differences in the laser systems, which may affect the efficiency or the smoothness of ablations, nor did we examine in detail the possibility of substantive and planned differences in the surgical goals for the three procedures. It is clear, for example, that the LASIK cohort was not designed to fully correct the cylinder error that was evident in the manifest refraction. This may have been planned as an adjustment to the specific laser system and tends to complicate a direct comparison of the cohorts. However, it should not be surprising to find that the correction of astigmatism with LASIK appeared to be less effective than that seen with LASEK because of this factor. Finally, we do have concerns about comparing data from two different topographic instruments. Although CTView is intentionally designed to perform cross-platform data analysis using one or more topographic or ocular wavefront systems, there is no published data that indicate that the result is valid under all corneal conditions and for the aberration orders we measured. One might speculate that because the EyeSys topographer

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has a lower spatial resolution than the Tomey system for recording data points, this might result in smoother approximations of the corneal surface and, consequently, smoother wavefronts (hence reduced aberrations). However, most of the preoperative aberrations of the two systems were not significantly different from one another. In instances in which there was a difference, such as with third-order coma, two different corneal topographers were alike (LASIK and LASEK data) and data from the same topographer differed (PRK and LASIK). The same was not true with spherical aberration, a fourth-order aberration, in which both PRK and LASIK differed from LASEK at the preoperative period. We suspect that any difference between EyeSys and Tomey topographers may arise in highorder aberration terms but may be less of a concern in the low-order terms. So, the question of inter-topographer variability is moot, given that we do not yet know the radial order cutoff frequency at which the Zernike coefficient fit differs substantially from the actual wavefront surface for either the EyeSys or Tomey topographers.

CONCLUSIONS There are some apparent topographical advantages with the LASEK procedure, particularly when compared to the PRK method. Although the attempted myopic astigmatism correction was higher in the LASEK cohort, the topographic result was generally better than that found with PRK or LASIK when measured with corneal wavefront aberrations. LASEK corneal aberrations tended to plateau at a constant value by 1 month, whereas PRK aberrations tended to drift for a longer period of time from an immediate postoperative extreme. LASIK aberrations tended to fall between the PRK and LASEK cohort values. Although some of the specific advantages of LASEK appear to be lost by 6 months, the LASEK method generally appeared to have less immediate postoperative variability, more stability over time, and less total and low-order aberrations in the early postoperative period. In particular, the correction of the astigmatism may be more effective with the LASEK approach. The initial worsening of BSCVA reported by LASEK patients at 1 month was unrelated to induced corneal aberrations and was temporary. Ideally, this comparative topographic aberration study should be repeated using a randomized, prospective approach with identical topographic measurement systems, identical laser systems, similarly selected cohorts, and the same refractive surgeon.

REFERENCES 1. Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol; 1983; 96:710–715. 2. Krueger RR, Trokel SL, Schubert HD. Interaction of ultraviolet laser light with the cornea. Invest Ophthalmol Vis Sci; 1985; 26:1455–1464. 3. Puliafito CA, Wong K, Steinert RF. Quantitative and ultrastructural studies of excimer laser ablation of the cornea at 193 and 248 nanometers. Lasers Surg Med; 1987; 7:155–159. 4. Hanna KD, Pouliquen Y, Waring GO, Savoldelli M, Cotter J, Morton K, Menasche M. Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation. Arch Ophthalmol; 1989; 107:895–901.

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5. Taylor DM, L’Esperance FA, Del Poro RA, Roberts AD, Gigstad JE, Klintworth G, Martin CA, Warner J. Human excimer laser lamellar keratectomy. A clinical study. Ophthalmology; 1984; 96:654–664. 6. L’Esperance FA, Taylor DM, Del Poro RA, Roberts A, Gigstad J, Stokes MT, Warner JW, Telfair WB, Martin CA, Yoder PR. Human excimer laser corneal surgery: preliminary report. Trans Am Ophthalmol Soc; 1988; 86:208–275. 7. McDonald M, Kaufman HE, Frantz JM, Shofner S, Salmeron B, Klyce SD. Excimer laser ablation in a human eye. Case report. Arch Ophthalmol; 1989; 107:641–642. 8. Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser refractive surgery. J Cataract Refract Surg; 1988; 14:46–52. 9. Loewenstein A, Lipshitz I, Varssano D, Lazar M. Complication of excimer laser photorefractive keratectomy for myopia. J Cataract Refract Surg; 1997; 23:1174–1176. 10. Brilakis HS, Deutsch TA. Topical tetracaine with bandage soft contact lens pain control after photorefractive keratectomy. J Refract Surg; 2000; 16:444–447. 11. Peyman GA, Katoh N. Effects of an erbium:YAG laser on ocular structures. Int Ophthalmol; 1987; 10:245–253. 12. Peyman GA. Excimer laser in situ keratomileusis under a corneal flap for myopia of 2 to 20 diopters. [Letter to editor]. Am J Ophthalmology; 1996; 122:284–285. 13. Pallikaris IG, Papatzanaki ME, Stathi EZ, Frenshock O, Georgiadis A. Laser in situ keratomileusis. Lasers Surg Med; 1990; 10:463–468. 14. Buratto L, Ferrari M. Excimer laser intrastromal keratomileusis: case reports. J Cataract Refract Surg; 1992; 18:37–41. 15. Buratto L, Ferrari M, Rama P. Excimer laser intrastromal keratomileusis. Am J Ophthalmol; 1992; 113:291–295. 16. Ambrosio R Jr, Wilson SE. Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surgery; 2001; 17:350–379. 17. Johnson JD, Azar DT. Surgically induced topographical abnormalities after LASIK: management of central islands, corneal ectasia, decentration, and irregular astigmatism. Curr Opinion Ophthalmol; 2001; 12:309–317. 18. Scerrato E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surgery; 2001; 17:S219–S221. 19. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 20. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opinion Ophthalmol; 2001; 12:322–328. 21. Smolek MK, Klyce SD, Sarver EJ. Inattention to nonsuperimposable midline symmetry causes wavefront analysis error. Arch Ophthalmol; 2002; 120:439–447.

18 LASEK Complications Jae Bum Lee, MD, PhD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA Laser epithelial keratomileusis (LASEK), is a modified photorefractive keratectomy (PRK) technique that is based on the detachment of an epithelial flap after the application of an alcohol solution. The flap is repositioned after laser ablation (1). In LASEK, there may be a slight learning curve as in PRK or laser in situ keratomileusis (LASIK). In our experience, most of the complications occurred in the initial 30 cases. Alcohol leakage during the surgery was the most common complication in the beginning. With experience, making the epithelial flap was relatively not so difficult after several cases. LASEK does not have the serious complications associated with LASIK because a stromal flap is not created. Figures 1 through 5 illustrate the stages involved in LASEK. The laser epithelial keratomileusis procedure was performed as follows. A preincision of the corneal epithelium was performed with a special microtrephine with 8.00-mm diameter, 70-µm-deep calibrated blade (Janach, J 2900S) (Fig. 1). The trephine was designed to leave a hinge of approximately 80 degrees at the 12 o’clock position. An alcohol solution cone (Janach, J 2905) with an 8.5-mm diameter was placed on the eye. Twenty percent alcohol solution, made with distilled water, was placed for 25 to 30 seconds (Fig. 2). A dry Weck cel sponge was used to remove the alcohol from the cone. The cornea and conjunctiva were washed thoroughly with a balanced salt solution. Epithelial debridement was performed with an epithelial microhoe (Janach, J 2915A) (Fig. 3). The epithelial flap was gently detached, gathered, and folded at the 12 o’clock position (Fig. 4). At this point, the treatment proceeded similar to traditional PRK. After laser ablation, the stromal surface was irrigated with balanced salt solution and the epithelial flap was repositioned using a spatula (Janach, J 2920A) (Fig. 5). After repositioning the epithelial flap, we left the epithelial flap to adhere to the underlying stromal bed for 1 minute. At the end of the surgery, a therapeutic contact lens (diameter 14.2 mm, base curve (BC) 8.7 mm) was applied to the eye. After complete reepithelialization, ofloxacine 0.3% and fluorometholon 0.1% were administered four times daily for the first postoperative month, three times daily for the second month, twice daily for the third month, and then once per day for the fourth month. We also checked uncorrected visual acuity, corrected visual acuity, and refractive errors after surgery. Subepithelial haze was graded from zero to four and postoperative pain was graded from zero to three. All patients were asked about their surgical preference.

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Figure 1 A special microtrephine is used in epithelial preincision.

Figure 2 20% alcohol solution is instilled inside a solution cone.

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Figure 3 Epithelial debridement is performed with an epithelial microhoe.

Figure 4 An epithelial hinge is preserved at the 12 o’clock position and laser treatment is applied.

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Figure 5 The epithelial flap is repositioned over the ablated stroma. SHORT-TERM COMPLICATIONS LASEK Procedure-Related Complications Alcohol Leakage During the Surgery Alcohol leakage during the surgery usually occurred in the initial cases. The rate of alcohol leakage decreased approximately 1% to 2% after the first several cases. When the alcohol solution cone is applied on the cornea, too much tension on the cone and high magnification of the operating microscope should be avoided to minimize the incidence of alcohol leakage. Before applying the alcohol solution cone, a brief explanation to anticipate pressure on the eye and blurred vision makes the patients more cooperative. When an alcohol leak occurs, it should immediately be absorbed with a dry cellulose sponge and the cornea and conjunctiva irrigated thoroughly with balanced salt solution. These patients reported postoperative pain, but no eye complications, such as conjunctival and corneal erosion or limbal cell deficiency, developed later. Incomplete Epithelial Detachment Incomplete epithelial detachment, such as tear in the flap, buttonhole, or fragmented flap, usually occurred in the initial cases (Fig. 6). The rate of incomplete epithelial detachment decreased to less than 5% after a brief learning curve.

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To avoid creating an incomplete epithelial flap, precise and sufficient epithelial trephinization on the cornea is required. When the initial trephinized edge is cut and lifted, the detachment can proceed in a similar fashion as a continuous curvilinear capsulorrhexis in cataract surgery. Too much tension during this step may result in a tear or buttonhole in the flaps. Alcohol exposure may be prolonged in contact lens wearers whose epithelium tends to be more adherent. If the epithelial detachment is difficult, an additional 10-second

Figure 6 Fragmented epithelial flaps are placed on the stromal bed after surgery. exposure to alcohol is usually helpful to facilitate flap creation. If flap detachment is unsuccessful, one can easily convert to PRK. Epithelial Healing The duration to complete epithelialization in LASEK seems similar to PRK. The epithelium usually healed in 3 to 5 days. Two to 3% of eyes healed 6 days after surgery. Epithelialization can be delayed in cases of incomplete epithelial detachment, contact lens intolerance, and severe infiltrate. In these situations, additional eye drops such as 1% hyaluronic acid may improve the epithelial healing.

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Pain The postoperative pain in LASEK is usually less than in PRK. On a four-point scale, the majority of patients reported +2 grade (mild) pain, 5% reported +3 grade (severe) pain, whereas 5% did not report any pain after surgery. Severe pain may be attributed to alcohol leakage during the surgery or tight contact lens syndrome. The peak time for pain after LASEK is usually on the second postoperative day because of discomfort from the contact lens, whereas in PRK it is usually on the first postoperative day (2). The reason for the reduced pain in LASEK treated eyes is probably because the epithelial flap acts as a biological therapeutic lens that protects the ablated stroma from lid action. Most of the pain after LASEK can be controlled by giving oral and eye drop preparations of nonsteroidal anti-inflammatory drugs until full epithelialization. Contact Lens Intolerance Contact lens intolerance occurs in approximately 5% of LASEK-treated eyes. Although the reason for the contact lens intolerance is not clear because most of the patients were observed to be older than 40, reduction in tear production and number of endothelial cells

Figure 7 Filamentary keratitis can be seen after application of the pressure patch and contact lens intolerance secondary to dry eye.

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might be the cause (3). Half of the eyes with contact lens intolerance, mostly in their 40s, had filamentary keratitis after the application of the pressure patch and with the cessation of eye drops including lubricant solution (Fig. 7). These observations suggest that performing LASEK in those older than 40 should be reconsidered. A flat base-curve therapeutic contact lens (BC 8.7-mm) and frequent lubrication with preservative-free artificial tears is recommended to minimize contact lens intolerance. Infiltrates Infiltrates seen after LASEK are usually mild and are frequently associated with postoperative pain and tearing (Fig. 8). These sterile infiltrates may be multiple with no associated ocular discharge and are typical when alcoholic exposure time exceeds 40 seconds. Infiltrates are less after LASEK compared to PRK, presumably because the epithelial flap covers the ablated stroma and prevents the migration of inflammatory cells from the tear fluid. The use of nonsteroidal anti-inflammatory eye drops in the first several postoperative days further lessens the accumulation of white blood cells in the cornea. Infections Corneal infection after LASEK is rare. In our experience, there was no severe infectious keratitis. The risk of infection is reduced because the epithelial flap acts as an effective protective barrier against microorganisms. If corneal infection occurs, it could be easily recognized before complete epithelialization. An enlarging white infiltrate indicative of infection should be treated with antibiotics immediately. In cases wherein there is no purulent discharge but there are multiple infiltrates, topical steroids could be cautiously added to counteract a possible immune reaction secondary to the nonsteroidal antiinflammatory drug. Dry Eye Of the patients who want to undergo refractive surgery, a large number cannot tolerate contact lenses because of either preexisting dry eye or secondary dry eye syndrome caused by long-term contact lens usage. Commonly, these patients continue to report dry eye after surgery. Despite an improvement of visual acuity and a grossly normal ocular surface after successful correction of the refractive error, symptoms such as ocular fatigue, discomfort, and irritation persist. Additionally, the signs of dry eye syndrome such as conjunctival injection and superficial punctate keratopathy were often observed (Fig. 9). A recent study (4,5) reported a decrease in tear flow and tear film stability after PRK. The decreased amount of tear secretion after PRK was attributed to sensory deprivation caused by corneal sensory nerve damage (6,7). Corneal sensitivity after PRK has been noted to be initially reduced, but it returns to almost normal levels within 3

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Figure 8 Corneal infiltrate in the periphery of the cornea is observed. months postoperatively (8–10). Therefore, dry eye symptoms are expected to improve approximately 3 to 6 months after surgery. There are several other possible causes of dry eye syndrome after LASEK. First, because of long-term use of multiple medications, including steroids, after surgery, these eye drops may have a toxic effect on the ocular surface. Second, the change of tear flow dynamics brought about by a flattened corneal surface result in an alteration of the surface tension and tear film layer stability. Third, most patients do not wear glasses after surgery, but if worn they could protect the eye from wind and prevent tear evaporation. Fourth, usage of the contact bandage lens might aggravate the dry eye symptom after LASEK. Dry eye symptoms might be worsened if patients have a Schirmer test of less than 5 mm before surgery or are older than 40. Careful observation and prompt treatment for dry eye are required after LASEK, particularly in the early postoperative period. Frequent lubrication with preservative-free artificial tears and ointment during nighttime is helpful. Humidification at home or office may also be beneficial. If the symptoms are severe, punctal plugs are recommended.

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Figure 9 Superficial punctate keratopathy from dry eye often observed after LASEK. Laser-Related Complications Undercorrection Residual myopia is caused by insufficient initial treatment more commonly observed with high degrees of myopia. If there is an undercorrection and the patient is not satisfied with the level of vision, additional treatment may be performed. It is usually best to wait until the refraction is stable. In our experience, when LASEK enhancement after primary LASEK was performed, there was no difficulty in making the epithelial flap using the same technique as in a primary LASEK procedure. Overcorrection Patients with overcorrection may experience blurred vision when viewing objects up close. LASEK has been observed to cause slight hypercorrection compared to PRK. A possible explanation is the hyperosomolar property of the 20% dilute alcohol solution absorbs some water content of the cornea during alcoholic application, resulting in relative dryness of the stroma and more ablation during the procedure. A nomogram adjustment of 5% to 10% reduction compared to the PRK computed treatment is recommended.

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LONG-TERM COMPLICATIONS Wound Healing-Related Complications Corneal Haze Corneal haze corresponds to a corneal healing response after excimer laser treatment induced by activation and migration of keratocytes and newly synthesized collagen (11). Factors that may be related to increased haze include depth of ablation, presence of an epithelial flap, and, to a lesser extent, laser beam homogeneity and epithelial removal

Figure 10 Corneal haze, +3 grade, seen in a case of high myopia after LASEK. method during treatment. One of the reported advantages of LASEK is it produces less corneal haze than PRK. For low to moderate myopia, using a four-point scale, the mean corneal haze score at 1 month after PRK was 0.86±0.45 compared to 0.46±0.24 after LASEK. This was found to be statistically significant (1). Twenty-three percent of LASEK-treated eyes showed a corneal haze of not less than +1 grade at 1 month. By 6 months, only 2% had a +1 grade corneal haze. Although the detailed underlying cellular events remain unclear, the epithelial flap is observed to expand and lengthen enough to cover the cut epithelial border and seal the bare stroma, thereby preventing or decreasing the release of cytokines and growth factors

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from the stroma and damaged epithelium. The decrease in the initial inflammatory damage to the stroma is believed to reduce anterior stromal keratocyte apoptosis and subsequent replenishment with activated keratocytes, leading to less synthesis of collagens (12). However, despite the presence of an intact epithelial flap, moderate to severe haze was still occasionally observed in high diopters of myopic treatment (Fig. 10). LASEK is therefore recommended in low to moderate myopia only. Corticosteroid-Induced Elevated Intraocular Pressure Raised intraocular pressure (IOP) related to topical steroid use occurs more frequently with high-potency steroids such as FML Forte 0.25% and dexamethasone phosphate 0.1%. In LASEK, in which the corneal haze is expected to be minimal, mild potency steroids may be sufficient to reduce haze formation. But it is still necessary to monitor the IOP after LASEK while the patient continues to use topical steroids. Laser-Related Complications Glare/Halos The incidence of glare and halo after LASEK seems to be similar to PRK. Halos occur when the pupil size in dim light exceeds the effective optical zone size or when there is decentered ablation. A halo may be a pronounced form of spherical aberration. Persistent halos are rare and, when present, their effect tends to diminish with time. Decentration Decentration can occur if the laser beam is not precisely aligned with the surgeon’s eyepiece before the procedure or if there is poor patient fixation. Maloney proposed that a decentration less than 0.50 mm would not cause subjective symptoms such as glare and halo (13). Machat suggested that decentration more than 1.0 mm would create significant monocular diplopia, asymmetric night glare, reduced image quality, and blurred visual acuity (14). Decentration may be less after LASEK than PRK. Although a histological evaluation was not performed, a smoother and more regular surface can be seen through the operating microscope after epithelial debridement with 20% ethanol in LASEK than mechanical debridement in PRK (15). Patients can therefore fixate better through the more regular surface during the laser ablation, decreasing the incidence of decentration. Although a number of approaches have been used to treat the effects of decentration, at present none has been proven to be completely satisfactory. When treating decentration, however, it is recommended to treat the residual myopia and to decenter the ablation in the opposite quadrant. The advent of eye-tracking and wavefront technology may further minimize the incidence or provide the solution to decentration problems.

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SUMMARY In summary, complications of LASEK are less than that of LASIK and comparable to PRK. It reduces the incidence of significant postoperative pain and corneal haze observed in PRK and avoids the various flap and interface-related problems associated with LASIK. Caution is needed in the use of alcohol and contact lenses. Patient selection criteria, including age, amount of refractive error, and dry eye status, should be considered. Further investigations in LASEK are needed with regard to experience flap viability, corneal haze response, and development of a standard nomogram.

REFERENCES 1. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 2. Cherry PM, Tutton MK, Adhikary H, Banerjee D, Garston B, Hayward JM, Ramsell T, Tolia J, Chipman ML, Bell A. The treatment of pain following photorefractive keratectomy. J Refract Corneal Surg; 1994; 10(2 Suppl):S222–S225. 3. Farris RL. Contact lenses and the dry eye. Int Ophthalmol Clin; 1994; 34(1):129–136. 4. Ozdamar A, Aras C, Karakas N. Changes in tear flow and tear film stability after photorefractive keratectomy. Cornea; 1999; 18(4):437–439. 5. Lee JB, Ryu CH, Kim J, Kim EK, Kim HB. Comparison of tear secretion and tear film instability after photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg; 2000; 26(9):1326–1331. 6. Trabucchi G, Brancato R, Verdi M. Corneal nerve damage and regeneration after excimer laser photokeratectomy in rabbit eyes. Invest Ophthalmol Vis Sci; 1994; 35:229–235. 7. Tervo K, Latvala TM, Tervo TM. Recovery of corneal innervation following photorefractive keratoablation. Arch Ophthalmol; 1994; 112:1466–1470. 8. Ishikawa T, Park SB, Cox C. Corneal sensation following excimer laser for photorefractive keratectomy in humans. J Refract Corneal Surg; 1994; 10:417–422. 9. Kohlhaas M, Klemm M, Bohm A. Corneal sensitivity after refractive surgery. Eur J Implant Refract Surg; 1994; 6:319–323. 10. Campos M, Hertzog L, Grabus JJ. Corneal sensitivity after photorefractive keratectomy. Am J Ophthalmol; 1992; 114:51–54. 11. Lee YC, Wang IJ, Hu FR, Kao WW. Immunohistochemical study of subepithelial haze after phototherapeutic keratectomy. J Refract Surg; 2001; 17(3):334–341. 12. Wilson SE. Keratocyte apoptosis in refractive surgery. CLAO; 1998; 24:181–185. 13. Maloney RK. Corneal topography and optical zone location in photorefractive keratectomy. Refract Corneal Surg; 1990; 6:363–371. 14. Machat JJ. Excimer laser refractive surgery. Practice and Principles. In: ED Amy, Ed. PRK complication and their management. 1st ed. Ontario, Canada: Slack Incorporated, 1996: 187– 189. 15. Agrawal VB, Hanuch OE, Bassage S, Aquavella JV. Alcohol versus mechanical epithelial debridement: Effect on underlying cornea before excimer laser surgery. J Cataract Refract Surg; 1997; 23:1153–1159.

19 Management of LASEK Complications Massimo Camellin, MD Sekal Rovigo MicroSurgery Rovigo, Italy

INTRODUCTION A complication usually involves making intraoperative decisions to manage the procedure well and avoid unwanted consequences in uncorrected visual acuity (UCVA) and of best spectacle corrected visual acuity (BCVA). It is important to keep in mind that some complications can happen in the postoperative period. Short-term and long-term complications must be distinguished because they may manifest differently.

MANAGEMENT OF INTRAOPERATIVE COMPLICATIONS An unavoidable complication that can occur, even with an experienced surgeon, is solution leakage on the conjunctiva. This is often caused by a sudden movement of the eye and immediately creates the burning sensation referred to by patients. Despite the lid edema and a hyperemia in the conjunctiva for the first few days, no other permanent lesions develop. If this occurs, we abundantly rinse the eye with diclofenac to reduce irritation. The use of a well for the alcohol (E.Janach S.r.L., Como, Italy) with a double edge reduces the risk of leakage (Fig. 1). After thoroughly drying the interior of the well with a cotton sponge, we always fill the cone with diclofenac to dilute the alcohol residue. The epithelium and stroma may be strongly adherent because of a previous inflammatory event. These adherences must be managed with care. However, sometimes they are so stuck that some tearing is unavoidable. Tears may not leave a trace either in the short-term or in the long-term. However, if the tears are too wide, it is possible that the patient will feel more pain postoperatively. The risk of losing the flap is increased and, in most cases, the more adherent portion is close to the hinge. Because in this area there is no epithelium precut that allows the solution to flow under the epithelium, it is possible to re-apply the alcohol solution for 5 to 10 seconds to increase the ease in detaching this portion. Only after a certain amount of training and experience will a surgeon be able to manage this hard portion with small but strong movements of the spatula. If the hinge is completely broken, the flap becomes free and needs two spatulas to be re-positioned well. It may be difficult to recognize which side should be in contact with the stroma. We do not worry too much about this because the protection realized from the basal layer is efficient. When the flap gets lost or completely broken, we apply autologous serum (1) to encourage more rapid epithelium regrowth.

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Figure 1 Well for the alcohol solution. Double edge. MANAGEMENT OF SHORT-TERM POSTOPERATIVE COMPLICATIONS Pain Pain is present in approximately 10% of cases. When we exclude intraoperative alcohol leakage as a cause, the pain must be controlled with general anti-inflammatory drugs (not very efficient) and with pupil dilation. The discomfort does not begin until 3 or 4 hours after surgery. This timeframe coincides with the reduced effect of the midriatic instilled at the end of the procedure. Henceforward, pain can be derived from the iris. These patients sometimes find comfort with ice application over the lids. A foreign body sensation is common after 3 days and is related to the debris present over the lens. Patients often feel relieved after lens removal. However, it is dangerous to take away the lens, too, because of the risk of flap damage. If flap healing is uncertain, our experience suggests exchanging the lens for a new one that is slightly wider. Lens Loss Loss of the contact lens may be caused by to the lens being too wide, excessive watering, or extreme eye movements while instilling drops. When this occurs during the first few hours, rarely does the flap stay attached. More commonly, lens loss results in flap loss. A new lens must be fitted and auto serum instilled. Postoperative care will likely be primary to photorefractive keratectomy (PRK).

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Flap Loss Unfortunately, lens presence is not always proof of flap presence. When the patient experiences sudden pain and the lens is still in place, we must look for flap signs. An excellent way to check flap presence is to dye the eye with macromolecular fluorescein. This coloring agent, flowing under the lens, dyes only the stroma and allows us to be certain the flap is still present. This simple procedure can also be used to check epithelium renewal, thereby helping to decide whether take to away the lens.

Figure 2 Re-epithelialization delay after an enhancement followed by a flap tearing. Flap Breaks A flap break can be small or large and is often related to the lens being removed too early. In our experience, it occurs rarely and does not create problems, except in one enhancement case that involved two points of re-epithelialization delay, both in the midperiphery (Fig. 2). We believe it is better to leave the lens 1 additional day if flap integrity is in question. Infection We have had two cases of infection. In one case, influenza developed the day after surgery, as did bilateral conjunctivitis with a lot of secretion. Infiltrates were seen at the periphery of the flap (Fig. 3). We immediately disinfected and rinsed the area with betadine. The postoperative care was uneventful, with no residual opacity in the

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Figure 3 Infiltration after influenza conjunctivitis. stroma. The second patient had an epithelial-stromal infiltrate at the 12 o’clock position (Fig. 4A). This case was also treated with betadine rinsing and showed evidence of a faint opacity 1 month later (Fig. 4B). Diffuse Opacities Diffuse opacities, presumably sterile, were observed in three cases. In two patients who had bilateral surgery, only one eye of each patient developed this complication. There was no conjunctival hyperemia, but pain was more intense compared to the other eye (Fig. 5). In our practice, the incidence of diffuse opacity is three out of 1,000 cases. It is a serious complication until its refractive effects are reduced. Hyperopic astigmatism may be noted during the first few months in these patients. The cause is related to an epithelial thinning that, by flattening the surface, results in a hyperopic shift. We tried to cure these cases with topical steroids, thinking that it was a form of diffuse lamellar keratitis. But after having noticed that the epithelium was thinner, we suspected the cause to be slower epithelium renewal (Fig. 6). We discontinued all therapy, except for artificial tears, and the curvature progressively improved. Only a light haze remained after several months.

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Figure 4 Light opacity immediately after resolution of an epithelial infiltrate (A) and 1 month later (B).

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Figure 5 Diffuse opacity after LASEK. MANAGEMENT OF LONG-TERM POSTOPERATIVE COMPLICATIONS Undercorrection/Overcorrection Undercorrection is not common in LASEK, but if it appears, it is usually related to laser problems. It can easily be managed with an enhancement procedure by removing the epithelium without alcohol and adding the undercorrected value to the laser. This maneuver has to be performed within 1 month after the surgery. Late regression is very rare and can be related to an optical zone being too small, or to a small transition zone. The initial regression, however, is caused by the epithelium (Fig. 7) and can be partially controlled by steroids. Aside from regression, the epithelial basal layer seems to also be responsible for haze production (2). We believe it is useful to try steroid therapy for 1 month, and only if the regression is persistent do we suggest re-treating the patient. Overcorrection is more common after LASEK. Using the Nidek EC 5000 laser, we had to reduce the planned treatments by 10% for myopia up to −10 diopters (D) and progressively up to 20% for myopia of –10 D up to −20 D. The Camellin formula for Nidek EC 5000 is: Laser setting=Myopia×(0.9+[myopia/200]) (1)

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Figure 6 The four pictures in the upper part are related to the case of diffuse opacity shown in fig 5, and they show a reduction in the hyperopic refraction over days (15–30–45–120). The three pictures in the lower part are instead related to a localized thinning of the epithelium, bilaterally occurred and progressively disappeared. Checks are at 10th, 20th, and 90th day.

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Figure 7 Early regression in high myopia (top right and left) and reduction in regression after 1 month of steroid therapy (bottom right and left). We have not had the same effect with the Schwind Esiris laser; however, with this laser, we reduce 5% for treatment up to −10 and 15% progressively for treatments up to −20 D. However, our experience with this laser is relatively sparse and may not be enough to propose the correct regression formula. The cause of overcorrection in laser subepithelial keratomileusis (LASEK) may be the same as that observed in laser in situ keratomileusis (LASIK), which is a decreased inflammatory reaction. Less apoptosis means less collagen production from the keratocytes, therefore resulting in higher effective correction. Haze At present, haze is an uncommon complication in PRK (3) and in LASEK for low moderate myopia (Fig. 8). The good quality of lasers has also contributed to this low incidence. However, a delay in epithelialization can occur and cause a high degree of haze (4). Epithelialization delay was rarely observed in LASEK. In our statistics, 83.8% were re-epithelialized within 4 days and 100% within 6 days. We realize that in some cases of LASEK, the flap can be lost during the first few days and the procedure converted to PRK. It is difficult to check flap presence underneath the contact lens, but based on the low percentage of haze observed, we may conclude that the flap was present and protected the stroma from apoptosis in the majority of cases. We had

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25% of haze in re-operations after cornea transplants. This value is strictly related to the presence of an incomplete flap. After PTK treatment only 10% developed haze again.

Figure 8 Incidence of haze after LASEK, including cases of LASEK in which the flap was lost or did not adhere (converted to PRK), showing +1 or more haze in 3.8% of patients. Foreign Body Sensation Dry eye and the related foreign body sensation are not common in LASEK. Only 25% experienced slight dry eye symptoms, mostly disappearing by 6 months. Only 3% had problems at 12 months (Fig. 9). This symptom is common only in the morning during the first lid opening and can be easily managed with artificial tears. We did not observe any late-onset epithelial keratitis or erosion.

CONCLUSIONS The low percentage and low degree of serious side effects related to LASEK confirm its feasibility as a useful refractive procedure, especially because these side effects can be managed effectively.

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Figure 9 Dry eye symptoms in LASEK eyes lasting 6 months or less (25%) and 12 months or less (3%). REFERENCES 1. Tsubota K, Goto E, Shimurra S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologus serum application. Ophthalmology; 1999; 10:1984–1989. 2. Lee YC, Wang IJ, Hu FR, Y-Kao WW. Immunohistochemical Study of Subepithelial Haze after Phototherapeutic Keratectomy. J Refract Surg; 2001; 17:334–341. 3. Zoltan Zsolt Nagy Z, Fekete O, Suveges I. Photorefractive Keratectomy for Myopia with the Meditec MEL 70 G-Scan Flying Spot Laser. J Refract Surg; 2001; 17:319–326. 4. Seiler T, Holschbach A, Derse M. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology; 1994; 101:153–160.

20 Wavefront Analysis, Principles, and LASEK Application Ronald R.Krueger, MD Cole Eye Institute, Cleveland Clinic Foundation Cleveland, OH Patrick C.Yeh, MD and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA

INTRODUCTION One of the major attractions of laser subepithelial keratectomy (LASEK) surgery is the potential application of customized wavefront-guided treatments. At the time of this writing, custom LASEK in the United States is primarily an off-label application. The preliminary results have been encouraging. This chapter focuses on the history, principles, and methods of wavefront analysis and their applications for customized LASEK surgery to correct high-order aberrations. The benefits of custom LASEK depend not only on accurate wavefront measurements but also on the state of accommodation and pupil size. The benefits are reduced when the pupil is small. The benefit would be greatest in patients in whom the pupil is larger and in scotopic situations, such as night driving. It is not clear whether eyes of keratoconus patients or those with debilitating induced aberrations secondary to previous refractive surgery will benefit from high-order corrections using custom LASEK surgery.

OCULAR ABERRATIONS AND WAVEFRONT ANALYSIS In physical optics terms, light is considered as a wave that spreads in all directions. A wavefront in turn describes the shape of light rays emanating from a source that are in phase (1). Rather than limited to any given refractive surface, the wavefront describes the total effects of the optical system of the whole eye as the light passes through the pupil. In an ideal eye that is free of any aberrations, the wavefront forms a perfect plane perpendicular to the visual axis (Fig. 1A). However, when optical aberrations are present in actual eyes, the wavefront forms an imperfect surface rather than a plane (Fig. 1B). Wavefront aberrations are defined as the difference between the actual, aberrated wavefront surface, and the ideal wavefront plane (Fig. 2). Wavefront errors are quantified in terms of root mean square (RMS) or square root of the sum of the squares of the deviation of the actual wavefront from the ideal wavefront

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of a given pupil size. The larger the deviations and the pupils, the higher the RMS error. The influence of aberration on retinal image quality can be simulated by computing the point-spread function (PSF) (Fig. 3). However, the resulting retinal image blur produced by ocular aberration is not always predictable by the RMS; some aberrations can act to cancel each other out, producing an overall better image (right), even though this image has a greater RMS wavefront error (Fig. 4). Refractive error exists when light does not focus perfectly onto the retina. Traditionally, spectacles, contact lenses, intraocular lenses, and refractive surgeries have been the only method available to correct the spherical and cylindrical components of refractive error. These are classified as low-order aberrations, which account for approximately 85% of wavefront error. It was not until recently that we have the means of measuring and treating high-order ocular aberration in a clinical setting. These are other components of refractive error that have been referred to as “irregular astigmatism,” which cannot be corrected with traditional spherocylinder lenses. They are believed to represent approximately 15% of the wavefront error. When the image is optically perfect, physiologic visual acuity is still limited to between 20/8 and 20/10 largely by the virtue of photoreceptor diameter and receptor packing (2) (Fig. 5). High-order ocular aberrations are also known as refractive distortions, which limit the vision of healthy eyes to less than the retinal limits. Laser refractive surgery, both photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK), is known to increase the high-order ocular aberrations, especially spherical aberration and coma (Fig. 6) (3–7). Wavefront aberrations are expressed mathematically using Zernicke polynomial expansions (8). There are three components to the low-order aberration: zero order (a constant), first order (tilt or prism), and second order (defocus and astigmatism). Loworder aberrations can be corrected with glasses, contact lenses, and conventional laser surgery (Fig. 7). High-order aberrations are fit to a more complex wavefront shape. Some of the more common higher-order aberrations include third order (coma and trefoil) (Fig. 8A) and fourth order (spherical aberration and secondary astigmatism) (Fig. 8B). Secondary coma and more complex situations are represented by aberrations of the fifth order and beyond (Fig. 9). Polynomials can be expanded up to any arbitrary order if sufficient numbers of measurements for calculations are made.

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Figure 1 (A) A perfect plane wave of light perpendicular to the visual axis in an ideal eye represented by the Hartmann-Shack wavefront aberrometer. (B) An imperfect wavefront surface in an eye with optical aberrations represented by the Hartmann-Shack wavefront aberrometer.

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Figure 2 The difference between the actual wavefront (red) and the ideal wavefront (yellow) in the plane of the eye’s exit pupil defines the optical aberrations of the eye, measured in RMS.

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Figure 3 The retinal image can be simulated by computing the point spread function (PSF) from the wavefront profile.

Figure 4 The resulting retinal image blur produced by the aberration is not always predicted by the RMS, as illustrated in this example. When defocus (left) and spherical aberration (middle) are combined, they tend to cancel each other out, producing an overall better image (right), even though this image has the greatest RMS wavefront error.

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Figure 5 If the letter “E” falls within a single photoreceptor, the visual system cannot differentiate the “E” from a period. The letter “E” must be sampled by enough photoreceptors to differentiate the letter’s component parts. Photoreceptors packing limits visual acuity to between 20/8 and 20/10.

Figure 6 LASIK is known to induce high-order aberrations.

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Figure 7 (A) Low-order, but not (B) high-order, aberrations can be corrected with glasses, contact lenses, and conventional laser surgery.

Figure 8 Three-dimensional wavefront pattern of (A) coma and (B) spherical aberration.

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Figure 9 Three-dimensional pictorial directory of Zernike aberration components. HISTORY AND TYPES OF WAVEFRONT SENSING Wavefront aberration detection and analysis have been based on either interferometry or ray tracing. The interferometric method has not been widely used because of difficulties in stabilizing the eye to construct proper reference surfaces for comparison. As a result, most of the current methods used for wavefront detection and reconstruction are based on ray-tracing principles (9). The concept was first introduced by Tscherning in the late 1800s and then later expanded by Hartmann in 1900. In 1971, Shack and Platt made modifications to the Hartmann wavefront sensor, which became known as the HartmannShack aberrometer (10). The Hartmann-Shack aberrometer was used to improve the images of satellites viewed from earth. In 1994, clinical application of this technology was first adapted successfully to ophthalmology by Liang et al in the measurement of the eye’s wave aberration (11,12). In 1997, this technology was furthered in its application, and high-resolution and noninvasive retinal imaging of microscopic structures the size of single photoreceptors in a living human retina was made possible for the first time (13,14). In general, the wavefront sensors can be classified into three types: (1) outgoing wavefront aberrometry, as is used in the Hartmann-Shack aberrometer; (2) ingoing adjustable aberrometry, as in slit skioloscopy and spatially resolved refractometer; and (3) retinal imaging aberrometry, as in Tscherning and Tracey retinal ray-tracing method.

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Principles of Outgoing Wavefront Aberrometry The Hartmann-Shack aberrometer is based on the principles of outgoing wavefront aberrometry. Incorporated in the Hartmann-Shack aberrometer is a sensor that consists of a matrix of small lenslets. The aberrometer projects a laser light into the eye to illuminate a small spot on the retina. The laser light reflects off the retina and emerges as a wavefront, which passes through the lenslet array and focuses into spots on a detector array captured onto a charge-coupled device (CCD) camera (Fig. 10A). For an ideal eye, the reflected plane wave would be focused into a perfect array of point images, with each image falling exactly on the optical axis of the corresponding lenslet (Fig. 10B). In an aberrated eye, however, the distorted wavefront would be focused into a displaced array of spots. The deviation of each spot from its corresponding lenslet axis is used to calculate the aberrations or the slope of the aberrated wavefront (Fig. 10C). Mathematical integration of the deviation yields the shape of the aberrated wavefront, expressed in terms of Zernike polynomials (15). Wavefront devices that use the Hartmann-Shack technology include (Alcon) (Fig. 11A), WaveScan WaveFront® (VISX) (Fig. 11B), ZyWave (Bausch & Lomb) (Fig. 11C), and WASCA Wavefron Aberrometer (Asclepion-Meditec) (Fig. 11D). Each Hartmann-Shack wavefront device is linked to its own specific excimer delivery system for customized laser treatment (Table 1). At the time of this writing, the LADARWave®, (CustomCornea®, Alcon Inc., Fort Worth, TX) and WaveScan system (Custom VISX, Inc., Santa Clara, CA) are currently the two Food and Drug Administration (FDA)-approved systems in the United States for wavefront-guided customized myopic LASIK treatment. ZyWave system (Bausch & Lomb, Roches- ter, NY) is expected to be the third wavefront device approved by the FDA for custom LASIK in the United States in the autumn of 2003.

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Figure 10 Principle behind the Hartmann-Shack aberrometer. (A) The laser light reflected from the retina focuses into spots on a detector array captured onto a CCD camera. (B) In an ideal eye without aberrations, the reflected plane wave is focused into a

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perfect array of point images, with each falling exactly on the optical axis of the corresponding lenslet. (C) In an actual eye with ocular aberrations, the distorted wavefront is focused into a displaced array of spots. The shape of the aberrated wavefront is the mathematical integration of the deviations.

Figure 11 (A) (Alcon) wavefront system. (B) WaveScan WaveFront® (VISX) system. (C) ZyWave (Bausch & Lomb) wavefront system. (D) WASCA (AsclepionMeditec) aberrometer. LADARWave® system captures approximately 240 wavefront data points in a dilated 7mm pupil. Most peripheral spots are filtered out, giving approximately 188 to 195 usable data points (Fig. 12). The limbus is used as a reference point for centration. The positioning of the pupil and limbal rings are then transferred to the laser system. Once the eye is dilated, the conjunctiva is manually marked using a gentian violet dye marking pen

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at the 3 and 9 o’clock positions 1 to 2 mm outside of the limbus while the patient is sitting upright behind the slit lamp. These reference marks are used to register the position of the wavefront measurement to ensure the customized ablation pattern is applied in the same orientation as the wavefront measured by the wavefront measurement device to account for cyclotorsion during ablation. The LADARVision® laser system uses a flying small-spot beam (0.8 mm) and a closed-loop tracking system to ensure continual proper orientation and alignment of the laser beam during custom treatment. WaveScan system also captures approximately 240 wavefront data points within a 7-mm pupil aperture (Fig. 13). VISX Star S4 laser uses variable-shaped beams ranging in size from 0.65 to 6.5 millimeters. It uses an active 60-Hz video eye tracking system to maintain pupil alignment during customized ablation. Registration of the wavefront profile is assumed based on the orientation of the undilated pupil. Using information from the WaveScan, the unique wavefront pattern can be placed on a lens (PreVue® Lens). The lens is then fitted in a trial frame, allowing refractive surgery candidates to “preview” the potential visual results before the actual procedure (Fig. 14). Zywave system captures approximately 70 to 75 wavefront data within a 7-mm pupil aperture. Its associated laser delivery system, Technolas® is a scanning/ flying spot laser with beam diameter of 2.0 mm (Fig. 15). An active 120-Hz video eye tracker is used to maintain pupil alignment. Similar to VISX Star S4, registration of the wavefront information is also based on the orientation of the undilated pupil.

Table 1. Clinical Hartmann-Shack Wavefront Sensors and Their Associated Excimer Laser Delivery Systems. Wavefront Sensing Device

Excimer Laser Delivery System

Alcon LADARWave

LADARVision Laser

Bausch & Lomb Zywave

Bausch & Lomb Technolas Planoscan

VISX Wavescan

VISX Star S4 Active Trak

WASCA Aberrometer

Asclepion MEL-80

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Figure 12 LADARWave device showing a two-dimensional wavefront map of (A) normal eye and (B) myopic eye.

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Figure 13 WaveScan device showing two-dimensional preoperative and postoperative aberration maps. Principles of Ingoing Adjustable Aberrometry Spatially resolved refractometry (SRR) and slit skioloscopy use the principles of ingoing aberrometry. In SRR, a reference light is fixated through the center of the pupil while a second light is passed through a 1-mm hole and directed toward the retina. The ingoing rays of light are then manually steered by the patient to overlap with the reference light to define the wavefront needed to cancel ocular aberration (Fig. 16A). Slit skioloscopy is an objective variant of SRR. Using the principle of retinoscopy, skiascopy optical path detection projects a moving slit into the eye. The projecting system consists of an infrared light emitting diode (LED) that emits light going through a chopper wheel with slit apertures. The wheel rotates constantly at high speed to scan the retina for each meridian. The slit light rays are reflected back through a receiving lens and are detected by sensors. The relative motion of the slit’s image is used to calculate the refractive error along each

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segment (16) (Fig. 16B). The Nidek OPD (Optical Path Difference) scanning system is an example of slit skioloscopy (Fig. 16C).

Figure 14 PreVue lens in trial frame.

Figure 15 Schematic diagram illustrating PlanoScan laser ablation pattern in progression.

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Figure 16 (A) Principle behind the spatially resolved refractometer. (B) Schematic diagram of wavefront sensor based on the principles of dynamic skioloscopy. (C) Nidek OPDScan scanning system.

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Principles of Retinal Image Aberrometry Both Tscherning aberrometry and Tracey sequential ray tracing are based on the principles of retinal image aberrometry. Tscherning aberroscope consists of a collimated laser beam that illuminates a mask with regular matrix pin holes, creating 168 single light rays. These form a bundle of thin parallel rays that project a retinal spot grid pattern on the retina. The spot pattern formed on the retina is distorted according to the eye’s aberrations. This retinal pattern is then imaged through a small aperture onto a CCD camera by indirect ophthalmoscopy. The deviations of all spots from their ideal positions are measured, and the optical aberrations are calculated based on these values (Fig. 17A and 17B)(17). Alegretto Wavefront Analyzer (Wavelight) (Fig. 17C) and ORK Wavefront Aberrometer (Schwind) are based on Tscherning aberrometry. Tracey sequential ray-tracing aberrometry also measures the position of a thin laser beam projected onto the retina. An individual laser ray, directed into the eye parallel to the visual axis, is very rapidly (within 10 to 20 msec) scanned through a multitude of entry points onto the retina. The scanned spots are captured and connected in a retinal spot diagram (Fig. 18). The measured location of each ray as it exits the eye is calculated against the known position, and the wave aberration function is described by Zernike polynomials (18).

WAVEFRONT PROFILES Each ocular aberration has a well-defined three-dimensional wavefront pattern. For instance, myopia assumes the shape of a bowl (Fig. 19A), whereas cylinder resembles a saddle (Fig. 19B). Coma has a comet-shaped pattern with restricted light passage directly adjacent to an area of accelerated light passage in the same meridian, resulting in a “bump and dip” configuration (Fig. 19C). Spherical aberration has a central focus on restricted light (area of hyperopia) surrounded by an accelerated ring of light (annulus of myopia), resembling a “sombrero hat” (Fig. 19D). Other high-order aberrations, such as trefoil (“Napoleon’s hat”) and quadrafoil (“plant stand”) (Fig. 19E), generally have lower values (Fig. 19F) (9). A normal cornea with its normal prolate pattern also contains some high-order aberrations, but in low magnitude. The asphericity of the cornea increased nonlinearly in a positive direction (oblate) with the amount of myopic excimer laser treatment. The greater the amounts of correction, the progressively more oblate the corneal surfaces become. As a result, the spherical aberration increases in numerical value and wavefront size (19,20).

CLINICAL EXPERIENCE WITH WAVEFRONT-GUIDED ABLATION AND LASEK APPLICATION The clinical results are promising to date, with a reduction in induced aberrations compared with conventional myopic treatment, as well as improvement in reduction of preoperative spherical aberration (Fig. 20).

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Standard LASIK are known to induce an increase in optical aberrations, especially spherical aberration and coma (3–7,21,22). These surgically induced aberrations are believed to contribute to the deterioration of vision under scotopic lighting conditions after excimer laser refractive surgery. These aberrations are further increased in eyes with a larger pupil size and with larger attempted correction (21,22). For a large pupil, LASIK has been shown to induce more spherical aberrations than PRK (6). Moreover, the formation of a LASIK flap alone is known to induce optical aberration (5). These changes are believed to be caused by biomechanical and biological responses of the corneal tissue after laser ablation as a result of structural and shape change (23–25). Because of the growing concern with LASIK-induced aberrations and their potential compromise on the outcomes of custom wavefront ablation, surface ablation such as PRK and LASEK regained its popularity among many refractive surgeons. Nonetheless, just as the biomechanical effects of the cornea limit the predictability with custom surface ablation, PRK procedures are also shown to increase high-order optical aberrations in human eyes (3,4,6,26,27). Moreover, there are yet controlled studies, to date, confirming the superiority of custom LASEK over custom LASIK surgery. Wavefront technology provides a sophisticated diagnostic tool that, combined with a flying spot excimer laser system and eye tracking system, allows measurement and correction of ocular aberrations that interfere with the quality of vision but cannot be improved with traditional spherocylindrical lenses. Short-term clinical results are promising, suggesting that customized treatments result in improved quality of vision than achieved with the conventional treatments in a great proportion of eyes. Nonetheless, practical challenges, such as the inability to predict and compensate for the biomechanical effects of the cornea after laser surgery, the effects of the flap, and corneal wound healing, need to be further evaluated and addressed before customized wavefrontguided treatments can be performed with greater precision and high fidelity.

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Figure 17 (A, B) Schematic diagram of wavefront sensor based on the principles of Tscherning aberrometry. (C) Allegreto wavefront analyzer (WaveLight).

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Figure 18 Schematic diagram of Tracey ray-tracing aberrometry. (A) The retina spot location is coupled with the laser, scanner, photodetector, and computer. (B) An individual laser ray is very rapidly scanned through a multitude of entry points onto the retina. (C) The scanned spots are captured and connected in a retinal spot diagram and transformed into an aberration map.

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Figure 19 Three-dimensional aberration pattern of (A) myopia, (B) cylinder, (C) coma, (D) spherical aberration, (E) trefoil, and (F) quadrafoil.

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Figure 20 Spherical aberrations before and after LASIK treatment using the CustomCornea® (Alcon Inc., Fort Worth, TX) and conventional technique. Eyes treated using the CustomCornea® system have 50% less spherical aberration postoperatively than eyes treated using the conventional technique. REFERENCES 1. Maeda N. Wavefront technology in ophthalmology. Curr Opin Ophthalmol; 2001; 12:294–299. 2. Applegate RA. Limits to vision: can we do better than nature?. J Refract Surg;() 2000; 16(suppl):S547–S551. 3. Seiler T, Kaemmerer M, Mierdel P, Krinke HE. Ocular optical aberrations after photorefractive keratectomy for myopia and myopic astigmatism. Arch Ophthalmol; 2000; 118:17–21. 4. Oliver KM, Memenger RP, Corbett MC. Corneal optical aberrations induced by photorefractive keratectomy. J Refract Surg; 1997; 13:246–254. 5. Pallikaris I, Kymionis GD, Panagopoulou S. Induced optical aberrations following formation of a laser in situ keratomileusis flap. J Cataract Refract Surg; 2002; 28:1737–1741. 6. Oshika T, Klyce SD, Applegate RA. Comparison of corneal wavefront aberrations after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol;() 1999; 127(1):1–7. 7. Moreno-Barriuso EM, Lloves JM, Marcos S. Ocular aberrations before and after myopic corneal refractive surgery: LASIK-induced changes measured with laser ray tracing. Invest Ophthalmol Vis Sci;() 2001; 42(6):1396–1403.

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8. Thibos LN. Wavefront data reporting and terminology. J Refract Surg;() 2001; 17(5): S578– S583. 9. Chalita MR, Krueger RR. Wavefront technology. Contemporary Ophthalmol;() 2002; 1(14): 1–7. 10. Shack RV, Platt BC. Production and use of a lenticular Hartmann screen. J Opt Soc Am; 1971; 61:656. 11. Liang J, Grimm B, Goelz S, Bille J. Ojective measurement of the wave aberrations of the human eye using a Hartmann-Shack wavefront sensor. J Opt Soc am A; 1994; 11:1949–1957. 12. Liang J, Williams DR. Aberrations and retinal image quality of the normal human eye. J Opt Soc Am A; 1997; 14:2873–2883. 13. Miller DT, Williams DR, Morris GM, Liang J. Images of cone photoreceptors in the living human eye. Vis Res; 1996; 36:1067–1079. 14. Liang J, Williams DR, Miller DT. Supernormal vision and high-resolution retinal imaging through adaptive optics. J Opt Soc Am A; 1997; 14:2882–2892. 15. Thibos LN. Principles of Hartmann-shack aberrometry. J Refract Surg;() 2000; 16(suppl): S563–S565. 16. MacRae SM, Fujeida M. Slit skiascopic-guided ablation using the Nidek laser. J Refract Surg; 2000; 16:S576–S580. 17. Mrochen M, Kaemmerer M, Mierdel P. Principles of Tscherning aberrometry. J Refract Surg; 2000; 16:S570–S571. 18. Molebny VV, Panagopoulou SI, Molebny SV. Principles of ray tracing aberrometry. J Refract Surg; 2000; 16:S572–S575. 19. Pettit GH, Campin J, Liedel K, Housand B. Clinical experience with the CustomCornea measurement device. J Refract Surg; 2000; 16:S581–S583. 20. Holladay JT, James JA. Topographic changes in corneal asphericity and effective optical zone after laser in situ keratomileusis. J Cataract Refract Surg;() 2002; 28(6): 942–947. 21. Lichter H, Staver PR, Thompson K. Frontiers in refractive surgery. Interwave aberrometry for custom ablation. Int Ophthalmol Clin; 2002; 42:41–54. 22. Oshika T, Miyata K, Tokunaga T. Higher order wavefront aberrations of cornea and magnitude of refractive correction in laser in situ keratomileusis. Ophthalmology; 2002; 109:1154–1158. 23. Roberts C, Mahmoud A, Herderick EE, Chan G. Characterization of corneal curvature changes inside and outside the ablation zone in LASIK. Invest Ophthalmol Vis Sci;() 2000; 41(suppl): S679. 24. Roberts C. The cornea is not a piece of plastic. J Refract Surg; 2000; 16:407–413. 25. Roberts C. Biomechanics of the cornea and wavefront-guided laser refractive surgery. J Refract Surg; 2002; 18:S589–S592. 26. Nagy ZZ, Palagyl-Deak I, Kovacs A. Wavefront-guided photorefractive keratectomy for myopia and myopic astigmatism. J Refract Surg; 2002; 18:S615–S619. 27. Nagy ZZ, Palagyl-Deak I, Kovacs A. First results with wavefront guided photorefractive keratectomy for hyperopia. J Refract Surg; 2002; 18:S620–S623.

21 Customized Ablation and LASEK Erin D.Stahl, MD and Daniel S.Durrie, MD Durrie Vision Research Overland Park, KS

WAVEFRONT MEASUREMENT AND CUSTOM ABLATION The Progression of Technology In looking back on the history of refractive surgery, one of the most notable elements of this surgical field is the rapid and profound advance of technology. What began as a very basic science has progressed into a field dependent on sophisticated systems for both diagnostics and treatment of errors in the human optical system. Focusing on the evolution of technology since the advent of excimer laser refractive treatment, we have seen extensive change and improvement. Laser engineers have moved from stationary, broad-beam lasers to a level of technology capable of creating small, flying spot lasers used in conjunction with extremely fast eye tracking systems. The current laser technology allows for a high level of precision in creating ablation patterns and ensuring correct alignment during treatment (Fig.1). The software that controls these lasers has progressed from treating simple myopia to treating astigmatism, and from there into the treatment of hyperopia, astigmatic hyperopia, and mixed astigmatism. With the combination of extremely sophisticated hardware and software, we now have the ability to treat nearly any spherocylindrical correction with accurate and predictable results. At this point in time, clinicians feel very confident in their ability to perform refractive surgery and bring patients a level of vision comparable with their preoperative vision in glasses or contact lenses. The question that arises is whether we can take patients to a level of vision quality that surpasses that of traditional spherocylindrical correction. To address this question, it is important to look at the current tools and technology used to determine the desired correction. Although we have sophisticated laser technology, the ability to make complex maps of the corneal surface with topography, and software that can be programmed to determine precise ablation patterns, we still determine treatment by sitting the patient in front of the phoroptor. We will never move beyond the visual capability of spherocylindrical correction if we do not begin to take a more sophisticated approach to measurement. Wavefront Diagnostics With the advent of the Star Wars anti-missile defense system, astronomers began trying to determine methods to detect and correct defects in long-range telescopes. They developed

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Figure 1 LADARVision®. Flying, small-spot laser beam. Courtesy of Alcon Laboratories. a system of measurement that traced light ray s through an optical sy stem and recorded defects or aberrations. As vision scientists, laser companies and clinicians began to search for a new system of diagnostics for the human eye; they turned to this concept of wavefront-sensing technology as an ideal method of measuring aberration in the human eye. Wavefront measurement of the human eye is achieved by passing light rays in the form of a small, low-intensity laser through the eye and onto the retina. As these rays are reflected off of the retina and travel out of the eye, their path is distorted by aberrations in the optical system. As they exit from the eye, the light rays are detected using a chargecoupled device (CCD) camera. Complex software is then used to determine where each light ray has landed and, from there, which aberrations are present in the eye (Fig. 2) (Fig. 3). Because wavefront measurement of the human eye is still a nascent technology, there are numerous unique methods in development with various detection and calculation techniques (Fig. 4). As wavefront engineers became confident in their abilities to accurately measure the human optical system, they once again returned to the realms of astronomy, physics, and optics to determine a method of analysis and interpretation for wavefront measurements. Past history with wavefront sensing suggested that engineers use the Zernike polynomial, a mathematical description of a two-dimensional surface with uniform radius, to describe optical aberrations. The Zernike equation assesses a wavefront image and breaks the complex image into an infinite number of surfaces for simple description. The optical surfaces used in a Zernike description are represented in a Zernike pyramid (Fig. 4). Each

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level of the Zernike pyramid represents an “order” for those aberrations. The secondorder aberrations as expressed on the top level of the pyramid represent the “lower-order” aberrations of defocus (sphere) and astigmatism (cylinder). These are the optical aberrations that are currently measured with a phoroptor. As we move down the pyramid

Figure 2 To collect wavefront measurements of the human optical system, a beam of light is projected into the eye, bounced off of the retina, and measured as it escapes through the cornea. A detection system then analyzes the returning beams and calculates wavefront aberrations.

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Figure 3 A returning wavefront from a perfect optical system will be planar, whereas an aberrated wavefront will have a varying slope at different points.

Figure 4 A brief overview of diagnostic wavefront technologies.

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into the “higher-order” aberrations, we begin to see terms such as coma, trifoil, and spherical aberration (Fig.5). The goal of wavefront measurement and analysis with the Zernike equation is to provide the clinician with superior tools to assess the optical system of the human eye. Instead of describing the eye with three terms (second order), as with the phoroptor, we now have the capabilities of accurately measuring and describing the eye with up to 18 terms (second through fifth order) (Fig. 6).

Figure 5 The Zernike pyramid visually describes aberrations.

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Figure 6 The phoroptor is capable of measuring second-order aberrations, whereas wavefront is capable of measuring second-order through fifthorder aberrations. Topographic Diagnostics Wavefront measurement is not the only way of describing and classifying aberrations in the human eye. Corneal topography has been a staple technology in refractive surgery for many years. Corneal topography enables clinicians to acquire detailed images of the anterior and posterior aspects of the cornea. Topographic systems are also capable of determining steepness and thickness measurements essential to accurate visualization of the cornea. Methods of topographic analysis include optical slit scanning, placido disk imaging, and linear computation. Topography will be important role in the future of diagnostic technology because of its ability to map aspects of the corneal surface. It is important to keep in mind that although wavefront diagnostics can accurately map the optical system, the corneal surface is the location of the laser treatment. It will be essential to correlate wavefront data to the corneal topographic data for treatment algorithm evaluation. Customized Ablation The marriage of diagnostic measurements and laser technology results in treatment algorithms individualized to each patient. These customized algorithms use the output from the wavefront sensor, topography device, or a combination of the two and designate a laser shot pattern that treats the surface of the cornea in a “pixel-by-pixel” approach to minimize aberrations at all points. In initial clinical studies, it has been demonstrated that laser treatments based on wavefront-guided custom patterns have achieved a reduction in aberrations and increased best corrected visual acuity (BCVA) in comparison with conventional treatment. In phase I clinical trials, Alcon Summit Autonomous showed that after wavefront-guided treatment with their CustomCornea system, 92% of custom eyes were 20/16 or better BCVA Fig. 7). It was also demonstrated that higher-order aberrations decreased after custom treatment (1). It is evident from these preliminary results that wavefront-guided ablation techniques can bring refractive techniques to the next level.

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Figure 7 Six months postoperatively, 92% of CustomCornea wavefrontguided PRK eyes achieved 20/16 or better BCVA. Although the first steps are being made into the realm of customized ablations, there are many questions that remain unanswered. One is, what is the optimal wavefront pattern for the human optical system? Many vision scientists have suggested that a flat wavefront (all terms equal to zero) may bring maximized vision. Others have suggested that it is possible that certain aberrations, namely spherical aberration (2) and vertical coma, may optimize the visual system at values other that zero. Further research into diagnostic technology will continue to shed light on this exciting and promising field.

LASEK AND CUSTOM ABLATION Flap Biomechanics The biomechanical response to corneal manipulation associated with refractive surgery is a complicated and elusive phenomenon currently being addressed by many researchers. It is evident from initial studies that these biomechanical effects significantly impact refractive error and topographic appearance of the cornea. Although all refractive treatments will create some biomechanical changes, it has been shown that the creation of the LASIK stromal flap elicits significant changes in corneal topography even without laser treatment (3). Inherently, it is understood that the introduction of biomechanical corneal response with the creation of the LASIK flap will increase variability in

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aberrations of the corneal structure and therefore affect total aberrations of the optical system. Laser In Situ Keratomileusis (LASIK) vs. Photorefractive Keratectomy (PRK) Preliminary Results It is evident that the creation of the LASIK flap has substantial effects on the biomechanics of the cornea and therefore causes aberration and distortion not present in the “virgin” eye. With a traditional spherocylindrical LASIK treatment, these flap effects have been too fine to affect treatment algorithms. As we move into the treatment specifics allowed by wavefront diagnostics and custom ablation, it is logical to assume that flap effects will have an impact on the treatment of higher-order aberrations. It will be virtually impossible to predict the aberrations induced by the flap and simultaneously determine a treatment algorithm for naturally occurring and flap-induced aberrations. To truly achieve precise and controlled customized ablations, we must move away from the variables introduced with the creation of the LASIK flap. In support of this argument, initial custom treatment results show that fewer higherorder aberrations (third and fourth order) are induced with PRK than with LASIK as demonstrated in the case study in Figure 8. The Alcon CustomCornea study found that the ratio of postoperative to preoperative higher-order aberrations was significantly less with PRK in comparison with LASIK. In addition, this study demonstrated that higher order-aberrations decreased in 46% of custom ablation PRK patients, whereas only 26% of custom ablation LASIK patients achieved a decrease in higher-order aberrations (Fig. 9) (4). These data support the hypothesis that a treatment mechanism that eschews the complicating biomechanics of the LASIK stromal flap induces fewer aberrations postoperatively. From this conclusion, it can be deduced that laser subepithelial keratomileusis (LASEK) treatment would accomplish a similar effect as PRK in inducing fewer higher-order aberrations than LASIK.

Figure 8 Change in higher-order (root mean squared) RMS wavefront error and BCVA with CustomCornea treatment.

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Figure 9 (A) More higher-order aberrations are induced in a conventional LASIK treatment than in a conventional PRK treatment. (B) A greater percentage of eyes experienced a decrease in higher-order aberrations with PRK treatment in comparison with LASIK.

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POSSIBLE DISADVANTAGES OF CUSTOM TREATMENT AND LASEK Stromal Biomechanics Poorly Understood Although LASEK seems to be the natural solution to the problems with LASIK flap biomechanics and intrastromal variables, the effects of laser treatment on the surface of the cornea are still only vaguely understood. As refractive techniques with excimer lasers have progressed, our understanding of corneal response to spherocylindrical correction has been greatly increased. This understanding has led to changes in nomogram and laser patterns leading to improved and more predictable results. A possible hurdle in the movement toward customized surface treatments with LASEK is the challenge of understanding the effects on the cornea when it is subjected to often asymmetric and highly variable ablation patterns. Healing Variables Another challenge in moving into more specific treatment parameters is understanding the effects of healing on stromal and epithelial biomechanics. Although single laser pulses

Figure 10 Case study. One eye LASIK and one eye LASEK. are capable of treating extremely small aberrations with tissue removal of approximately 0.25 microns, it seems logical that a single epithelial cell (5 microns) may have the capability of filling in that treatment site and negating its effect. Additionally, the epithelial surface is not perfectly uniform, because the cells in different areas will

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undergo hypertrophy and hyperplasia in a natural effort to smooth the surface. Epithelial remodeling will undoubtedly affect small treatments to some extent. Healing variables will need to be addressed in determining the treatment capabilities of custom treatments.

PRELIMINARY DATA-LASEK HIGHER-ORDER ABERRATIONS Although we are still very early in our experience with analyzing wavefront effects of LASEK treatment, the initial clinical data reveal positive results. We present a case study looking at the higher-order aberrations of trifoil, coma, tetrafoil (4,2), and spherical aberration induced by a single patient with the LASIK procedure in one eye and the LASEK procedure in the other eye. The graph in Figure 10 demonstrates that postoperative LASIK aberrations (blue bars) are higher than postoperative LASEK aberrations (yellow bars) in trifoil, coma, tetrafoil, and spherical aberration (4,2). Additionally, the magnitudes of trifoil are (4,2) decreased preoperatively to postoperatively in the eye treated with LASEK, whereas the LASIK eye experienced increased postoperative aberrations in all terms. These results suggest that the techniques of the LASEK procedure, most notably the abandonment of the stromal flap, help to decrease postoperative aberrations associated with refractive surgery.

CONCLUSIONS The field of refractive surgery has made incredible strides in the past decade. We have made the leap from incisional surgery to precise excimer laser ablations. With the excimer laser, we have seen further evolution from broad-beam lasers to small flying spot lasers coupled with sophisticated eye-tracking systems. Wavefront technology is helping us transition from a point at which the current lasers are capable of performing more precise treatments than we can measure with the phoropter to a new position at which we can now measure with more accuracy than we can treat. This will help spur laser companies and surgeons to further improve lasers and refractive surgical techniques to keep up with the diagnostic equipment. The LASEK procedure may help keep aberrations created by the surgery itself to a minimum and thus is showing promise in helping us with this next step in the evolution of refractive surgery.

REFERENCES 1. McDonald MB. Presentation, Wavefront-Guided PRK with CustomCornea®. American Society of Cataract and Refractive Surgery, April 2001. 2. Holladay JT, Dudeja DR, Chang J. Functional vision and corneal changes after laser in situ keratomileusis determined by contrast sensitivity, glare testing, and corneal topography. J Cataract Refract Surg; 1999; 25(5):663–669. 3. Roberts C. The cornea is not a piece of plastic. J Refract Surg; 2000 (16(4)):407–413. 4. McDonald MB, Magruder GB. Presentation,“Wavefront-Guided Outcomes with CustomCornea®.” American Academy of Ophthalmology, November 2000.

22 Comparison of Wavefront-Guided Photorefractive Keratectomy and LASEK Treatments for Myopia and Myopic Astigmatism Zoltán Z.Nagy, MD Semmelweis University Budapest, Hungary

INTRODUCTION Wavefront measurement is a new tool for determination of the visual performance of the eye and for developing a treatment plan to abolish higher-order aberrations to provide supervision for the patient. It is known that laser in situ keratomileusis (LASIK) treatment causes significant increase in higher-order aberrations because of the corneal cut (Krueger RR. Wavefront technology. 1st International LASEK Congress, March 21– 23,2002, Houston, TX); therefore, attention of the refractive surgeons focuses again to advanced surface ablation techniques such as photorefractive keratectomy (PRK) with sophisticated flying spot laser beam delivery technology and laser intraepithelial keratomileusis (LASEK) (1–5), which seems to be a viable alternative to LASIK technology. In this study, authors compared the results with wavefront-guided refractive treatments using PRK and LASEK technology in eyes with spherical myopia and myopic astigmatism.

PATIENTS AND METHODS Two groups were formed for the purpose of the study. Group 1 (n=40) included the PRKtreated eyes, and group 2 (n=40) included the LASEK-treated eyes. The mean age of patients in group 1 was 32.2±3.42 years (range, 23 to 48 years); in group 2, mean age was 31.4±4.02 years (range, 22 to 40 years). The preoperative mean correction to obtain the spectacle-corrected visual acuity was −4.08±1.06 diopters (D) (spherical equivalent −1.5 D to −6.0 D; spherical range and 0 to −2.5 D in the cylindrical range) in group 1 and −4.12±0.98 D spherical equivalent (−1.25 D to −6.0 D and 0 to −2.0 D in cylindrical range. Follow-up is 6 months for each patient. During preoperative assessment, uncorrected visual acuity and spectacle-corrected visual acuity were tested and authors performed topography (Tomey-III, New York, NY), ultrasound pachymetry (Humphrey Model 850, San Leandro, CA), automated

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refractometry without and with pupil dilation, retinoscopy, Goldmann applanation tonometry, and wavefront-supported customized ablation (WASCA) measurements with the Asclepion WASCA workstation. WASCA measurements were performed in a dimly lit room without and with pupil dilation, calculation was based on the result obtained with undilated pupil, and the central 5.5-mm diameter measurements were considered at the determination of higher-order aberrations of the eye, i.e., the treatment plan. Wavefront measurements (WASCA) were performed with the Asclepion-Meditec WASCA workstation (Wavefront Sciences, Albuquerque, NM). A plane infrared laser wave is emitted at the lowest possible energy with 0.45 µW, which forms a small spot on the patient’s foveola. This spot acts as a secondary light source. The distortion of wavefront emitted by this point source is then analyzed by the machine. In an ideal nonaccommodating emmetropic eye, the wavefront exiting the eye is a plane wave again. In all other cases, the exiting wavefront will deviate from the original plane. The ShackHartmann sensor analyzes the deviation of the exiting wavefront from normal. The sensor consists of an array of microlenses (1452 altogether). Each lens defines a subaperture focusing a small portion of the incident wavefront on the sensor, leading to a pattern of focal spots on the detector surface. This pattern contains the information about the spatial phase and intensity distribution of the incident wave with a resolution determined by the number of lenslets per unit area, i.e., the overall lower-order and higher-order aberrations of the eye can be described in this way. By a mathematical program, the lower-order aberration (sphero-cylindrical refractive error) can be distracted from the overall aberration, and then the higher-order (third and fourth order) aberrations can be obtained. WASCA-guided PRK treatments were performed with the Asclepion-Meditec MEL 70 G-scan flying spot excimer laser. The laser operates with 250 mJ/cm2 fluency, with 38Hz frequency, and with a 1.8-mm diameter flying spot beam, and with an active eye tracker. Exclusion criteria were: blepharitis, dry eye syndrome, amblyopia worse than 20/40, connective tissue disease, keratoconus, keratoglobus, previous corneal scars, progressive myopia (more than 15% progression of refractive error during a year), pregnancy, and pacemaker. During PRK treatment, patients received three drops of oxybucaine hydrochloride anaesthetic eye drops, and then the epithelium was removed with a blunt hockey knife (4 seconds), a 12.0-mm metal ring was placed onto the eye, and the optical center of the eye was identified with the eye tracker, which recognized the geometrical center of the metal ring. Treatment data of higher-order aberration were transported via a zip disc to the computer panel of the excimer laser. At first the lower-order aberrations were treated and then identified again in the pupillary center. The higher-order aberrations were also treated during the same session. After WASCA-guided PRK, patients received tobramycine drops and topical fluorometholone. A soft bandage lens was applied for the first 3 postoperative days, then it was removed. The postoperative treatment protocol was the same as with traditional PRK, i.e., tobramycin drops four times daily for 5 days, then fluorometholone drops four times daily in a gradually tapering dose for 3 months. Patients were followed-up on the first postoperative day, on the fifth postoperative day, and at 1 month, 3 months, and 6 months after PRK. Postoperatively, the uncorrected visual acuity, spectacle-corrected visual acuity, Goldmann tonometry, ultrasound pachymetry, and WASCA measurements were

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tested and recorded. Subepithelial haze was assessed by slit-lamp biomicroscopy using Hanna’s scale (6).

RESULTS During the early postoperative period, patients in both groups had the usual mild symptoms of tearing, slight irritation, and photophobia. In group 1, the early postoperative symptoms were much milder because of the bandage contact lens than after traditional PRK. Symptoms were less pronounced in group 2 compared to group 1. Epithelial healing was normal in group 1 within 4 days. None of the patients had corneal infiltrates during the early postoperative period. Postoperative healing was normal in group 2, and no epithelial irregularity was found during the early postoperative period. Before PRK treatment, the uncorrected visual acuity was, on average, 0.06 (20/300) in both groups; in group 1, spectacle-corrected visual acuity was 0.96 (less than 20/20) in group 2 it was 0.94 (less than 20/20). Postoperatively in group 1, uncorrected visual acuity was 1.04±0.06 (better than 20/20); refraction was −0.12±0.02 D; spectacle-corrected visual acuity was 1.21± 0.04 (>20/15); 85% (34/40) were within ±0.25 D; 97.5% (39/40) were within ±0.5 D of intended refraction; and 100% (40/40) were within ±1.0 D. In group 2, postoperative uncorrected visual acuity was 1.02±0.04; spectacle-corrected visual acuity was 1.22± 0.06; 82.5% (33/40) were within 0.25 D of intended refraction; 95% (38/40) were within ±0.5 D, and 100% (40/40) were within ±1.0 D (Figs. 1–3). Interestingly, best results with uncorrected visual acuity and spectacle-corrected visual acuity was reached after 3 months and occurred mainly in eyes with a preoperative refractive error less than −3.5 D of spherical equivalent. Concerning safety, in group 1, 72.5% (29/40) of the eyes had spectacle-corrected visual acuity the same as that preoperatively; 20.0% (8/40) gained one line; 7.5% of the eyes (3/40) had spectacle-corrected visual acuity with a gain of two or more Snellen lines; none of the eyes lost any lines of spectacle-corrected visual acuity. In group 2, 70% (28/ 40) had the same spectacle-corrected visual acuity as that preoperatively; 12.5% of eyes (5/40) gained one line; 5% (2/40) gained two lines; and 12.5% (5/40) lost one line; however, none lost two or more lines (Fig. 4). Root mean squared (RMS) values increased from a preoperative value of 0.14 to 0.21 and from 0.12 to 0.23 in group 1 and group 2, respectively. Slit-lamp biomicroscopy revealed normal corneal wound healing in all case. None of the eyes had more than grade 1 haze according to Hanna’s scale (2). Intraocular pressure was not increased during the follow-up in any of the patients.

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Figure 1 The change of correction after WASCA-guided PRK and LASEK.

Figure 2 Predictability after WASCAguided PRK and LASEK.

Figure 3 The change of uncorrected visual acuity after WASCA-guided PRK and LASEK.

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Figure 4 Change of spectaclecorrected visual acuity (safety) after WASCA-guided PRK and LASEK. DISCUSSION Wavefront analysis provides a new and comprehensive information about the overall visual performance of the eye. Frits Zernicke, the Dutch Nobel Prize holder, developed a method in the 1940s to express wavefront function as a series of polynomials in such a way that each of these polynomials describes a characteristic aberration of the human optical system. This is achievable by software developed for WASCA Analyzer, which is able to examine higher-order aberration up to the fourth order. The first-order and second-order aberrations describe the lowest-order aberration of the eye, i.e., the spherocylindrical refractive error, which can be corrected with glasses, and was the basis of traditional refractive surgery (PRK, LASIK, LASEK) until today. With a mathematical tool, it is possible to separate the lower-order and higher-order aberrations from the overall distortion of wavefront to obtain the third-order and fourth-order Zernicke polynomials. We think that by abolishing the higher-order aberrations, it is possible to obtain supervision in some of the patients. In the literature there is still a debate regarding which refractive surgical procedure gives the best result and which is the most suitable for the purpose of wavefront-guided refractive treatments. Today, most authors agree that LASEK provides better results than LASIK (1–3), and LASEK results are comparable with results of traditional PRK (5). We can also support this finding, because in our results there was no significant difference between PRK and LASEK. Using wavefront-guided algorithms, both methods could increase spectacle-corrected visual acuity. We also know from the work of Krueger that LASIK creates more higher-order aberrations than LASEK or PRK (Krueger RR. Wavefront technology. 1st International LASEK Congress, March 21–23, 2002, Houston, TX). Based on our results, we can conclude that WASCA-guided PRK and LASEK treatments are safe, efficient, and predictable, and that both methods provided similar

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results. Despite a slight increase in RMS values, it was possible to improve spectaclecorrected visual acuity using the WASCA method in both treatment groups. The increase of spectacle-corrected visual acuity occurred at approximately the third postoperative month after surgery. WASCA-guided treatments gave better results in the lower diopter range (less than −3.5 D of spherical equivalent). Still, longer follow-up and a higher number of treated eyes are needed to judge the real value of the method.

REFERENCES 1. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12:323–328. 2. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs LASEK). J Refract Surg; 2001; 17(S):219–221. 3. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(S):222–223. 4. Claringbold TV. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg; 2002; 28:18–22. 5. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 6. Hanna KD, Pouliquen YM, Waring GO, Savoldelli M, Fantes K, Keith P, Thompson KP. Corneal wound healing in monkeys after repeated excimer laser photorefractive keratectomy. Arch Ophthalmol; 1992; 110:1286–1291.

23 Wound Healing After PRK, LASIK, and LASEK Takuji Kato, MD Juntendo University Tokyo, Japan In recent years, excimer laser has provided safe and effective approaches for the correction of refractive errors. Among the various refractive surgery procedures, photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) have been the most frequently performed for the treatment of myopia and astigmatism. Although PRK offers satisfactory refractive results for low myopia, subepithelial haze and refractive regression still remain significant concerns, especially when higher correction is attempted (1,2). LASIK is currently gaining acceptance as a more sophisticated procedure (3). Despite the fact that it leads to minimal haze and rapid recovery of vision, LASIK has its own drawbacks (4–6). More recently, laser epithelial keratomileusis (LASEK) has been introduced as a new surgical technique (7,8), which may combine the advantages and reduce the disadvantages of PRK and LASIK. The characteristics of corneal wound-healing response after refractive surgery are variable with each surgical procedure. Furthermore, the corneal wound-healing response can directly affect the surgical correction of refractive errors and is closely associated with complications after refractive surgery. It is therefore clear that scientific understanding of corneal woundhealing process will lead us to the therapeutic successes after the surgery. This chapter describes the characteristics of the corneal wound healing after PRK and LASIK, and the limitation of each procedure, then further discusses the possible advantage of LASEK.

PRK Epithelial Wound Healing The corneal wound-healing response to PRK is basically similar to that after mechanical debridement. A deposition of fibronectin and fibrinogen is observed on the ablated surface 24 hours after PRK. These components provide a temporary scaffold for corneal epithelial migration and adhesion (9). The epithelial covering of the ablated area takes 2 to 3 days after the surgery (Fig. 1A). The completion of the epithelial coverage, however, does not mean complete recovery in terms of barrier function. It takes several more weeks until

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Figure 1 Figure 1. Schematic drawing of corneal wound healing after refractive surgery. (A) PRK. (1) Apoptosis of anterior keratocyte. (2) Activation of epithelium. (3)

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Activation and transformation of keratocyte. (4) Extracellular matrix deposition. (B) LASIK. (1) Necrosis and apoptosis of keratocyte around the lamellar incision. (2) Epithelial plug formation. (3) Activated keratocytes at the wound edge. the corneal epithelium regains its functional barrier (10). A number of growth factors, including epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF), play an important role in completing re-epithelialization of the excimer wound (11). Because the epithelial basement membrane is absent at the laser-ablated area, the newly covered epithelial cells produce basement membrane components, including collagens (types IV and VII) and laminins (types 1 and 5). Adhesion complexes (hemidesmosomes) are then formed 4 to 6 weeks after PRK in the rabbit cornea (11,12). Until the epithelial barrier is reestablished, the greater risk of bacterial infection should be remembered. Epithelium-Keratocyte Interaction and Extracellular Matrix The regression of the correction and subepithelial haze have been reported as problems after PRK. These undesirable phenomena are caused by an excessive expression of extracellular matrix from both keratocyte and epithelial cells in the ablated zone. The interaction between corneal epithelial cells and keratocytes is a key concept in understanding of the corneal wound-healing after PRK. Nakayasu described that the anterior corneal stroma became acellular after an atraumatic removal of the corneal epithelium (13). More recently, the disappearance of anterior stromal keratocytes in response to epithelial scrape has been shown to be the result of programmed cell death (apoptosis), which is mediated by cytokines released from the injured epithelium (14– 16). The other factors, including inflammatory cell infiltration (17–19) and oxygen free radicals (20), have been proposed as mechanisms responsible for the disappearance of stromal keratocyte after PRK. The death of the keratocytes may trigger proliferation and migration of remaining peripheral and posterior keratocytes (13,21). During the repopulation of the area of cell death, a change in keratocyte phenotype to a myofibroblastlike cell (22) and overexpression of extracellular matrix components are observed. Biochemical and histochemical studies have revealed that the composition of the subepithelial haze includes collagens (type III, type IV) and glycosaminoglycans (hyaluronan, condroitin sulfate) (9,23–27). Among these extracellular components, type III collagen is one of the key molecules that relates to a persistent corneal haze (9,23) (Fig. 2A). An increase of type III collagen is a prominent phenomenon common to various forms of wound healing (28). It has been reported that the deposition of type III collagen increases near the incision of the cornea (29,30). The content of type III collagen in the normal cornea is only approximately 10% of its dry weight (31). However, type III collagen begins to increase at the site of the wound relatively early after injury. In a study in which fibroblast were cultured in various three-dimensional collagen gels, type III

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collagen gel showed the highest contraction rate (32,33). Therefore, type III collagen is presumed to play an important role in the contraction and closure of the wound. In PRK, the excessive expression of such extracellular matrix components may be a significant factor in limiting visual correction, especially in the treatment of patient with high myopia.

LASIK Currently, LASIK is the most commonly performed refractive surgical procedure. The rapid recovery of vision, minimal risk of corneal haze, and refractive predictability are the main advantage of LASIK. Because of the minimum activation of corneal epithelial cells and keratocytes (Fig. 2B), subepithelial haze is not observed, and refractive changes are stable after the surgery. However, we still do not know whether the structural strength of the cornea is completely restored after LASIK. There are two different kinds of wounds after LASIK. One is an incision wound at the flap margin and the other is an intrastromal lamellar wound in the central stroma (34). The characteristics of woundhealing response are completely different from each other. The wound-healing response at the flap margin is quite similar to that after incisional keratotomy. Immediately after the microkeratome incision, the corneal epithelium covers the wound margin, followed by the formation of an epithelial plug (35). Keratocytes migrate into the wound (the cutting edge) and transform into myofibroblastlike cells. These cells then produce extracellular matrix, such as collagens and proteoglycans. In contrast with the healing process at the flap margin, the healing reaction of the intrastromal lamellar wound in the central cornea is much weaker. After LASIK, one initial response at the stroma is the disappearance of keratocyte on both sides of the lamellar cut (34,36). Helena et al. reported that keratocyte apoptosis was noted within a zone approximately 50-µm anterior and posterior to the lamellar cut (37). Because such a keratocyte death does not induce strong activation of remaining keratocyte, the healing reaction around the intrastromal lamellar wound is relatively weak. Based on the results from an animal experiment, the healing process of intralamellar wound is not complete even 9 month after the surgery (Fig. 2), indicating that a much longer time than expected is required for corneal wound healing after LASIK (35). The data obtained from animal experiments are in agreement with the clinical experience. It is relatively easy to lift a corneal flap during retreatment even months after the initial LASIK surgery. Moreover, the cases of late-onset traumatic dislocation of the flap have been reported (38–40). These cases indicate that the paucity of wound-healing response after LASIK surgery may render the flap susceptible to late dislocation with trauma. As for the adhesion of LASIK flap, various mechanisms, including endothelial pumping, capillarity, and fiber interlacing, have been proposed (40,43). However, the exact mechanism by which lamellar flap adheres to the stromal bed is not known.

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Figure 2 Figure 2. (A) Immunohistochemical staining of type III collagen at subepithelial haze. (3 weeks after PRK; rabbit). (B) periodic acid schiff (PAS) staining of rabbit cornea after LASIK. Arrowheads indicate PAS-positive material at the lamellar incision (9 months after LASIK).

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One more potential problem of LASIK is considerable damage to corneal innervation. During this procedure, microkeratome cuts the anterior stromal nerves at the flap margin. Perez-Santonja et al. (44) showed that corneal sensitivity was more decreased after LASIK than after PRK during the first 3 months after surgery, and only after 6 months did it return to its preoperative value. The recovery of superficial stromal nerves took more than 5 months in a rabbit experiment (45). Because the corneal epithelium is known to derive neurotrophic factors from the corneal nerves, corneal surface abnormalities that develop after LASIK may be attributable to LASIK-induced neurotrophic epitheliopathy (46). Impaired innervation may also affect the keratocyte population (34) and the stromal wound-healing response.

LASEK LASEK has been introduced as a new surgical technique that seeks to minimize the drawbacks of both PRK and LASIK by making an epithelial flap. This procedure involves using alcohol to create an epithelial flap, followed by excimer laser ablation and repositioning of the epithelial flap. The preserved integrity of the corneal stroma and the minimal activation of both epithelial cells and keratocytes are the main advantages of LASEK. In theory, LASEK can avoid the haze and regression, which result from the excessive interaction between the corneal epithelial cells and activated keratocytes after excimer laser ablation. This procedure also offers the advantage of avoiding the flap complication of LASIK (7). In LASEK, whether the corneal epithelial cells are still vital after the exposure to alcohol is a very important point, but this fundamental question has not been definitely answered. Initial Trials of Alcohol-Assisted Epithelial Removal The corneal epithelium is frequently removed before PRK to obtain a smooth surface for laser ablation. Corneal epithelial debridement has been performed with a variety of techniques, including mechanical debridement (47), a rotating brush (48), transepithelial laser ablation (49,50) and chemical de-epithelialization (51,52). Among them, chemical de-epithelialization with alcohol is one of the most effective techniques. Several alcohol concentrations were initially tried in rabbits. Campos et al. showed that chemical deepithelialization with 100% ethanol caused more keratocyte loss when compared with mechanical techniques in a rabbit model (53). Helena et al. reported the same phenomena using a 50% solution. They selected 50% ethanol because more diluted solutions did not prove to be reproducibly effective in rabbit (54). Other authors reported favorable clinical results using lower concentrations and shorter durations (55–57). They indicated that chemical de-epithelialization with alcohol was more effective in performance than was mechanical scraping. However, almost all of the previous studies on chemical deepithelialization focused on the stromal changes after the epithelial debridement, and little is known about the epithelial changes after the alcohol exposure.

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Epithelial Viability After Alcohol Exposure Alcohol has been known to have direct toxic effects on cells. It is likely that alcohol produces its cytotoxicity through more than one mechanism. Postulated mechanisms include cell membrane damage (58,59), the suppression of membrane-associated enzymes (60), the inhibition of cell-cell communication (60), the disruption of cytoskeleton (61), and apoptosis (62). Presumably the cell membrane disorganizing effect of alcohol is more significant than another effect. The cell membrane consists of lipid molecules, which are arranged as a continuous double layer. It has been suggested that alcohol interacts with the bilayer to distort and expand the membrane, thereby increasing its fluidity (59). Although various cells have been used for toxicity studies, little information is available on the cytotoxicity of alcohol to corneal cells. To investigate the viability of corneal epithelial cells after LASEK, Gabler et al. stained the epithelial flap of human cadaver eyes with 0.1% trypan. They found that vital epithelial cells were seen with up to 45 seconds of exposure to 20% alcohol, and longer exposure killed the most epithelial cells (63). Electron Microscopic Study in Human We recently conducted electron microscopic analysis on an epithelial flap obtained from alcohol-assisted epithelial removal before PRK. Transmission electron micrographs showed a regular arrangement of epithelial cell layers after exposure of 18% alcohol for 30 seconds. The normal junctional complexes were seen between each cell, indicating alcohol solution at that condition did not affect junctional complexes. Although some of the nucleus showed irregular clumping of chromatin, all of the cells seem to be vital. At the posterior surface of the flap, irregular fragments of basement membrane were still attached to the basal cells. Bowman’s layer was completely absent in this flap. Both the number and the morphology of the hemidesmosomes were normal. These results indicate that the plane of alcohol separation might be within the basement membrane or between the basement membrane and the Bowman’s layer. Electron Microscopic Study in Rabbit To investigate the effects of alcohol exposure on the corneal epithelial cells, we further performed LASEK on rabbit eyes and conducted transmission electron microscopy. Previous studies indicated that 18% to 20% alcohol solution for 20 to 40 seconds is the optimal condition for the human cornea (55–57). We were, however, not able to make a LASEK flap on rabbit cornea in these conditions. However, when we use 40% alcohol for 3 minutes, an epithelial flap could be created easily. Electron microscopic examination revealed distention of intracellular spaces, particularly at the level of the middle or basal cell layer. Epithelial cells demonstrated swelling of mitcondria and degeneration of their cytoplasmic structure. The clumping of chromatin was noted in the nucleus. The overall configuration of the cell is maintained despite the disorganization of the plasma membrane. These findings are compatible with the characteristics of necrosis.

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The results indicate that a higher concentration of alcohol has a cytotoxic effect and induces necrosis of the epithelial cells. Role of Basement Membrane and Adhesion Complex During the PRK operation, both epithelial cell layers and basement membrane are removed, which distinguishes PRK from LASEK. One of the theoretical advantages of LASEK, compared with PRK, is the preservation of adhesion complex and basement membrane fragments at the epithelial flap. These components may play an important role in the wound-healing process after LASEK. Basement membrane influences the biological behavior of epithelial cells and vice versa. Until recently, basement membrane was simply thought to be a scaffold for epithelial cells. It has recently become apparent that the basement membrane plays a far more active and complex role in regulating the behavior of cells. Basement membrane can affect the shape, adhesion, and migration of cells by transmitting extracellular positional information to the intracellular cytoskeletal system via transmembrane receptor molecules (64). In an unwounded stable state, the epithelial cells are joined to neighboring cells by cell-cell junctions called desmosomes and to basement membrane by hemidesmosomes. Even in wound-healing process, desmosomes are retained as the cell-cell adhesion junction, thus enabling cells to move as a sheet rather than as individual cells (65). However, hemidesmosomes disappear from the basal cell when epithelial cells begin to migrate to cover a wound (66). The adhesion to basement membrane via hemidesmosome is essential to the stability of epithelial cells. The loss of this adhesion induces a different signal transduction, then triggers a cascade of cell activation. It is known that activated cells produce a variety of chemokine and extracellular matrix, which subsequently results in corneal haze and regression in the case of PRK. As mentioned, transmission electron micrographs showed that LASEK flap has a regular arrangement of hemidesmosomes and fragments of basement membrane after exposure to 18% alcohol for 30 seconds. These adhesion complexes enable epithelial cells to avoid an excessive activation after the surgery. Therefore, LASEK ensures quick wound healing with minimal tissue proliferation, which is in contrast to the excessive cellular activity after PRK. Inflammation and Role of Epithelial Flap It has been shown that neutrophils from the tear film are more prominent than those migrating from the limbus in early inflammation of the central cornea cells (67), and basement membranes are a physical barrier against such an influx of inflammatoty cells. Because, in PRK, the central cornea does not have epithelial basement membrane just after laser ablation, one of the early histologic findings after PRK is an influx of inflammatory cells into stroma (19). Infiltrating neutrophil generates oxygen radicals and matrix metalloproteinases, which may partially be responsible for initial stromal degradation. Therefore, as has previously been pointed out (68), it is likely the LASEK flap may act as a physical barrier to the infiltration of inflammatory cells from tears and consequently protects the corneal stroma from the inflammatory damage.

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CONCLUSIONS AND PERSPECTIVES LASEK can offer faster epithelial healing, stromal integrity, and avoidance of excessive cellular activation. This procedure can be a feasible alternative to conventional refractive surgery. However, our understanding of cellular and molecular mechanisms associated with LASEK is still incomplete. We are just beginning to understand some of the biological mechanisms responsible for wound healing after LASEK. At the molecular level, the identification of precise mechanisms by which alcohol facilitates the epithelial flap separation is an important challenge for the future. At the cellular level, a clear goal of future studies will be to further define cell kinetics, cell adhesion, and cell viability after this technique. We also need to understand the toxicity of alcohol and long-term effects after the surgery. Clinical progress over the past several years sets the stage for exploring a number of key unresolved issues. Further research in this area is bound to be exiting.

REFERENCES 1. Loewenstein A, Lipshitz I, Varssano D, Lazar M. Complications of excimer laser photorefractive keratectomy for myopia. J Cataract Refract Surg; 1997; 23:1174–1176. 2. Seiler T, Holschbach A, Derse M, Jean B, Genth U. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology; 1994; 101:153–160. 3. Pallikaris IG, Papatzanaki ME, Stathi EZ, Frenschock O, Georgiadis A. Laser in situ keratomileusis. Lasers Surg Med; 1990; 10:463–468. 4. Davis EA, Hardten DR, Lindstrom RL. LASIK complications. Int Ophthalmol Clin; 2000; 40: 67–75. 5. Farah SG, Azar DT, Gurdal C, Wong J. Laser in situ keratomileusis: literature review of a developing technique. J Cataract Refract Surg; 1998; 24:989–1006. 6. Holland SP, Srivannaboon S, Reinstein DZ. Avoiding serious corneal complications of laser assisted in situ keratomileusis and photorefractive keratectomy. Ophthalmology; 2000; 107: 640–652. 7. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser epithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol; 2001; 12:242–249. 8. Camellin M. LASEK technique promising after 1 year of experience. Ocular Surg News; 2000; 18:14–17. 9. Malley DS, Steinert RF, Puliafito CA, Dobi ET. Immunofluorescence study of corneal wound healing after excimer laser anterior keratectomy in the monkey eye. Arch Ophthalmol; 1990; 108:1316–1322. 10. Chang SW, Hu FR, Hou PK. Corneal epithelial recovery following photorefractive keratectomy. Br J Ophthalmol; 1996; 80:663–668. 11. Fagerholm P. Wound healing after photorefractive keratectomy. J Cataract Refract Surg; 2000; 26:432–447. 12. Fountain TR, de la Cruz Z, Green WR, Stark WJ, Azar DT. Reassembly of corneal epithelial adhesion structures after excimer laser keratectomy in humans. Arch Ophthalmol; 1994; 112:967–972. 13. Nakayasu K. Stromal changes following removal of epithelium in rat cornea. Jpn J Ophthalmol; 1988; 32:113–125.

Wound Healing After PRK, LASIK, and LASEK

285

14. Wilson SE. Molecular cell biology for the refractive corneal surgeon: programmed cell death and wound healing. J Refract Surg; 1997; 13:171–175. 15. Wilson SE. Everett Kinsey Lecture. Keratocyte apoptosis in refractive surgery. Clao J; 1998; 24:181–185. 16. Wilson SE. Role of apoptosis in wound healing in the cornea. Cornea; 2000; 19:S7–S12. 17. Choi YS, Kim JY, Wee WR, Lee JH. Effect of the application of human amniotic membrane on rabbit corneal wound healing after excimer laser photorefractive keratectomy. Cornea; 1998; 17:389–395. 18. Ramirez-Florez S, Maurice DM. Inflammatory cells, refractive regression, and haze after excimer laser PRK. J Refract Surg; 1996; 12:370–381. 19. Phillips AF, Szerenyi K, Campos M, Krueger RR, McDonnell PJ. Arachidonic acid metabolites after excimer laser corneal surgery. Arch Ophthalmol; 1993; 111:1273–1278. 20. Hayashi S, Ishimoto S, Wu GS, Wee WR, Rao NA, McDonnell PJ. Oxygen free radical damage in the cornea after excimer laser therapy. Br J Ophthalmol; 1997; 81:141–144. 21. Zieske JD, Guimaraes SR, Hutcheon AE. Kinetics of keratocyte proliferation in response to epithelial debridement. Exp Eye Res; 2001; 72:33–39. 22. Jester JV, Petroll WM, Cavanagh HD. Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog Retin Eye Res; 1999; 18:311–356. 23. Anderson JA, Binder PS, Rock ME, Vrabec MP. Human excimer laser keratectomy. Immunohistochemical analysis of healing. Arch Ophthalmol 1996; 114:54–60. 24. Kato T, Nakayasu K, Hosoda Y, Watanabe Y, Kanai A. Corneal wound healing following laser in situ keratomileusis (LASIK): a histopathological study in rabbits. Br J Ophthalmol; 1999; 83:1302–1305. 25. Fitzsimmons TD, Fagerholm P, Harfstrand A, Schenholm M. Hyaluronic acid in the rabbit cornea after excimer laser superficial keratectomy. Invest Ophthalmol Vis Sci; 1992; 33: 3011– 3016. 26. Hanna KD, Pouliquen Y, Waring GO, 3rd, Savoldelli M, Cotter J, Morton K, Menasche M. Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation. Arch Ophthalmol; 1989; 107:895–901. 27. Rawe IM, Zabel RW, Tuft SJ, Chen V, Meek KM. A morphological study of rabbit corneas after laser keratectomy. Eye; 1992; 6:637–642. 28. Clore JN, Cohen IK, Diegelmann RF. Quantitation of collagen types I and III during wound healing in rat skin. Proc Soc Exp Biol Med; 1979; 161:337–340. 29. Kato T, Nakayasu K, Kanai A. Corneal wound healing: Immunohistological features of extracellular matrix following penetrating keratoplasty in rabbits. Jpn J Ophthalmol; 2000; 44: 334– 341. 30. Cintron C, Hong BS, Covington HI, Macarak EJ. Heterogeneity of collagens in rabbit cornea: type III collagen. Invest Ophthalmol Vis Sci; 1988; 29:767–775. 31. Newsome DA, Gross J, Hassell JR. Human corneal stroma contains three distinct collagens. Invest Ophthalmol Vis Sci; 1982; 22:376–381. 32. Ehrlich HP. The modulation of contraction of fibroblast populated collagen lattices by types I, II, and III collagen. Tissue Cell; 1988; 20:47–50. 33. Ehrlich HP. Wound closure: evidence of cooperation between fibroblasts and collagen matrix. Eye; 1988; 2:149–157. 34. Vesaluoma M, Perez-Santonja J, Petroll WM, Linna T, Alio J, Tervo T. Corneal stromal changes induced by myopic LASIK. Invest Ophthalmol Vis Sci; 2000; 41:369–376. 35. Kato T, Nakayasu K, Ikegami K, Obara T, Kanayama T, Kanai A. Analysis of glycosaminoglycans in rabbit cornea after excimer laser keratectomy. Br J Ophthalmol; 1999; 83:609–612. 36. Wachtlin J, Langenbeck K, Schrunder S, Zhang EP, Hoffmann F. Immunohistology of corneal wound healing after photorefractive keratectomy and laser in situ keratomileusis. J Refract Surg; 1999; 15:451–458.

LASEK, PRK, and excimer laser stromal surface ablation

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37. Helena MC, Baerveldt F, Kim WJ, Wilson SE. Keratocyte apoptosis after corneal surgery. Invest Ophthalmol Vis Sci; 1998; 39:276–283. 38. Lemley HL, Chodosh J, Wolf TC, Bogie CP, Hawkins TC. Partial dislocation of laser in situ keratomileusis flap by air bag injury. J Refract Surg; 2000; 16:373–374. 39. Chaudhry NA, Smiddy WE. Displacement of corneal cap during vitrectomy in a post-LASIK eye. Retina; 1998; 18:554–555. 40. Melki SA, Talamo JH, Demetriades AM, Jabbur NS, Essepian JP, O’Brien TP, Azar DT. Late traumatic dislocation of laser in situ keratomileusis corneal flaps. Ophthalmology; 2000; 107: 2136–2139. 41. Perez EP, Viramontes B, Schor P, Miller D. Factors affecting corneal strip stroma-to-stroma adhesion. J Refract Surg; 1998; 14:460–462. 42. Holly FJ. Biophysical aspects of epithelial adhesion to stroma. Invest Ophthalmol Vis Sci; 1978; 17:552–557. 43. Maurice DM, Monroe F. Cohesive strength of corneal lamellae. Exp Eye Res; 1990; 50:59–63. 44. Perez-Santonja JJ, Sakla HF, Cardona C, Chipont E, Alio JL. Corneal sensitivity after photorefractive keratectomy and laser in situ keratomileusis for low myopia. Am J Ophthalmol; 1999; 127:497–504. 45. Linna TU, Perez-Santonja JJ, Tervo KM, Sakla HF, Alio y Sanz JL, Tervo TM. Recovery of corneal nerve morphology following laser in situ keratomileusis. Exp Eye Res; 1998; 66: 755– 763. 46. Ambrosio R, Jr, Wilson SE. Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surg; 2001; 17:350–379. 47. Seiler T, Wollensak J. Myopic photorefractive keratectomy with the excimer laser. One-year follow-up. Ophthalmology; 1991; 98:1156–1163. 48. Pallikaris IG, Karoutis AD, Lydataki SE, Siganos DS. Rotating brush for fast removal of corneal epithelium. J Refract Corneal Surg; 1994; 10:439–442. 49. Alio JL, Ismael MM, Artola A. Laser epithelium removal before photorefractive keratectomy. Refract Corneal Surg; 1993; 9:395. 50. Gimbel HV, DeBroff BM, Beldavs RA, van Westenbrugge JA, Ferensowicz M. Comparison of laser and manual removal of corneal epithelium for photorefractive keratectomy. J Refract Surg; 1995; 11:36–41. 51. Aron-Rosa DS, Colin J, Aron B, Burin N, Cochener B, Febraro JL, Gallinaro C, Ganem S, Valdes R. Clinical results of excimer laser photorefractive keratectomy: a multicenter study of 265 eyes. J Cataract Refract Surg; 1995; 21:644–652. 52. Abad JC, Talamo JH, Vidaurri-Leal J, Cantu-Charles C, Helena MC. Dilute ethanol versus mechanical debridement before photorefractive keratectomy. J Cataract Refract Surg; 1996; 22:1427–1433. 53. Campos M, Raman S, Lee M, McDonnell PJ. Keratocyte loss after different methods of deepithelialization. Ophthalmology; 1994; 101:890–894. 54. Helena MC, Filatov VV, Johnston WT, Vidaurri-Leal J, Wilson SE, Talamo JH. Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy. Cornea; 1997; 16:571–579. 55. Carones F, Fiore T, Brancato R. Mechanical vs. alcohol epithelial removal during photorefractive keratectomy. J Refract Surg; 1999; 15:556–562. 56. Abad JC, An B, Power WJ, Foster CS, Azar DT, Talamo JH. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology; 1997; 104:1566–1574. 57. Shah S, Doyle SJ, Chatterjee A, Williams BE, Ilango B. Comparison of 18% ethanol and mechanical debridement for epithelial removal before photorefractive keratectomy. J Refract Surg; 1998; 14:8212–8214.

Wound Healing After PRK, LASIK, and LASEK

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58. Mailliard ME, Sorrell MF, Volentine GD, Tuma DJ. Impaired plasma membrane glycoprotein assembly in the liver following acute ethanol administration. Biochem Biophys Res Commun; 1984; 123:951–958. 59. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev; 1972; 24: 583–655. 60. Bailey RE, Nandi J, Levine RA, Ray TK, Borer PN, Levy GC. NMR studies of pig gastric microsomal H +, K+-ATPase and phospholipid dynamics. Effects of ethanol perturbation. J Biol Chem; 1986; 261:11086–11090. 61. Banan A, Smith GS, Kokoska ER, Miller TA. Role of actin cytoskeleton in prostaglandininduced protection against ethanol in an intestinal epithelial cell line. J Surg Res; 2000; 88: 104– 113. 62. Baroni GS, Marucci L, Benedetti A, Mancini R, Jezequel AM, Orlandi F. Chronic ethanol feeding increases apoptosis and cell proliferation in rat liver. J Hepatol; 1994; 20:508–513. 63. Gabler B, Winkler von Monrenfels C, Lohmann CP. LASEK: a histological study to investigate the vitality of corneal epithlial cells after alcohol exposure. Invest Ophthalmol Vis Sci; 2001; 42:s600. 64. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell; 1992; 69: 11– 25. 65. Gipson IK. Adhesive mechanisms of the corneal epithelium. Acta Ophthalmol Suppl; 1992: 13– 17. 66. Buck RC. Hemidesmosomes of normal and regenerating mouse corneal epithelium. Virchows Arch B Cell Pathol Incl Mol Pathol; 1982; 41:1–16. 67. Sloop GD, Moreau JM, Conerly LL, Dajcs JJ, O’Callaghan RJ. Acute inflammation of the eyelid and cornea in Staphylococcus keratitis in the rabbit. Invest Ophthalmol Vis Sci; 1999; 40:385–391. 68. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570.

24 Biochemical Basis of Epithelial Dehiscence and Reattachment After LASEK Eric E.Gabison, MD, Hailton B.Oliveira, MD, Jin-Hong Chang, PhD, and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA Several questions have to be answered by refractive surgeons performing laser subepithelial keratomileusis (LASEK) surgery. Is the epithelial sheet viable after alcohol injury? What is the mechanism of epithelial detachment after alcohol application? Can the detached epithelium readhere after stroma injury? The aim of this chapter is to describe the key component of corneal epithelium to the stroma and to provide insight into the role of these molecules in governing the performance of LASEK as well as healing after LASEK.

MOLECULAR BIOLOGY OF THE CORNEAL BASEMENT MEMBRANE: ULTRASTRUCTURE AND MOLECULAR COMPOSTION To understand the principle of LASEK, the molecular basis of the corneal epithelialstromal adhesion complex must be understood. This adhesion complex, coined by Gipson et al. (1,2) and Espana et al. (3), is composed of several linked components including intermediate filaments, hemidesmosomes, anchoring fibrils, and anchoring plaques (Figs. 1 and 2) (1–3). The aim of diluted alcohol application, the first step of the LASEK procedure, is to temporarily dissociate this complex. Hemidesmosomes—Anchoring Fibrils Adhesion Complex Intermediate Filament Keratins are the intermediate filaments that connect the nuclear membrane to the hemidesmosomes of corneal epithelial cell plasma membrane. They are responsible for maintaining corneal epithelium structure. Several keratins have been detected in the corneal epithelium, each with a differential pattern of expression. Whereas K12 keratin is a cornea-specific intermediate filament distributed in the epithelium and sparing the limbus area, the K14 keratin is ubiquitous

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Figure 1 Schematic illustration of the interaction between the basal epithelial cell and the underlying basement membrane, which consists of the lamina densa made of collagen IV and the lamina lucida made of laminins. Hemidesmosomes are formed by integrin and laminin 5. Collagen VII is distributed in the lamina densa and superficial stroma. (With permission from Espana et al. J Cataract Refract Surg 2003; 29(6):1192–1197.) and localized to the basal epithelial cells. The K3 keratin is localized to the limbal and peripheral basal and wing cells, and to all the central corneal layers (4,5). Hemidesmosomes The hemidesmosomes are connections between basal epithelial cells and the underlying basal lamina. Their structure is divided into outer and inner plaques. The inner plaques are mainly composed of the desmoplakins, connecting the intermediate filament network to the outer plaques. The outer plaques are primary components of α6β4 integrin and the cytoplasmic domain of the 180-kD bullous pemphigoid antigen (BPA type II). This antigen corresponds to the newly discovered type XVII collagen, a membraneintercalated molecule that participates in hemidesmosome formation (6).

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Anchoring Filaments Anchoring filaments connect hemidesmosomes to anchoring fibrils throughout the lamina lucida. Many authors have described the lamina lucida as a transmission electron microscopy (TEM) fixation artifact, and this area may represent a weakness in the epitheliostromal adhesion complex. Anchoring filaments are mainly composed of laminin 5 and of the extracellular domain of the type XVII collagen (BPA type II). The anchoring filaments are connected to the lamina densa.

Figure 2 Representative microphotographs showing the effects of ethanol in cadaver corneas in creating LASEK flaps. (A) Hematoxylin and eosin staining of the lifted epithelial flap. (B) Collagen VII immunofluorescence staining in the area of the lifted flap showing linear staining in the corneal bed but not in the flap. (C) Laminin 5 staining in the area of the lifted flap showing linear

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staining in the corneal bed and a patchy pattern in the basal cells of the lifted flap. (D) Patchy staining for integrin β4 predominantly localized in the basal area of the lifted flap. (E) Intercellular and pericellular staining in the lifted epithelial flap but not on the stromal bed. (With permission from Espana et al. J Cataract Refract Surg 2003; 29(6): 1192–1197.) Lamina Densa The lamina densa is an electron-opaque region composed of type IV collagen, laminins, nidogen-entactin and proteoglycans. Anchoring Fibrils The lamina densa is also connected to anchoring fibrils, composed of type VII collagen. This molecule extends from the lamina densa to the anchoring plaques. The globular domains of type VII collagen are present in the lamina densa of the basement membrane and in the anchoring plaque. Therefore, this molecule acts as a “cufflink” between the epithelium and the stroma. Focal Contacts and Integrins Focal contacts are inter-hemidesmosomal adhesion molecules essentially composed of integrins and laminins. Like other stratified epithelia, corneal epithelium expresses a combination of integrins, including α2β1, α3β1, α6β1, αvβ1, that mediate attachment to the basement membrane and cell-cell interactions (7–15).

INTERCELLULAR JUNCTIONS IN THE CORNEAL EPITHELIUM Intercellular junctions constitute the second ocular surface barrier (after the tear film) protecting the stroma (and therefore the intraocular space) from chemical, bacteriological, or viral threats. The corneal epithelium is composed of four to six layers of stratified squamous nonkeratinized epithelium. Four types of intercellular junctions have been identified in the corneal epithelium: gap junctions, desmosomes, adherens junctions, and tight junctions. The LASEK procedure relies on one premise: intercellular junctions and cell-matrix junctions do not share the same properties. Accordingly, although cell-matrix junctions may be completely released during the first step of the procedure, most intercellular junctions remain functional, allowing the epithelial sheet to remain coherent.

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TIGHT JUNCTIONS: ZONULA OCCLUDENS Tight junctions serve a barrier function in epithelia. Only found in polarized epithelial cells, they are localized to the apical side, forming a continuous band around the cells. Tight junctions include the association of three membrane-bound proteins (the occludins 1 and 2 and the claudins) with intra-cytoplasmic proteins (Z0, 1, 2, and 3). In the normal rat cornea, immunoreactivity of Z0–1, Z0–2, and occludins has been detected in the superficial epithelial cell layers (16–20).

ZONULA ADHERENS Like the tight junctions, zonula adherens are localized to the apical side of the epithelial and form a continuous band. They are calcium-dependent junctions comprising the association of membrane-bound glycoproteins (the E-cadherins) with cytoplasmic plaques linked to the actin network. In the normal cornea, they are localized to all three epithelial layers (basal, intermediate, superficial). Zonula occludens play a role in the maintenance of the cell shape.

DESMOSOME: MACULA ADHERENS Desmosomes and adherens junctions belong to the cadherin family of adhesion proteins. Like adherens junctions, they are calcium-dependent and are involved in cell shape maintenance. However, they are not linked to the actin network (they attach to intermediate filaments) and do not form continuous bands around the cells (they are separate junctions). Desmoglein and desmoplakins are the main adhesion proteins of the desmosomes. Unique among stratified epithelia, corneal epithelium expresses only a single pair of desmosomal glycoproteins. Whereas Dsc2 and Dsg2 are expressed in the cornea, expression of Dsc3 and Dsg3 is only present in the limbus and conjunctiva. The association of desemosomes with cell proliferation seen in other epithelia has not been confirmed in corneal epithelial cells during re-epithelialization. Absence of Dsc1 and Dsg3 correlates with lack of keratinization in ocular epithelia (21–26).

GAP JUNCTIONS Gap junctions are localized to the lateral sides of basal corneal epithelial cells, excluding those of the limbal area. Formed by the association of connexin proteins, GAP junctions mediate intercellular signaling and thereby allow functional synchronization among neighboring cells (27).

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WOUND HEALING PROCESS Cell-Basement Membrane Junctions In the absence of a wound, the normal corneal epithelium undergoes a continuous process of regeneration. As basal cells undergo mitosis, daughter cells differentiate in the upper layers and desquamate 7 days later. Therefore, these cells must constantly break and then reform their hemidesmosomes: the newly formed hemidesmosome is a combination of newly synthesized integrins associated with an already-formed anchoring complex (anchoring fibrils and plaques). During the wound-healing process, hemidesmosomes are disassembled as confirmed by the loss of immunoreactivity for the β4 integrin subunit in the leading edge of the migrating corneal epithelium. While the β4 integrin subunit is not present in the corneal epithelial leading edge, the α6 subunit remains and co-localizes with the β1 subunit. After re-epithelialization, the hemidesmosomes completely regenerate within 4 weeks. Intercellular Junctions Each layer of the intact corneal epithelium expresses a different combination of intercellular junctions. Gap junctions (connexin 43 and 50) are present in the basal cell layer, desmosomes (desmoglein 1 and 2) in the wing cell layer, adherens junctions (Ecadherin) in all cell layers, and tight junctions (occluding) in the superficial cell layers of the epithelium. Although migrating epithelial cells lack connexins 43 and 50 during wound-healing processes, these components are present in the transition zone between migrating and nonmigrating cells. Tight junctions represent the main intercellular junction of migrating epithelial cells that do not express gap junctions, E-cadherins, or desmosomes. Alcohol Treatment Local application of 20% ethanol for 30 seconds on the corneal surface has been proven to be a safe technique to remove the corneal epithelium preceding photorefractive keratectomy (PRK). However, little is known concerning the mechanism of alcohol action. Accordingly, alcohol-assisted removal of corneal epithelium has been primarily tested “empirically” and established by the majority of corneal surgeons performing LASEK (28,29). Vitality of corneal epithelial cells after the exposure to 20% alcohol has been recently assessed. In this study, vital epithelial cells were seen after up to 45 seconds of exposure to 20% alcohol, whereas longer exposition times (up to 120 seconds) have been shown to be lethal for these cells. Because TEM is the “gold standard” to study epithelial cell adhesion molecules, we used TEM to evaluate epithelial sheets removed after 20% alcohol exposure. Results from this investigation revealed that the site of cleavage may be the anchoring fibrils and that most of the basement membrane is preserved during this process. In light of these

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findings, alcohol mode of action may be compared with that of dithiothreitol (DTT) (30,31). This molecule is an alcohol and a reducing agent, and it has been shown to disrupt basement membrane adhesion complexes at the level of the anchoring fibrils. Therefore, the DTT has been used to cleave adhesion molecules of several mucosa to study type VII collagen distribution in adhesion complex (Figure 1). Other techniques of corneal sheet removal include incubating with EDTA or dispase II. The action of EDTA and dispase II appears different from that of EtOH, because EDTA, acting as a calcium chelator, disrupts intracellular junctions and dispase II disconnects epithelial cells at the hemidesmosome level (2,32–36).

REASSEMBLY OF CORNEAL EPITHELIAL ADHESION STRUCTURES AFTER LASEK Gipson et al have studied hemidesmosome formation in vitro and in vivo. Sheets of epithelium removed using dispase II and then placed on corneal stroma were able to reform their hemidesmosomes. They subsequently described treatment of corneal wounds with corneal epithelium transplantation in vivo. Sheets of corneal epithelium removed using the same technique were placed on abraded (basement membrane intact) or keratectomized corneas and protected with soft contact lenses. After 24 hours, the transplanted epithelium was adherent to both abraded and keratectomized corneas. Hemidesmosomes formation between basal cells of donor epithelium and denuded host membrane were detected. Interestingly, transplants of corneal epithelial sheets to abraded corneas were most successfully maintained if the host basement membrane was present. This pioneering in vivo experiment has been followed by ex vivo experiments studying epithelial-basement membrane interaction after recombination of epithelial sheets with basement membrane denuded corneal stromas. Results from these investigations revealed the viability of epithelial sheets transplanted on corneal stromas (in rats), that 6 hours were necessary for hemidesmosome reformation in epithelial basement membrane recombination, and that hemidesmosomal reformation requires both healthy epithelium and stroma (37–40). Viability of Epithelial Cells in LASEK Several studies have evaluated the viability of epithelial cells after LASEK. Chen et al. determined the effect of dilute alcohol on human corneal epithelial cellular morphology and viability (41). A 20-second time exposure of cultured immortalized human cells to various concentrations of EtOH-H2O showed significant reduction of viable cells when EtOH-H2O concentration exceeded 25% (v/v) (P=0.005). Increasing the duration of 20% EtOH-H2O beyond 30 seconds resulted in a significant reduction in viable cells. TdTmediated dUTP nick-end labeling (TUNEL) assay for apoptosis of cultured human corneal epithelial cells exposed to 20% EtOH-H2O for 20 and 40 seconds showed maximal labeling at 24 hours (58.05%±33.10%) and 8 hours (94.12%±1.21%), respectively. Gabler et al. evaluated the vitality of epithelial cells after various exposure times to 20% ethanol and epithelial flap preparation in laser-assisted subepithelial keratectomy

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(LASEK) (42). Human cadaver eyes were exposed to 20% ethanol for 15, 30, 45, 60, and 120 seconds, respectively. After a 15-and 30-second exposure, most epithelial cells were vital. This changed substantially after 45 seconds, when viable and dead cells were approximately equal in number. Longer exposure times (60 seconds and 120 seconds) showed predominantly dead epithelial cells. Lee et al. evaluated the morphologic changes in the white leghorn chick cornea caused by 20% alcohol after LASEK surgery (43). Exposure of the corneal epithelium to 20% alcohol for 30 seconds or longer allowed reproducible separation of epithelial flaps from stroma in white leghorn chick eyes. Transmission electron microscopy immediately after alcohol treatment showed that exposure to 20% alcohol for 30 seconds or less had minimal adverse effects on the corneal epithelium structure. TUNEL-positive cells in the central superficial stroma around the epithelial flap margin and in the epithelial flap itself were identified (particularly in the basal epithelial layer). Transmission electron microscopy showed similar evidence of apoptosis in the epithelium and anterior stroma. Importance of Basement Membrane Integrity It is not known whether the separation of the basement membrane from Bowman’s layer and its replacement after laser offer LASEK an advantage over PRK. The layer at which epithelium and stroma separates depends on the particular LASEK surgical technique. In Azar’s and Chen’s studies, variable morphologic patterns of separation were seen in the basement membrane zone by electron microscopy. Various basement complex configurations were observed beneath the epithelial basal cells including unilamellar basement membrane, irregular basement membrane with intact hemidesmosomes, and basement membrane containing dense bundles of anchoring fibrils. Similarly, Browning et al. have shown that a small amount of basement membrane was left attached to the LASEK flap; thus, this remaining basement membrane was of variable thickness (44). The residual basement membrane also had an undulating appearance, coinciding with the position of hemidesmosomes. The action of alcohol may in part be caused by disruption of the binding of hemidesmosomes to basement membrane. During corneal wound healing, the disruption of the basement membrane has been shown to induce inflammatory cytokine production. Stramer et al. have demonstrated that penetrating incision or ablation injury to the corneal stroma stimulates a typical fibrotic repair response involving hypercellularity, expression of smooth muscle actin, and deposition of a disorganized extracellular matrix (45). The fibrotic response in vascularized tissues is controlled by bioactive substances, including PDGF and TGF-β, which are released from platelets at the wound site. In the cornea, TGF-β2 may be produced by epithelial cells activated by injury. Thus, debridement of corneal epithelium from basement membrane causes stromal cell apoptosis but no obvious hypercellularity or deposition of matrix. Nakamura et al. have shown that the fibrotic response is stimulated in PRK; thus, less fibrotic response was found in LASIK and, thus, TGF-β2 induced by injured corneal epithelium may play a role in the fibrotic phenotype. Whether these inflammatory cytokines are produced during LASEK is not yet known. There may be a difference in the release of TGF-β2 between surviving epithelium vs. killed epithelium after LASEK procedures and the barrier function offered by the

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presence of intact basement membrane in the prevention of scar formation. Preliminary results, using rabbit and chicken models, show that corneal scarring may be greater in PRK than in LASEK. Because the experimental evidence is limited, further experiments are needed to determine whether LASEK induces less scarring than PRK in human subjects.

CONCLUSION Several lines of evidence suggest the feasibility of LASEK as a good alternative procedure to PRK in reducing scar formation. Our theory based on current data is that alcohol weakens the adhesions between epithelium and stroma, and the mechanical separation between the two layers during surgery depends on the plane of the mechanical cut. In general, one can assume that with current technologies and techniques, the separation of corneal epithelial layer from stromal layer is within the basement membrane. The preservation of an intact, viable layer in conjunction with intact basement membrane may explain the potential reduction in stromal complications after LASEK as compared to PRK. We hypothesize that the intact basement membrane may reduce the alteration of fibrotic pheno-type. Despite the potential for LASEK, important questions remain. Will LASEK patients have a greater rate of recurrent erosion syndromes given the effect of EtOH on hemidesosomes? Will diabetic patients be particularly prone to recurrent erosions after LASEK? Ultimately, will the benefits of LASEK justify the greater complexity of the procedure?

REFERENCES 1. Gipson IK, Spurr-Michaud SJ, Tisdale AS. Anchoring fibrils form a complex network in human and rabbit cornea. Invest Ophthalmol Vis Sci; 1987; 28(2):212–220. 2. Gipson IK, Spurr-Michaud SJ, Tisdale AS. Hemidesmosomes and anchoring fibril collagen appear synchronously during development and wound healing. Dev Biol; 1988; 126(2): 253– 262. 3. Espana EM, Grueterich M, Mateo A, Romano AC, Yee SB, Yee RW, Tseng SC. Cleavage of corneal basement membrane components by ethanol exposure in laser-assisted subepithelial keratectomy. J Cataract Refract Surg; 2003; 29(6):1192–1197. 4. Chaloin-Dufau C, Pavitt I, Delorme P, Dhouailly D. Identification of keratins 3 and 12 in corneal epithelium of vertebrates. Epithelial Cell Biol; 1993; 2(3):120–125. 5. Elder MJ, Hiscott P, Dart JK. Intermediate filament expression by normal and diseased human corneal epithelium. Hum Pathol; 1997; 28(12):1348–1354. 6. Gordon MK, Fitch JM, Foley JW, Gerecke DR, Linsenmayer C, Birk DE, Linsenmayer TF. Type XVII collagen (BP 180) in the developing avian cornea. Invest Ophthalmol Vis Sci; 1997; 38(1):153–166. 7. Latvala T, Paallysaho T, Tervo K, Tervo T. Distribution of alpha 6 and beta 4 integrins following epithelial abrasion in the rabbit cornea. Acta Ophthalmol Scand; 1996; 74(1):21–25. 8. Latvala T, Tervo K, Tervo T. Reassembly of the alpha 6 beta 4 integrin and laminin in rabbit corneal basement membrane after excimer laser surgery: a 12-month follow-up. CLAO J; 1995; 21(2):125–129.

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9. Paallysaho T, Tervo K, Tervo T, van Setten GB, Virtanen I. Distribution of integrins alpha 6 and beta 4 in the rabbit corneal epithelium after anterior keratectomy. Cornea; 1992; 11(6): 523– 528. 10. Paallysaho T, Tervo T, Virtanen I, Tervo K. Integrins in the normal and healing corneal epithelium. Acta Ophthalmol Suppl; 1992; 202:22–25. 11. Stepp MA, Spurr-Michaud S, Gipson IK. Integrins in the wounded and unwounded stratified squamous epithelium of the cornea. Invest Ophthalmol Vis Sci; 1993; 34(5):1829–1844. 12. Tervo K, Paallysaho T, Virtanen I, Tervo T. Integrins in human anterior chamber angle. Graefes Arch Clin Exp Ophthalmol; 1995; 233(5):291–295. 13. Tervo K, Tervo T, van Setten GB, Virtanen I. Integrins in human corneal epithelium. Cornea; 1991; 10(6):461–465. 14. Tervo T, van Setten GB, Paallysaho T, Tarkkanen A, Tervo K. Wound healing of the ocular surface. Ann Med; 1992; 24(1):19–27. 15. Virtanen I, Tervo K, Korhonen M, Paallysaho T, Tervo T. Integrins as receptors for extracellular matrix proteins in human cornea. Acta Ophthalmol Supp; 1992; 202:18–21. 16. Petroll WM, Hsu JK, Bean J, Cavanagh HD, Jester JV. The spatial organization of apical junctional complex-associated proteins in feline and human corneal endothelium. Curr Eye Res; 1999; 18(1):10–19. 17. Ryeom SW, Paul D, Goodenough DA. Truncation mutants of the tight junction protein ZO-1 disrupt corneal epithelial cell morphology. Mol Biol Cell; 2000; 11(5):1687–1696, 18. Suzuki K, Tanaka T, Enoki M, Nishida T. Coordinated reassembly of the basement membrane and junctional proteins during corneal epithelial wound healing. Invest Ophthalmol Vis Sci; 2000; 41(9):2495–2500. 19. Vanderburg CR, Hay ED. E-cadherin transforms embryonic corneal fibroblasts to stratified epithelium with desmosomes. Acta Anat; 1996; 157(2):87–104. 20. Yi X, Wang Y, Yu FS. Corneal epithelial tight junctions and their response to lipopolysaccharide challenge. Invest Ophthalmol Vis Sci; 2000; 41(13):4093–4100. 21. Drenckhahn D, Franz H. Identification of actin-, alpha-actinin-, and vinculin-containing plaques at the lateral membrane of epithelial cells. J Cell Biol; 1986; 102(5):1843–1852. 22. Kapprell HP, Owaribe K, Franke WW. Identification of a basic protein of Mr 75,000 as an accessory desmosomal plaque protein in stratified and complex epithelia. J Cell Biol; 1988; 106(5):1679–1691. 23. Messent AJ, Blissett MJ, Smith GL, North AJ, Magee A, Foreman D, Garrod DR, Boulton M. Expression of a single pair of desmosomal glycoproteins renders the corneal epithelium unique amongst stratified epithelia. Invest Ophthalmol Vis Sci; 2000; 41(1):8–15. 24. Okada Y, Saika S, Shirai K, Hashizume N, Yamanako O, Ohnishi Y, Senba E. Disappearance of desmosomal components in rat corneal epithelium during wound healing. Ophthalmologica; 2001; 215(1):61–65. 25. Rubinstein N, Stanley JR. Pemphigus foliaceus antibodies and a monoclonal antibody to desmoglein I demonstrate stratified squamous epithelial-specific epitopes of desmosomes. Am J Dermatopathol; 1987; 9(6):510–514. 26. Shi Y, Tabesh M, Sugrue SP. Role of cell adhesion-associated protein, pinin (DRS/memA), in corneal epithelial migration. Invest Ophthalmol Vis Sci; 2000; 41(6):1337–1345. 27. Matic M, Petrov IN, Chen S, Wang C, Dimitrijevich SD, Wolosin JM. Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation; 1997; 61(4): 251– 260. 28. Abad JC, An B, Power WJ, Foster CS, Azar DT, Talamo JH. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology; 1997; 104(10):1566–1574; discussion 1574–1575, 29. Aron-Rosa DS, Colin J, Aron B, Burin N, Cochener B, Febraro JL, Gallinaro C, Ganem S, Valdes R. Clinical results of excimer laser photorefractive keratectomy: a multicenter study of 265 eyes. J Cataract Refract Surg; 1995; 21(6):644–652.

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30. Osawa T, Abe M, Morigami A; Nozaka Y. Distribution of type VII collagen in the epithelial basement membranes of mouse palate, tongue and lip mucosa. Arch Oral Biol; 2000; 45(5): 419–424. 31. Osawa T, Nozaka Y. Fine structure of the epidermal basement membrane of the lip: applications of dithiothreitol separation and ultrathin frozen sectioning. Acta Anat; 1995; 153(2):106–110. 32. Gipson IK. Adhesive mechanisms of the corneal epithelium. Acta Ophthalmol Suppl; 1992; 202:13–17. 33. Gipson IK, Friend J, Spurr SJ. Transplant of corneal epithelium to rabbit corneal wounds in vivo. Invest Ophthalmol Vis Sci; 1985; 26(4):425–433. 34. Gipson IK, Grill SM. A technique for obtaining sheets of intact rabbit corneal epithelium, Invest Ophthalmol Vis Sci; 1982; 23(2):269–273. 35. Gipson IK, Grill SM, Spurr SJ, Brennan SJ. Hemidesmosome formation in vitro. J Cell Biol; 1983; 97(3):849–857. 36. Gipson IK, Spurr-Michaud S, Tisdale A, Keough M. Reassembly of the anchoring structures of the corneal epithelium during wound repair in the rabbit. Invest Ophthalmol Vis Sci; 1989; 30(3):425–434. 37. Azar DT, Gipson IK. Repair of the corneal epithelial adhesion structures following keratectomy wounds in diabetic rabbits. Acta Ophthalmol Suppl; 1989; 192:72–79. 38. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK. Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol; 1992; 110(4):537–540. 39. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK. Decreased penetration of anchoring fibrils into the diabetic stroma. A morphometric analysis. Arch Ophthalmol; 1989; 107(10): 1520– 1523. 40. Azar DT, Spurr-Michaud SJ, Tisdale AS, Moore MB, Gipson IK. Reassembly of the corneal epithelial adhesion structures following human epikeratoplasty. Arch Ophthalmol; 1991; 109(9):1279–1284. 41. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43(8):2593–2602. 42. Gabler B, Winkler von Mohrenfels C, Dreiss AK, Marshall J, Lohmann CP. Vitality of epithelial cells after alcohol exposure during laser-assisted subepithelial keratectomy flap preparation. J Cataract Refract Surg; 2002; 28(10):1841–1846. 43. Lee JB, Javier JA, Chang JH, Chen CC, Kato T, Azar DT. Confocal and electron microscopic studies of laser subepithelial keratomileusis (LASEK) in the white leghorn chick eye. Arch Ophthalmol; 2002; 120(12):1700–1706. 44. Browning AC, Shah S, Dua HS, Maharajan SV, Gray T, Bragheeth MA. Alcohol debridement of the corneal epithelium in PRK and LASEK: an electron microscopic study. Invest Ophthalmol Vis Sci. 2003; Feb; 44(2):510–513. 45. Stramer BM, Zieske JD, Jung JC, Austin JS, Fini ME. Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest Ophthalmol Vis Sci; 2003; 44(10):4237–4246.

25 Refractive Surgical Wound Healing Mechanisms Revisited: A Glimpse at the Future of LASEK James V.Jester, PhD University of Texas Southwestern Medical Center at Dallas Dallas, TX

INTRODUCTION Refractive surgery, from keratomileusis to laser-assisted in situ keratectomy (LASIK), have sequentially offered the promise of permanently correcting refractive visual errors. However, as these procedures have gained initial acceptance and then wider application, invariably problems have been encountered, ranging from regression and reduced visual acuity to progressive corneal instability that ultimately limit the successfulness of these procedures, seemingly leaving unfulfilled the promise of perfectly corrected vision. Although refractive surgery has developed rapidly over the past 30 years, progress in understanding the basic mechanisms underlying these complications has been limited and at times superficial. For the most part, corneal wound healing has been implicated as a major contributor to the lack of success; however, even with this consensus opinion, the underlying pathophysiology is unknown at the molecular level and even remains controversial at the cellular and tissue level. Furthermore, although experimentation and development of refractive surgery techniques has led to an abundance of clinical experience, this knowledge has yet to be translated into a unified understanding of the basic corneal response to refractive surgery that can help in the development of predictive refractive surgical techniques. As part of the First International LASEK Congress it is perhaps important to ask the questions as to what differentiates laser-assisted subepithelial keratectomy (LASEK) from its predecessors, photorefractive keratectomy (PRK) and LASIK, and can previous clinical experience combined with basic research on the biology of corneal wound healing provide insights into the success, failure, and future development of this new refractive surgical modality? In addressing these questions, this article reviews our current understanding of the cellular and molecular mechanism underlying the development of corneal haze after PRK, the possible explanations for the absence of haze after LASIK, and assesses the future ability of LASEK and other advanced surface ablation techniques to surgically provide refractive correction without the development of haze.

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CELLULAR AND MOLECULAR MECHANISMS FOR DEVELOPMENT OF CORNEAL HAZE Recent studies clearly demonstrate that corneal haze results from the activation of normally quiescent keratocytes to a stromal wound-healing fibroblast or myofibroblast (Fig. 1). This conclusion is derived from a series of in vivo confocal microscopic studies conducted in human patients and in rabbits that were performed to assess the corneal wound-healing response after PRK. In vivo confocal microscopy has the unique ability not only to provide high-resolution images of cellular structure at the microscopic level in intact living tissue (1) but also to objectively measure sublayer thickness and, more importantly, the back-scattering of light sequentially over time in the same cornea (2). Using in vivo confocal microscopy, animal studies of PRK have shown that light scattering or haze 1 week after surgery is localized to the photoablated stromal surface and at a region 100 µm deep within the anterior corneal stroma (Fig. 2B, arrows) (3). The area between the surface and the deeper light-scattering region correlates histologically with the area of keratocyte apoptosis that is known to occur after scrape injury to the cornea (4,5), explaining the separation between the stromal surfaces and underlying light scattering structure. Over the next week, the region of deeper stromal haze dramatically increases in intensity while appearing to move toward the photoablated surface (Fig. 2C). Peak haze is detected on completion of migration anteriorly with gradually decreasing levels of haze detected up to 6 months after surgery. This progression of haze as detected by in vivo confocal microscopy also directly correlates with the clinical assessment of haze by trained refractive surgeons in the rabbit model of PRK and in human patients (6).

Figure 1 Recent in vivo confocal microscopic studies have shown that corneal haze is uniquely associated with the appearance of corneal woundhealing fibroblasts and myofibro-

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blasts. This association has lead to the hypothesis that normally quiescent corneal keratocytes are transparent within the clear cornea, whereas fibroblasts and myofibroblasts markedly scatter light, leading directly to corneal haze.

Figure 2 Three-dimensional reconstructions taken form in vivo confocal microscopy scans of the same rabbit cornea before (A) and after photorefractive keratectomy (PRK) at 1 week (B), 2 weeks, (C) 3 weeks (D), 7 weeks (E), and 17 weeks (F). In the normal cornea, three reflective layers are detected (white arrows), the surface epithelium, basal lamina, and endothelium, respectively. After PRK, a fourth reflective layer appears

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separated from the epithelial/stromal interface by approximately 100 µm (black arrows). This fourth reflective layer appears to move anteriorly by 2 weeks (C) and reaches the epithelial/stromal interface at 3 weeks (D), reaching maximum lightscattering. By 17 weeks, lightscattering has decreased, along with an increase in stromal thickness. Bar indicates 100 µm in the x-axis and 70 µm in the z-axis. Taken from Figure 4 in Moller-Pedersen T, Li HF, Petroll WM, Cavanagh HD, Jester JV. Confocal microscopic characterization of wound repair after photo-refractive keratectomy. Invest Ophthalmol Vis Sci 1998a; 39:487–501. The haze detected by in vivo confocal microscopy is also directly related to specific changes within the corneal keratocytes that were immediately adjacent to the area of injury (Fig. 3). Specifically, when evaluating haze in patients after PRK, increased scattering of light is detected from the enlarged cell bodies of keratocytes at the stromal/epithelial interface (Figs. 3A and 3B). In the rabbit PRK model, early stromal haze is associated with elongation of keratocytes to form spindle-shaped, migratory fibroblasts (Fig. 3C). Importantly, however, after migration of keratocytes/fibroblasts to the stromal surface, there is a dramatic change in keratocyte differentiation to an enlarged cell that markedly scatters light and has broad cellular processes extending and interconnecting to adjacent cells (Fig. 3D). These cells have been identified in other wound models (7) as well as PRK (8) as corneal myofibroblasts, based on detailed immunocytochemical and biochemical characterizations. While the explanation for the dramatic increase in light-scattering from fibroblasts and myofibroblasts remains unclear, recent studies suggest that keratocytes express abun-

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Figure 3 Human patient (A and B) and rabbit (C and D) cornea after PRK. (A) Slit-lamp photograph of patient’s cornea showing presence of central corneal haze. (B) In vivo confocal microscopy showing broadly thickened and distinct keratocyte cell bodies in the region of haze. (C) Rabbit cornea 7 days after PRK showing migration of spindle-shaped fibroblasts within fourth reflective layer noted in Figure 2B. (D) Same rabbit cornea, 3 weeks after PRK, showing the presence of highly reflective myofibroblasts forming a broad, interconnected meshwork of cells. Bar indicates 100 µm. Taken from Figure 2 of Jester JV, Moller-Pedersen T, Huang J, Sax CM, Petroll WM, Cavanagh HD, Piatigorsky J. The cellular basis of corneal transparency: Evidence for “corneal crystallins.” J Cell Sci 1999b; 112:613–622

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dant amounts of a few water-soluble proteins that have been called corneal crystallins (9,10). These proteins at high concentrations are thought to have similar properties as lens crystallin proteins and may contribute to the transparent state of the cornea by destructively interfering with scattered light through short-range physical interactions. Interestingly, water-soluble proteins isolated from rabbit keratocytes obtained from transparent rabbit corneas show high levels of expression of aldehyde dehydrogenase class 1 (ALDH1) and transketolase (TKT). When cells are obtained from hazy corneas, the level of expression of ALDH1 and TKT is markedly reduced or abolished compared to the level of expression within keratocytes from transparent regions immediately adjacent to the hazy corneal regions. Support for a cellular rather than extracellular basis for haze may also be seen in patients who show marked improvement in haze over time, and in patients who show fluctuations in haze that are unlikely to be explained by a simple fibrotic mechanism (11). Together, these findings point to the possibility that corneal haze after refractive surgery represents a defect in the light-scattering properties of keratocytes and is not related to collagen deposition or fibrosis. This possibility is critically important given that transparency may be easily re-established in keratocytes but permanently lost with corneal fibrosis. Additional support for the cellular basis of haze has also come from basic studies of keratocyte activation and differentiation. Recent developments using defined cell culture systems have been able to establish keratocyte cultures that maintain normal keratocyte differentiation (12–14). Using this serum-free culture system, studies show that transform-ing growth factor-beta (TGF-β) specifically induces activation and myofibroblast differentiation of corneal keratocytes (13,15). Importantly, TGF-β is synthesized by the corneal epithelium and keratocytes and may play a role in epithelialkeratocyte interactions during normal growth and wound repair (16). Importantly, recent studies also show that blocking antibodies to TGF-β when applied topically after stromal injury (17) or PRK (8) remarkably reduces the development of corneal haze. Interestingly, blocking the TGF-β effect on keratocyte differentiation does not block stromal re-growth and regression in the rabbit eye model of PRK, again suggesting that the deposition of new stromal matrix or stromal fibrosis after refractive surgery does not account for corneal haze development. Overall, these finding suggest that corneal haze develops not from corneal fibrosis but from the differentiation of normal stromal keratocytes to an altered phenotype, the myofibroblast, that apparently scatters light to a much greater extent than the normal keratocyte (Fig. 1). The light-scattering by these cells may in part be explained by their failure to express abundant quantities of keratocyte crystallins that act as stealth-like proteins making normal keratocytes transparent. This change in the differentiated state of the keratocyte can be induced in culture by TGF-β and the development of haze clinically blocked by treatment with antibodies that neutralize this important cytokine. Because the normal cornea expresses TGF-β, interactions between the epithelium and keratocytes after injury most likely regulate and control the effects of TGF-β on keratocyte differentiation and development of haze. Understanding these cellular and molecular interactions may ultimately provide us with the tools to control corneal haze after refractive surgery using advanced surface ablation techniques.

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ABSENCE OF HAZE AFTER LASIK The explanation for why LASIK surgery normally heals without the development of corneal haze is not clearly known. Several hypotheses have been set forth, with the most popular related to the fact that LASIK surgery does not induce the same degree of keratocyte apoptosis at the interface of the microkeratome flap as that observed in the stroma after PRK (5,18). Alternative possibilities include the fact that the corneal epithelium is not injured or Bowman’s/epithelial basement membrane complex remains intact. Keratocyte apoptosis or programmed cell death after simple epithelial abrasion was first demonstrated by Wilson et al. in 1996 (4). Continued work has suggested that epithelial-derived cytokines, perhaps including interleukin-1α (4) and fas-fas ligand (19), are released during epithelial injury, inducing programmed cell death of the underlying keratocytes. Differing degrees of keratocyte apoptosis have been noted after different refractive surgical procedures with scrape injury and PRK after scrape injury producing significant levels of apoptosis. Other refractive surgical approaches such as LASIK, which does not damage the epithelium except at the edge of the flap, and transepithelial photoablation of the epithelium, which presumably vaporizes any epithelial cytokines, produce little or no apoptosis compared to normal corneas. Based on these findings, it has been hypothesized that the differing degrees of apoptosis may explain the differences between haze and regression after these procedures (5,18). Unfortunately, detailed studies of haze after manual scrape compared to laser epithelial debridement in patients (20) and laboratory animals (21) have failed to detect any relationship between apoptosis and haze. No difference in the amount of haze was observed in a prospective, paired-eye clinical study of PRK patients for whom one eye received manual debridement while the opposite eye received laser-scraping (20). Additionally, when comparing manual scrape injury to simple laser scrape injury in a rabbit model, haze was noted only to occur in the laser-scraped eye (21), which is the opposite result predicted by the apoptotic hypothesis. Importantly, manual and laserscrape procedures were noted to produce keratocyte cell death, presumably by different mechanisms, i.e., apoptosis and necrosis, respectively. Why, then, was only laser-scrape removal associated with the development of corneal haze? A closer look at the regions where haze developed showed that activation and differentiation of keratocytes to myofibroblasts occurred only in regions where the epithelial basement membrane had been photoablated and removed (Fig. 4). In immediately adjacent regions, where the basement membrane remained intact after photoablation, keratocytes remained quiescent and did not produce haze. Interestingly, the only parameter that correlated with haze that was identified in this study was the amount of stromal tissue that was photoablated. Overall, this study convincingly shows that apoptosis does not cause corneal haze. Although keratocyte death may be important in the development of haze, the mechanisms by which keratocytes die is not a critical factor, and eliminating apoptosis is not likely to have a major impact on reducing corneal haze after refractive surgery. Rather, the critical factor appears to be the Bowman’s/epithelial basement membrane complex, which may act as a barrier to epithelial-keratocyte interactions, or it regulates the expression of epithelial cytokines that are important in myofibroblast differentiation.

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While the definitive experiments with LASIK are still required to answer the question as to why LASIK does not develop haze, the aforementioned experiments suggest that

Figure 4 In vivo morphology of the photoablation edge after excimer laser transepithelial photoablation. (A) Sharply defined epithelial basal lamina at the photoablation edge (arrows) by 1 week after surgery. (B) Immediately below the edge shown in (A), keratocytes outside the photoablation (left side of arrows) appeared quiescent, whereas keratocytes inside the photoablation (right side of arrows) appeared activated with increased nuclear reflectivity. (C) By 3 weeks after ablation, quiescent keratocytes were found immediately outside the photoablation (left side of arrows), whereas stellate wound-healing fibroblasts were found immediately inside the photoablation (right side of arrows). (D) The edge (arrows) appears more irregular by 6 weeks,

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with cavity-like structures inside the photoablation (right side of arrows). Bar indicates 100 µm. Taken from Figure 3 of Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive kerate ctomy. A 1-year confocal microscopic study. Ophthalmology 2000; 107:1235–1245.

Figure 5 Proposed mechanism for the development of corneal haze after PRK. Removal of the Bowman’s/epithelial basement membrane complex allows interactions between the regenerating corneal epithelium and quiescent corneal keratocytes. These interactions modulate the expression and effects of TGF-β, leading to myofibroblast differentiation and haze progression.

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preserving the Bowman’s epithelial basement membrane complex is critical. Damage to the epithelium and the induction of epithelial migration and proliferation would seem to be less important, given that simple scrape injury, which causes both keratocyte apoptosis and epithelial regeneration, does not produce significant haze compared to PRK. In support of this hypothesis is the clinical finding that haze in LASIK is limited to the edge of the microkeratome flap, a region where Bowman’s membrane has been transected, allowing direct interaction between the epithelium and underlying keratocytes. Haze may also occur where epithelium is deposited at the flap interface, again pointing to the importance of direct epithelial-keratocyte interactions in controlling the differentiation of keratocytes to a myofibroblast phenotype and the production of haze (Fig. 5).

HAZE AFTER LASEK AND THE FUTURE OF ADVANCED STROMAL ABLATION While experimental studies of LASEK and the development of haze remain to be conducted, there is no sound biological reason that is currently known to support the contention that LASEK as currently performed will provide improved results over PRK in regard to development of haze. While LASEK may limit keratocyte apoptosis by limiting the release of pro-apoptotic signalling peptides, the reduction of apoptosis using transepithelial laserscraping techniques has not reduced the amount of haze in standard PRK. Furthermore, LASEK ultimately results in the photoablation of Bowman’s/epithelial basement membrane complex, thus allowing direct interactions between the epithelium and keratocyte that lead to myofibroblast differentiation and haze. Although it is possible that maintaining an intact epithelial sheet might limit the release of the epithelial cytokines affecting this process, it is more likely that ultimate control involves important interactions between the epithelium and Bowman’s/basement membrane complex. Because LASEK techniques thus far developed do not clearly maintain this important structural complex, it is not likely that simply maintaining the epithelium intact without its associated attachment structures will affect the long-term development of haze. Nevertheless, LASEK may prove to be the first step in the development of more advanced surface ablation techniques that will in the future achieve the promise of stable and effective visual correction without the complication of haze. This point of view is based on the fact that the LASEK procedure recognizes that the key to surgically providing complication-free visual correction is the maintenance of normal corneal epithelial differentiation. In this regard, modifications of LASEK already have focused on the maintenance of the Bowman’s/epithelial basement membrane complex as recently discussed at this conference by Pallikaris (22). Whether this approach, removing both epithelium and underlying basement membrane, will be achieved remains to be shown; however, other approaches may also be successful. These might include the control of the epithelial cell TGF-β expression directly by controlling gene transcription through antisense gene therapy or blocking TGF-β synthesis, the major cytokine responsible for myofibroblast differentiation and haze. Alternatively, replacement of critical basement membrane components that control epithelial gene expression through novel coating strategies may limit or block epithelial-keratocyte interactions and lead to the rapid

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recovery of normal epithelial differentiation similar to scrape injury without photoablation. Finally, epithelial/basement membrane grafting techniques may be used to entirely replace the Bowman’s/epithelial basement membrane complex as proposed by Tseng et al. (23). Overall, each of these approaches appears promising and technically feasible in the near future, suggesting that in the next 10 years, refractive surgery may obtain the “Holy Grail” of perfect refractive correction without visual loss using an advanced surface ablation approach.

REFERENCES 1. Petroll WM, Jester JV, Cavanagh HD. In vivo confocal imaging: General principles and applications. Scanning; 1994; 16:131–149. 2. Jester JV, Petroll WM, Cavanagh HD. Measurement of tissue thickness using confocal microscopy Conn PM, Ed. Confocal Microscopy. San Diego. CA: Academic Press, 1999a:230– 245. 3. Moller-Pedersen T, Li HF, Petroll WM, Cavanagh HD, Jester JV. Confocal microscopic characterization of wound repair after photorefractive keratectomy. Invest Ophthalmol Vis Sci; 1998a; 39:487–501. 4. Wilson SE, He YG, Weng J, Li Q, McDowall AW, Vital M, Chwang EL. Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing. Exp Eye Res; 1996a; 62:325–327. 5. Wilson SE. Everett Kinsey Lecture. Keratocyte apoptosis in refractive surgery. CLAO J; 1998; 24:181–185. 6. Moller-Pedersen T, Vogel M, Li HF, Petroll WM, Cavanagh HD, Jester JV. Quantification of stromal thinning, epithelial thickness, and corneal haze after photorefractive keratectomy using in vivo confocal microscopy. Ophthalmol; 1997; 104:360–368. 7. Jester JV, Petroll WM, Barry PA, Cavanagh HD. Expression of alpha-smooth muscle (alphaSM) actin during corneal stromal wound healing. Invest Ophthalmol Vis Sci; 1995; 36: 809– 819. 8. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Neutralizing antibody to TGFb modulates stromal fibrosis but not regression of photoablative effect following PRK. Curr Eye Res 1; 998b; 17:736–747. 9. Piatigorsky J. Gene sharing in lens and cornea. Facts and implications. Prog Retinal Eye Res; 1998; 17:145–174. 10. Jester JV, Moller-Pedersen T, Huang J, Sax CM, Petroll WM, Cavanagh HD, Piatigorsky J. The cellular basis of corneal transparency: Evidence for “corneal crystallins.” J Cell Sci; 1999b; 112:613–622. 11. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive keratectomy. A 1-year confocal microscopic study. Ophthalmology; 2000; 107:1235–1245. 12. Kirschner SE, Ciaccia A, Ubels JL. The effect of retinoic acid on thymidine incorporation and morphology of corneal stromal fibroblasts. Curr Eye Res; 1990; 9:1121–1125. 13. Jester JV, Barry PA, Cavanagh HD, Petroll WM. Induction of a-smooth muscle actin (a-SM) expression and myofibroblast transformation in cultured keratocytes. Cornea; 1996; 15: 505– 516. 14. Beales MP, Funderburgh JL, Jester JV, Hassell JR. Proteoglycan synthesis by bovine keratocytes and corneal fibroblasts: Maintenance of the keratocyte phenotype in culture. Invest Ophthalmol Vis Sci; 1999; 40:1658–1663.

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15. Jester JV, Huang J, Barry-Lane PA, Kao WW, Petroll WM, Cavanagh HD. TGFb-mediated myofibroblast differentiation and a-smooth muscle actin expression in corneal fibroblasts requires actin re-organization and focal adhesion assembly. Invest Ophthalmol Vis Sci 1; 999b; 40:1959–1967. 16. Wilson SE, Schultz GS, Chegini N, Weng J, He Y-G. Epidermal growth factor, transforming growth factor alpha, transforming growth factor beta, acidic fibroblast growth factor, basic fibroblast growth factor, and interleukin-1 proteins in the cornea. Exp Eye Res; 1994; 59: 63– 72. 17. Jester JV, Barry-Lane PA, Petroll WM, Olsen DR, Cavanagh HD. Inhibition of corneal fibrosis by topical application of blocking antibodies to TGF beta in the rabbit. Cornea; 1997; 16: 177– 187. 18. Helena MC, Baerveldt F, Kim WJ, Wilson SE. Keratocyte apoptosis after corneal surgery. Invest Ophthalmol Vis Sci; 1998; 39:276–283. 19. Wilson SE, Li Q, Weng J, Barry-Lane PA, Jester JV, Liang Q, Wordinger RJ. The Fas-Fas ligand system and other modulators of apoptosis in the cornea. Invest Ophthalmol Vis Sci; 1996b; 37:1582–1592. 20. Lee YG, Chen WY, Petroll WM, Cavanagh HD, Jester JV. Corneal haze after photorefractive keratectomy using different epithelial removal techniques: mechanical debridement versus laser scrape. Ophthalmology; 2001; 108:112–120. 21. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Corneal haze development after PRK is regulated by volume of stromal tissue removal. Cornea; 1998c; 17:627–639. 22. Pallikaras I. SEL, Sub Epithelial LASIK. 1st International LASEK Conference. In: Krueger RWYRR, Ed. Houston. Texas, 2002. 23. Tseng SCG. Role of basement membrane in corneal wound healing. 1st International LASEK Conference. In: Krueger RWYRR, Ed. Houston. Texas, 2002.

26 Mitomycin C and Haze: Natural Progression Mujtaba A.Qazi, MD, and Jay S.Pepose, MD, PhD Pepose Vision Institute Chesterfield, MO; Washington University School of Medicine St. Louis, MO Irwin Y.Cua, MD, Saira A.Choudhri, MD, and M.Azim Mirza, MD Pepose Vision Institute Chesterfield, MO

INTRODUCTION Laser subepithelial keratomileusis (LASEK) offers a means of improving the safety profile of refractive procedures while potentially providing a smoother stromal surface for ablation than photorefractive keratectomy (PRK) (1–3). For these reasons, LASEK has carved out a niche in the repertoire of the refractive surgeon for patients with steeper, flatter, and thinner corneas than average and in whom anatomical considerations, such as deep-set eyes and narrow orbits, may preclude microkeratome use (4). In fact, some surgeons have selected LASEK as their vision correction technique of choice, with excellent outcomes and minimal adverse events (5). Furthermore, the advent of customized interventions draws attention to refractive procedures such as LASEK that avoid the biomechanical shifts induced by lamellar flap formation (6,7). The term corneal haze has been used since 1988 (8) to describe alterations in corneal transparency caused by the reflection or scattering of light after refractive surgery (Fig. 1). The relationship between corneal haze and regression has been well-documented in PRK literature; as a result of aggressive wound healing, stromal thickness and subsequent corneal refractive power increase, resulting in a myopic shift (Fig. 2) (9–13). As with PRK, corneal haze and myopic regression are among the most significant short-term and long-term complications associated with LASEK (Fig. 3) and decrease the predictability of refractive results (3,14). There has been a great deal of discussion recently as to whether PRK and LASEK are in fact different surgeries. Although some investigators (1–3,15–17) find support for one technique over the other, it appears that the postoperative discomfort and healing time are similar for each and are certainly greater than that of laser in situ keratomileusis (LASIK). However, preservation of an epithelial flap and its basement membrane components (3,18) over an ablated stromal bed may modify the risk of corneal haze and regres-

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Figure 1 Dense, central, reticular corneal haze after photorefractive keratectomy. (Courtesy of J.S.Pepose). sion. This chapter reviews the natural history, pathophysiology, and treatment of haze formation after LASEK. Because of its recent introduction (1) in 1998, there are relatively few experimental, histological, in vitro, in vivo, and clinical descriptions of the changes induced by LASEK. For this reason, we review findings seen in PRK, given the similarity of these two techniques, and highlight how an epithelial flap may modulate wound healing after excimer photoablation. Visual Consequences of Haze Subepithelial fibrosis, or haze, has been described after myopic epikeratoplasties (19) and radial keratotomy (Fig. 4). Most researchers agree that some degree of corneal haze is seen after all cases of PRK, with an onset of 2 days to 2 months, a peak intensity between 1 and 6 months, and resolution by 3 to 24 months postoperatively (Fig. 5) (8–12,20–22) This variability is related to differences in species studied, targeted refractions, lasers used, postoperative regimens, and techniques for assessing haze. A number of investigators (12,23) have appreciated the importance of a clinical grading system to describe the quality or pattern of haze. The most common method uses a scale from zero to four based on slit-lamp findings (Fig. 6). The slit-lamp appearance of corneal haze, being a composite of reflected and back-scattered light, is highly dependent, however, on

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Figure 2 Correlation of corneal haze with myopic regression. Corresponding changes in refraction (A), corneal haze (B), and stromal (C) and epithelial (D) thickness during 12 months after PRK (29). “Reprinted from Opthalmology, © 2000, with permission from the American Academy of Ophthalmology.”

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Figure 3 Corneal haze after laser subepithelial keratomileusis. (Courtesy of J.S.Pepose.)

Figure 4 Corneal haze after radial keratectomy. (Courtesy of PA Majmudar, with permission.)

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the viewing angle of the observer and does not necessarily correlate with effect on visual function (24). It is only the forward-scattered light that degrades the retinal image. More objective techniques (25,26) have also been developed, including analysis of digital images to detect light-scatter and corneal opacification. In fact, assessment with scatterometers has shown closer correlation with logMAR acuity than the clinical evaluation of haze (27). Another diagnostic modality is confocal microscopy, a noninvasive technique for obtaining high-resolution microscopic images of the cornea in vivo. Digital image analysis of continuous, high-speed confocal z-scans (confocal microscopy through focusing [CMTF]; Fig. 7) has been used to observe details of ultrastructural changes in multiple layers of the cornea after excimer refractive surgery in animals (28) and humans (24,29,30). While mild haze has been routinely reported in the early postoperative period after PRK and generally resolves without visual sequelae after several months, a dense, lateronset, reticular haze has been noted to reduce visual acuity in 1% to 3% of cases overall, but in up to 10% to 15% of eyes with myopia greater than −10 diopters (D) (31,32). Difficulties with night vision and diminished contrast sensitivity appear to correlate with the extent of corneal haze after PRK (24). Visual compromise is rare in patients with attempted correction less than 5 D and increases in frequency with

Figure 5 Timeline of haze formation after excimer photorefractive keratectomy. Grading of early and late phases of corneal haze, including lateonset corneal haze (LOCH), which is generally associated with higher haze gradings (21). “Reprinted from the Journal of Cataract and Refractive Surgery, © 2001, with permission from the ASCRS & ESCRS.”

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Figure 6 Slit-lamp grading of corneal haze is based upon the pattern of translucence (reticular versus confluent) and degree of obscuration of iris details. “Courtesy of J.S. Pepose.” larger (Fig. 8) and multiple treatments (11,22,32,33). Patients with atopy or autoimmune conditions are also at higher risk for corneal haze after excimer photoablation (34). The timeline of haze formation after LASEK is similar to that in PRK, Claringbold (5) notes trace haze in 13% of 222 eyes 3 months after LASEK (mean myopia −4.89, 6.0mm ablation zone, VISX Star S2), with resolution of all cases by 12 months. Another series (14) (n=58, mean myopia −7.80, Alcon Autonomous) reports 8% of eyes with visually significant haze after LASEK. A retrospective review of 62 eyes (mean myopia −7.96, VISX Star S3) at our center, with at least 3 months of follow-up after LASEK, demonstrates a haze rate of 47%, with almost all receiving only the lowest grading. Three eyes (4.8%) had a haze grading of 2 or more, of which one eye required surgical intervention (see later) because of loss of best-corrected visual acuity (BCVA). The preoperative spherical equivalence of this eye was −8.38 D. The higher haze rate in our series appears to be related to greater attempted correction, and supports Yee, who identified an ablation depth of more than 100 µm and an ablation depth-to-corneal thickness ratio more than 0.18 as independent risk factors for haze formation after LASEK (35). In a prospective study of 27 patients with low to moderate myopia who were randomized to LASEK in one eye and PRK in the fellow eye, Lee et al. (17) found

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lower clinical haze ratings in the LASEK eyes at 1 month (p=0.02). Comparable gradings were described between eyes by 3 months of follow-up (p=0.22).

Figure 7 Anterior stromal wound healing morphologic characteristics (A-D) and corresponding CMTF profiles (A’-D’) obtained from the same patient before and after PRK. Images obtained within the anterior 50 µm of the stroma. (A) Preoperative normal quiescent keratocyte nuclei (arrows). (B) One month after PRK, activated keratocytes with increased reflectivity of both nuelei (arrows) and cell bodies. (C) Six months after PRK, increased density of activated

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keratocytes (arrows). Bar indicates 110 µm. (D) Twelve months after PRK, return to moderately reflective, quiescent keratocyte nuclei (arrows). (A’) preoperative CMTF peaks corresponding to epithelium (a), subepithelial nerve plexus (b), anterior layer of keratocytes (c), and endothelium (d). (B’, C’) One and 6 months after PRK, the peak corresponding to subepithelial haze (c’) dominates the CMTF profile. (D’) By 12 months, the degree of reflectivity of the anterior stromal keratocyte layer (c’) has declined. Clinically on the slit-lamp, the patient had grade 1 subepithelial haze at 1 month and grade 0 haze at 12 months (29). “Reprinted from Ophthalmology, © 2000, with permission from the American Academy of Ophthalmology.” Location and Components of Haze In vivo investigations of the components responsible for corneal haze after PRK reveal a nontranslucent layer at the epithelial-stromal junction (Fig. 9) that develops 1 week postoperatively, peaks between 1 and 3 months, and declines gradually thereafter. This sequence is characteristic of the onset and duration of mild, early haze after both PRK and LASEK. Histological studies in primates confirm that the subepithelial haze is restricted to the ablation zone itself (23), which becomes comprised of proliferating keratocytes and atypical extracellular matrix (ECM) components, including glycosaminoglycans (GAGs), such as heparan and keratan sulfate, newly synthesized collagen (types III, IV, V, and VII), fibronectin, laminin, tenascin, and hyaluronic acid (Fig. 10) (36,37). The new collagen fibrils are placed in a nonorthogonal arrangement with consequent alteration of corneal transparency. There is evidence to suggest that deeper ablation causes greater accumulation of these materials.

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Figure 8 Correlation of CMTF-haze with attempted correction. In 15 patients with moderate light scattering, a cumulative measure of CMTF haze development over a 12-month followup period correlated significantly (r=0.68, p<0.01) with the photoablation depth [preoperative stromal thickness (STpreop)-stromal thickness at 1 month (ST1m)], demonstrating that higher PRK corrections generally are associated with more corneal opacification (29). “Reprinted from Ophthalmology, © 2000, with permission from the American Academy of Ophthalmology.” Overall, the temporal patterns and levels of messenger RNAs (mRNA) for ECM proteins measured after PRK reveal a series of sequential phases that combine to heal the wound. In a study of rat corneas after PRK (36), mRNA levels for fibronectin increased from undetectable preoperatively to more than 600 copies per cell within 1 week after PRK, suggesting that this factor is important in initiating wound healing; fibronectin is known to promote migration of corneal epithelial cells. Meanwhile, levels of other ECM proteins such as collagen IV do not peak until after 3 months.

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Figure 9 Location of haze after excimer photoablation. Light micrograph (hematoxylin and eosin staining, ×200) of rabbit corneas before (A) and 1 week (B) after PRK. At 1 week after PRK, the epithelium (E) is thickened and keratocytes (arrows) have proliferated in the subepithelial region (S) (65). “Reprinted from the Journal of Refractive Surgery, © 2001, with permission from Slack, Inc.”

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Figure 10 Pathology of excised corneal button with subepithelial haze after phototherapeutic keratectomy. (A, B) Antibodies against heparin sulfate (HSPG) and keratin sulfate (KSPG) proteoglycan react in both the anterior stroma and basal epithelium. (C)

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Antibodies against laminin-labeled basal epithelium in ablated and adjacent nonablated regions. Weak staining of the basement membrane was also noted (arrow). (D) Antibodies against fibronectin label both basal epithelium and anterior stroma of the ablated region. (E) Lysozyme expression is shown in basal epithelium and anterior stroma of the ablated area. (F–H) Antibodies against collagen type III, IV, and VII label subepithelial haze. Arrows indicate positive findings (37). “Reprinted from the Journal of Refractive Surgery, © 2001, with permission from Slack, Inc.” Animal studies further reveal that within 24 hours after excimer laser treatment, the anterior stroma beneath the treatment zone is transiently hypocellular, with few stromal keratocytes (22). Soon thereafter, in mammals and primates, activated keratocytes migrate into the treated zone and begin to synthesize new collagen and ECM. Stromal fibroblasts within haze tissue contain vimentin and smooth muscle actin, cytoskeletal components characteristic of myofibroblasts (37). Vimentin is also manufactured by sliding corneal epithelial cells during wound healing. Myofibroblasts may contain greater quantities of cytosolic, water-soluble proteins such as crystallins (29), which appear to affect the optical properties of keratocytes, suggesting an intracellular contribution to corneal haze. Myofibroblasts are characterized by greater light reflectivity during CMTF and play a significant role in corneal light back-scatter. Restoration of keratocyte densities and reflectivity to preoperative levels, as myofibroblast activity subsides, is temporally associated with the disappearance of haze. In 1968, Dohlman et al. (38) described the disappearance of superficial keratocytes after corneal epithelial injury. Wilson et al. (39) later reported that this was mediated by apoptosis, programmed cell death in which the cell is dismantled and eliminated with negligible release of intracellular components and minimal damage to surrounding tissues. Many investigators believe that the transient hypocellularity seen as an early event in PRK models is caused by keratocyte apoptosis (Fig. 11) (22). Support for this hypothesis stems from the finding that many regulators of apoptosis, including interleukin-1 (IL-1), Fas ligand, and tumor necrosis factor alpha (TNF-α), are constitutively produced and stored by the epithelium, and then instantly released upon injury to bind to keratocyte receptors. Increased levels of TNF-α have been identified in human tear fluid collected within 2 days of PRK. Injection of IL–1α into mouse central stroma has been shown to trigger keratocyte apoptosis (39). Furthermore, topical

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application of factors that inhibit apoptosis can prevent the loss of superficial keratocytes in rabbit corneas after mechanical epithelial debridement (40). Other cytokines implicated in regulation of epithelial and stromal healing after excimer laser keratectomy include epidermal growth factor, keratinocyte growth factor, hepatocyte growth factor, fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta (TGF-β) (22,39,41–43). Potential sources for these agents include the main and accessory tear glands, corneal epithelial and stromal cells, conjunctival cells and vessels, and inflammatory cells.

Figure 11 Location of apoptotic keratocytes 1 week after phototherapeutic keratectomy in a rabbit cornea. (A) Thymidine-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay detects apoptotic keratocytes in the subepithelial stroma. (B) Propidium iodide staining of nucleic acid shows the position of all epithelial and stromal cells (70). “Reprinted from the Journal of Cataract and Refractive Surgery, © 2001, with permission from the ASCRS & ESCRS.” TGF-β is a major player in fibrosis and scar formation in many tissues, including skin, lung, and liver (36). TGF-β treatment markedly increases the levels of mRNAs for fibronectin and type I collagen in cultures of mouse 3T3 fibroblasts. A TGF-β response element is found in the promoter region of the α1 (1) collagen gene. TGF-β may modulate some of its effects via connective tissue growth factor (CTGF), which has been shown to mediate increases in matrix synthesis. TGF-β has also been reported to suppress production of matrix metalloproteinases (MMP) and increase production of tissue inhibitors of metalloproteinases (TEIMP), having the overall effect of preventing scar tissue remodeling.

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All three TGF-β isoforms are expressed in regenerating epithelial cells of rats after PRK (36). The rate of release of TGF-β1 into tears increases approximately 18-fold within 2 days after PRK. Furthermore, 4 weeks after PRK, the expression of TGF-β isomers is upregulated in keratocytes that proliferate in the subepithelial fibrous layer (44). The increase in expression of key components of the TGF-β system coincides with an increase in synthesis of ECM proteins deposited subepithelially after PRK (Fig. 12), supporting the hypothesis that TGF-β is a key growth factor promoting corneal stromal haze formation and suggests that limiting the TGF-β system may reduce corneal scarring after excimer laser ablation. Systemic administration of TGF-β neutralizing antibody during the first 10 days after PRK in rats reduces stromal cell density and immunostaining of laminin and fibronectin in the subepithelial stroma (36). Topical treatment of rabbit corneas with neutralizing antibodies to TGF-β for the first 3 days after PRK mitigates subsequent haze formation as quantified by light reflectivity measurements. Further investigations may demonstrate a role for topical anti-TGF elements in the prophylaxis and treatment of corneal haze formation in humans after excimer refractive surgery. Modification of corneal stromal structure can also occur via activity of oxygen free radicals, which may form directly from ultraviolet (UV) irradiation during laser treatment or postoperatively from ambient UV exposure and after infiltration of leukocytes (45,46). Polymorphonuclear cells (PMN) first appear at the ablated margin within 6 hours of excimer application, with cytokines such as IL-1 serving as chemotactic mediators. They release oxygen free radicals, which cause tissue damage by reacting with lipid components of the cell membranes, nucleic acids and sulfur-containing enzymes. Lipid peroxidation has been identified in superficial corneal stroma after laser photoablation (47). Another facet of wound healing after excimer laser treatment of the cornea is the role of matrix metalloproteinases (MMP), a group of proteolytic enzymes responsible for remodeling the extracellular matrix. They require zinc and calcium for catalytic activity. Among the MMPs operating in the cornea are collagenases, gelatinases, and stromelysin. The transcription of MMP genes is regulated by several agents. Steroids, TGF-β, IL-1 receptor antagonist (IL-1ra), and chelating agents such as cysteine, EDTA, and tetracycline inhibit MMP synthesis (48). The major collagenase of the cornea is MMP-1, which is secreted by keratocytes and leukocytes. It cleaves the helical structure of the collagen (types I, II, and III) fibrils, thereby making them susceptible to the action of gelatinases such as MMP-2 and MMP-9. Although the latter two MMPs have the same activity, they have different predominant sites of production: MMP-2 by keratocytes and MMP-9 by epithelium. In the normal cornea, MMP-2 is present as an inactive proenzyme that is locally activated to metabolize damaged stromal collagen molecules. The active form of MMP-2 is detected within the first week after stromal injury and may remain elevated for at least 9 months. MMP-9 is not expressed in the normal cornea, but its activity increases immediately after injury, then falls rapidly as re-epithelialization occurs, until it is absent at 2 weeks. This, together with its epithelial site of production, suggests that it may be involved in the degradation and reassembly of the epithelial basement membrane. Additional investigations may unveil modes of intervention to promote or inhibit, appropriately, MMP activity to prevent tissue damage from these agents or to use them to reverse haze formation.

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Figure 12 Levels of mRNA for the TGF-βs, TGF-β receptor (TGF-β II), and ECM proteins in pooled rat corneas before and after PRK. Competition-based quantitative reverse transcription polymerase chain reaction was performed on pooled rat corneas before (day 0) and at 1.5 days, 6 days, 21 days, 42 days, and 91 days after PRK (36). “Reprinted from Investigative Opthalmology & Visual Science, © 2000, with permission from the Association for Research in Vision and Ophthalmology.”

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Summary of Mechanisms of Stromal Haze Formation As we have seen, a key event after excimer photoablation, regardless of technique used, is epithelial injury, which triggers release of cytokines by the lacrimal gland and epithelium. Epithelial-keratocyte interactions initiate epithelial regeneration and keratocyte apoptosis. This is accompanied by inflammatory cell infiltration, which further mediates corneal injury directly through free radical formation and indirectly through the release of additional cyto- kines. The cytokine milieu, particularly TGF-β, promotes transformation of keratocytes at the borders of the ablation zone into myofibroblasts, which migrate into the subepithelial space. These highly reflective cells and the atypical matrix elements that they synthesize combine to reduce light transmission. Once the epithelial defect is healed, there is a shift in the cytokines expressed by mature epithelial cells, with disappearance of myofibroblasts and a return to quiescent keratocytes with normal morphology. Metalloproteinases then assist in remodeling stromal tissue, restoring a more orthogonal arrangement of collagen fibrils. Any imbalance, particularly prolonged delay in epithelial healing or sloughing of the epithelial sheet, in this complex process of wound healing may shift the equilibrium to formation of subepithelial haze, and also permits a number of entry points for pharmacological and surgical intervention (Fig 13. ). Strategies for the prevention and treatment of post-LASEK haze are discussed below. Once again, these are often extensions of our experience with haze after PRK. Research has been directed toward controlling postoperative development of haze with agents such as corticosteroids, nonsteroidal anti-inflammatory agents (NSAIDs), mitomycin C (MMC), idoxuridine, a-interferon, and others (45,48–53). Steroids Corticosteroids specifically inhibit phospholipase A2, preventing arachidonic acid production. They down-regulate DNA synthesis in stromal fibroblasts and, therefore, limit subepithelial collagen deposition and corneal haze in animal models (45). While experimental models show a beneficial effect of topical corticosteroid use, clinical trials have, for the most part, shown mixed result (54,55). Vertugno et al. (56), in a randomized, double-masked trial, compared outcomes of a cohort of PRK patients given 0.1% fluoromethalone versus 0.5% ketorolac during the re-epithelialization phase. Both groups received a topical steroid for a number of months after re-epithelialization. Twelve months after PRK, mean refractive error in the NSAID group was −1.1 D, but only −0.65 D in the steroid group (p<0.0001). Haze was significantly reduced in the steroid group (p=0.005), especially for myopic correction greater than −5 D. Interestingly, despite this topical regimen, the authors describe grade 2 haze in 12.5% and 20% of myopes below and above −5 D, respectively.

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Figure 13 Schematic diagram indicating some of the important aspects of the wound healing cascade in the cornea (22). “Reprinted from Archives of Ophthalmology, © 2001, with permission from the American Medical Association. All rights reserved.”

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Because of the well-known ocular complications, such as prolonged epithelial healing, increased risk for microbial infection, elevated ocular tensions, and cataract formation, associated with topical corticosteroid therapy, some investigators have suggested that their routine use after laser refractive procedure ought to be curtailed (57). Other authors (58) have recommended continued use for deeper PRK ablations. In 1996, Arshinoff (59) reported that 86% of PRK surgeons prescribed steroids immediately after PRK. There are no surveys as such with respect to topical steroid use after LASEK, although most reports in the literature proscribe a regimen similar to what the surgeon used with PRK. We routinely prescribe, after bandage contact lens removal, prednisolone acetate 1% four times daily to all PRK and LASEK patients, with a conservative taper regimen. It may be that earlier implementation of corticosteroids is required to more effectively short circuit the cycle of cytokine activity and myofibroblast activation. Mitomycin C Mitomycin-C (MMC) is derived from Streptomyces caespitosus. Its alkylating properties enable it to cross-link DNA between adenine and guanine, thereby inhibiting DNA synthesis. It has been widely used as a systemic chemotherapeutic agent, because rapidly dividing cells are most susceptible to its effects. Over the past years, the use of topical MMC has gained popularity in ophthalmologic surgery. Intraoperative MMC is commonly utilized in glaucoma surgery to prevent scarring of filtering blebs through its ability to inhibit subconjunctival fibroblast proliferation (60). It is also used topically intraoperatively and postoperatively after pterygium surgery (61) to prevent recurrence and has been advocated for the treatment of conjunctival and corneal intraepithelial neoplasia (62). Application of MMC after excimer laser surgery was first investigated by Talamo et al. (63). Rabbit eyes after PRK were randomized for treatment with topical mitomycin C 0.05%, steroids, and erythromycin or topical steroids and erythromycin or simply erythromycin alone. All treatment regimens started immediately after surgery and were instituted twice daily for 2 weeks. Results of light, fluorescence, and electron microscopy showed reduced subepithelial collagen formation in the group treated with MMC, corticosteroid, and erythromycin. Yamamoto et al. (64) found that mitomycin C 0.001%, 0.01%, and 0.1% could suppress proliferation of keratocytes in vivo, with greater effect at higher concentrations. Several investigators have shown a decrease in keratocyte proliferation in rabbits treated with topical MMC after PRK. In one report (65), immediately after a bilateral −10-D ablation, a 5-minute application of 0.02% MMC was placed on the ablated stromal bed of one eye only. Decreased corneal haze was noted in eyes treated with MMC. Histopathological findings showed a significantly lower keratocyte density in the anterior stroma of the rabbits treated with MMC at 1, 2, and 4 weeks after PRK. However, there was no statistically significant difference in keratocyte density between the PRK alone and PRK+MMC groups by week 12. Lamellar arrangement in the anterior stroma of the PRK+MMC group was more orderly (Fig. 14). Additionally, the corneal epithelium of

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Figure 14 Transmission electron micrograph of PRK alone and PRK+MMC group corneas (×6,000). (A) At 1 week after PRK, the arrangement of lamellae (L) in the anterior stroma of the PRK alone group is wavier than normal. (B) At 1 week, the lamellae in the anterior stroma of the PRK+MMC group are arranged more smoothly. (C) At week

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12, the lamellae in the anterior stroma of the PRK alone group have become more regular and smooth. (D) At week 12, the lamellae in the anterior stroma of the PRK+MMC group were arranged normally (65). “Reprinted from the Journal of Refractive Surgery, © 2001, with permission from Slack, Inc.” the mitomycin C group was thinner than in the control group, although this finding is not seen by other investigators after single-dose application of similar concentrations of MMC (0.02%−0.04%) (51). The ability of a brief exposure of MMC to inhibit fibrosis may be the result of sustained tissue binding and possible modulation of cell migration and extracellular matrix production. It is unclear what role intraoperative MMC application may have in the regulation of keratocyte apoptosis. While all of these refer to prophylactic measures, Majmudar et al. (66) illustrate the use of MMC as an adjunct to debridement for the treatment of subepithelial scarring after refractive corneal surgery. They describe that a 2-minute intraoperative application of MMC (0.02%) after epithelial and stromal debridement results in recovery of BCVA and successfully prevents recurrence of subepithelial fibrosis. The mean interval between initial surgery and MMC treatment was 31 months (range, 5–60 months), during which time topical steroids were used in each case without significant effect. We report a 21-year-old patient in our experience in whom gradual onset of significant haze developed within 3 months of bilateral LASEK. Preoperative spherical equivalence was −8.38 D right eye (OD) and −9.00 D left eye (OS), with BCVA of 20/20 each eye (OU). Delayed epithelial healing in the right eye marked the early postoperative course. At 6 months, 3+ haze was noted centrally OD and 2+ haze OS, with loss of four lines of BCVA OD (UCVA 20/20 OS). After manual debridement with adjuvant MMC OD, as described by Majmudar et al. (66), UCVA improved to 20/25 with only 1+ haze after 1 week. Some myopic regression was noted over the next few months along with return of corneal haze despite a regimen of prednisolone acetate 1% four times daily with monthly taper. A repeat debridement/MMC procedure was performed OD within 10 months of the original LASEK surgery. After bandage contact lens removal, the patient had gained two lines of BCVA with 1+ haze visible on biomicroscopy (Fig. 15). This illustrates the applicability of interventions (67) used to successfully treat post-PRK haze to cases after LASEK as well. The long-term use of topical MMC may be associated with significant ocular toxicity. Transient side effects, such as hyperemia, pain, and punctate epithelial keratopathy, have been noted with topical application of MMC 0.02% to 0.04%, but resolve with cessation of the drug. More serious complications include corneal perforation, iritis, and secondary glaucoma (68). However, these adverse outcomes are seen, as a rule, after prolonged topical administration in eyes with underlying pathologic conditions. Single intraoperative application of MMC has the advantages of full compliance, minimal side effects, and controlled

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Figure 15 A 21-year old with postLASEK haze treated with manual debridement and intraoperative MMC 0.02%. (A) At 6 months after LASEK, 3+ haze is noted centrally. (B) Central cornea 4 days after repeat manual debridement with intraoperative MMC. (Courtesy of J.S.Pepose.) drug delivery. Although previous studies recognize the potential of MMC for preventing the development of stromal haze and in reducing pre-existing stromal scarring, further studies are needed to define the optimal method of application and dosage before its routine use in patients undergoing excimer laser surgery. Jain et al. (69) have suggested, based on their observations after phototherapeutic keratectomy (PTK) in rabbits, that annular application of MMC may more effectively reduce light-scatter and corneal toxicity. To minimize complications, the lowest possible therapeutic concentration should be applied for the shortest effective period, ensuring minimal corneal contact, particularly when epithelial defects are present. The authors currently prophylactically use 2-minute application of MMC 0.02% to the stromal bed for all cases of LASEK −6 D or higher. We have not noted any adverse intraoperative events or significant delay in epithelial healing postoperatively. We have not made any nomogram adjustments when using intraoperative MMC.

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Figure 16 External appearance of a representative pair of rabbit eyes immediately after PTK with (b) and without (a) an amniotic membrane graft (70). “Reprinted from the Journal of Cataract and Refractive Surgery, © 2001, with permission from the ASCRS & ESCRS.”

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Amniotic Membrane After surface ablation, most LASEK surgeons apply a bandage contact lens to facilitate epithelial healing. Some investigators (46,70) have suggested that placement of amnion membrane graft may be a more effective measure (Fig. 16). The amnion is the innermost layer of the placenta. This semitransparent membrane consists of a simple cuboidal epithelium, a thick basement membrane, and an avascular mesenchymal stroma. Because of its ability to facilitate proliferation and differentiation of epithelial cells, minimize vascularization, and decrease inflammation, amniotic membrane transplantation has proven to be effective in the treatment of persistent epithelial defects, neurotrophic ulcers, and chemical injury of the cornea. Rabbit corneas transplanted with a temporary amniotic membrane patch immediately after surface excimer ablation for 2 (46) to 7 (70) days maintained keratocyte densities (Fig. 17) and had limited leukocyte infiltration of the stroma. PMNs became adherent to

Figure 17 Comparison of apoptosis, measured by in-situ TUNEL assay, between the control cornea (upper panel) and the amniotic membrane (AM)-treated cornea of a rabbit 1 week after PTK. Location of all nuclei in the control (b) and AM cornea (d) is

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identified by the propidium iodide (red) fluorescence. Apoptotic nuclei, detected by apop-FITC (green) fluorescence, are readily seen in the subepithelial region of the control cornea (a), but not in the experimental cornea (c) (70). “Reprinted from the Journal of Cataract and Refractive Surgery, © 2001, with permission from the ASCRS & ESCRS.” the amniotic membrane stromal matrix instead, where they exhibited markers of apoptosis. Histopathological findings in these eyes also demonstrated a lesser degree of subsequent epithelial hyperplasia and keratocyte proliferation. Amniotic membrane transplantation is an impractical procedure to perform customarily in patients undergoing refractive surgery but may be attempted in patients with severe corneal scarring after PRK or LASEK. In situations in which mechanical debridement of the scar tissue is performed, removal of the overlying epithelium may restart the cascade of haze formation. Application of amniotic membrane after mechanical debridement may be beneficial in preventing recurrent inflammation and scarring. The routine use of amniotic membranes after LASEK, however, may require their incorporation into a contact lens placed intraoperatively, as described by Wang (71). Superficial Lamellar Keratectomy In cases in which medical therapy fails and the scarring involves deeper layers of the cornea, penetrating keratoplasty has been the procedure of last resort. Rasheed and Rabino witz (72) instead advise superficial lamellar keratectomy, microkeratome-assisted excision of a corneal cap. If deep enough, this technique results in a smooth optical surface, which would be difficult to achieve via freehand mechanical debridement or dissection. In their case report, a 180-µm footplate was used. The treated patient regained good BCVA. Some authors (73), however, advise that this technique be used only before proceeding to penetrating keratoplasty in patients with severe corneal haze, especially given the encouraging results of manual debridement techniques with MMC, as described.

CONCLUSION Several studies correlate severity of epithelial trauma to the degree of subsequent anterior stromal hypocellularity (22,46,70), presumably because more cytokines are released and can access stromal receptors to induce keratocyte apoptosis. In vitro studies (41) confirm the role of differentiating epithelium in the recruitment of fibroblasts to a wound. Nakamura et al. (74) have, in fact, demonstrated subepithelial fibrosis after LASIK when

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the epithelium is denuded intraoperatively. They identified myofibroblast activity in rabbit corneas after PRK and LASIK with epithelial debridement, but not after debridement alone or LASIK alone, suggesting that epithelial and stromal injury are required for haze formation. This has certain implications in LASEK, in which an epithelial flap is maintained to protect the ablated stromal surface; the preserved epithelium and basement membrane complex (3) may act as a barrier to cytokine penetration and PMN infiltration of the stroma, thereby reducing the extent of keratocyte apoptosis and ensuing myofibroblast activation. Although there is a certain amount of epithelial cell death related to chemical injury in a LASEK flap, it is likely that the overall cytokine load within the ablated zone is reduced because of both relative preservation of epithelial cells and alcohol denaturing of acutely released cytokines. Furthermore, Marshall (75) has suggested that there is a temporal window after stromal ablation during which keratocytes are more susceptible to apoptotic signals. It is possible that modification of epithelial regeneration patterns via formation of a central epithelial flap may shift the timeline for introduction of apoptotic cytokines outside the susceptibility period of stromal fibroblasts. These considerations may explain the observation by Carones et al. (2) of lower haze rates (p=0.04) in human eyes treated with the excimer laser after de-epithelialization using 20% alcohol versus those de-epithelialized manually. They felt that this was related to a smoother Bowman’s surface and improved corneal regularity after alcohol-assisted debridement. This result is corroborated by Lee et al. (42) in a prospective study comparing LASEK and PRK in the same patient, in which haze scores were significantly lower at 1 month (p=0.005) in LASEK eyes. This was associated with lower tear TGF-β levels and release of TGF-β during the early postoperative period in LASEK eyes. Tseng (76) has suggested that some constituents of the basement membrane and subepithelial region after LASEK are also found in amniotic membranes and thus may inhibit haze formation. Further developments in LASEK flap creation, such as the use of methylcellulose (77) to dissect free an epithelial flap or microkeratome-assisted (78) epithelial flap formation, may offer even more protection by preserving the integrity of epithelial cells and basement membrane components. The complex wound healing response of the cornea has important implications in refractive surgery. The end result is variable stromal remodeling and epithelial hyperplasia associated with myopic regression and haze. Although the specific cellular events of corneal wound healing after LASEK remain unclear, it is speculated that the epithelial flap protects the bare surface of the stroma and prevents the influx of cytokines and inflammatory cells from the tears, reducing the apoptotic and inflammatory insult to the stroma. This may decrease the initial loss of anterior stromal keratocytes and late subepithelial myofibroblast activity, effectively reducing haze formation. Experimental and in vivo investigations are required to confirm this premise. While several researchers have identified keratocyte apoptosis blockers, further investigations are needed to determine the efficacy of topical agents (40) and vector gene therapy (79) for the management of postsurgical corneal haze. Controlled clinical trails may reveal the benefits of surgical techniques that further preserve epithelial integrity, or of earlier and more uniform use of modulating agents such as corticosteroids, MMC, IL-1 inhibitors, TGF-β inhibitors, or amniotic membrane factors.

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REFERENCES 1. Camellin M. LASEK may offer the advantages of both LASIK and PRK. Ocular Surgery News. Thorofare, NJ: Slack, Inc; 1999. 2. Carones F, Fiore T, Brancato R. Mechanical vs. alcohol epithelial removal during photorefractive keratectomy. J Refract Surg 1999; 15:556–562. 3. Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E, Abad JC. Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol 2001; 12:323–328. 4. Pepose JS. Optimizing patient outcomes with state of the art laser techniques and technologies. Ophthalmology Management. Fort Washington, PA; Boucher Communications, Inc; 2001. 5. Claringbold TV 2nd. Laser-assisted subepithelial keratectomy for the treatment of myopia. JCataract Refract Surg 2002; 28(1):18–22. 6. McDonald MB. Custom ablation with the Summit/Autonomous excimer laser. AAO subspecialty day-refractive surgery 2000, Dallas, TX. 7. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg 2001; 17:S219–S221. 8. Marshall J, Trokel SL, Rothery S, Krueger RR. Long-term healing of the central cornea after photorefractive keratectomy using the excimer laser. Ophthalmology 1998; 95:1411–1421. 9. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser photorefractive keratectomy: 18-month follow-up. Ophthalmology 1992; 99:1209–1219. 10. Seiler T, Holschbach A, Derse M, Jean B, Genth U. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology 1994; 101:153–160. 11. Hersh PS, Stulting RD, Steinert RF, Waring GO, Thompson KP, O’Connell M, Doney K, Schein OD. The Summit PRK Study Group. Results of Phase III excimer laser photorefractive keratectomy for myopia. Ophthalmology 1997; 104:1535–1553. 12. Kremer I, Kaplan A, Novikov I, Blumenthal M. Patterns of late corneal scarring after photorefractive keratectomy in high and severe myopia. Ophthalmology 1999; 106:467–473. 13. O’Brart DPS, Corbett MC, Verma S, Heacock G, Oliver KM, Lohmann CP, Kerr Muir MG, Marshall P. Effects of ablation diameter, depth, and edge contour on the outcome of photorefractive keratectomy. J Refract Surg 1996; 12:50–60. 14. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg 2002; 18:217–224. 15. Kunal DK, Camp J, Humble H, Shen DJ, Wang MX. Pain after epithelial removal of ethanolassisted mechanical versus transepithelial excimer laser debridement. J Refract Surg 2000; 16: 519–522. 16. Litwak S, Chayet A, Missiroli F, Garcia-de-Quevedo V, Robledo N. Laser sub-epithelial keratomileusis versus photorefractive keratectomy for the correction of myopia and astigmatism: a comparative study. ISRS Fall symposium 2001, New Orleans, LA. 17. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg 2001; 27:565–570. 18. Gabler B, Winkler von Mohrenfels C, Lohmann CP. Laser epithelial keratomileusis (LASEK): a histological study to investigate the vitality of corneal epithelial cells after alcohol exposure. ARVO annual meeting 2001, Ft. Lauderdale, FL.. 19. Bechera SJ, Grossniklaus HE, Waring GO III. Subepithelial fibrosis after myopic epikeratoplasty: report of a case. Arch Ophthalmol 1992; 110:228–232. 20. Lipshitz I, Loewenstein A, Varssano D, Lazar M. Late onset corneal haze after photorefractive keratectomy for moderate and high myopia. Ophthalmology 1997; 104:369–374. .

Mitomycin C and Haze

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21. Stojanovic A, Nitter TA. Correlation between ultraviolet radiation level and the incidence of late-onset corneal haze after photorefractive keratectomy. J Cataract Refract Surg 2001; 27: 404–410. 22. Wilson SE, Mohan RR, Hong JW, Lee JS, Choi R, Mohan RR. The wound healing response after laser in situ keratomileusis and photorefractive keratectomy. Arch Ophthalmol 2001; 119:889–896. 23. Fantes FE, Hanna KD, Waring GO III, Pouliquen Y, Thompson KP. Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys. Arch Ophthalmol 1990; 108:665–675. 24. Corbett MC, Prydol JI, Verma S, Oliver KM, Pande M, Marshall J. An in vivo investigation of the structures responsible for corneal haze after photorefractive keratectomy and their effect on visual function. Ophthalmology 1996; 103:1366–1380. 25. Alleman N, Chamon W, Silverman RH, Azar DT, Reinstein DZ, Stark WJ, Coleman DJ. Highfrequency ultrasound quantitative analysis of corneal scarring following excimer laser keratectomy. Arch Ophthalmol 1993; 111:968–973. 26. Maldanado MJ, Arnau V, Navea A, Martinez-Costa R, Mico FM, Cisneros AL, Menezo JL. Direct objective quantification of corneal haze after excimer laser photorefractive keratectomy for high myopia. Ophthalmology 1996; 103:1970–1978. 27. Braunstein RE, Jain S, McCally RL, Stark WJ, Connolly PJ, Azar DT. Objective measurement of corneal light scattering after excimer laser keratectomy. Ophthalmology 1996; 103:439–443. 28. Chew SJ, Beuerman RW, Kaufman HE, McDonald MB. In vivo confocal microscopy of corneal wound healing after excimer laser photorefractive keratectomy. CLAO J 1995; 25: 273– 280. 29. MØller-Pedersen T, Cavanaugh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive keratectomy-a 1-year confocal microscopic study. Ophthalmology 2000; 107:1235–1245. 30. Lee YG, Chen WYW, Petroll WM, Cavanaugh HD, Jester JV. Corneal haze after photorefractive keratectomy using different epithelial removal techniques-mechanical debridement versus laser scrape. Ophthalmology 2001; 108:112–120. 31. Seiler T, McDonnell PJ. Excimer laser photorefractive keratectomy. Surv Ophthalmol 1995; 40:89–118. 32. Carson CA, Taylor HR. Excimer laser treatment for high and extreme myopia. Arch Ophthalmol 1995; 113:431–436. 33. Corbett MC, O’Brart DPS, Warburton FG, Marshall J. Biological and environmental risk factors for regression after photorefractive keratectomy. Ophthalmology 1996; 103:1381–1391. 34. Cua IY, JS Pepose. Late corneal scarring post-photorefractive keratectomy concurrent with the development of systemic lupus erythematosus. J Refract Surg: In press. 35. Yee RW. First International LASEK Conference 2001, Dallas, TX. 36. Chen C, Michelini-Norris B, Stevens S, Rowsey J, Ren X, Goldstein M, Schultz G. Measurement of mRNAs for TGFβ and extracellular matrix proteins in corneas of rats after PRK. Invest Ophthalmol Vis Sci 2000; 41:4108–4116. 37. Lee Y, Wang I, Hu F, Kao WW. Immunhistochemical study of subepithelial haze after phototherapeutic keratectomy. J Refract Surg 2001; 17:334–341. 38. Dohlman CH, Gasset AR, Rose J. The effect of the absence of corneal epithelium or endothelium on stromal keratocytes. Invest Ophthalmol Vis Sci 1968; 7:520–534. 39. Wilson SE, He YG, Wang J, Li Q, McDowall AW, Vital M, Chwang EL. Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing. Exp Eye Res 1996; 62:325–328. 40. Kuo IC, Seitz B, LaBree L, McDonnell PJ. Can zinc prevent apoptosis of anterior keratocytes after superficial keratectomy? Cornea 1997; 16:550–555. 41. Daniels JT, Khaw PT. Temporal stimulation of corneal fibroblast wound healing activity by differentiating epithelium in vitro. Invest Ophthalmol Vis Sci 2000; 41:3754–3762.

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42. Lee JB, Choe CM, Kim HS, Seo KY, Seong GJ, Kim EK. Comparison of TGF-β1 in tears following laser subepithelial keratomileusis and photorefractive keratectomy. J Refract Surg 2002; 18:130–134. 43. Tuominen ISJ, Tervo TMT, Teppo AM, Valle TU, Gronhagen-Riska C, Vesaluoma MH. Human tear fluid PDGF-BB, TNF-α and TGF-β1 vs. corneal haze and regeneration of corneal epithelium and sub-basal nerve plexus after PRK. Exp Eye Res 2001; 72:631–641. 44. Kaji Y, Soya K, Amano S, Oshika T, Yamashita H. Relation between corneal haze and transforming growth factor-β1 after photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 2001; 27:1840–1846. 45. Bilgihan K, Ozdek S, Ozogul C, Gurelik G, Bilgihan A, Hasanreisoglu B. Topical vitamin E and hydrocortisone acetate treatment after photorefractive keratectomy. Eye 2000; 14: 231–237. 46. Park WC, Tseng SCG. Modulation of acute inflammation and keratocyte death by suturing, blood, and amniotic membrane in PRK. Invest Ophthalmol Vis Sci 2000; 41:2906–2914. 47. Hayashi S, Ishimoto S, Wu G, Wee W, Rao N, McDonnell PJ. Oxygen free radical damage to the cornea after excimer laser therapy. Br J Ophthalmol 1997; 81:141–144. 48. Corbett MC, O’Brart DPS, Patmore AL, Marshall J. Effects of collagenase inhibitors on corneal haze after PRK. Exp Eye Res 2001; 72:253–259. 49. Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, Gobbi PG, Carones F, Donnini M, Lapucci A, Capaccioli S. Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte apoptosis after excimer laser photoablation in rabbits. J Refract Surg 2002; 18:135–139. 50. Gomez S, Herreras JM, Merayo J, Garcia M, Argueso P, Cuevas J. Effect of hyaluronic acid on corneal haze in a photorefractive keratectomy experimental model. J Refract Surg 2001; 17:549–554. 51. Schipper I, Suppelt C, Gebbers JO. Mitomycin C reduces scar formation after excimer laser (193 nm) photorefractive keratectomy in rabbits. Eye 1997; 11:649–655. 52. Sadeghi HM, Seitz B, Hayashi S, LaBree L, McDonnell PJ. In vitro effects of mitomycin-C on human keratocytes. J Refract Surg 1998; 14:534–540. 53. Gillies MC, Garrett SKM, Shina SM, Morlet N, Taylor HR. Topical interferon alpha 2b for corneal haze after excimer laser photorefractive keratectomy. J Cataract Refract Surg 1996; 22:891–900. 54. Gartry DS, Kerr Muir MG, Lohmann CP, Marshall P. The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy. A prospective, randomized, double-blind trial. Arch Ophthalmol 1992; 110:944–952. 55. O’Brart DP, Lohmann CP, Klonos G, Corbett MC, Pollock WS, Kerr-Muir MG, Marshall J. The effect of topical corticosteroids and plasmin inhibitors on refractive outcome, haze, and visual performance after photorefractive keratectomy. A prospective, randomized, observermasked study. Ophthalmology 1994; 101:1565–1574. 56. Vetrugno M, Quaranta GM, Cardia AML. A randomized, comparative study of fluorometholone 0.2% and fluorometholone 0.1% acetate after photorefractive keratectomy. Eur J Ophthalmol 2000; 10:39–45. 57. Corbett MC, O’Brart DP, Marshall J. Do topical corticosteroids have a role following excimer laser photorefractive keratectomy? J Refract Surg 1995; 11:380–387. 58. Baek SH, Chang JH, Choi SY, Kim WJ, Lee JH. The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy. J Refract Surg 1997; 13:644–652. 59. Arshinoff S A, Mills MD, Haber S. Pharmacotherapy of photorefractive keratectomy. J Cataract Refract Surg 1996; 22:1037–1044. 60. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 1991; 98:317–321.

Mitomycin C and Haze

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61. Helal M, Messiha N, Amayem A, el-Maghraby A, Elsherif Z, Debees M. Intraoperative mitomycin-C versus postoperative topical mitomycin-C drops for the treatment of pterygium. Ophthalmic Surg Lasers 1996; 27:674–678. 62. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997; 124:303–311. 63. Talamo JH, Gollamudi S, Green WR, De La Cruz Z, Filatov V, Stark WJ. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol 1991; 109:1141–1146. 64. Yamamoto T, Varani J, Soong HK, Lichter PR. Effects of 5-fluorouracil and mitomycin C on cultured rabbit subconjunctival fibroblasts. Ophthalmology 1990; 97:1204–1210. 65. Xu H, Liu S, Xia X, Huang P, Wang P, Wu X. Mitomycin C reduces haze formation in rabbits after excimer laser photorefractive keratectomy. J Refract Surg 2001; 17:342–349. 66. Majmudar PA, Forstot SL, Dennis RF, Nirankari VS, Damiano RE, Brenar R, Epstein RJ. Topical mitomycin C for subepithelial fibrosis after refractive corneal surgery. Ophthalmology 2000; 107:89–94. 67. Meyer JC, Stulting RD, Thompson KP, Durrie DS. Late onset of corneal scar after excimer laser photorefractive keratectomy. Am J Ophthalmol 1996; 121:529–539. 68. Rubinfeld RS, Pfister RR, Stein RM, Foster CS, Martin NF, Stoleru S, Talley AR, Speaker MG. Serious complication of topical mitomycin C after pterygium surgery. Ophthalmology 1992; 99:1647–1654. 69. Jain S, McCally RL, Connolly PJ, Azar DT. Mitomycin C reduces corneal light scattering after excimer keratectomy. Cornea 2001; 20:45–49. 70. Wang MX, Gray TB, Park WC, Prabhasawat P, Culbertson W, Forster R, Hanna K, Tseng SCG. Reduction in corneal haze and apoptosis by amniotic membrane matrix in excimer laser photoablation in rabbits. J Cataract Refract Surg 2001; 27:310–319. 71. Wang MX. personal communication. 72. Rasheed K, Rabinowitz YS. Superficial lamellar keratectomy using an automated microkeratome to excise corneal scarring caused by photorefractive keratectomy. J Cataract Refract Surg 1999; 25:1184–1187. 73. Raviv T, Majmudar PA, Dennis RF, Epstein RJ. Mitomycin-C for post-PRK corneal haze. J Cataract Refract Surg 2000; 26:1105–1106. 74. Nakamura K, Kurosaka D, Bissen-Miyajima H, Tsubota K. Intact corneal epithelium is essential for the prevention of stromal haze after laser assisted in situ keratomileusis. Br. J Ophthalmol 2001; 85:209–213. 75. Marshall J. First International LASEK Conference 2001, Dallas, TX. 76. Tseng SCG. First International LASEK Conference 2001, Dallas, TX. 77. Piechocki M. Alcohol-free LASEK procedure proves effective in pilot study. Ocular Surgery News. Thorofare, NJ: Slack, Inc.; 2002. 78. Pallikaris IG. ASCRS Symposium on Cataract, IOL and Refractive Surgery. Philadelphia, PA, 2001. 79. Kampmeier J, Behrens A, Wang Y, Yee A, Anderson WF, Hall FL, Gordon EM, McDonnell PJ. Inhibition of rabbit keratocyte and human fetal lens epithelial cell proliferation by retrovirusmediated transfer of antisense cyclin G1 and antisense MAT1 constructs. Hum Gene Ther 2000; 11:1–8.

27 Mitomycin C and Surface Ablation Scott D.Barnes, MD and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA Excimer keratectomy has been effectively used to correct mild to moderate myopia (1–4), astigmatism (5–7), and hyperopia (8–10). However, such laser ablations appear to activate keratocytes leading to their proliferation (11,12). A number of reports have documented irregularities in basement membrane configuration (13,14), the presence of vacuoles in and around keratocytes (11,12), and disorganization in the lamellar structure of the corneal stroma (11,12,14,15). These changes have been theorized to be responsible for corneal light scatter and the cause of corneal haze formation and refractive regression (16,17). Compared to early reports, the incidence of visually significant haze has been decreasing with the continued advances in laser technology and refinements of surgical technique (18–21). However, it has not been eliminated, particularly in the highly myopic patient (22,23). Corticosteroids have been a main agent in prophylaxis against excessive haze formation as well as treatment once visually significant haze presents (17,24–26). However, the possibility of steroid-induced adverse effects (27,28) and cases of treatment failures (29) have led to the investigation of mitomycin C (MMC) as a possible alternative treatment. In 1991, Talamo, et al. began to investigate the use of MMC to modulate corneal wound healing after laser keratectomy (30). The initial success in rabbits and cats did not quickly transition into human trials, perhaps because of the advent of LASIK (with associated reduction in haze formation) as well as a number of reported complications with conjunctival- and scleral-based applications of MMC (31,32). However, patients with an inadequate corneal thickness for LASIK combined with recent reports of intraoperative and postoperative complications of LASIK have led to a renewed interest in surface based ablations. An interest in methods of prevention and treatment of corneal haze (LASEK vs. PRK; MMC vs. steroids) has likewise arisen.

PHARMACOLOGY OF MMC MMC is a potent alkylating agent with antineoplastic and antibiotic properties. MMC can be isolated from the fermentation filtrate of Streptomyces caespitosus. The ability to crosslink DNA between adenine and guanine is responsible for inhibition of DNA synthesis. The inhibition by MMC of DNA, cellular RNA, and protein synthesis is

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thought to suppress proliferation of fibroblasts and keratocytes. While its actions occur primarily during the late G1 and S phases, MMC is not limited to this phase. However, rapidly dividing cells are preferentially sensitive to MMC (33,34). Ocular Applications of MMC Local application of MMC has long been used with glaucoma filtration (35,36), pterygium excision (37,38), and in treating conjunctival/corneal intraepithelial neoplasia (39–41). Recent reports with dacryocystorhinostomy (42), conjunctival/corneal melanoma (43), ocular cicatricial pemphigoid (44), and as prevention in posterior capsule opacification after lens removal (45) have shown a growing interest in the potential of MMC. Ocular Complications With MMC Originally used as a systemic antineoplastic agent, bone marrow suppression, mucous membrane ulceration, and renal insufficiency were concerning side effects (46). While numerous reports of topical application have not shown any such systemic effects, caution is still necessary in using MMC based on the occurrence of ocular complications found in these reports (31,32,35–45). The reactions range from mild (delayed conjunctival re-epithelialization, SPK, mild anterior chamber inflammation, hyperemia) to more vision-threatening (secondary glaucoma, corneal edema, corneal perforation, corneoscleral melt). However, most of these adverse outcomes were associated with prolonged topical administration rather than a single application. One case report does describe a corneoscleral melt and perforation with mild ocular trauma 5 weeks after pterygium surgery (47). The surgery involved a single application of 0.2 mg/mL MMC to bare sclera for 3 minutes. This unique complication may be caused, in part, by MMC application involving the limbal region, which may have led to ischemia-induced damage. A balancing view is seen in the most recently published study of MMC use with pterygium resection. Avisar et al. (48) compared the recurrence rate using 0.2 mg/mL MMC for 3-minute and 5-minute applications. They followed-up 143 consecutive patients over 26 months and found no instances of ocular toxicity or alteration in corneal epithelium healing. They further reported that the longer duration was associated with significantly less recurrences, again sparking the debate over the optimum concentration and duration of application. While the data related to pterygium and glaucoma surgery are enlightening, the results with corneal intraepithelial neoplasia (CIN) may have played a more direct part in considering MMC in refractive surgery. Frucht-Pery et al. (39) reported their success using 0.2 mg/mL MMC drops to treat CIN involving the central visual axis. All three of their patients’ abnormal cells were replaced with normal epithelium without evidence of dysplasia during the 12 months of follow-up examinations. Wilson et al. (40) reported on the use of 0.4 mg/mL MMC drops with surgically unresponsive corneal epithelial dysplasia and neoplasia. Six of seven eyes showed complete resolution and one eye showed partial resolution. In both reports, the patients experienced transient toxic side

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effects (hyperemia, pain, blepharospasm, tearing, punctuate epithelial keratopathy), which resolved with cessation of the MMC. No permanent effects or delayed epithelial healing was noted. The step toward using MMC for refractive surgery is based on a theory that subepithelial haze/fibrosis may result from abnormal activation and/or proliferation of stromal keratocytes. In this regard, such development may be similar to that seen in neoplastic proliferation (basis for using MMC in CIN). The experience with CIN, combined with the reported lack of permanent damage to corneal structures other than in direct application to the exposed vascular limbus, led to further investigation of MMC use and the eventual desire for a single application to the avascular cornea.

CONCENTRATION AND DURATION OF APPLICATION Most of the studies regarding concentration and duration are related to pterygium and glaucoma surgery. While there are differences in what are considered optimal outcomes, there is unanimity in a desire to use the lowest concentration for the least amount of time to minimize the complications while still achieving “success;” however, the “ideal” parameters are yet to be defined. Decisions on concentration and duration have their origins in various laboratory studies and clinical experience with pterygium excision. Jampel (49) found that a 0.4 mg/mL concentration had a similar effect on fibroblast inhibition whether applied for 1 minute or 5 minutes in vitro. Ando and Yamamoto (50) reported that MMC was able to suppress keratocyte proliferation in vivo using concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. While the effect increased proportionally to the concentration, it is interesting to note that suppressive effects were seen even with the lowest concentration studied. Concentration and duration of application are important in effectiveness and toxicity of MMC. Intraoperative concentrations of 0.4 mg/mL for 3 minutes was found similarly effective to 0.2 mg/mL applied for 5 minutes. Lam et al (51) found that 0.2 mg/mL concentration was less effective in preventing recurrences of pterygium when applied for 3 minutes than when applied for 5 minutes. Cano-Perra et al. (52) found a recurrence rate of 3.3% using 0.1 mg/mL MMC for 5 minutes as compared to Helal’s (53) rate of 5.8% when using the same concentration for only 3 minutes. Ando et al. (50) found that concentrations of MMC less than 0.4 mg/mL had no deleterious effect on corneal epithelial growth. Manning (37) and Frucht-Pery (38) found that MMC at 0.4 mg/mL and 0.2 mg/mL concentrations in pterygium surgery was not associated with delayed corneal epithelial healing. Methods of Application of MMC Similar to the varied course regarding concentration and duration of application, the mode of application has also been evolving. Although a clear consensus has not been reached, most ophthalmologists seem to be finding that lower concentrations, shorter application times and minimizing the necessary contact area are proving successful in addressing corneal haze/scarring while avoiding previously noted toxic effects.

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Talamo’s rabbits received twice daily dosing of 0.5 mg/mL MMC (along with steroids and erythromycin) for 14 days after laser keratectomy. Talamo et al.’s (30) initial use of MMC was similar to the topical drop application later seen in Singh et al.’s (54) report with pterygium surgery. Borrowing from glaucoma filtration surgery, Schipper et al. (24) began the current trend of a single intraoperative application, using a 6-mm sponge soaked in 0.4 mg/mL MMC. This sponge was left on the rabbit’s recently ablated corneal surface for 5 minutes, after which the surface was irrigated with 250 mL of balanced salt solution (BSS). Majmudar et al. (29) reported using 0.2 mg/mL MMC to treat subepithelial fibrosis found in five patients after RK or PRK. A Beaver blade was used to remove the corneal epithelium and fibrosis. A 6-mm “corneal light shield” was soaked in 0.2 mg/mL MMC and then placed on the surface for 2 minutes. The ocular surface was then irrigated with 30 mL of BSS. Xu et al. (17) and Carones et al. (22) have published reports in which they have used the technique described by Majmudar, although Xu extended the application time to 5 minutes. While it appears the concentration/technique described by Majmudar is the most widely accepted, there are other styles of application being reported. Maldonado (55) has described using Majmudar’s technique supplemented by a 2-week postoperative course of 0.2 mg/mL MMC eye drops in his most severe cases. Azar and Jain (56) reported using MMC-soaked (0.25 mg/mL and 0.5 mg/mL) filter paper discs compared to annular rings placed on de-epithelized rabbit corneas for 1 minute, after which a 100-micron PTK was performed. Results of MMC Application The results of MMC use in surface ablation have to be approached with caution. Applying findings in rabbits or other animal models to humans may be misleading, as seen with the early PRK experience; laser ablation in animals revealed a much greater tendency toward postoperative haze than actually seen when human trials were conducted (57–64). The data relating to preventing haze development may not directly correlate to using MMC to treat the actual presence of subepithelial fibrosis. However, even using the proper caution, the various reports are quite promising. Prophylactic Use in Animals Talamo et al.’s (30) initial study actually involved 14 rabbit eyes randomized into one of three groups receiving different postoperative medications twice daily for 14 days after a 100-micron ablation (erythromycin alone, erythromycin plus steroids, or erythromycin/ steroids and 0.5 mg/mL MMC). There was no statistical difference noted in haze, with haze developing in all eyes by 14 to 21 days, which measured 1 to 2+ haze by the time of enucleation at 10 weeks. However, histological analysis showed none to mild subepithelial scarring in the eyes receiving MMC, moderate to severe scarring in the erythromycin only group, and mild to moderate scarring in the erythromycin/steroid treated group. Fluorescence microscopy revealed new collagen deposition directly

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proportional to the subepithelial scarring. There were no reports of ocular toxicity attributed to the use of MMC. Schipper et al. (24) studied a 5-minute application of 0.4 mg/mL MMC to eight rabbit eyes after an 81-micron PRK compared to eight rabbit eyes receiving BSS after similar PRK. Like Talamo’s study, there appeared no statistically significant difference in clinical haze during the examinations as the rabbits were killed between week 1 and 26. Light and electron microscopy revealed significant scar tissue on only one of eight corneas in the MMC group as compared to five of eight in the BSS group. Schipper further reported that a significant decrease in number of keratocytes was found in the MMC group as compared to the BSS or control group (nonoperated rabbit corneas). While they reported no ocular toxicity with the MMC eyes, one rabbit developed a severe, acute infection in its MMC-treated eye (the one of eight that had scar tissue on histopathology). The source of this infection was not adequately addressed, causing one to wonder about the role of MMC on the involved rabbit’s ocular health. Xu et al. (17) performed bilateral 120-micron PRK in 20 rabbits. The right corneas received a 5-minute application of 0.2 mg/mL MMC while the left corneas received nothing. During all examinations from weeks 2 to 26, corneal haze was significantly less in the MMC group (P<0.01). On a scale of 0 to 4, the majority of the PRK alone group measured grade 1 or 2 with a few at grade 3, while no MMC cornea measured more than grade 1. The number of keratocytes in the MMC corneas was significantly less and the number of keratocytes in the PRK alone group was significantly greater (four-fold) than those found in nonablated control corneas. This difference returned to baseline by the twelfth week in both groups. The lamellar arrangement of the anterior stroma was markedly more irregular in the PRK alone group as compared to the minimal irregularities in the MMC group; once again, the lamellar arrangement in both groups returned to “normal” by the twelfth week. As a measure of effect on epithelium, time to re-epithelialization and thickness of corneal epithelium were measured; epithelial thickness was increased in both groups compared to control eyes, but no difference was noted between the two groups. The time to re-epithelialize was equal between the groups as well. No reports of ocular toxicity was noted during the course of the study. Azar and Jain (56,65), using a previously developed scatterometer, measured corneal after which, a 100-micron PTK was performed. Corneal light scatter was least in the eyes light scatter in rabbits after PTK. MMC-soaked (0.25 mg/mL and 0.5 mg/mL) filter paper discs were compared to annular rings placed on de-epithelized rabbit corneas for 1 minute, treated with annular rings, greater in the PTK control eyes, and, surprisingly, greatest in the eyes treated with the paper disc. Azar and Jain felt these results suggest the annular zone of MMC application might suppress/minimize the centripetal migration of keratocytes with subsequent collagen deposition. Therapeutic Use in Humans Armed with the early success in animal studies and perhaps frustrated with repeated failures with multiple debridements, Majmudar et al. (29) reported using MMC to treat subepithelial fibrosis found in five patients after RK or PRK. After manual debridement, 0.2 mg/ mL MMC was applied to the cornea for 2 minutes. The results were very impressive as all corneas remained clear and visual acuity improved in every case. These

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findings remained consistent throughout the entire follow-up period (6–25 months, mean 14 months). The most marked improvement was found in the four PRK cases (i.e., 20/400 to 20/20); they had more central fibrosis than seen in the eyes with RK. Of note is the fact that no incidence of ocular toxicity was found. One year after his original publication, Majmudar further reports that he has had excellent outcomes using MMC debridement in an additional 20 eyes with visually significant haze. Maldonado (55) has described using Majmudar’s technique in 13 eyes, adding a 2week postoperative course of 0.2 mg/mL MMC eyedrops in his most severe cases. Maldonado indicated “the efficacy of treatment was spectacular…and no noticeable complication developed.” The lack of ocular toxicity is encouraging but it was not stated how many eyes received the supplemental drops nor how long the eyes were followedup. Maldonado further noted “even in the most favorable cases…the central cornea was not crystal clear long after the application…of the discs.” The lack of central clarity was thought to be in the deeper corneal layers and not to be visually significant by Majmudar (66). However, this central finding was alluded to in Azar and Jain’s rabbit study showing more scatter using MMC discs vs. annular rings (56,65). While they point out that the study did not address the annular ring effect on human eyes with preexisting corneal haze/scar, their case report on using a 0.2 mg/mL MMC-soaked annular ring to treat a 44year-old patient with visually significant post-PRK haze was promising (67). The patient’s reticular haze was eliminated within 2 months of the treatment. The central cornea remained clear and the patient was symptom-free during the 5 months of reported follow-up. Prophylactic Use in Humans Carones et al. (22) recently addressed the issue of prophylactic use of MMC in patients undergoing PRK because of refractive errors too high to allow at least 250 microns of residual stromal thickness after LASIK. A prospective, randomized study of 60 consecutive eyes in 60 patients with thin corneas and spherical equivalents between −6.00 and −10.00 diopters was conducted. Epithelial removal was accomplished with dry microsponges after 20 seconds of exposure to a 20% alcohol solution. After laser ablation (6.0-mm optical zone with 3.0-mm transition zone), 30 eyes had a 0.2 mg/mL MMCsoaked 8.0 mm Merocel (Xomed) sponge placed over the ablation area for 2 minutes, followed by vigorous irrigation with BSS. The 30 control eyes had laser ablation without any MMC or BSS irrigation. All eyes were treated with a bandage contact lens, diclofenac for 24 hours, tobramycin until re-epithelialization, artificial tears, and fluorometholone drops tapered over 2 months. Specific areas of interest during the 6 months of postoperative measurements were rate and quality of re-epithelialization, refractive error, uncorrected corrected visual acuity (UCVA) and best corrected visual acuity (BCVA), and the development and quality of corneal haze. Re-epitheliazation was complete in all eyes between days 2 and 5. No differences in the quality or rate of re-epithelialization was found between groups. There was no difference noted with regard to discomfort, side effects, or ocular toxicity. No eye in

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either group had an epithelial defect or any signs of ocular toxicity after reepithelialization. Mean preoperative refractive error was nearly identical for both groups. Although the absolute difference was greatest at 1 month (−0.67 D for MMC, −0.87 D for control) and identical at 3 months (−0.44 D vs. −0.33 D) and 6 months (−0.12 D vs. −0.21 D), the smaller absolute difference at 6 months was found to be statistically significant. While no statistically significant difference in UCVA was noted at 1 month, a significant difference was present at the 3-and 6-month examinations. Comparing the MMC-treated eyes to the controls at 6 months, 100% and 83%, respectively, attained 20/40 or more acuity. The difference was even greater for those eyes achieving acuity of 20/20 or better: 60% for the MMC group compared to 30% for the control eyes. Perhaps the most impressive observation was found in the development of corneal haze, reported on a 0 to 4 scale. At the 1-month examinaiton, 27% of the MMC-treated eyes had grade 1 haze, with the remainder either having zero or grade 0.5 haze; 53% of control eyes had haze of grade 1 or higher. The results at 6 months were even more impressive; 60% of the MMC group had zero to grade 0.5 haze and 40% had grade 1 haze, whereas 40% of the controls had grade 1 haze and 40% had grade 2 to 4 haze. The BCVA change from baseline to 6 months after treatment is also notable. More than 50% (16/30) of eyes in the MMC group experienced an increase of one to two lines of acuity compared to approximately 17% (5/30) in the control group. While the significant corneal haze may be responsible for close to 25% (7/30) of the eyes in the control group losing between one and three lines of acuity, the fact that no eyes in the MMC group experienced any such loss speaks favorably for the safety of the MMC use in this study.

MMC USE IN LASEK Currently, there are no published studies regarding use of MMC with LASEK, either prophylacticly or in treating postoperative corneal haze. This may be caused in part by less clinically significant corneal haze reported with LASEK and in part with a smaller number of clinicians performing this fairly new technique. While one theoretical advantage of LASEK is a decreased incidence of corneal haze caused by the epithelial sheet, larger numbers are needed to ascertain whether this is a consistent finding or somehow related to the numerous surgical variables found among clinicians. If there is a need to address corneal haze in LASEK, it would appear reasonable to apply the principles associated with the PRK experience. While the physiology of LASEK and PRK are different, they do share similarities, such as ablation effects on Bowman’s layer and the anterior stroma, which may allow similar actions with MMC. Therapeutic or Prophylactic Use? With the advent of better lasers and surgical techniques, postoperative corneal haze is not as common as during the early days of PRK (18–21). Does one subject all surface ablation patients to MMC in the attempt to prevent corneal haze in a small percentage?

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For what level of refractive error does the percentage become high enough to justify the application? The correlation of clinically observed haze (back-scatter) to functional impairment (front-scatter) is not so clearly established. While “clinically significant” generally is taken as an objective decrease in previously attained visual acuity, would corneal haze associated with a change from 20/10 to 20/15 or from 20/15 to 20/20 be “clinically significant” enough to warrant treatment with MMC? All of these questions basically address one point: is it reasonable to use MMC as a prophylactic measure or only as a therapeutic treatment? Given the success in treating postoperative corneal haze with no reports of actual toxic effects, therapeutic use of MMC seems quite reasonable. However, justification for prophylactic use is not as obvious. There will likely always be two camps when it comes to the risk-to-benefit ratio of using MMC to prevent corneal haze. The main argument would seem to settle on toxic effects or complications associated with MMC. Most of the ocular complications have been associated with continued topical application or direct application to vascularized tissues seen in pterygium or glaucoma surgery. All of the recent studies involving a single intraoperative application of MMC to prevent or treat corneal haze/fibrosis have failed to show any such complications to date (17,22,29,55,56,65–67). While it is difficult to assure long-term safety with follow-up times ranging from 6 to 26 months at the time of publication, it is helpful to note that the reported complications with MMC in ocular surgery generally developed within 6 months. While the animal studies had definite end points in their follow-up, quite a number of years have passed since the first human applications in 1998, and there continues to be no reports of toxicity or complications associated with those applications of MMC. If the risk of corneal haze is high (Carones showed a 40% rate of grade 2 to 4 in patients with −6.00 D or more), the tolerance for variable visual acuity caused by severity and duration of such haze is low, and the prospect of long-term corticosteroid use is undesirable, a case could be made for prophylactic use of MMC. However, one must step cautiously until further studies involving larger numbers of patients followed-up for greater lengths of time can more definitively answer the question of the wisdom, safety, and best application of this impressive agent.

REFERENCES 1. Brancato R, Tavola A, Carones F. Excimer laser photorefractive keratectomy for myopia: Results in 1165 eyes. Refract Corneal Surg; 1993; 9:95–104. 2. Tengroth B, Epstein D, Fagerholm P. Excimer laser photorefractive keratectomy for myopia: Clinical results in sighted eyes. Ophthalmology; 1993; 100:739–745. 3. Maguen E, Salz JJ, Nesburn JJ. Results of excimer laser photorefractive keratectomy for the correction of myopia. Ophthalmology; 1994; 101:1548–1556; discussion by MJ Mannis 1556– 1557. 4. Carones F, Brancato R, Morico A. Evaluation of three different approaches to perform excimer laser photorefractive keratectomy for myopia. Ophthalmic Surg Lasers; 1996; 27 (suppl): S458– S465. 5. McDonnell PJ, Moreira H, Garbus J. Photorefractive keratectomy to create toric ablations for correction of astigmatism. Arch Ophthalmol; 1991; 109:710–713.

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6. Carones F, Brancato R, Morico A. Compound myopic astigmatism correction using a mask inthe-rail excimer laser delivery system: Preliminary results. Eur J Ophthalmol; 1996; 6: 221–233. 7. Alpins NA, Tabin GC, Adams LM. Refractive versus corneal changes after photorefractive keratectomy for astigmatism. J Refract Surg; 1998; 14:386–396. 8. Dausch D, Klein R, Schroder E. Excimer laser photorefractive keratectomy for hyperopia. Refract Corneal Surg; 1993; 9:20–28. 9. Brancato R, Carones F, Morico A. Hyperopia correction using an erodible mask excimer laser delivery system coupled to an axicon: Preliminary results. Eur J Ophthalmol; 1997; 7:203–210. 10. Carones F, Gobbi PG, Vigo L, Brancato R. Photorefractive keratectomy for hyperopia: Longterm nonlinear and vector analysis of refractive outcome. Ophthalmology; 1999; 106: 1976– 1982; discussion by MA Lawless, 1982–1983. 11. Wu WC, Stark WJ, Green WR. Corneal wound healing after 193-nm excimer laser keratectomy. Arch Ophthalmol; 1991; 109:1426–1432. 12. Rawe IM, Zabel RW, Tuft SJ. A morphological study of rabbit corneas after laser keratectomy. Eye; 1992; 6:637–642. 13. Fountain TR, de la Cruz Z, Green WR. Reassembly of corneal epithelial adhesion structures after excimer laser keratectomy in humans. Arch Ophthalmol; 1994; 112:967–972. 14. Goodman GL, Trokel SL, Stark WJ. Corneal healing following laser refractive keratectomy. Arch Ophthalmol; 1989; 107:1799–1803. 15. Tuft S, Marshall J, Rothery S. Stromal remodeling following photorefractive keratectomy. Lasers Ophthalmol; 1987; 1:177–183. 16. Braunstein RE, Jain S, McCally RL. Objective measurement of corneal light scattering after excimer laser keratectomy. Ophthalmology; 1996; 103:439–443. 17. Xu H, Liu S, Xia X. Mitomycin C reduces haze formation in rabbits after excimer laser photorefractive keratectomy. J Refract Surg; 2001; 17:342–349. 18. Pop M, Payette Y. Photorefractive keratectomy versus laser in situ keratomileusis. Ophthalmology; 2000; 107:251–257. 19. Tole DM, McCarty DJ, Couper T. Comparison of laser in situ keratomileusis and photorefractive keratectomy for the correction of myopia of −6.00 diopters or less. 0 diopters or less. Melbourne Excimer Laser Group. J Refract Surg; 2001; 17:46–54. 20. Lee JB, Seong GL, Lee JH. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 21. Lohmann CP, vonMohrenfels W, Gabler B. LASEK: A new surgical procedure to treat myopia. Invest Ophthalmol Vis Sci; 2001; 42:S599 [Abstract]. 22. Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylactic use of mitomycinC to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg; 2002; 28:2088–2095. 23. Kruger RR, Talamo JH, McDonald MB. Clinical analysis of excimer laser photorefractive keratectomy using a multiple zone technique for severe myopia. Am J Ophthalmol; 1995; 119: 263–274. 24. Schipper I, Suppelt C, Gebbers J. Mitomycin-C reduces scar formation after excimer laser (193 nm) photorefractive keratectomy in rabbits. Eye; 1997; 11:649–655. 25. Zabel RW. Myopic excimer laser keratectomy: A preliminary report. Refract. Corneal Surg; 1990; 6:329. 26. 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 study. Arch Ophthalmol; 1992; 110:944–952. 27. Morales J, Good D. Permanent glaucomatous visual loss after photorefractive keratectomy. J Cataract Refract Surg; 1998; 24:715–718. 28. Levy Y, Nemet P. Increased intraocular pressure with corticosteroid medication after photorefractive keratectomy (letter). Surv Ophthalmol; 1995; 41:187–188.

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29. Majmudar PA, Forstot SL, Dennis RF. Topical mitomycin-C for subepithelial fibrosis after refractive corneal surgery. Ophthalmology; 2000; 107:89–95. 30. Talamo JH, Gollamundi S, Green WR. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol; 1991; 109: 1141–1146. 31. Rubinfeld RS, Pfister RR, Stein RM. Serious complications of topical mitomycin C after pterygium surgery. Ophthalmology; 1992; 99:1647–1654. 32. Gupta S, Basti S. Corneoscleral, ciliary body and vitreoretinal toxicity after excessive instillation of mitomycin C (letter). Am J Ophthalmol; 1992; 114:503–504. 33. Calabrisi P, Chabner B A. Antineoplastic agents. Goodman LS, Gilman AG, Eds. Pharmacological Basis of Therapeutics, 8th ed. . New York: Pergamon Press, 1990:1247–1248. 34. Crooke ST, Bradner WT. Mitomycin C: A review. Cancer Treat Rev; 1976; 3:121–139. 35. Bergstrom TJ, Wilkinson WS, Skuta G. The effects of subconjunctival mitomycin C on glaucoma filtration surgery in rabbits. Arch Ophthalmol; 1991; 109:1725–1730. 36. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology; 1991; 98:317–321. 37. Manning CA, Kloess PM, Diaz D, Yee RW. Intraoperative Mitomycin in primary pterygium excision. Ophthalmology; 1997; 104:844–848. 38. Frucht-Pery J, Siganos CS, Ilsar M. Intraoperative application of topical mitomycin C for pterygium surgery. Ophthalmology; 1996; 103:674–677. 39. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol; 1994; 117:164–168. 40. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol; 1997; 124:303–311. 41. Heigle TJ, Stulting RD, Palay DA. Treatment of recurrent conjunctival epithelial neoplasia with topical mitomycin C. Am J Ophthalmol; 1997; 124:397–399. 42. You YA, Fang CT. Intraoperative mitomycin C in dacryocystorhinostomy. Ophthal Plast Reconstr Surg; 2001; 17:115–119. 43. Shields CL, Shields JA, Armstrong T. Management of conjunctival and corneal melanoma with surgical excision, amniotic membrane allograft, and topical chemotherapy. Am J Ophthalmol; 2001; 132:576–578. 44. Donnenfeld ED, Perry HD, Wallerstein A. Subconjunctival Mitomycin C for the treatment of ocular cicatricial pemphigoid. Ophthalmology; 1999; 106:72–79. 45. Chung HS, Lim SJ, Kim HB. Effect of mitomycin-C on posterior capsule opacification in rabbit eyes. J Cataract Refract Surg; 2000; 26(10):1537–1542. 46. Physician’s Desk Reference. Oradell. NJ: Medical Economics Books; , 1990: 750–751. 47. Dougherty PJ, Hardten DR, Lindstrom RL. Corneoscleral melt after pterygium surgery using a single intraoperative application of mitomycin C. Cornea; 1996; 15:537–540. 48. Avisar R, Gaton DD, Loya N. Intraoperative mitomycin C 0.02% for pterygium: Effect of duration of application on recurrence rate. Cornea; 2003; 22:102–104. 49. Jampel HD. Effect of brief exposure to mitomycin C on viability and proliferation of cultured human Tenon’s capsule fibroblasts. Ophthalmology; 1992; 99:1471–1476. 50. Ando H, Ido T, Kawai Y, Yamamoto T, Kitazawa Y. Inhibition of corneal wound healing. Ophthalmology; 1992; 99:1809–1814. 51. Lam DSC, Wong AKK, Fan DSP. Intraoperative mitomycin C to prevent recurrence of pterygium after excision: A 30-month follow-up study. Ophthalmology; 1998; 105:901–905. 52. Cano-Perra J, Diaz-Llopis M, Maldonado MJ. Prospective trial of intraoperative mitomycin C in the treatment of primary pterygium. Br J Ophthalmol; 1995; 79:439–441. 53. Helal M, Messiha N, Amayen A. Intraoperative mitomycin C versus postoperative topical mitomycin C drops for the treatment of pterygium. Ophthalmol Surg Lasers; 1996; 27:674–678.

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54. Singh G, Wilson MR, Foster CS. Mitomycin eye drops as treatment for pterygium. Ophthalmology; 1988; 95:813–821. 55. Maldonado MJ. Intraoperative MMC after excimer laser surgery for myopia (letter). Ophthalmology; 2002; 109:826. 56. Jain S, McCally RL, Connolly PJ, Azar DT. Mitomycin C reduces corneal light scattering after excimer keratectomy. Cornea; 2001; 20:45–49. 57. Sher NA, Barak M, Daya S. Excimer laser photorefractive keratectomy in high myopia: A multicenter study. Arch Ophthalmol; 1992; 110:935–943. 58. Sher N, Chen V, Bowers RA. The use of the 193-nm excimer laser for myopic photorefractive keratectomy in sighted eyes: A multicenter study. Arch Ophthalmol; 1991; 109:1525–1530. 59. Salz JJ, Maguen E, Macy JI. One-year results of excimer laser photorefractive keratectomy for myopia. Refract Corneal Surg; 1992; 8:269–273. 60. O’Brart DPS, Corbett MC, Lohmann CP. The effects of ablation on the outcome of excimer laser photorefractive keratectomy. Arch Ophthalmol; 1995; 113:438–443. 61. Pop M, Aras M. Multizone/multipass photorefractive keratectomy: Six month results. J Cataract Refract Surg; 1995; 21:633–643. 62. Kalski RS, Sutton G, Bin Y. Comparison of 5-mm and 6-mm ablation zones in photorefractive keratectomy for myopia. J Cataract Refract Surg; 1996; 12:61–67. 63. Morris AT, Ring CP, Hadden OB. Comparison of photorefractive keratectomy for myopia using 5–mm and 6–mm diameter ablation zones. J Refract Surg; 1996; 12:S275–S277. 64. O’Brart DPS, Corbett MC, Verma S. Effects of ablation diameter, depth, and edge contour on the outcome of photorefractive keratectomy. J Refract Surg; 1996; 12:50–60. 65. Azar DT, Jain S. Topical MMC for subepithelial fibrosis after refractive corneal surgery (letter). Ophthalmology; 2001; 108:239–240. 66. Majmudar PA, Epstein RJ. Intraoperative MMC after excimer laser surgery for myopia (author reply to letter). Ophthalmology; 2002; 109:828. 67. Dudenhoefer EJ, Jain S, Azar DT. Intraoperative MMC after excimer laser surgery for myopia (author reply to letter). Ophthalmology; 2002; 109:826–828.

28 Use of Autologous Serum to Reduce Haze After LASEK Steven B.Yee, MD, Ning Lin, MD, OD, Alice Z.Chuang, PhD, and Richard W.Yee, MD Hermann Eye Center, University of Texas Health Science Center at Houston, Houston, TX

BACKGROUND In years past, excimer laser photorefractive keratectomy (PRK) has been a popular surgical modality for the correction of myopia. The postoperative pain, corneal haze, and slower visual rehabilitation after PRK prompted a large number of patients to select laser in situ keratomileusis (LASIK) instead. However, LASIK involves cornea flap creation, repositioning, and a healing process and, accordingly, flap-associated complications and aberrations compromised visual outcome. In addition, LASIK may not be suitable for patients with high myopia, thin corneas, or large pupils. Additional concern regarding loss of the LASIK flap may be a relative contraindication to individuals who are at higher risk for ocular trauma (law enforcement, military personnel, emergency medical personnel, and athletes in contact sports). To overcome the previously mentioned limitations and to enhance visual recovery, a new refractive surgery technique was developed, laser epithelial keratectomy (LASEK), with promising results (1–4). After application of 18% to 20% ethanol on the corneal epithelium for 25 to 45 seconds, a superiorly hinged epithelial flap is created and laser ablation is then performed. The epithelial flap is then replaced and a bandage contact lens is applied. LASEK offers a major advantage over LASIK in that no true flap is created. Accordingly, flap-associated complications and aberrations arising from LASIK flap creation are avoided. Patients with thin corneas, large pupils, or those who may sustain ocular trauma (and loss of a LASIK flap) could also benefit from LASEK. The uncorrected visual acuity of postoperative LASEK and LASIK are comparable.

HAZE As in PRK, haze (loss of corneal transparency) is a major postsurgical complication of LASEK. Histopathologically, haze is characterized by the confluence and activation of keratocytes (fibroblasts), and the accumulation of abnormal collagen and other substances in the extracellular matrix (5–7). The development of haze after PRK has been associated with increased cellular reflectivity from high numbers of wound-healing

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keratocytes (17). The proliferative capability of keratocytes isolated from a corneal haze has been found to be significantly greater than that of keratocytes from normal cornea in tissue cultures (8, 9). Haze is associated with a decrease in contrast sensitivity, development of halos and glare, decrease in the predictability of the correction of refractive error, and regression of acquired correction (3–11). Several animal studies have shown reduction of corneal haze by a single intra-operative application of topical mitomycin C (10), by postoperative application of topical synthetic inhibitor of metalloproteinase (11), tranilast (8), collagenase inhibitors (10% ascorbate, 0.1 M cysteine, 0.37% EDTA, and 1% tetracycline) (12), and plasmin inhibitors (aprotinin) (13). The use of corticosteroids in the modulation of haze has yielded equivocal results. Corticosteroids either have had no effect on haze (9,13) or have appeared to reduce the incidence of haze (14). Use of corticosteroids entails the well-known untoward effects of elevation of intraocular pressure (IOP) and risk of cataract. Oral supplementation with vitamin A (25,000 IU retinol palmitate) and vitamin E (230 mg α-tocopheryl nicotinate) may reduce haze formation in humans after PRK (15). Intact corneal epithelium has been shown to play an important part in curbing haze and in the differentiation of myofibroblasts in corneal wound healing (16). Corneal haze has been shown to be correlated with ablation depth. Haze is seen more frequently and is denser in high myopes. In the −3.00-diopter (D) groups, haze appears to be maximal at approximately 3 months, whereas in the −6.00-D group, haze is maximal at 5 to 6 months (9). There is a correlation between increased ablation depth/corneal thickness (AD/CT) ratio (e.g., more than 0.18) and an increased incidence of corneal haze (21). Fortunately, the treatment and control groups were well-matched, with each group containing eyes with low AD/CT and eyes with high AD/CT ratios. Serum has been used effectively as treatment for intractable aqueous-deficient dry eyes (18). Serum is the fluid portion of blood that is devoid of clotting factors and cellular components. It has been used in cell cultures for many years. The growth factors and other components found in serum may help cell adhesion, cell migration, cell proliferation, wound healing, and remodelation. Serum is known to be rich in epithelial growth factor (EGF) and other components known to accelerate corneal epithelial wound healing through stimulation of cell proliferation and of migration and antipoptotic effects (22). Autologous serum has been efficacious in the treatment of persistent corneal epithelial defects in dry eyes associated with Sjogren syndrome (19,20).

OUR EXPERIENCE All consecutive patients undergoing LASEK procedure for refractive errors at the Hermann Eye Center, The University of Texas Health Science Center at Houston, from 1999 to 2002 were included in our study. The LASEK procedures were performed by a single surgeon (R.W.Y.) using an Alcon Autonomous LADARVision 4000 Excimer Laser (Alcon Laboratories, Fort Worth, TX). During the initial patient encounter, a complete medical and ophthalmic history was taken (including the history and stability of refractive error). A complete eye examination was also performed, including the determination of visual acuity (both uncorrected and

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best-corrected), manifest refraction, and cycloplegic refraction. The cycloplegic refraction was performed after topical administration of phenylephrine 2.5%, tropicamide 1.0%, and cyclopentolate 0.5%. Corneal topography and pachymetry were obtained on all patients, as well. Eleven consecutive patients undergoing LASEK using a modified Camellin LASEK procedure received a 20% autologous serum solution (in balanced salt solution) as eye drops. During the surgery, two drops of the autologous serum solution was administered to the cornea before and after repositioning the epithelial flap. The patient applied one drop of serum solution as an ophthalmic drop six times per day for 4 days. On postoperative day 0, the patient started the serum solution 3 hours postoperatively. If reepithelialization was not completed by postoperative day 4, the patients continued administration of the serum solution for an additional 1 to 2 days until completion of reepithelialization and removal of the bandage contact lenses. The control group was a historical control. These patients also underwent LASEK (same modified Camellin LASEK technique as the “serum” group) and had complete haze data in each follow-up. The control group patients were participants in another study investigating LASEK patients and haze formation in relation to the ablation depth/cornea thickness ratio. The sole difference between the “serum” group and the control group was the use of autologous serum eye drops in the “serum” group. The two groups (“serum” and control) were matched for age and for amount of refractive error.

LASEK TECHNIQUE After standard preparation, draping and placement of an eyelid speculum, the cornea is marked at the 3 o’clock and 9 o’clock positions. A stencil is used to mark the area at 6 o’clock. Using a 60-to 80-µm trephine, epithelial microtrephination is performed resulting in a 60-degree to 80-degree hinge at the 12 o’clock location. An alcohol well/alcohol cone (whose circumference is greater than that of the incision) is then placed over the eye and filled with an 18% ethanol solution. The alcohol solution is left in place for 45 seconds. A weck sponge is then used to remove the alcohol solution, followed by rinsing with balanced salt solution. Epithelial detachment is then performed using an epithelial hoe followed by a flap spatula. The epithelial flap is then folded back at the 12 o’clock position. After small spot excimer treatment is completed, the flap is then repositioned with a fine cannula and/or a small spatula. A bandage soft contact lens is then applied to the cornea to keep the flap in place until completion of re-epithelialization (normally 3 to 5 days). After LASEK, patients were examined daily or every other day until reepithelialization is accomplished. Thereafter, the patients were examined at 1 week, 1 month, 3 months, 6 months, and 12 months postoperatively. Assessment of visual acuity (both uncorrected and best-corrected) and slit-lamp examination were included in each visit. In addition to performing the standard slit-lamp examination, the post-LASEK corneas were also evaluated for corneal haze by two independent evaluators (Fig. 1). The ratings for corneal haze from the two evaluators were averaged and recorded. The relative scale is as follows: 0=no haze

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0.5+=trace haze 1+=mild easily, easily seen on slit-lamp biomicroscopy 2+=moderate haze 3+=marked haze, iris details still visible 4+=severe haze, iris details obscured

Figure 1 An example of haze. (A) 0.50+ haze. (B) 1.0+ haze. Serum Preparation Twenty milliliters of the patient’s blood is collected in two red top tubes (no preservatives, no wax) and centrifuged at 4,000 rpm for 4 minutes. Using sterile technique, the serum is then drawn off and diluted with balanced salt solution to arrive at a final concentration of 20%. The autologous serum solution is then packaged into individual single-use ampoules and stored at −80°F until the day of surgery, when it is thawed at room temperature. The patient is then instructed on the use of the autologous serum eye drops and is advised to store the eye drops in a refrigerator at 40°F. Statistical Methods For each eye, the AD/CT ratio was computed and categorized into high or low AD/CT based on AD/CT ratio being less than or greater than 0.18. The maximum haze during the postoperative follow-up was recorded for each eye. If the maximum haze was equal to or greater than 1+, the eye was categorized into the haze group. Otherwise, it was included in the no haze group. The baseline characteristics, age, refractive error, AD, and AD/CT are reported as mean ±SD are compared between two groups using two-sample t tests. Categorical variables are reported as frequency (%). The Fisher exact test was used to examine significant differences in distribution or in frequency between the groups. Stepwise logistic regression was further used to compare the treatment effects and other baseline characteristics (age, refractive error, and AD/CT).

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All statistical computations were accomplished with SAS for Window NV, version 6.12 (Cary, NC). A p value of 0.05 was regarded as significant.

RESULTS A total of 106 LASEK-treated eyes from 63 patients were included in this study. Of these, 21 (20%) LASEK-treated eyes from 11 patients received 20% autologous serum treatment; 85 (80%) LASEK-treated eyes from 52 patients did not receive serum treatment. The age of patients in the treatment group ranged from 27 to 45 years (mean age was 38.2±5.1 years), and the age of the control group ranged from 24 to 67 years (mean age was 40.9±9.6 years). There were no statistical differences in age range between the treatment and the control groups (P=0.10). The mean refractive error for the treatment group was −5.23 (±2.02) D. The mean refractive error for the control group was −5.46 (±3.74) D. There were no statistical differences in the mean refractive error between the treatment and control groups (P=0.70). The mean follow-up duration was 306±66 days for the treatment group and 192 ±107 days for the control group. The mean ablation depth for the eyes receiving treatment was 74.70±22.93—m, with a mean AD/CT ratio of 0.14±0.04. The mean ablation depth for eyes not receiving treatment was 93.0±45.0 µm, with a mean AD/CT of 0.18±0.09. There were no statistical differences in mean ablation depth and in AD/CT between the treatment and control groups (P=0.07 and 0.08, respectively); 45 (42%) eyes had a high AD/CT ratio (AD/CT > 0.18). Fifty-eight percent had a low AD/CT ratio. Of the high AD/CT eyes, seven (16%) eyes received serum and 38 (84%) eyes received no treatment. Of the eyes with low AD/ CT ratio, 14 (23%) received serum treatment and 47 (77%) received no treatment. There were no statistical differences in distribution of high or low AD/CT between treatment groups (P=0.46, Fisher exact test). It was found that in eyes with both high and low AD/CT ratios, the use of autologous serum was associated with a lower incidence of corneal haze. This lower incidence of haze with serum use was statistically significant in eyes with high AD/CT ratio with a p value of 0.0068. Although a lower incidence of corneal haze was associated with autologous serum use in eyes with low AD/CT ratio, this finding was not considered statistically significant with a p value of 0.5803 (Fig. 2). The stepwise logistic regression analysis showed that the significant factors associated with developing haze were high AD/CT ratio (odds ratio=103, p <0.001) and the nonuse of serum treatment. The use of serum drops was associated with the significant reduction of corneal haze after LASEK (Fig. 3).

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Figure 2 Comparison of maximal corneal haze between serum group and nonserum group. Among 85 nonserum-treated eyes, 47 eyes were in the lower ratio group (AD/CT ratio <0.18) and 38 eyes were in higher ratio group (AD/CT ratio ≥0.18). Forty-two of 47 eyes (89%) in the no serum/lower ratio group developed no corneal haze during the follow-up period. Only five of 47 eyes (11 %) in the no serum/lower ratio group showed 1+or more haze. In the no serum/higher ratio group, 35 of 38 eyes (92%) developed 1+or more corneal haze during follow-up period. In the no serum/higher ratio group, three of 38 eyes (8%) had no corneal haze. Among 21 serum-treated eyes, seven eyes were in the higher ratio group and 14 eyes were in the lower ratio group. Three of seven eyes (42%) in the autologous serum/higher ratio group had no corneal haze during the follow-up period. In the autologous serum/lower ratio group, all 14 eyes were free of corneal haze.

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Figure 3 Comparison of average corneal haze between serum-treated group and nonserum-treated group. The average corneal haze in the serumtreated group was 0.54±0.18 (range from 0 to 1+). While in the nonserumtreated group, the average corneal haze was 0.79±0.61 (range from 0 to 2+). Autologous serum was identified as a significant factor (p=0.0005) in developing corneal haze by using the stepwise logistic regression.

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DISCUSSION LASEK is becoming increasingly popular since its introduction to the United States in 1999. LASEK appears to be a safe and efficacious alternative to LASIK, even in patients with higher amounts of myopia (21). LASEK has also been shown to be superior to LASIK in terms of postoperative topographical results and in the correction of cylinder error (second-order astigmatism) (22). In contrast to LASIK, LASEK avoids the use of a microkeratome and thus avoids the complications associated with flap creation. In contrast to PRK, LASEK offers the advantage of less postoperative pain and less time required for re-epithelialization. LASEK is particularly attractive to patients with thin corneas, high myopia, flat corneas, and those prone to ocular trauma (e.g., police officers, members of the armed forces, participants in contact sports). LASEK shares with PRK the potential complication of corneal haze. Corneal haze may result in: (1) decrease in the predictability of correction/refraction; (2) reduction in the quality of vision; (3) decrease in contrast sensitivity; (4) increase in cornea irregularity; (5) regression of visual acuity; and (6) an increase in recovery time. Corneal haze remains the most important factor in the determination of LASEK outcome. Although it is believed that the risk of corneal haze is lower for LASEK than for PRK, there does remain the real risk of corneal haze among LASEK patients. Our grading is based on the appearance of the corneal haze on slit-lamp biomicroscopy. It is compatible with the system proposed by Hanna (23). Serum (e.g., fetal calf) has played a prominent role in promoting cell growth in culture. Tsubota et al. demonstrated that fetal calf serum accelerated corneal epithelial cell migration in vitro (19). There are many precedents for the clinical use of autologous serum. Autologous serum has been successfully used in the rehabilitation of the ocular surface in patients with severe dry eye caused by ocular pemphigoid, Stevens-Johnson syndrome, and Sjögren syndrome. The rationale for using autologous serum is based on the observation that factors present in tears are also present in serum, but not in commercially available artificial tears (20). Autologous serum has also been found to be efficacious in the therapy of persistent epithelial defects (25). The selection of 20% autologous serum came about from the successful use of 20% autologous serum by Tsubota et al. (20). Although the exact mechanism of how autologous serum may decrease corneal haze is not well-understood, there are numerous components in serum that may play a role in the decrease of corneal haze. The serum components believed to promote epithelial healing are EGF, basic fibroblast growth factor (bFGF), and fibronectin (25). EGF found in human tears and serum has proven efficacious in the healing of corneal abrasions (27). The bFGF and acidic fibroblast growth factor (aFGF) have been shown to promote faster healing of epithelial defects in rabbit corneas (26). In our study, patients with AD/CT ratio of more than 0.18 were at greater risk for corneal haze. We found that the use of 20% autologous serum (intra-operatively and also as postoperative eye drops) reduced the incidence of corneal haze, regardless of the AD/ CT ratio. We demonstrated that 20% autologous serum may be of benefit to patients undergoing LASEK. The use of serum was correlated with a lower incidence of corneal haze. Given

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that corneal haze is a major factor in LASEK outcome and that the use of the patient’s own serum under proper settings not associated with major untoward effects, one could make the case for use of 20% autologous serum in LASEK patients with high AD/CT ratios.

REFERENCES 1. Shah S, Sebai Sarhan AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85(4):393–396. 2. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(2 Suppl):S222–S223. 3. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg; 2001; 17(2 Suppl):S219–S221. 4. Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27(4):565–570. 5. Malley DS, Steinert RF, Puliafito CA, Dobi ET. Immunofluorescence study of corneal wound healing after excimer laser anterior keratectomy in the monkey eye. Arch Ophthalmol; 1990; 108(9):1316–1322. 6. Fantes FE, Hanna KD, Waring GO 3rd, Pouliquen Y, Thompson KP, Savoldelli M. Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys. Arch Ophthalmol; 1990; 108(5):665–675. 7. Fitzsimmons TD, Fagerholm P, Harfstrand A, Schenholm M. Hyaluronic acid in the rabbit cornea after excimer laser superficial keratectomy. Invest Ophthalmol Vis Sci; 1992; 33(11): 3011–3016. 8. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive keratectomy: a 1-year confocal microscopic study. Ophthalmology; 2000; 107(7):1235–1245. 9. Okamoto S, Sakai T, Iwaki Y, Tobari I, Hamano S. Effects of tranilast on cultured rabbit corneal keratocytes and corneal haze after photorefractive keratectomy. Jpn J Ophthalmol; 1999; 43(5):355–362. 10. Gartry DS, Kerr Muir M, 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(Pt 4):584–590. 11. Xu H, Liu S, Xia X, Huang P, Wang P, Wu X. Mitomycin C reduces haze formation in rabbits after excimer laser photorefractive keratectomy. J Refract Surg; 2001; 17(3):342–349. 12. Chang JH, Kook MC, Lee JH, Chung H, Wee WR. Effects of synthetic inhibitor of metalloproteinase and cyclosporin A on corneal haze after excimer laser photorefractive keratectomy in rabbits. Exp Eye Res; 1998; 66(4):389–396. 13. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18(3):217–224. 14. Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology; 1999; 106(10):1984–1989. 15. Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, Shimmura S. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol; 1999; 83:390–395. 16. Pastor JC, Calonge M. Epidermal growth factor and corneal wound healing: a multicenter study. Cornea; 1992; 11:311. 17. Moller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal wound healing explains refractive instability and haze development after photorefractive keratectomy: a 1-year confocal microscopic study. Ophthalmology 2000 Jul; 107(7):1235–45.

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18. Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 2001 Apr; 42(5):948–56. 19. Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology 1999 Oct; 106(10):1984–9. 20. Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, and Shimmura S. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999; 83: 390–395. 21. Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg 2002 May–Jun; 18(3):217–24. 22. Smolek MK, Yee RW, McDonald MB, Klyce SD, Nguyen L, Stokes JP. A Comparison of LASEK, PRK, and LASIK Topographies and Wavefront Analysis. 23. Hann KD, Pouliquen YM, Waring GO II, et al. Corneal wound healing in monkeys after repeated excimer laser photorefractive keratectomy. Arch Ophthalm 1992; 110:1286–1291. 24. Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 2001 Apr; 42(5):948–56. 25. Poon AC, Geerling G, Dart JK, Fraenkel GE, and Daniels JT. Autologous serum drops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol 2001; 85:1188–1197. 26. Fredj-Reygrobellet D, Plouet J, Delayre, et al. Effects of a FGF and bFGF on wound healing in rabbit corneas. Curr Eye Res 1987; 6:1205–9. 27. Pastor JC, Calonge M. Epidermal growth factor and corneal wound healing: a multicenter study. Cornea 1992; 11:311.

29 LASEK After Corneal and Intraocular Procedures Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute, Harvard Medical School Boston, MA The goal of refractive surgery is to correct refractive error, allowing patients to be independent of spectacles or contact lens. Ideally, surgeons aim to accomplish this goal with a single procedure. However, variability in biological response to laser or incisional procedures compromise postoperative predictability and stability. Therefore, retreatment or enhancement is often necessary to achieve satisfactory results. Patients’ preoperative characteristics such as relatively thin cornea may also dictate that a combined procedure be performed to save the tissue and reduce the risk of postoperative ectasia. Various ocular surgeries may affect the refractive status of the eye. Refractive surgery has been increasingly used to improve the postoperative refractive errors. This chapter discusses the possible roles for LASEK after corneal surgeries.

LASEK RETREATMENT If the decision for enhancement is made at a relatively short period of time after the primary procedure, the retreatment of LASEK is relatively simple and straight-forward. The surgeon recreates the epithelial flap by applying alcohol in a similar manner to that of the original procedure. However, after prolonged wound healing, the re-elevation of the epithelial flap may be difficult. The surgeon may need to apply alcohol for longer duration. An alternative is to perform transepithelial photorefractive keratectomy (PRK) for laser subepithelial keratomileusis (LASEK) enhancement after prolonged wound healing.

LASEK AFTER PRK LASEK procedure can be used for enhancement of the patient who underwent PRK. These patients already experienced postoperative discomfort and delayed visual recovery associated with PRK. Therefore, they may be more open to the possibility of similar procedure and possibly reduced discomfort associated with LASEK. The epithelial flap has been shown to be viable after brief alcohol exposure (1). The presence of this protective layer may provide optimal environment for corneal wound healing (2).

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Regression caused by epithelial hyperplasia or higher aberrations induced by abnormal stromal fibrosis may also be reduced. As with the case of retreatment after LASEK, surgeon may encounter difficulty in reelevation of epithelial flap, especially after prolonged periods after the primary procedure. Thus, there may be a need for longer duration of alcohol application.

LASEK AFTER LASIK PRK has been used after laser in situ keratomileusis (LASIK) in the treatment of extremely high myopia either simultaneously (3) or as a two-stage procedure (4). Guell et al. (5) reported the use of intraepithelial PRK, in which a photoablation was performed directly in the epithelium, without damage to Bowman’s membrane, to treat regression after LASIK. Eight of the 21 eyes (38%) were emmetropic at 6 months and 11 (52.4%) had a refraction between −0.50 and +0.50 diopters (D). Refraction was stable from the second week to the first year, with no significant differences among the mean standard errors (SEs) at 10 days, 6 weeks, 6 months, and 12 months. As a treatment of incomplete LASIK flaps, Bond et al. suggested performing 180 to 220 phototherapeutic keratectomy (PTK) pulses, then proceeding with PRK as if the flap had never been created (6,7). It is observed that haze formation is significantly greater in PRK after LASIK compared to that seen in primary PRK (8,9). This higher risk of haze may be the result of laser impact on the Bowman’s layer of a previously ablated cornea. LASEK may be considered when a surgeon contemplates a retreatment of residual refractive errors in patients with high myopia who have thin corneas to allow for sufficient stromal bed thickness. In theory, LASEK should offer comparable visual outcomes to those of PRK after LASIK.

LASEK AFTER RK It has been reported that the need for retreatment after radial keratotomy (RK) ranges from 30% to 33% of cases (10). The Perspective Evaluation of Radial Keratotomy (PERK) study (11) reported that after 10 years of treatment, 25% to 30% of patients who underwent RK had hyperopia. PERK also revealed that as many as 43% of post-RK patients had hyperopic shift of 1 D or more. Furthermore, the same study reported that 17% of eyes had a residual myopia of greater than 1 D. LASIK has been used to treat residual myopia and astigmatism, as well as hyperopic shift after RK (12–15). There is a theoretical risk associated with applying suction to post-RK cornea. However, it has been shown that the use of suction is relatively safe in these eyes (16). One of the challenges of performing LASIK in an eye that had RK is the “pizza slice” effect. This complication occurs when the incisions extend inside the 8 to 9 mm of the central cornea. After the microkeratome cut, the flap separates into triangular shape as a result of inadequate healing of the RK incision. Even seemingly well-healed incisions may contain epithelial plugs on close inspection by slit-lamp examination. These epithelial plugs within RK incisions can lead to epithelial in-growth and precipitate

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“pizza slice” effect. Other complications include epithelial in-growth, interface wrinkling, central-island flap tear or dislocation, and infection. Surface ablation procedure such as LASEK is an excellent alternative to avoid pizza slice effect after RK. The epithelial flap can still be easily manipulated to cover the stroma, should the pizza slicing effect occurs. The bandage contact lens provides added stability to the flap. In a large multicenter retrospective study of PRK after RK, Azar et al. (17) found that patients with lower original and residual myopia (6 D or less) achieved better visual outcomes after PRK than did those with higher myopia. The amount of myopic correction achieved using RK was not predictive of the amount of myopic correction using PRK. Several studies have demonstrated lower predictability of the refractive outcomes in patients who underwent PRK after RK compared to those with no previous surgery (18– 23). It remains to be seen if LASEK after RK will lead to a more optimal wound-healing response and enhance the postoperative predictability. Yong et al. reported a five-fold to 10-fold increase in haze formation after performing PRK after RK. Because several reports have suggested that LASEK resulted in less haze than PRK (2,24,25), it is not unreasonable to extrapolate that LASEK may also lead to less haze formation after RK. However, an adjunctive use of mitomycin C may be considered in the case of high residual refractive error.

LASEK AFTER INTRAOCULAR SURGERY Astigmatism is often induced after scleral buckling surgery, trabeculectomy, extracapsular cataract extraction, and penetrating keratoplasty. Despite the advances in intraocular surgical techniques, many patients still have to endure suboptimal vision, compared to their visual potential, because of corneal irregularities (26,27). A myriad of factors exert influences on postoperative refractive error and astigmatism. In penetrating keratoplasty, the antemortem corneal curvature of the donor, trephination, graft sizing, and suturing techniques have profound effects on the final result. The possibility of using refractive surgery to eliminating postoperative astigmatism after intraocular surgery has profound implications. The popularity of refractive surgery has raised the patients’ expectation regarding the optical result of their surgery. In elderly patients, the contact lens alternative is often not accepted because the patient may not be able to tolerate a contact lens. LASIK have been performed after penetrating keratoplasty (PK) and other intraocular surgical procedures (28–33). The optimal time to perform refractive surgery is still debatable. To ensure postoperative stability, it is important to delay the refractive surgery as much as possible after the intraocular procedure. The presence of a good wound scar and the stable refraction and topography for at least 3 months after vitrectomy, scleral buckling, extracapsular cataract extraction (ECCE), and keratoplasty may be necessary before LASIK surgery (29). Most of the LASIK complications after intraocular surgery occur during dissection of the flap. The high intraocular pressure exerted during the application of the suction ring may lead to wound dehiscence. In patients with steep corneas after PK, the risks of flap

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complications (such as incomplete flap, buttonhole, or free flap) are increased after LASIK. PRK has been used to treat myopia and astigmatism after intraocular surgery (34–39). Complications from PRK after PK include regression (34,37) and haze (34,37,38). There were two single case reports of graft rejection associated with surface ablation using excimer laser. One case was an endothelial rejection diagnosed 2 weeks after PRK for recurrent lattice corneal dystrophy 6 years after the original PK (40). Another case involved endothelial rejection occurring 5 days after using excimer laser for treatment of myopia and astigmatism in a 3-year-old graft (41). In both cases, the rejections were successfully reversed without loss of corneal clarity by prompt treatments with corticosteroid. It was unclear whether the rejections were precipitated by the excimer laser, soft contact lens placement, epithelial ablation, or changes in the patient’s medical regimen (40). Stulting et al. (42) prospectively investigated the effect of excimer laser PRK for myopia on the corneal endothelium in 142 eyes. They concluded that for the correction of up to 6.0 D of myopia, PRK does not cause detectable changes in central corneal endothelial cell density, but it does cause a transient, modest loss of peripheral corneal endothelial cells at 1 year. Central endothelial cell density remained stable at any of the postoperative examinations. The peripheral cell density decreased 4.1% (P=0.003) at 3 months and 6.2% (P=0.0001) at 1 year. However, the peripheral cell density was not significantly different from the preoperative value at 2 years. The decrease in peripheral endothelial cell density at 1 year correlated with the amount of attempted correction, but there was no correlation between attempted correction and the change in central or peripheral endothelial cell density 2 years postoperatively. There is a theoretical risk of damaging or loss of endothelial cells as a consequence of elevated intraocular pressure. LASEK avoids the potential endothelial damages from raised intraocular pressure during the flap cutting. Because LASEK does not require cutting of the flap, it eliminates most of the risks of performing refractive surgery after PK. Despite potential beneficial wound healing response in LASEK, there is still a risk of postoperative haze, especially in treatment of high refractive errors. It is also important to realize that the goal of refractive surgery after PK is not necessary to obtain good uncorrected visual acuity by eliminating most of the refractive errors but to lessen the amount of astigmatism and anisometropia.

REFERENCES 1. Chen CC, Chang JH, Lee JB, Javier J, Azar DT. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci; 2002; 43:2593–2602. 2. Dastjerdi MH, Soong HK. LASEK (laser subepithelial keratomileusis). Curr Opin Ophthalmol; 2002; 13:261–263. 3. Astudillo IM, Ortiz CI. Combined laser in situ keratomileusis and photorefractive keratectomy for extreme myopia. J Refract Surg; 1999; 15:58–60. 4. Pallikaris IG, Siganos DS. Excimer laser in situ keratomileusis and photorefractive keratectomy for correction of high myopia. J Refract Corneal Surg; 1994; 10:498–510. 5. Guell JL, Lohmann CP, Malecaze FA. Intraepithelial photorefractive keratectomy for regression after laser in situ keratomileusis. J Cataract Refract Surg; 1999; 25:670–674.

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6. Bond WI. PRK over incomplete LASIK flap. J Refract Surg; 2000; 16: 483. 7. Jain VK, Abell TG, Bond WI, Stevens G, Jr. Immediate transepithelial photorefractive keratectomy for treatment of laser in situ keratomileusis flap complications. J Refract Surg; 2002; 18:109–112. 8. Buratto L, Brint SF, Ferrari M. Complications Buratto L, Brint SF, Eds. LASIK Principles and Techniques. Thorofare. NJ: SLACK;, 1998:113–132. 9. Probst LE, Machat JJ. LASIK enhancement techniques and results Buratto L , Brint SF, Eds. LASIK Principles and Techniques. Thorofare. NJ: SLACK;, 1998:358–360. 10. Gayton JL, Van der Karr M, Sanders V. Radial keratotomy enhancements for residual myopia. J Refract Surg; 1997; 13:374–381. 11. Waring GO, 3rd, Lynn MJ, McDonnell PJ. Results of the prospective evaluation of radial keratotomy (PERK) study 10 years after surgery. Arch Ophthalmol; 1994; 112:1298–1308. 12. Yong L, Chen G, Li W. Laser in situ keratomileusis enhancement after radial keratotomy. J Refract Surg; 2000; 16:187–190. 13. Forseto AS, Nose RA, Francesconi CM, Nose W. Laser in situ keratomileusis for undercorrection after radial keratotomy. J Refract Surg; 1999; 15:424–428. 14. Gimbel HV, Sun R, Chin PK, van Westenbrugge J. Excimer laser photorefractive keratectomy for residual myopia after radial keratotomy. Can J Ophthalmol; 1997; 32:25–30. 15. Gimbel HD. Photorefractive keratectomy and laser in situ keratomileusis hyperopic correction of overcorrected radial keratotomy. J Refract Surg; 1998; 14:205–206. 16. Guell JL, Gris O, de Muller A, Corcostegui B. LASIK for the correction of residual refractive errors from previous surgical procedures. Ophthalmic Surg Lasers; 1999; 30:341–349. 17. Azar DT, Tuli S, Benson RA, Hardten DR. Photorefractive keratectomy for residual myopia after radial keratotomy. PRK after RK Study Group. J Cataract Refract Surg; 1998; 24: 303– 311. 18. McDonnell PJ, Garbus JJ, Salz JJ. Excimer laser myopic photorefractive keratectomy after undercorrected radial keratotomy. Refract Corneal Surg; 1991; 7:146–150. 19. Hahn TW, Kim JH, Lee YC. Excimer laser photorefractive keratectomy to correct residual myopia after radial keratotomy. Refract Corneal Surg; 1993; 9:S25–S29. 20. Durrie DS, Schumer DJ, Cavanaugh TB. Photorefractive keratectomy for residual myopia after previous refractive keratotomy. J Refract Corneal Surg; 1994; 10:S235–S238. 21. Meza J, Perez-Santonja JJ, Moreno E, Zato MA. Photorefractive keratectomy after radial keratotomy. J Cataract Refract Surg; 1994; 20:485–489. 22. Ribeiro JC, McDonald MB, Lemos MM. Excimer laser photorefractive keratectomy after radial keratotomy. J Refract Surg; 1995; 11:165–169. 23. Maloney RK, Chan WK, Steinert R, Hersh P, O’Connell M. A multicenter trial of photorefractive keratectomy for residual myopia after previous ocular surgery. Summit Therapeutic Refractive Study Group. Ophthalmology; 1995; 102:1042–1053. 24. Lee JB, Seong GJ, Lee JH. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27:565–570. 25. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy for myopia: two-year follow-up (1). J Cataract Refract Surg; 2003; 29:661–668. 26. Reign CS, Speaker MG. Postkeratoplasty astigmatism Krachmer JH, Mannis MJ, Holland EJ, Eds. Cornea: Surgery of Cornea and Conjunctiva. St. Louis: Mosby;, 1997:1675–1686. 27. Kirkness CM, Ficker LA, Steele AD, Rice NS. Refractive surgery for graft-induced astigmatism after penetrating keratoplasty for keratoconus. Ophthalmology; 1991; 98:1786– 1792. 28. Donnenfeld ED, Kornstein HS, Amin A. Laser in situ keratomileusis for correction of myopia and astigmatism after penetrating keratoplasty. Ophthalmology; 1999; 106:1966–1975. 29. Forseto AS, Francesconi CM, Nose RA, Nose W. Laser in situ keratomileusis to correct refractive errors after keratoplasty. J Cataract Refract Surg; 1999; 25:479–485.

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30. Webber SK, Lawless MA, Sutton GL, Rogers CM. LASIK for post penetrating keratoplasty astigmatism and myopia. Br J Ophthalmol; 1999; 83:1013–1018. 31. Arenas E, Maglione A. Laser in situ keratomileusis for astigmatism and myopia after penetrating keratoplasty. J Refract Surg; 1997; 13:27–32. 32. Parisi A, Salchow DJ, Zirm ME, Stieldorf C. Laser in situ keratomileusis after automated lamellar keratoplasty and penetrating keratoplasty. J Cataract Refract Surg; 1997; 23: 1114– 1118. 33. Koay PY, McGhee CN, Weed KH, Craig JP. Laser in situ keratomileusis for ametropia after penetrating keratoplasty. J Refract Surg; 2000; 16:140–147. 34. John ME, Martines E, Cvintal T. Photorefractive keratectomy following penetrating keratoplasty. J Refract Corneal Surg; 1994; 10:8206–8210. 35. Campos M, Hertzog L, Garbus J, Lee M, McDonnell PJ. Photorefractive keratectomy for severe postkeratoplasty astigmatism. Am J Ophthalmol; 1992; 114:429–436. 36. Nordan LT, Binder PS, Kassar BS, Heitzmann J. Photorefractive keratectomy to treat myopia and astigmatism after radial keratotomy and penetrating keratoplasty. J Cataract Refract Surg; 1995; 21:268–273. 37. Tuunanen TH, Ruusuvaara PJ, Uusitalo RJ, Tervo TM. Photoastigmatic keratectomy for correction of astigmatism in corneal grafts. Cornea; 1997; 16:48–53. 38. Lazzaro DR, Haight DH, Belmont SC. Excimer laser keratectomy for astigmatism occurring after penetrating keratoplasty. Ophthalmology; 1996; 103:458–464. 39. Amm M, Duncker GI, Schroder E. Excimer laser correction of high astigmatism after keratoplasty. J Cataract Refract Surg; 1996; 22:313–317. 40. Hersh PS, Jordan AJ, Mayers M. Corneal graft rejection episode after excimer laser phototherapeutic keratectomy. Arch Ophthalmol; 1993; 111:735–736. 41. Epstein RJ, Robin JB. Corneal graft rejection episode after excimer laser phototherapeutic keratectomy. Arch Ophthalmol; 1994; 112:157. 42. Stulting RD, Thompson KP, Waring GO, 3rd, Lynn M. The effect of photorefractive keratectomy on the corneal endothelium. Ophthalmology; 1996; 103:1357–1365. 43. Kent DG, Solomon KD, Peng Q. Effect of surface photorefractive keratectomy and laser in situ keratomileusis on the corneal endothelium. J Cataract Refract Surg; 1997; 23:386–397. 44. Perez-Santonja JJ, Sakla HF, Gobbi F, Alio JL. Corneal endothelial changes after laser in situ keratomileusis. J Cataract Refract Surg; 1997; 23:177–183. 45. Perez-Santonja JJ, Sahla HF, Alio JL. Evaluation of endothelial cell changes 1 year after excimer laser in situ keratomileusis. Arch Ophthalmol; 1997; 115:841–846. 46. Bourne WM, Hodge DO, Nelson LR. Corneal endothelium five years after transplantation. Am J Ophthalmol; 1994; 118:185–196.

30 LASEK After Penetrating Keratoplasty Steven B.Yee, MD, Ning Lin, MD, OD, Corey B.Westerfeld, MD, and Richard W.Yee, MD Hermann Eye Center, University of Texas Health Science Center at Houston Houston, TX

LASEK IN THE PATIENT AFTER PENETRATING KERATOPLASTY As microsurgical techniques have improved, penetrating keratoplasty (PKP) has become more commonly performed with a higher probability of success. In the United States alone, more than 40,000 PKPs are performed annually (1). Anisometropia remains a challenging problem in the patient after PKP and the rehabilitation of this has changed little. The majority of patients are unable to tolerate more than 3 diopters (D) (sphere) of anisometropia because of the resulting aniseikonia (2,3). An astigmatism of 1.5 to 3 D is likewise poorly tolerated (2,3). Anisometropia may result in ocular burning, tearing, blurry vision, photophobia, diplopia, and headache. Many of the patients who cannot achieve adequate rehabilitation with spectacles can do so with contact lenses. Ten percent to 30% of patients wear contact lenses after PKP (4). Both soft and rigid gas-permeable contact lenses can be effective for visual rehabilitation after PKP (5). However, there remains a significant percentage of PKP patients (10%–20%) who cannot achieve adequate rehabilitation with spectacles or contact lenses (5). Anisometropia aside, there are numerous concerns related to contact lens wear that can be problematic for patient status after PKP. They include topographical abnormalities resulting from the PKP wound, dry eyes, blepharitis, lid abnormalities, corneal neovascularization, occupational/environmental factors (wind, dust, smoke, chemical fumes, etc.), patient limitations (e.g., poor manual dexterity), and poor patient compliance. In the past, various forms of refractive surgery have been attempted on cornea transplantation patients. Radial keratotomy (RK) in post-PKP patients has been fraught with problems, namely refractive instability, glare, haloes, increased risk of traumatic ruptured globe, and progressive hyperopia (6). Photorefractive keratectomy (PRK) in post-PKP patients has been associated with increased incidence of irregular astigmatism and corneal scarring (5). Laser in situ keratomileusis (LASIK) has been performed in post-PKP patients, also, and has shown better results than with RK and PRK. These advantages include rapid visual rehabilitation, less irregular astigmatism, less regression, and the ability to correct a greater range of refractive errors (7,8). However, even the proponents of LASIK have conceded that LASIK itself can induce irregular astigmatism.

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Furthermore, there remain the risks associated with the creation of the lamellar flap. Buttonholes, partial flaps, thin/irregular flaps, and free flaps may occur (7–11). Laser epithelial keratectomy (LASEK) offers the exciting possibility of visual rehabilitation in the post-PKP patient who has not had satisfactory rehabilitation with spectacles or contact lenses. Unlike LASIK, LASEK avoids flap creation and, thus, the problems associated with a flap. Compared to PRK, retaining the epithelium, as is performed in LASEK, would theoretically promote better healing and less postoperative haze (loss of corneal opacity).

OUR EXPERIENCE We followed-up two patients with a previous PKP who underwent LASEK for myopia and astigmatism. Patient 1 was a 59-year-old woman with a history of Fuchs endothelial dystrophy (with corneal decompensation). She has undergone the following operations: PKP right eye (OD) 1993, PKP left eye (OS) 1996, actinic keratosis (AK) OD 1994, AK OS 1998, and phacoemulsification with posterior chamber intraocular lens (PCIOL) OD 1994. Before LASEK, her manifest refraction was +1.25+3.00×043 (OD), and −10.25+4.25×175 (OS). She found her anisometropia to be extremely troubling; she reported constant blurry vision. She was unable to tolerate a contact lens in her left eye; her steep K reading (OS) was 52.59 at axis 164. She underwent LASEK OS using the Alcon Autonomous LADARVision 4000 Excimer Laser. Preoperative medications were ketorolac tromethamine ophthalmic solution (Acular) 0.5% one drop (gtt) OS four times daily and ofloxacin 0.3% one gtt OS four times daily both for 3 days before LASEK. Postoperative medications were ofloxacin 0.3% one gtt OS four times daily for 7 days, fluorometholone 0.1% 1 gtt OS four times daily for 7 days, autologous serum solution 1 gtt OS every 30 minutes for 4 days, then every 1 hour for 7 days, then four times daily. Ketorolac tromethamine (Acular) 0.5% 1 gtt OS four times daily was resumed 3 weeks after LASEK as treatment of overcorrection. Post-LASEK use of ketorolac tromethamine is reserved for overcorrection. Patient 2 was a 16-year-old boy with a history of keratoconus of his right eye. He underwent PKP OD. After PKP OD and before LASEK, his manifest refraction was −5.00, +4.00, ×145 (OD), and Plano +0.25 and ×080 (OS). The patient was unable to tolerate a contact lens in his right eye. He underwent LASEK OD 6 months after PKP. LASEK was performed using the Alcon Autonomous LADARVision 4000 Excimer Laser. Preoperative medications were ketorolac tromethamine ophthalmic solution (Acular) 0.5% 1 gtt OS four times daily for 3 days before LASEK. Postoperative medications were ofloxacin 0.3% 1 gtt OD four times daily for 7 days, fluorometholone 0.1% 1 gtt OD four times daily for 7 days, then twice daily for 7 days, autologous serum solution 1 gtt OD every 30 minutes for 4 days, then every 1 hour for 7 days, then every 2 hours for 3 days, then four times daily. Prednisolone (Pred Forte) 1% 1 gtt OD four times daily was begun 1 month after LASEK as therapy for “undercorrection” (residual myopia). After a standard preparation and drape, the cornea was marked at the 6 o’clock position. Using a LASEK trephine (60-to 80-—m trephine), epithelial micro-trephination

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was performed, leaving a hinge of approximately 60 degrees to 80 degrees at the 12 o’clock position (Fig. 1). A LASEK alcohol well was then placed on the eye and filled with a 20% ethanol solution for 40 seconds (Fig. 2). The ethanol solution was then blotted with a dry Weck sponge and rinsed with balanced salt solution (BSS). The epithelium was then detached using an epithelial hoe (Fig. 3). The epithelium was peeled back resulting in

Figure 1 Epithelial trephination.

Figure 2 Instillation of 20% alcohol

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Figure 3 Epithelial detachment.

Figure 4 Recession of the epithelial flap. a hinge at the 12 o’clock position (Fig. 4). After laser ablation by small spot-tracking laser (Fig. 5), mitomycin-C (0.05%) was applied to the stroma and left in place for 90 seconds before being rinsed with BSS (Fig. 6). The epithelium was then replaced with a spatula (Fig. 7). A soft bandage contact lens was applied. The soft bandage contact lens was removed in the clinic using jeweler’s forceps on post-LASEK day 4. Patient 1 had preoperative manifest refractions of +1.25, +3.00, ×043 (OD), and −10.25, +4.25, ×175 (OS). Preoperative BCVA was 20/20 in both eyes. LASEK was

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performed on her left eye, and the sphere was reduced to −2.50 D at 12 months after LASEK. Her spherical equivalent was reduced from –8.13 D preoperatively to +3.25 D at 3 weeks after LASEK, +1.12 D at 4 weeks after LASEK, −0.75 D at 3 months after LASEK, and −2.00 D at 12 months after LASEK. The cylinder before the surgery was +4.25 D, and at 5 months after LASEK it was +1.00 D. Topography revealed a preLASEK color unit (CU) index of 50% (Fig. 8) and a post-LASEK CU index of 20% (Fig. 9). At 3 months after LASEK, the CU index was 50%, and at 5 months after LASEK,

Figure 5 Small spot excimer treatment.

Figure 6 Mitomycin-C (0.05%) administration the CU index was 50%. The slit-lamp examination on post-LASEK day 5 revealed a central epithelial defect (OS). A soft bandage contact lens was placed, and 3 days later, the defect had healed completely. The slit-lamp examinations postoperatively revealed a clear cornea, completely free of haze. Her spherical equivalent anisometropia was

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reduced from 11.88 D to 4.75 D. Her BCVA in the postoperative eye was 20/20 at 12 months postoperatively (uncorrected visual acuity was 20/80). (Figs. 8 and 9) Patient 2 had preoperative manifest refractions of −5.00, +4.00, and ×145 (OD), and Plano +0.25 and ×080 (OS). Preoperative BCVA was 20/20 OD and 20/30 OS. LASEK was performed on his right eye, and the sphere was reduced to −0.75 D at 9 months after LASEK. His spherical equivalent was reduced from −3.00 D preoperatively to −0.38 D at 4 weeks after LASEK and −0.25 D at 9 months after LASEK. The cylinder before the surgery was +4.00 and at 1 month after LASEK was +0.75. At 9 months after LASEK, the cylinder was +1.00. Topography revealed a pre-LASEK CU index of 40% (Fig. 10) and a post-LASEK CU index of 60% (Fig. 11). The CU index at 3 months after LASEK was 90%. The slit-lamp examination on post-LASEK day 4 revealed no epithelial defects (OD). However, the right eye was somewhat red, and the patient reported light sensitivity. His medications were continued, and on post-LASEK day 6, the patient’s symptoms had abated. The slit-lamp examination at 1 week found the cornea to be clear and free of haze. The slit-lamp examinations at 1 month and 3 months revealed trace corneal haze. His BCVA in the postoperative eye was 20/20 at 9 months postoperatively (uncorrected visual acuity [UCVA] was 20/25). (Figs. 10 and 11)

Figure 7 Repositioning epithelial flap

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Figure 8 Patient 1. Preoperative topography showing astigmatism: +2.57 D, axis 167.

Figure 9 Patient 1. Postoperative (2 months) topography showing astigmatism: +0.92 D, axis 85.

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Figure 10 Patient 2. Preoperative topography showing astigmatism: +3.42 D, axis 138.

Figure 11 Patient 2. Postoperative (1 month) topography showing astigmatism: +1.29 D, axis 93. BCVA remained within two lines of preoperative visual acuity in both patients. At the last follow-up visit, the mean sphere was reduced by 6.0 D (78%), and the mean cylinder

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was reduced by 3.12 D (76%) from the preoperative values. The mean spherical equivalent was reduced by 4.44 D (80%) from preoperative values. The complications related to LASEK surgery included a central epithelial defect in patient 1 and trace cornea haze in patient 2. However, both complications resolved satisfactorily. No graft rejection was associated with LASEK. No other intra-operative or postoperative complications were observed.

CONCLUSION We demonstrated that LASEK can be safely performed in post-PKP patients to reduce significant anisometropia and myopia. One of our patients demonstrated more irregular astigmatism at the center of the cornea at 2 months after LASEK than preoperatively. However, at 3 and 4 months after LASEK, additional time and healing resulted in an improvement in the patient’s irregular astigmatism. LASEK did decrease the amount of anisometropia in both post-PKP patients. Both patients were extremely pleased with the reduction in the amount of anisometropia that LASEK afforded them. Our hope is that in the future, more patients who are post-PKP, anisometropic, and unable to tolerate contact lenses will be able to benefit from LASEK on several counts: (1) reduction of anisometropia; (2) reduction of astigmatism; and (3) avoid the potential complications involving flap creation by a microkeratome (as in the case of LASIK). LASEK coupled with wavefront-guided or custom cornea ablation may provide even better outcomes.

REFERENCES 1. Statistical Report, Eye Bank Association of America. Washington. DC, 1993. 2. Brooks SE, Johnson D, Fischer N. Anisometropia and binocularity. Ophthalmology; 1996; 103:1139–1143. 3. Rubin ML. Anisometropia Faunfelder FT, Hampton RF, Grove J, Eds. Current Ocular Therapy 4. Philadelphia: Saunders, 1995:757–758. 4. Donnenfeld ED, Kornstein HS. LASIK for correction of myopia and astigmatism after penetrating keratoplasty. Ophthalmology; 1999; 106(10):1966–1975. 5. Lopatynsky MO, Cohen EJ. Post-keratoplasty fitting for visual rehabilitation Kastl PR, Ed. Contact Lenses: The CLAO Guide to Basic Science and Clinical Practice. Dubuque. Iowa: Kendal/Hunt Publishing Co., 1995:79–90. 6. Waring GO III, Lynn MJ, Gelender H. Results of the Prospective Evaluation of Radial Keratotomy (PERK) Study one year after surgery. Ophthalmology; 1985; 92:177–198, 307. 7. Pallikaris IG, Papatzanski ME, Stathi EZ. Laser in situ keratomileusis. Lasers Surg Med; 1990; 10:463–468. 8. Azar DT, Farah SG. Laser in situ keratomileusis versus photorefractive keratectomy. An update on indications and safety. Ophthalmology; 1998; 105:1357–1358. 9. Malecha MA, Holland EJ. Correction of Myopia and Astigmatism after Penetrating Keratoplasty with Laser in Situ Keratomileusis. Cornea; 2002; 21(6):564–569. 10. da Lima GS, Moreira H, Wahab S A. Laser in situ keratomileusis to correct myopia, hypermetropia and astigmatism after penetrating keratoplasty for keratoconus: a series of 27 cases. Can J Ophthalmol; 2001; 36(7):391–397.

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11. Kwitko S, Marinho DR, Rymer S, Ramos Filho S. Laser in situ keratomileusis after penetrating keratoplasty. J Cataract Refract Surg; 2001; 27(3):374–379.

Index Page numbers followed by f indicate figures. Those followed by t indicate tables.

Aberrometry ingoing adjustable, 215–217 outgoing wavefront, 211–215 retinal image, 218 Acremonium astrogriseum, treatment of, 124 Adhesion complex, basement membrane, role of, 247 Advanced laser surgery ablation, hydrodissection/viscodissection, 89−109 alcohol application, 97–98, 98f Azar-Camellin LASEK I & A trephine, 90 bladeless microkeratome flap retraction technique, 103–106 Burrato LASIK cannula, 96f Camellin LASEK technique, 92 cannula, 65, 94–97, 94f epithelial flap manipulation, 100–101 epithelial sanctity, 101–102 fluidic dissection, 97 GenTeal barrier, 102, 103f GenTeal viscodissection, 92f Guell LASIK cannula, 96f haze prevention, 102–103 hydroviscodissection mediae, 91–93 hydroviscodissection technique, 93–94 loosening epithelium, 97 McDonald McLasek cannula, 95f Melki M-LASEK alcohol well, 98f Merocel sponge, 98f, 103f mitomycin C, 102–103 contained within GenTeal barrier, 103f Rashid, 65, 94f Seibel LASIK cannula, 95f Slade LASIK cannula, 93f “wow” phenomena, 89 Advanced stromal ablation, future of, 269–270 Advantages of LASEK over PRK, LASIK, 3–8 Aerobics, eye trauma in, 26 Aesthesiometry, corneal, 38 Alcohol, surface ablation without. See Epi LASIK Alcohol absorption, 59f Alcohol-assisted epithelial flap reattached over PRK, 2

Index

382

Alcohol circulation, 58–59 Alcohol leakage, during surgery, 186 Alcohol solution cone, Janach, 55 Alcohol well, 55–57, 84f, 98f Janach, 56–57, 76ƒ, 84f Melki M-LASEK, 98f Shahinian, 55 Alcon LADARWave, 213 ALSA. See Advanced laser surgery ablation Aminoglycoside, organisms not covered by, 124t Amniotic membrane, 289–290 Asclepion MEL-80, 213 ASICO AE-2918. See Azar-Carones LASEK I & A trephine Aspergillus flavus, treatment of, 124 Autologous serum, for haze reduction, after LASEK, 307–315 Automated refractors, 36 Azar-Camellin LASEK I & A trephine, 90 Azar-Carones LASEK I & A trephine, 55, 56, 56f Azar LASEK scissor, flap elevation by, 62f Azar LASEK technique, 2, 3, 48f, 83, 317–322 Basement membrane, integrity of, 259 Basketball, eye trauma in, 26 Bausch & Lomb Technolas Planoscan, 213 Bausch & Lomb Zywave, 213 Bichromatic refraction test, 36–37 Bichromatic test, 36–37 Binocular balancing, 37 Biomicroscopic examination, 38 Bladeless microkeratome flap retraction technique, 103–106 Bow dissector, 79f Burrato LASIK cannula, 96f Butterfly LASEK, Vinciguerra technique, 2–3, 83–87, 85f Cadaver bovine corneas, excimer laser application on, 2 Camellin LASEK technique, 2, 3, 63, 73–82, 92, 127 alcohol solution, 73–75 bow dissector, medium adherent epithelium, 79f dragging epithelium, 78f edge detachment, 75–77 epithelial precut, 73 flap re-positioning, 79 flap sliding, 78–79 Johnston applanator, 81f lens removal, 79 microhoe, for detaching epithelium, 77f microtrephine, 74f rotation, 75f PRK, 79 well, for containing alcohol solution, 75, 76f Cannulas, 65, 94–97, 94f

Index

383

Burrato, 96 Guell, 96 LASIK, Slade, 93 McDonald, 95 Rashid, 65, 94f Seibel, 95 Carones LASEK pump, 55, 56 OZ chambers, 55, 56, 56f Carones LASEK spatula, 61f Centration, pupil, 28 Colvard pupillometer, 40f Combining of elements of PRK, LASIK, in LASEK, 1 Compact placido-based corneal topographical unit, 42f Complications of LASEK, 6, 13, 161–163, 183–192, 188f–191f, 195–203, 196–199f, 202f, 298–299 corneal haze, 190–191 corticosteroid-induced elevated intraocular pressure, 191 decentration, 192 glare/halos, 191–192 infections, 188 infiltrates, 188 laser-related complications, 190, 191–192 overcorrection, 190 undercorrection, 190 wound healing-related complications, 190–191 Complications of LASIK, 6, 13, 161–163, 183–193, 195–203, 298–299 Complications of PRK, 6, 13, 161–163, 183–203, 298–299 Cone, alcohol solution, Janach, 55 Conjunctiva, infection of, as contraindication for LASEK, 22 Consent to procedure, by patient, informed, 44 Contact lens application, 69–70 complications, 125t intolerance, 187–188 removal, 126 Contraindications to LASIK, 6, 22 Contraindications to PRK, 6 Contrast sensitivity, 43–44 Cornea aesthesiometry, 38 curvatures, 27–28 diameters, small, 28 infection of, as contraindication for LASEK, 22 thickness, 27 tissue integrity, 27 wound healing cascade, 284f Corneal basement membrane, molecular biology of, 253–256 Corneal epithelium. See Epithelium Corneal haze. See Haze Corneal topography, 41–43 methods of measuring, 41 Corticosteroid-induced elevated intraocular pressure, 191 Cross-cylinder refraction, Jackson, 36

Index

384

Cruciform LASEK, 87 Curvatures, corneal, 27–28 Curvularis organisms, treatment of, 124 Custom ablation disadvantages of, 232–233 healing variables, 232–233 stromal biomechanics poorly understood, 232 preliminary data-LASEK higher-order aberrations, 233 wavefront measurement, 225–230, 230–232 customized ablation, 229–230 flap biomechanics, 230–231 LASIK vs. PKR, 231–232 progression of technology, 225 topographic diagnostics, 229 wavefront diagnostics, 225–229 CustomCornea wavefront-guided PRK, 230f Customized corneal ablation, 2 Cycloplegia, 35 Cylindrical correction, refinement of, 37 Deposits on contact lens, 125 Desmosome, 256–257 Development of LASEK, history of, 1–3 Diameters, corneal, small, 28 Dry eye, 22, 28–29, 189 with contact lens, 125 PRK, LASIK compared, 6 Duochrome refraction test, 36–37 Duochrome test, 36–37 Dynamic skioloscopy, wavefront sensor principles, 217f schematic diagram, 217f Elements of PRK, LASIK, combining of, in LASEK, 1 Elevation-based topographical unit, 42f Elevation of flap drying time, 69 electron microscopy, 66–67, 67 epithelial sheets, electron microscopic analyses, 167 instrumentation, 69 irrigation, 67–69 reapproximation, 67–69 Enhancements, LASEK, 133–135 Enterovirus, treatment of, 124 Epi LASEK, 3 Epi LASIK, 115–121 Epithelial abrasion, after lens removal, 125 Epithelial cell viability in LASEK, 2 Epithelial defect management, postoperative, 126–127 Epithelial dehiscence, reattachment, after LASEK, 253–262 Epithelial flap. See also Epithelium

Index

385

edge revelation, 60f generation of, 64f hydrodissection/viscodissection, 89–109, 97–98, 98f inflammation of, 247 Epithelial ingrowth, 21 Epithelium obtaining sheets of, 2 technique for obtaining sheets of, 2 ETDRS visual acuity chart, 34f Ethanol, preparation of, 51 Excimer Laser Delivery System, 213 External eye examination, 37 Eye examination, pre-procedure, 37 Firefighters, eye trauma in, 26 First LASEK procedure, performance of, 1 Fixation ring, globe, 56, 57, 57f Flap breaks, 197 Flap elevation, 59–70 alternative techniques, 63–65 Azar LASEK technique, 60–63 drying time, 69 electron microscopy, 66–67, 67 epithelial sheets, electron microscopic analyses, 167 instrumentation, 69 irrigation, 67–69 LASEK spatulas, 59–60 reapproximation, 67–69 Flap hydrodissection, 89–109 Flap loss, 196 Flap marking, 49–50 chemical agents, for epithelial removal, 51 epithelial survival, after alcohol application, 51–55 instruments used, 49 Fluorescein viability stain, 52f Fluoroquinolone, organisms not covered by, 124t Foreign body sensation, 202 Functional vision recovery, PRK, LASIK compared, 6 Fundus examination, 38–39 Fungus treatment, 124 Fusarium solani, treatment of, 124 Future of LASEK, 263–271 Gap junctions, 257 Gel-assisted LASEK, 2, 65, 111–112, 111–121. See also McDonald LASEK technique GenTeal gel barrier, 102, 103f GenTeal viscodissection, 92f Glare, 140–141, 146–147, 191–192 Globe fixation ring, 56, 57, 57f Golf, eye trauma in, 26

Index

386

Gram-negative organisms, 124 Guell LASIK cannula, 96f Halos, 140–141, 146–147, 191–192 Hartmann-Shack aberrometer, 212f Hartmann-Shack wavefront sensing, 2, 213t Haze, 2, 20, 102–103, 140, 146, 190–191, 201–202, 264–270, 269f, 273–295, 307–315 Hemidesmosomes-anchoring fibrils adhesion complex, 253–255 Herpes simplex, treatment of, 124 Herpes zoster ophthalmicus, as contraindication of LASEK, 22 High myopia, LASEK in, glare, 140–141, 146–147 History of development of LASEK, 1–3 Hydrodissection alcohol application, 97–98, 98f Azar-Camellin LASEK I & A trephine, 90 bladeless microkeratome flap retraction technique, 103–106 Burrato LASIK cannula, 96f Camellin LASEK technique, 92 cannula, 65, 94–97, 94f epithelial flap manipulation, 100–101 epithelial sanctity, 101–102 fluidic dissection, 97 GenTeal barrier, 102, 103f GenTeal viscodissection, 92f Guell LASIK cannula, 96f haze prevention 102–103 hydroviscodissection mediae, 91–93 hydroviscodissection technique, 93–94 loosening epithelium, 97 McDonald McLasek cannula, 95f mediae, 91–93 Melki M-LASEK alcohol well, 98f Merocel sponge, 98f, 103f mitomycin C, 102–103, 103f Rashid, 65, 94f Seibel LASIK cannula, 95f Slade LASIK cannula, 93f technique, 93–94 viscodissection and, 2, 89–109 “wow” phenomena, 89 Hypoxic edema, with contact lens, 125 Incomplete epithelial detachment, 186–187 Indications for LASEK, 19–21 Infection, 188, 197–198. See also under specific infectious organism of conjunctiva, cornia, as contraindication for LASEK, 22 minimizing risk of, 26 prophylaxis, 128–129 Infectious keratitis, with contact lenses, 125 Infiltrates, 188

Index

387

Informed consent, 44 Ingoing adjustable aberrometry, 215–217 Intact corneal epithelium, technique for obtaining sheets of, 2 Integrins, focal contacts and, 256 Integrity of tissue, corneal, quality, 27 Intercellular junctions, in epithelium, 256 Intraocular pressure, corticosteroid-induced elevated, 191 Jackson cross-cylinder refraction, 36 Jackson cross-cylinder technique, 36 Janach alcohol solution cone, 55 Janach alcohol well, 56–57, 76ƒ, 84f Janach bow dissector, 79f Janach epithelial detaching spatula, 61f Janach globe fixation ring, 56, 57, 57f Janach microhoe, 61f, 77f Janach microtrephine, 56–57 alcohol well, 56–57 Janach trephine, 55, 57ƒ, 84f Jeweler’s forcep, flap elevation by, 62f Johnston applanator, 81f Keratectomy, 290 Keratitis, with contact lenses, 125 Keratoconus, 22 Keratometer, manual, 41f Keratopathy, with contact lenses, 125 LADARVision Laser, 213, 226f LADARWave wavefront system, 213f, 214f Lamina densa, 255 LASEK, 1–11 advantages of, over PRK, LASIK, 3–8 after penetrating keratoplasty, 323–330 alcohol, instillation of, 325f astigmatism, preoperative topography, 328f, 329f epithelial detachment, 325f epithelial flap, recession of, 326f epithelial trephination, 325f mitomycin C administration, 327f repositioning epithelial flap, 327f small spot excimer treatment, 326f autologous serum to reduce haze after, 307–315 Azar technique, 3, 317–322 better choice, characteristics for, 20 butterfly technique, 2, 3, 83–87, 84 Camellin LASEK technique, 3 Camellin technique, 73–82 coinage of term, 2 combining of elements in, PRK, LASIK, 1 complications of, 183–193, 185f–191f, 195–203, 197ƒ, 199f, 202f

Index

388

corneal haze, 190–191 corticosteroid-induced elevated intraocular pressure, 191 decentration, 192 glare/halos, 191–192 infections, 188 infiltrates, 188 laser-related complications, 190–192 overcorrection, 190 PRK, LASIK compared, 6 undercorrection, 190 wound healing-related complications, 190–191 contraindications to, 19–24 PRK, LASIK compared, 6 conventional LASEK surgery, 2 corneal haze, and pain scores after, 20 customized ablation and, 225–234 derivation of term, 1 differences PRK, LASIK, 6 dry eye sensation, PRK, LASIK compared, 6 efficacy, advantages over PRK, LASIK, 3 enhancements, 133–135 Epi-LASEK, 3 epithelial cell viability in, 2 epithelial dehiscence, reattachment after, 253–262 excimer laser subepithelial ablation, 3 first procedure, 1 functional vision recovery, PRK, LASIK compared, 6 future of, 263–271 gel-assisted, 111–121 greatest problem of, 30 in high, low myopia, 137–147 history of development of, 1–3 indications, 19–24 PRK, LASIK compared, 6 laser epithelial keratomileusis, 3 LASIK, compared, 13–18, 21, 155–167 mitomycin C haze, 273–295 surface ablation and, 297–306 pain scores after, 20 Pallikaris Epi LASEK technique, 3 popularization of technique, 2 postoperative management, 123–131 postoperative medications, PRK, LASIK compared, 6 postoperative pain, PRK, LASIK compared, 6 predictability, 3 preoperative evaluation, 25–31, 33–46 PRK, compared, 21, 149–153, 235–240 range of correction, PRK, LASIK compared, 6 refractive stability achieved, PRK, LASIK compared, 6 safety, advantages over PRK, LASIK, 3 scarring, PRK, LASIK compared, 6

Index

389

stability, advantages over PRK, LASIK, 4–8 subepithelial photorefractive keratectomy, 3 techniques, 3, 47–71 terminology, 3 thin corneas, PRK, LASIK compared, 6 topography-based aberration in, 169–182 vs. PRK and LASIK, 169–182 Vinciguerra butterfly technique, 2–3, 3, 83–87 wavefront analysis, 205–223 wavefront-guided photorefractive keratectomy, compared, 235–240 wound healing after, 241–250 Laser epithelial keratomileusis, 3 Laser in situ keratomileusis. See LASIK Laser subepithelial keratomileusis. See LASEK LASIK complications of, 13 epi-LASIK, surface ablation without alcohol, 115–121 LASEK after, 318 LASEK compared, 6, 13–18, 21 complications, 6 medications, 6 pain, 6 range of correction, 6 refractive stability achieved, 6 visual outcomes, 6, 155–167 limits of, 17 PRK compared, 6 complications, 6 functional vision recovery, 6 postoperative medications, 6 postoperative pain, 6 preliminary results, 231–232 range of correction, 6 refractive stability achieved, 6 topography-based aberration in, 169–182 wound healing after, 241–250 Lattice degeneration, 29 Law enforcement, eye trauma in, 26 Lens loss, 196 Long-term postoperative complications, 199–202 Low myopia, LASEK in, 137–147 clinical examination, 141 corneal haze, 140 postoperative, 146 glare, 140–141, 146–147 halos, 140–141, 146–147 pain, postoperative, 140, 141 postoperative management, 140 refraction, 141–144 surgical techniques, 138–140 visual acuity, 144–145

Index

390

Macula adherens, 256–257 Manual keratometer, 41f Martial arts, eye trauma in, 26 Massachusetts Eye and Ear Infirmary, first LASEK procedure performed, 1 McCannula, 95. See also Cannulas; McDonald LASEK technique McDonald LASEK technique, 2, 65, 111–112 McDonald McLasek cannula, 95f Medications, postoperative, PRK, LASIK, LASEK, compared, 6 Melki M-LASEK alcohol well, 98f Merocel sponge, 64f, 98f, 103f Microhoe, Janach, 61f, 77f Microtrephine, 74f during rotation, 75f Mitomycin C, 2, 102–103, 103f, 273–295, 327f components of, 278–283 formation mechanisms, 283–285 haze, visual consequences of, 275–278 slip-lamp grading, 277f steroids, 285 visual consequences of haze, 275–278 wound healing cascade, 284f Monocular patients, treatment of, 22 Mycobacterial organisms, prophylactic treatment of, 124 Nidek OPD-Scan scanning system, 217f Nocardia asteroids, prophylactic treatment of, 124 Norwood Abbey Eyecare Australia, 116f Objective refraction, 35 Ocular dominance, 40 Opacities, diffuse, 198–199 Optic nerve, 29 Orthoptic examination, 40–41 Outgoing wavefront aberrometry, 211–215 Overcorrection, 190, 199–201 Pachymetry, 43, 43f Pain, postoperative, 6, 20, 127–128, 140, 141, 187, 196 Pallikaris Epi LASEK technique, 3 Patient education, 30–31 Patient positioning, preparation, 49 application of drape, 49 speculum placement, 49 Penetrating keratoplasty, LASEK after, 323–330 alcohol, instillation of, 325f astigmatism, preoperative topography, 328f, 329f epithelial detachment, 325f

Index

391

mitomycin C administration, 327f recession of flap, 326f repositioning epithelial flap, 327f small spot excimer treatment, 326f trephination, 325f Photoablation, 2 Photorefractive experiments on animals, 2 Photorefractive keratectomy. See PRK PlanoScan laser ablation pattern, 216f Pneumatonometer, 39f Postoperative management, 123–131 aminoglycoside, organisms not covered by, 124t contact lens-related complications, 125t contact lens removal, 126 epithelial defect management, 126–127 fluoroquinolone, organisms not covered by, 124; infection prophylaxis, 128–129 medications, 6, 123–129 observation schedule, 124 organisms, prophylactic treatment, 124t pain, 6, 20, 127–128, 140, 141, 187, 196 Preoperative evaluation, 21–22, 25–31, 33–46 automated refractors, 36 biomicroscopic examination, 38 Colvard pupillometer, 40f compact placido-based corneal topographical unit, 42f contrast sensitivity, 43–44 corneal aesthesiometry, 38 corneal topography, 41–43 methods of measuring, 41 cycloplegia, 35 elevation-based topographical unit, 42f ETDRS visual acuity chart, 34f external eye examination, 37 fundus examination, 38–39 informed consent, 44 manual keratometer, 41f objective refraction, 35 occupational history, 34 ocular dominance, 40 ocular history, 33 orthoptic examination, 40–41 pachymetry, 43 patient characteristics, 25–26 patient medical history, 33 pneumatonometer, 39f pupil size, 39–40 refinement of cylindrical correction, 37 refraction, 35 social history, patient, 34 subjective refraction, 36–37 binocular balancing, 37

Index

392

Jackson cross-cylinder technique, 36 red-green (duochrome, bichromatic) test, 36–37 tonometry, 39 ultrasonic pachymetry, 43f visual acuity, 34–44 Preoperative medication, 47–48 anesthetics, 47 antibiotics, 47–48 application, topical medication, 48 NSAIDS, 47 Previous ocular surgery, impact of, 29–30 PreVue lens, 216f PRK, 79 alcohol-assisted epithelial flap reattached over, 2 on blind eye, 2 complications of, 13 corneal haze, and pain scores after, 20 LASEK after, 317–318 LASEK compared, 6, 21, 149–153, 235–240 LASIK compared, 6, 231–232 combining of elements in, 1 on normal sighted eye, 2 pain scores after, 20 sighted eye, slated for exenteration days after PRK, 2 topography-based aberration in, 169–182 wound healing after, 241–250 Prophylaxis, for infection, 128–129 Pump, LASEK Carones, 55, 56 OZ chambers, Carones, 55, 56f Pupil size, 28, 39–40 Range of correction, PRK, LASIK compared, 6 Reassembly, epithelial adhesion structures, after LASEK, 258–259 Red-green (duochrome bichromatic) refraction test, 36–37 bichromatic) test, 36–37 Refraction binocular balancing, 37 Jackson cross-cylinder technique, 36 red-green (duochrome, bichromatic) test, 36–37 subjective, 36–37 Refractive stability achieved, PRK, LASIK compared, 6 Refractometer, spatially resolved, principle behind, 217f Retinal image aberrometry, 218 Retinal vascular changes, 29 Scarring, PRK, LASIK compared, 6 Scedosporium apiospermum, treatment of, 124 Seibel LASIK cannula, 95f Shahinian alcohol wells, 55

Index

393

Shahinian epithelial trephine, 55 Short-term postoperative complications, 196–199 Size of pupil, effect of, 28 Sjögren syndrome. See Dry eye Skioloscopy, dynamic, wavefront sensor principles, 217f schematic diagram, 217f Slade LASIK cannula, 93f Small corneal diameters, 28 Spatially resolved refractometer, principle behind, 217f Spatulas, 59–60 Carones, 61f Janach, 61f Stability, advantages of LASEK over PRK, LASIK, 4–8 Staphylococcal organisms, prophylactic treatment of, 124 Sterile hypopyon, with contact lenses, 125 Sterile subepithelial infiltrates, 125 Steroids, use of, 285 Streptococcal organisms, prophylactic treatment of, 124 Stromal haze, 283–285. See also Haze Subepithelial infiltrates, with contact lenses, 125 Subepithelial photorefractive keratectomy, 3 Subepithelial separator, 116f Subjective refraction, 36–37 binocular balancing, 37 Jackson cross-cylinder technique, 36 red-green (duochrome, bichromatic) test, 36–37 Superficial lamellar keratectomy, 290 Surface ablation, 297–306 duration of application, 299–302 without alcohol (See Epi LASIK) Swimming, eye trauma in, 26 Thickness, corneal, impact of, 27 Thin corneas, PRK, LASIK compared, 6 Tight lens syndrome, 125 Tissue integrity, corneal, quality, 27 Tonometry, 39 Topography, corneal, 41–43 Toxic keratopathy, with contact lenses, 125 Trauma, risk for 26 Trephination, 55–58. See also Trephines purpose, 55 sizing, 55 success, 55–57 Trephines Azar-Camellin LASEK I & A, 90 Azar-Carones LASEK I & A, 55, 56, 56f Janach, 55–57, 57ƒ, 84f alcohol well, 56–57

Index

394

microtrephine, 74f rotation, 75f Shahinian epithelial, 55 sizing profile of, 55 TUNEL labeling, cultured epithelial cells, 54f Ultrasonic pachymetry, 43f Undercorrection, 190, 199–201 Vascular changes, retinal, 29 Viability, epithelial cells, in LASEK, 258–259 Vinciguerra, 61f, 85f Vinciguerra butterfly LASEK, 2–3, 63, 83–87, 85f Vinciguerra LASEK spatula, 61ƒ, 85f Viscodissection advanced laser surgery ablation, 89–109 alcohol application, 97–98, 98f Azar-Camellin LASEK I & A trephine, 90 bladeless microkeratome flap retraction technique, 103–106 Burrato LASIK cannula, 96f Camellin LASEK technique, 92 cannula, 65, 94–97, 94f epithelial flap manipulation, 100–101 epithelial sanctity, 101–102 fluidic dissection, 97 GenTeal, 92f, 102, 103f Guell LASIK cannula, 96f haze prevention, 102–103 hydroviscodissection, 91–93, 93–94 loosening epithelium, 97 McDonald McLasek cannula, 95f Melki M-LASEK alcohol well, 98f Merocel sponge, 98f, 103f mitomycin C, 102–103, 103f Rashid, 65, 94f Seibel LASIK cannula, 95f Slade LASIK cannula, 93f “wow” phenomena, 89 Vision recovery, functional, PRK, LASIK, LASEK, compared, 6 Visual acuity, pre-procedure evaluation, 34–44 VISX Star S4 Active Trak, 213 VISX Wavescan, 213 WASCA aberrometer, 213, 213f Wavefront analysis, 205–211, 205–223, 210f clinical experience with, 218–222 custom ablation, 225–230, 230–232 flap biomechanics, 230–231 ingoing adjustable aberrometry, 215–217 LASIK vs. PKR, 231–232 outgoing wavefront aberrometry, 211–215

Index

profiles, 218 progression of technology, 225 retinal image aberrometry, 218 topographic diagnostics, 229 wavefront diagnostics, 225–229 Wavefront-guided PRK, 235–240. See also PRK Wavefront sensors dynamic skioloscopy, 217f types of, 211–218 WaveScan device, 215f WaveScan WaveFront system, 213f Well, alcohol, 55–57, 75, 76ƒ, 84ƒ, 98f Janach, 56–57, 76f, 84f Melki M-LASEK, 98f Shahinian, 55 Wound healing, 257–258 alcohol treatment, 257–258 cascade, 284f cell-basement membrane junctions, 257 complications 190–191 intercellular junctions, 257 “Wow” phenomena, 89 Yields, preparation of, 48 Zonula adherens, 256 Zonula occludens, 256 ZyWave (Bausch & Lomb) wavefront, 213f

395