Excimer laser refractive surgery : corneal wound ... - Helda - Helsinki.fi

Department of Ophthalmology 

University of Helsinki 

Finland 

EXCIMER LASER REFRACTIVE SURGERY; 

CORNEAL WOUND HEALING AND CLINICAL 

RESULTS 

Waldir Neira Zalentein 

ACADEMIC DISSERTATION 

To be presented for public examination with the permission of the Medical Faculty of 

the University of Helsinki in the Lecture Hall 2 of the Haartman Institute, 

Haartmaninkatu 3, Helsinki on June 10, 2011, at 12 noon. 

Helsinki 2011

Supervisors 

Timo Tervo 

Professor 


Helsinki University Central Hospital, Finland 

Juha M. Holopainen 

Adjunct Professor 


Helsinki University Central Hospital, Finland 

Reviewers 

Charlotta Zetterstrøm 

Professor of Ophthalmology 


Ullevål University Hospital, Norway 

Olavi Pärssinen 

Adjunct Professor 


University of Turku 

Opponent 

José M. Benítez del Castillo 

Professor of Ophthalmology 


Universidad Complutense de Madrid, Spain 

ISBN 978-952-92-8703-1 (paperback) 

ISBN 978-952-10-6834-8 (pdf version, http://ethesis.helsinki.fi) 

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“When you want something, all the universe conspires in helping you to achieve it” 

Paulo Coelho, The Alchemist 

To Mikaela, Ricardo, Daniela and Manuela 

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TABLE OF CONTENTS 

TABLE OF CONTENTS 4 

LIST OF ORIGINAL PUBLICATIONS 8 

ABBREVIATIONS 9 

ABSTRACT 11 

1 INTRODUCTION 13 

2 REVIEW OF THE LITERATURE 14 

2.1 GROSS CORNEAL ANATOMY 14 

2.1.1 Tear film 14 

2.1.2 Corneal structure 14 

2.1.3 Corneal innervation 16 

2.2 REFRACTIVE ERRORS 17 

2.3 EXCIMER LASER 18 

2.3.1 Principle 18 

2.3.2 Interaction of excimer laser with the cornea 19 

2.3.3 Phototherapeutic keratectomy (PTK) 19 

2.3.4 Photorefractive keratectomy (PRK) 20 

2.3.5 Laser assisted in situ keratomileusis (LASIK) 20 

2.4 CORNEAL WOUND HEALING 22 

2.5 PREOPERATIVE ASSESSMENT OF REFRACTIVE SURGERY 25 

2.6 VISUAL ACUITY AND REFRACTIVE RESULTS AFTER EXCIMER 

LASER SURGERY 26 

2.6.1 PRK outcomes 26 

2.6.2 LASIK outcomes 29 

2.6.3 Comparison of myopic outcomes after PRK and LASIK 29 

2.7 PRK AND LASIK COMPLICATIONS 31 

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3 AIMS OF THE STUDY 35 

4 PATIENTS AND METHODS 36 

4.1 PATIENTS 36 

4.2 PROTOCOLS 37 

4.3 METHODS 37 

4.3.1 PRK/LASIK preoperative therapy 37 

4.3.2 PTK procedure 37 

4.3.3 PRK procedure 38 

4.3.4 LASIK procedure 38 

4.3.5 PTK/PRK postoperative therapy 38 

4.3.6 LASIK postoperative therapy 38 

4.3.7 Study subjects 39 

4.3.8 Statistical methods 40 

5 RESULTS 42 

5.1 STUDY I AND II (PRK and LASIK long-term follow-up) 42 

Efficacy: 42 

PRK 42 

LASIK 43 

PRK VISX vs. LASIK VISX 43 

Safety 44 

PRK 44 

LASIK 44 

PRK VISX vs. LASIK VISX 44 

Stability 45 

PRK 45 

LASIK 45 

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VISX PRK VS. VISX LASIK 46 

Patient satisfaction after LASIK 46 

5.2 STUDIES III AND IV. Regular and irregular astigmatism 47 

5.2.1 Regular astigmatism 47 

PRK vs. LASIK 47 

Efficacy 47 

Safety 48 

Stability 49 

PRK 49 

LASIK 49 

PRK vs. LASIK 49 

5.2.2 Irregular astigmatism 52 


Safety 53 

Irregular astigmatism and VK 53 

5.3 STUDY V. PRK after LASIK 53 


Safety 53 

6 DISCUSSION 54 

STUDIES I AND II. PRK/LASIK follow-up 54 

PRK 54 

LASIK 55 

PRK VISX vs. LASIK VISX in moderate myopia 56 

STUDIES III AND IV. Regular and irregular astigmatism 56 

Regular astigmatism 56 

Irregular astigmatism 57 

6

STUDY V. PRK enhancement 58 

7 SUMMARY AND CONCLUSIONS 59 

8 ACKNOWLEDGEMENTS 60 

REFERENCES 62 

ORIGINAL PUBLICATIONS 79 

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LIST OF ORIGINAL PUBLICATIONS 

This thesis is based on the following original publications, which will be referred to in the 

text by their Roman numerals: 

I. Neira Zalentein, W., Tervo, T. M. T., and Holopainen, J. M. Long-term follow- 

up of photorefractive keratectomy for myopia: Comparative study of excimer 

lasers. J Cataract Refract Surg. 2011; 37: 138-143. 

II. Neira Zalentein, W., Tervo, T. M. T., and Holopainen, J. M. Seven-year follow- 

up of LASIK for myopia. J Refract Surg. 2009; 25: 312-318. 

III. Neira Zalentein, W., Tervo, T. M. T., and Holopainen, J. M. A comparative 

study of correction of moderate-to-high astigmatism by PRK and LASIK. 

Submitted. 

IV. Neira Zalentein. W., Holopainen, J. M., and Tervo, T. M. T. Phototerapeutic 

keratectomy for epithelial irregular astigmatism. J Refract Surg. 2007, 23: 50- 

57. 

V. Neira Zalentein, W., Moilanen, J.A.O., Tuisku, I.S.J., Holopainen, J.M., and 

Tervo, T. M. T. Photorefractive keratectomy enhancement after Laser in situ 

keratomileusis. J Refract Surg. 2008; 24: 710-712. 

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ABBREVIATIONS 

ArF Argon Fluoride 

AS Axis shift 

BB Broad beam laser 

BCVA Best Corrected (spectacle) Visual Acuity 

CL Contact lens 

CM Corneal Confocal Microscopy 

CR Correction ratio 

D Diopters 

DLK Diffuse Lamellar Keratitis 

EA Error of angle 

ECM Extracellular matrix 

EM Error of magnitude 

ER Error ratio 

EV Error vector 

FDA Food and Drug Administration 

FS Femtosecond Laser 

HOA High order aberration 

LASEK Laser assisted subepithelial keratomileusis 

LASIK Laser in-situ keratomileusis 

MRSE Manifest refraction of spherical equivalent 

NEV Normalized error vector 

PRK Photorefractive keratectomy 

PTK Phototherapeutic keratectomy 

SIRC Surgically induced refraction correction 

SphEq Spherical equivalent 

SS Scanning slit laser 

SSL Scanning spot laser 

TLSS Transient light-sensitive syndrome 

TEV Treatment error vector 

UCVA Uncorrected visual acuity 

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US Ultrasound pachymetry 

UV Ultraviolet 

VK Videokeratography 

WF Wavefront 

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ABSTRACT 

Although the first procedure in a seeing human eye using excimer laser was reported in 

1988 (McDonald et al. 1989, O'Connor et al. 2006) just three studies (Kymionis et al. 

2007, O'Connor et al. 2006, Rajan et al. 2004) with a follow-up over ten years had been 

published when this thesis was started. 

The present thesis aims to investigate 1) the long-term outcomes of excimer laser 

refractive surgery performed for myopia and/or astigmatism by photorefractive 

keratectomy (PRK) and laser-in situ- keratomileusis (LASIK), 2) the possible differences 

in postoperative outcomes and complications when moderate-to-high astigmatism is 

treated with PRK or LASIK, 3) the presence of irregular astigmatism that depend 

exclusively on the corneal epithelium, and 4) the role of corneal nerve recovery in corneal 

wound healing in PRK enhancement. 

Our results revealed that in long-term the number of eyes that achieved uncorrected 

visual acuity (UCVA) ≤0.0 and ≤0.5 (logMAR) was higher after PRK than after LASIK. 

Postoperative stability was slightly better after PRK than after LASIK. In LASIK treated 

eyes the incidence of myopic regression was more pronounced when the intended 

correction was over >6.0 D and in patients aged

Based on these results, we demonstrated that the long-term outcomes after PRK and 

LASIK were safe and efficient, with similar stability for both procedures. The PRK 

outcomes were similar when treated by broad-beam or scanning slit laser. LASIK was 

better than PRK to correct moderate-to-high astigmatism, yet both procedures showed a 

tendency of undercorrection. Irregular astigmatism was proven to be able to depend 

exclusively from the corneal epithelium. If this kind of astigmatism is present in the 

cornea and a customized PRK/LASIK correction is done based on wavefront 

measurements an irregular astigmatism may be produced rather than treated. Corneal 

sensory nerve recovery should have an important role in the modulation of the corneal 

wound healing and post-operative anterior stromal scarring. PRK enhancement may be an 

option in eyes with previous LASIK after a sufficient time interval that in at least 2 years. 

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1 INTRODUCTION 

Refractive errors have a major impact on public health questions, such as visual 

requirements at work. It has been calculated that 2.5-4.3 billion dollars are spent each year 

in the USA only for the inspection and correction of myopia (Sandoval et al. 2005). 

Spectacles are the most used and safest choice for correcting refractive errors, followed by 

contact lenses and refractive surgery. 

The number of corneal refractive surgeries grows every year (Sandoval et al. 2005) despite 

the fact that risks, such as breaking of the spectacles and infections associated with contact 

lenses, appear minimal in relation to the risks of refractive surgery even though the 

complication rates are considered low. 

Corneal refractive surgery aims at controlled alteration of the shape of the cornea. Such 

surgery performed on a completely healthy eye places high demands on the control of 

wound healing. 

Corneal refractive procedures are divided into those that change the corneal curvature with 

relaxing incisions and those that add or remove tissue from the cornea to change its 

curvature (Barraquer JI 1964). The corneal refractive results are based in the law of 

thickness introduced by Barraquer in 1964 (Barraquer JI 1964) “changing the thickness of 

the cornea follows the idea that the cornea is a stable lens, removing tissue in the center or 

adding tissue on the periphery therefore flattens the cornea.” The argon fluoride (193 nm) 

excimer laser permits the excision of corneal tissue with minimal damage to the adjacent 

tissues. It uses high energy ultraviolet radiation to break the covalent bonds between 

molecules in the corneal stroma without generating high levels of heat (Krauss et al. 

1986). This procedure has been termed photoablative process and is the principal reason 

making laser refractive surgery a relative predictable and safer procedure. 

The therapeutic treatment of corneal opacities and irregularities by excimer laser is called 

phototherapeutic keratectomy (PTK) (Fagerholm 2003). In refractive corrections, 

photorefractive keratectomy (PRK) modifies the anterior corneal surface ablating the 

anterior corneal stroma and generating a new radius of curvature to decrease refractive 

error. The most popular refractive surgery is Laser in-situ keratomileusis (LASIK) 

(Sandoval et al. 2005). This uses PRK technology but performs the procedure at the 

stromal level after the creation of a lamellar flap formed with a mechanical microkeratome 

(Updegraff and Kritzinger 2000). 

The present study was undertaken to assess the long-term postoperative outcomes of the 

two most common laser refractive surgeries (PRK and LASIK) to treat myopia. The effect 

of excimer laser surgery in the treatment of regular astigmatism by these two different 

techniques was analysed. The presence of irregular astigmatism secondary to epithelial 

irregularities was also evaluated. In addition, it was also of interest to study the correlation 

of corneal nerve density and postoperative corneal wound healing after excimer laser 

refractive surgery. 

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2 REVIEW OF THE LITERATURE 

2.1 GROSS CORNEAL ANATOMY 

The cornea is an avascular and transparent structure situated in front of the eye. The 

structural and physiological properties of the cornea determine its optical performance to 

refract light. The cornea is the most powerful refractive lens of the eye comprising on 

average 45 D of the approx. 60-70 D total refractive power of the eye. The central 

thickness of the cornea is between 500 to 550 µm and 600 to 700 µm at the corneal 

periphery (Doughty and Zaman 2000, Ehlers and Hjortdal 2004, Salvetat et al. 2010). This 

difference in thickness between the periphery and central corneal generates a disparity in 

curvature creating an aspheric optical system. The cornea has an elliptical shape when 

viewed frontally; this configuration arises from an extension of opaque sclera tissue that 

covers the cornea superiorly and inferiorly. In the adult cornea, the horizontal and vertical 

average diameters are 12 mm (range 11 to 12.5 mm) and 11 mm (range, 10 to 11.5 mm), 

respectively (Rufer et al. 2005). 

2.1.1 Tear film 

The pre-corneal tear film supports and maintains the ocular surface. It lubricates the 

epithelium, protects the cornea from external agents, modulates wound healing through its 

components and, secondary to the air-tear interface, creates the first refractive surface. 

Three different layers constitute the tear film (Prydal and Campbell 1992, Prydal et al. 

1992); a. The inner hydrophilic mucous layer derived from the conjunctival goblet cells 

and corneal epithelial cells (Chao et al. 1980). This layer is attached to the superficial cells 

of the corneal epithelium and its essential role is to allow spreading of the tear film, and to 

prevent the adhesion of foreign pathogens and debris onto the ocular surface. b. The 

aqueous layer is derived from the main and accessory lacrimal glands. It contains proteins, 

electrolytes, cytokines and growth factors that modulate the ocular surface and the 

response to damage. c. The external lipid layer derived from the meibomian glands 

prevents the evaporation of tears (Mishima and Maurice 1961, Rolando and Refojo 1983) 

and stabilizes the tear film. 

2.1.2 Corneal structure 

The cornea is built of around 200 collagen sheets, which are laid at approximately 90 

degrees to each other. This collagen structure provides mechanical strength and 

transparency and allows for undisturbed image formation on the retina. It is composed 

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from anterior to posterior by the epithelium, Bowman’s layer, stroma, descemet’s 

membrane and endothelium. 

The corneal epithelium is the most external layer of the cornea, with a thickness of 

approximately 50 µm and an estimated turnover rate of 5 to 7 days (Cenedella and 

Fleschner 1990, Hanna et al. 1961). Before the time of stems cells Thoft and Friend and 

others (Buck 1979, Buck 1985, Haddad 2000, Thoft and Friend 1983) proposed that 

corneal basal epithelial cells moved by a centripetal movement from the periphery to the 

central area and thereby replaced the exfoliating cells. The finding that the epithelial stem 

cells are located at the limbus strengthened this view (Dua and Azuara-Blanco 2000, 

Tseng 1989). Yet new evidence suggests that in some species stem cells are located over 

the entire ocular surface (Majo et al. 2008). 

The corneal epithelium consists of 5 to 6 layers of non-keratinized squamous stratified 

epithelial cells which are morphologically divided into three different types (Ehlers 1970). 

The apical cells consist of two to three layers of exfoliating superficial, flat cells 

joined by desmosomes, intercellular junctions and zonulae occludentes, tight junctional 

complexes (Ban et al. 2003, Hsu et al. 1999). These junctions maintain a barrier 

preventing the flow of substances and impurities into the stroma. The surface of these cells 

is covered with microvilli and microplicae. These structures promote the absorption of 

metabolites and oxygen and also stabilize the tear film. The apical surface is coated by the 

glycocalix, composed of glycoproteins and glycolipid molecules which interact with the 

mucous layer of the tear film (Ubels et al. 1995). It is believed that the glycocalix plays a 

role in maintaining the hydrophilic properties of the cornea and smoothing the optical 

surface required for clear vision. 

The wing cells consist of 2 to 3 layers of wing-like cells located below the apical cells. 

They correspond to an intermediate cell type between basal and apical cells. 

The basal cells form a single, cuboidal, columnar layer of cells above the basement 

membrane. This layer is the source of wing and apical cells. Neighbouring basal cells are 

joined by desmosomes, gap junctions and junctional complex. The basal cells secrete and 

form the basement membrane (Hogan MJ et al. 1971), which provides the matrix where 

cells can attach and migrate. Hemidesmosomes connect the basal cells with the basement 

membrane (Gipson et al. 1987). Basal cells also secrete anchoring fibrils that penetrate 

the basement membrane and reach the stroma (Gipson et al. 1987) increasing the adhesion 

to Bowman’s layer and stroma. 

Bowman’s layer is located between the epithelium and stroma. It is composed of 

proteoglycans and collagen fibres I, III, V, and VI (Marshall et al. 1993). This acellular 

layer, is 8 -12 µm thick (Komai and Ushiki 1991) and does not regenerate. Bowman’s 

layer increases the biomechanical strength of the cornea, and enhances the adhesions of 

epithelial cells and stroma secondary to anchoring fibers. 

The stroma composes almost 90% of the thickness of the cornea. It is formed of 

collagen (types I, III, IV, and VI), extracellular matrices, nerve fibers and cells (Ihanamaki 

et al. 2004). Keratan sulfates are the major proteoglycans, helping to regulate the 

hydration and structural properties of the stroma. The corneal transparency has been 

related to the distance and regular arrangement of collagen fibers (Maurice 1957). Stromal 

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fibroblasts (keratocytes) are the primary cellular elements of the stroma (Hay 1979, West- 

Mays and Dwivedi 2006); they lie between the collagen lamellae organized in a 

clockwise, spiral arrangement (Muller et al. 1995). Keratocyte density is higher in the 

anterior stroma than in the posterior stroma (Erie et al. 2006, Moller-Pedersen et al. 1997, 

Patel et al. 2001).These cells constantly maintain the stromal structure interacting through 

gap junctions and similar innervations. After stromal damage keratocytes begin to migrate 

to restore the tissue (Fini and Stramer 2005, Jester et al. 1999, West-Mays and Dwivedi 

2006). Depending on the extent and type of stromal damage an activation of fibroblast can 

lead to the loss of corneal transparency (Fini and Stramer 2005, Jester et al. 1999). 

Descement’s membrane is the basement membrane of the corneal endothelium. It is 

composed mainly of collagen type IV (Marshall et al. 1991), laminins and glycoproteins 

(Beuerman and Pedroza 1996, Marshall et al. 1993). Similarly to Bowman’s layer, it does 

not regenerate, but shows an age-dependent increase in thickness. 

The endothelium is composed by a single layer of endothelial cells. At birth the cell 

density is about 3500 cells/mm 2 (Waring 1982, Waring et al. 1982). The endothelial cell 

count decreases with age by ~2% per year. The major function of the endothelium is to 

regulate the hydration level of the corneal stroma and maintain the corneal transparency. 

This hydration level is regulated by ionic pumps located on the endothelial plasma 

membrane. The “pump leak” hypothesis established that the amount of water and solutes 

that leak into the stroma are compensated by the rate of pumping of excess water from the 

stroma back to the aqueous humor (Maurice 1972, Waring et al. 1982). Furthermore, the 

endothelial cells control the transport of nutrients from the aqueous humor to the other 

corneal layers by active transport mechanisms. 

2.1.3 Corneal innervation 

The sensory innervation of the cornea derives principally from the ophthalmic division of 

the trigeminal nerve via the nasociliary nerves. In some cases, the second branch of the 

trigeminal nerve, the maxillary nerve through the infraorbital nerve, carries sensory 

innervations for the inferior cornea (Rozsa and Beuerman 1982, Ruskell 1974, Zander and 

Weddell 1951). 

Nerve bundles from the two long ciliary nerves, which are branches of the nasociliary 

portion of the trigeminal nerve, enter the cornea in the middle third of the stroma in a 

radial fashion. Once they enter the stromal cornea, the peripheral bundles lose the myelin 

sheaths retaining only their Schwann cells sheaths and run toward the centre of the cornea 

(Muller et al. 1996, Muller et al. 2003). In their trajectory some fibres innervate individual 

keratocytes. The stromal nerve sub divides extensively into smaller branches bending 90 

degrees toward the surface of the cornea. After penetrating Bowman’s layer they lose the 

remaining Schwann cell sheath and bend 90 degree another time forming the subbasal 

nerve plexus located between the Bowman’s layer and the basal epithelial cells (Muller et 

al. 1997). Nerve terminals then protrude between the epithelial cells and terminate in the 

superficial layers of the corneal epithelium (Chan-Ling 1989, Muller et al. 1997, Zander 

and Weddell 1951). Electrophysiological studies (Belmonte and Giraldez 1981, Belmonte 

16

et al. 1991, Gallar et al. 1993, Tanelian and Beuerman 1984) have found three different 

types of corneal sensory fibres: a) mechano-nociceptors (20% of fibres) that react to 

mechanical forces. b) polymodal nociceptors (70% of fibres) that react to mechanical 

energy, heat and chemical irritants, and c) cold-sensitive receptors (10-15% of fibres) that 

react to a decrease in corneal temperature. 

2.2 REFRACTIVE ERRORS 

The different anatomical parts of the eye can be compared to a camera, where the cornea, 

lens, iris and retina have a function similar to that of the lenses, diaphragm and film to 

refract the rays of light at a determined point. The refractive state where the focus parallels 

rays of light from a distant point to the retina is called emmetropia. Yet the point of focus 

can also be located in front (myopia) or behind (hypermetropia) the retina, causing 

ametropia. A balance between the refractive power and axial length of the eye is required 

to focus the light on a desired point of the retina. 

A long axial length of the eye or a steep cornea that increases the refractive power of the 

eye is the principle cause of myopia. By contrast, hypermetropia eyes have a short axial 

length of the eye or a too flat cornea. In myopia the image is formed anterior to the retina 

and in hypermetropia at a point posterior to the retina. 

Spherical refracting surfaces have constant curvature in all meridians, yet with 

astigmatism, disparity in the curvature of the refractive surface of the eye at different 

meridians causes the refractive surface of the eye to assume a cylindrical shape avoiding 

the rays of light to focus on a single point of the retina. Cylinders show a maximum 

curvature along their circumferential direction and zero curvature along their length. The 

zero curvature is 90 degrees to the maximum curvature. This toric form creates two line 

images of a point at right angles to each other and at different distances along the axis. 

In regular astigmatism the meridians’ directions are constants and located at 90 

degrees to each other. This type of astigmatism is correctable with a cylindrical lens. The 

corneal toric shape explains most astigmatisms. If the vertical meridian is steepest (the 

principal meridian lies at close to 90 degrees), the astigmatism is with-the-rule, and it is 

correctable with a plus cylinder near to 90 degrees or a minus cylinder close to 180 

degrees. If the horizontal meridian is the steepest (the principal meridian lies is close to 

180 degrees), the astigmatism is against-the-rule and a plus cylinder close to 180 degrees 

or a minus cylinder close to 90 degrees can be used. Oblique astigmatism will occur when 

the principal meridians lie between 30 to 60 degrees, or 120 – 150 degrees. 

Irregular astigmatism shows a disparity in the principal meridians, not being located at 

90 degrees to each other. This was defined by Duke-Elder as a refractive condition in 

which the refraction in meridians conforms to no geometrical plan and the refracted rays 

have no planes of symmetry (Duke-Elder S 1970). The refractive surfaces might present 

multiple zones of increased or decreased surface power, depending on the cause of the 

astigmatism. Cylindrical lenses cannot correct these types of defects. In the topography 

there may be multiples zones of flat or steep areas at least 2 mm in diameter in any area of 

the cornea. 

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2.3 EXCIMER LASER 

2.3.1 Principle 

The corneal refractive procedures can be divided into those that change the corneal 

curvature with relaxing incisions or radio frequency energy (conductive keratoplasty) and 

those that add or remove tissue from the cornea to change its curvature (Barraquer JI 1964, 

Barraquer JI 1989). Since its introduction in the 1980’s and its first application to the 

human eye the excimer laser has changed the world of refractive surgery. The term 

excimer arises from “excited dimer” that describes an energized molecule with two 

identical components. Rare gas atoms interact with a halogen molecule when they are 

stimulated by an electrical discharge (about 30,000 electron volts) within the laser cavity 

(Tasman W 2001). These energized atoms emit photons of ultraviolet light which, when 

released, emit the laser light. 

In 1981, Taboada and Archibald (1981) reported that the argon fluoride (ArF) excimer 

laser emits high-power ultraviolet (UV) radiation at 193 nm that could reshape the corneal 

epithelium. Trokel et al. (1983) reported in 1983, that the excimer laser permits the 

excision of corneal stromal tissue with minimal damage to the adjacent tissues. Later 

studies (Krauss et al. 1986, Puliafito et al. 1985, Seiler and Wollensak 1986, Srinivasan 

and Sutcliffe 1987) showed that the excimer laser uses this high energy ultraviolet 

radiation to break the covalent bonds between molecules in the corneal stroma without 

generating heat. This has been termed a photoablative process and is the principal reason 

making refractive surgery a more predictable and safe procedure. In 1985, Seiler 

performed the first procedure on a human blind eye (Seiler and Wollensak 1986), yet it 

was only in 1988 that McDonald and co-workers performed the first procedure on a seeing 

human eye (McDonald et al. 1989). 

To date several different excimer laser systems have been developed: 

a. Broad-beam laser (BB): This system can adjust the spot size between 0.6 mm to 8 mm. 

It starts at the centre and moves to the periphery of the cornea. A shorter operating time, 

and less need for eye-tracking systems are the relative advantages of this system. 

However, higher incidence of central islands and a higher energy output are considered its 

disadvantages. 

b. Scanning slit laser (SS): This system uses a rectangular beam. The size of the 

rectangular spot can be adjusted up to 2 x 9 mm. Improvement in beam homogeneity and 

uniformity as well as a decreased incidence of central islands are the advantages of this 

type of laser. Longer operating times and lack of more accurate tracking systems are 

considered disadvantages of this laser instrument. 

c. Scanning-spot lasers (SSL): This system uses a spot beam between 0.5 and 2.0 mm that 

travels across the cornea reducing the need for laser energy. The advantage of this type of 

laser is also that it permits custom-design ablations, but such laser delivery systems 

require an accurate tracking system. 

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2.3.2 Interaction of excimer laser with the cornea 

The photoablative process is a reduction procedure involving the excision of tissue. Once 

the 193 nm UV energy emitted by the ArF excimer laser is absorbed by the solid 

component of the cornea (Krauss et al. 1986), it breaks the carbon-carbon and carbon– 

nitrogen bonds that form the corneal collagen molecule generating a decomposing ablative 

process that produces minimal thermal damage in the corneal tissue (Bende et al. 1988). 

Immediately after the breakage the kinetic energy created ejects the molecular fragments 

from the place on impact (Krauss et al. 1986, Trokel et al. 1983). The energy emitted by 

the laser is inversely proportional to the pulse repetition, the higher the repetition rate, the 

smaller the energy emitted by the pulse. The available lasers have a repetition rate 

between 10 (BB) and 750 (SSL) Hz. Several studies (Krueger and Trokel 1985, Krueger et 

al. 1985, Puliafito et al. 1987, Seiler et al. 1990) have calculated the laser fluence or 

energy density per unit area projected (irradiance) necessary to ablate the cornea. The 

threshold to ablate the corneal surface with the ArF excimer laser is 50 mJ/cm 2 , yet the 

most efficient fluence in human eyes should be higher than 120 mJ/cm 2 . Commercially 

available excimer lasers work with a fluence between 120 and 180 mJ/cm 2 (Duffey and 

Leaming 2002). The amount of corneal tissue ablated by the pulse of the laser is directly 

proportional to the amount of energy and the depth of ablation increases in proportion to 

the square of the ablation diameter (Munnerlyn et al. 1988). Using a fluence of 160 – 180 

mJ/cm 2 an ablation rate between 0.21 and 0.27 microns per pulse is obtained (Seiler et al. 

1993). 

2.3.3 Phototherapeutic keratectomy (PTK) 

The therapeutic treatment of corneal opacities and irregularities by excimer laser is called 

phototherapeutic keratectomy (PTK) (Fagerholm 2003). It refers to a regular and 

sequential ablation of the anterior layers of the cornea. In general, PTK has been used to 

remove superficial opacities, treat surface irregularities, and correct complications after 

photorefractive keratectomy (PRK) and Laser in-situ keratomileusis (LASIK). The best 

candidates for PTK are patients with anterior opacities or anterior elevated stromal 

changes; deep stromal changes do not response positively to PTK. Reshaping of a surface 

irregularity has been performed using masking fluids (Kornmehl et al. 1991). Commonly 

hyperopic postoperative changes in refractive error are found after PTK (Fagerholm et al. 

1993, Sher et al. 1991, Stark et al. 1992, Starr et al. 1996). Stability of the mean refraction 

and best corrected visual acuity (BCVA) is usually achieved by the third postoperative 

month (Fagerholm 2003, Maloney et al. 1996, Ohman et al. 1994). Long-term studies after 

PTK have reported statistically improved corneal clarity, BCVA, and reduced surface 

irregularity (Fagerholm et al. 1993, Fagerholm 2003, Maloney et al. 1996, Rapuano 1997). 

PTK is effective for the relief of pain and cure of spontaneous epithelial detachments 

in recurrent corneal erosion syndrome (Cavanaugh et al. 1999, Dinh et al. 1999, Maini and 

Loughnan 2002, Rapuano and Laibson 1993, Rapuano and Laibson 1994, Rapuano 1997, 

Zuckerman et al. 1996), as it stimulates the formation of new anchoring fibrils in the 

19

stroma and results in enhanced epithelial adhesion (Davis and Lindstrom 2001, Wu et al. 

1991). However, postoperative pain during the first 48 hours may be severe, and the 

recurrence rate of erosion has been reported to be 13.8% to 26.3% during a 12-month 

follow-up period (Cavanaugh et al. 1999, Rapuano 1997, Reidy et al. 2000). 

2.3.4 Photorefractive keratectomy (PRK) 

Photorefractive keratectomy (PRK) modifies the anterior corneal surface after removal of 

the corneal epithelium ablating the anterior corneal stroma and generating a new radius of 

curvature to decrease refractive error. Attempts to restore the epithelium on top of the 

stromal wound have led to alternative techniques, such as Laser-Assisted Sub-Epithelial 

Keratomileusis (LASEK). In this procedure dilute alcohol suspension is used to detach the 

epithelium which can thereafter be lifted. Alternatively, in Epi-LASIK a mechanical 

microkeratome is used to scrape the epithelium. In 1995, the US Food and Drug 

Administration (FDA) approved the use of PRK for spherical myopic correction, followed 

by myopic astigmatism in 1997. In 1998, the FDA approved hyperopic correction pursued 

by hyperopic astigmatism in 2000. A wide spectrum of PRK corrections has been 

approved by the FDA, myopic corrections up to -12.0 D, hyperopic corrections up to +6.0 

D and astigmatism corrections up to 4.0 D, yet for PRK myopic manifest refraction of 

spherical equivalent (MRSE) correction between -1.0 diopters (D) to -7.0 (D) are, 

however, closer to today’s criteria (Waring 2008). After Bowman’s layer exposure the 

laser is directed to ablate the corneal surface. Myopic treatments primarily ablate the 

central cornea, and hyperopic treatments perform an annular shape ablation at the 

periphery. Astigmatism treatments have different approaches depending on type of 

astigmatism. Earlier, smaller optical ablations zones (4 to 4.5 mm) were used to reduce 

the depth of ablation, yet the presence of glare and halos led to an increase in the size of 

the ablation (Epstein et al. 1994, Kalski et al. 1996, Kim et al. 1996, Morris et al. 1996). 

Large ablation diameters and the use of transition zones have improved the postoperative 

results (Dausch et al. 1993, O'Brart et al. 1995, O'Brart et al. 1996, Rajan et al. 2006). 

Nowadays, the most commonly used optical zones of 6.5 mm and 7 mm are used for 

myopic and hyperopic treatments respectively, both of them surrounded by a transition 

zone of 9 mm (Albert and Jakobiec's. 2008). 

2.3.5 Laser assisted in situ keratomileusis (LASIK) 

LASIK uses the same PRK laser technology but performs the procedure at the stromal 

level after the creation of a lamellar flap consisting of epithelium, Bowman’s layer and 

anterior stroma (Updegraff and Kritzinger 2000). Corneal lamellar dissection was first 

described in 1949 by Jose Barraquer (Barraquer JI 1949) known to many as "the father of 

modern refractive surgery.” At that time Professor Barraquer introduced the 

microkeratome, a high precision surgical device that enabled the creation of a flap of 

corneal tissue. In 1964, Barraquer performed the first successful reported lamellar surgery, 

20

at that time an extracorporeal treatment that he called keratomileusis (Barraquer JI 1964) 

derived from the Greek root keratos (cornea) and mileusis (carving) for sculpture. After 

the manual dissection of a corneal cap with a microkeratome, a cutting machine modelled 

after a carpenter’s plane, the corneal cap was reshaped in a laboratory. During the 1980s, 

Luis A. Ruiz developed the first automated microkeratome that made it possible to create 

a corneal cap, and to remove a second corneal disc performing the first keratomileusis in 

situ or automatic lamellar keratoplasty (ALK) (Ruiz and Rowsey 1988). In 1990, 

Pallikaris (Pallikaris et al. 1990) described the use of a microkeratome in junction with the 

excimer laser, and coined the term Laser in-situ keratomileusis (LASIK). Later advances 

included the use of laser to create a corneal flap. The femtosecond lasers (FS) use an 

infrared (1053 nm) scanning pulses to cut the corneal stroma creating precise lamellar 

flaps for LASIK (Nordan et al. 2003, Sugar 2002). 

LASIK has become the most widely performed refractive surgery nowadays (Sandoval et 

al. 2005). This preference over PRK is based in less postoperative pain, haze formation 

and regression and faster visual recovery (Azar and Farah 1998, el Danasoury et al. 1999, 

Helmy et al. 1996, Shortt and Allan 2006, Steinert and Hersh 1998). 

2.3.5.1 Microkeratome 

Manual microkeratomes evolved from the Barraquer device. This apparatus performs a 

manual horizontal lamellar cut using a translational movement across the cornea, yet it 

required high surgical skills to create reproducible flaps, making them obsolete. In 1986 

Ruiz and Rowsey (Ruiz and Rowsey 1988) introduced the automated mechanical 

microkeratome that performed constant flaps with smooth surfaces. Since then, several 

microkeratomes have been developed and are currently available, each of them with 

different specifications in oscillation, blade angle, hinge location and flap thickness. 

Basically, the microkeratome consists of a corneal shaper head, a motor, and a pneumatic 

fixation ring. Once these parts are assembled they are connected to a control unit that 

contains the electrical source power and a suction pump. A blade (stainless steel or plastic) 

is inserted inside the corneal shape head that oscillates in a range of 2000 to 20000 rpm 

depending of the microkeratome (Belin and Schultze 2000). The suction rings which allow 

the ocular globe to be hold have differents diameter varying from 8 to 10.75 mm. The 

diameter of the flap has a direct relation to the size of the suction ring and the keratometric 

values (Belin and Schultze 2000). Large ring diameters or steeper corneas (high K values) 

result in larger flaps, small ring diameters or flatter corneas (low K values) generate 

smaller flaps. Yet the microkeratome footplate is the most important factor that influences 

flap thickness. Hinge location can be nasally or superiorly, yet less compromise of the 

corneal sensitivity has been found with superior hinge flaps (Kumano et al. 2003). 

In 2000, the FDA approved the IntraLase femtosecond laser (FS) for corneal surgery. 

This solid state laser creates lamellar flaps using infrared scanning pulses that create small 

cavitations burbles (Ratkay-Traub et al. 2003) without damage of the adjacent tissue with 

an accuracy of 1 µm. It employs a suction ring, with an applanating glass contact lens that 

creates low pressure (between 10 and 35 mmHg) (Sugar 2002). Initially it used pulse rates 

21

of 10 kHz requiring relatively a long time of flap creation, but, nowadays the current FS 

laser fires at a rate of 60 kHz resulting in much lower times for flap creation. Fifth 

generation FS have even reached a firing rate of 150 kHz further reducing the flap creation 

time and decreasing the energy needed. The major advantages of FS laser systems over 

microkeratomes are increase in flap homogeneity and a higher rate of reproducibility. A 

capacity to create flaps of different diameters and thicknesses, even under 90 µm have 

decrease the flaps related complications (Durrie and Kezirian 2005, Kezirian and 

Stonecipher 2004) and increases postoperative flap adhesion (Knorz and Vossmerbaeumer 

2008). Complications with FS are rare, being most commonly transient light-sensitive 

syndrome (TLSS) and diffuse lamellar keratitis (DLK). The mechanism of TLSS is still 

unknown, yet it seems to be secondary to an inflammatory response to the gas bubbles or 

keratocytes’ response to laser ablation. 

Postoperative visual outcomes between microkeratomes and FS have not shown any 

differences (Javaloy et al. 2007, Montes-Mico et al. 2007a), although the contrast 

sensitivity seems to be better after FS (Montes-Mico et al. 2007b), yet the complication 

rate between both groups is similar (Moshirfar et al. 2010). 

2.4 CORNEAL WOUND HEALING 

Wound healing is essential to maintain the transparency and optical properties of the 

cornea. Physiology diversity in response to injury is a major factor in outcome results after 

refractive surgery. PRK and LASIK differ in the intensity of corneal wound healing. This 

difference seems to be secondary to the preservation of epithelium and Bowman’s layer 

after LASIK (Ambrosio and Wilson 2003, Helena et al. 1998, Mohan et al. 2003, Tervo 

and Moilanen 2003, Wilson et al. 2007) and the amount of depth of photoablation in both 

procedures (Moller-Pedersen et al. 1998, Moller-Pedersen et al. 2000). 

The mechanisms behind corneal wound healing response form a complex cascade of 

events involving epithelial cells, keratocytes, corneal nerves, lacrimal glands, tear film, 

and cells of the immune system. Cytokines and growth factors are the soluble factors that 

mediate the signals and interaction between different cells and components to restore 

corneal functionality. In the following I will describe corneal wound response in different 

layers of the cornea in more detail. 

Epithelial corneal debridment from its basement membrane generates apoptosis in 

keratocytes followed by simple epithelial replacement by mitosis without any fibrosis. If 

epithelial injury compromises the basement membrane it stimulates a fibrotic response 

(Zieske et al. 2001). In the case of PRK the fibrotic response involves a higher area 

compared to LASIK in which the fibrosis response is limited to the edges of the flap 

created by the microkeratome. 

Immediately after an epithelial injury an anterior stromal keratocyte apoptosis can be 

observed (Dupps and Wilson 2006, Wilson et al. 1996). This continues for at least one 

week. This response is mediated by the release of cytokines such as Interleukin (IL)- 

1(Wilson et al. 1996), tumour necrosis factor (TNF)-α (Wilson et al. 2001), epidermal 

growth factor (EGF) and platelet derived growth factor (PDGF) (Tuominen et al. 2001). 

22

Twelve to 24 hours after the onset of keratocyte apoptosis keratocytes start to migrate and 

proliferate in the anterior stroma along with differentiation in myofibroblasts more 

posteriorly (Helena et al. 1998, Jester et al. 1992, Mohan et al. 2003, van Setten et al. 

1992). These events are probably mediated by various tear fluid and tissue-derived growth 

factors such as transforming growth factor beta (TGF-B), hepatocyte growth factor (HGF) 

and other cytokines that increase in tears following corneal wounding (Tervo et al. 1997). 

Inflammatory cells (macrophages/monocytes, T cells and polymorphonuclear cells) are 

attracted into the corneal stroma from the limbal blood supply and the tear film (Helena et 

al. 1998) to eliminate the apoptotic cells and necrotic debris. Activated keratocytes start to 

deposit new extracellular matrix (ECM) that can be observed as early as seven days after 

injury (Linna and Tervo 1997) followed by a stromal re-growth already documented in 

three-dimensional images (Jester et al. 1999, Moller-Pedersen et al. 1997). Different 

factors (Moller-Pedersen et al. 1997, Netto et al. 2006, Tuunanen et al. 1997) such as the 

volume of stromal tissue removed or irregularities of the stroma have been shown to act in 

concert and to regulate the stromal repair and formation of scar tissue or “haze”. 

After an epithelial injury, the first observable change at the stroma is the keratocyte 

apoptosis followed by the activation of quiescent keratocytes. Helena et al. (Helena et al. 

1998) showed that the extension and location of epithelial injury correlates with the 

keratocytes response. Anterior stromal fibrosis (haze) is caused by a synthesis of a new 

ECM by activated keratocytes (Moller-Pedersen et al. 1997, West-Mays and Dwivedi 

2006) that lose their ability to express corneal crystalline proteins (Pei et al. 2004) and a 

secondary increase in cellular reflectivity (Moller-Pedersen et al. 2000) that decreases the 

normal corneal transparency. 

The central keratocyte density measured by corneal confocal microscopy (CM) 

reported a density of 22 522 ± 2 981 cells/mm 3 (mean ± SD) in normal corneas (Moilanen 

et al. 2008, Patel et al. 2001) with a higher density in the anterior than in the posterior 

stroma (Erie et al. 2006, Moilanen et al. 2008, Moller-Pedersen et al. 1997, Prydal et al. 

1998). Earlier reports (Muller et al. 1996, Muller et al. 2003) have demonstrated the direct 

innervations of individual keratocytes by nerve bundles at the central stroma. Six months 

postoperatively the keratocyte apoptosis is more extensive in the anterior stroma after 

PRK than after LASIK. CM after PRK has shown that there is a concomitant decrease in 

the number of keratocytes in the anterior corneal stroma that continues as long as five 

years after the procedure and starts to compromise the middle and posterior stroma after 

this time (Erie et al. 2006, Moilanen et al. 2008). In the case of LASIK, the keratocyte 

density is also decreased in the anterior and posterior stromal flap and in the anterior 

retroablation zone (Erie et al. 2006, Moilanen et al. 2008, Vesaluoma et al. 2000a) even 

after five years (Erie et al. 2006). Flap denervation (Mitooka et al. 2002, Vesaluoma et al. 

2000a) and chronic liberation of cytokines secondary to arrested corneal epithelial cells 

located in the flap interface (Erie et al. 2006, Wilson et al. 2001) have been proposed to 

explain the chronic decrease of keratocytes in the anterior flap. A question that remains 

unanswered is the clinical significance of this decrease in keratocytes as well the 

minimum number of keratocytes required to keep the cornea viable. 

Both PRK and LASIK damage corneal nerves and generate changes in corneal 

sensitivity (Benitez-del-Castillo et al. 2001, Campos et al. 1992, Erie et al. 2005, Ishikawa 

23

et al. 1994, Kanellopoulos et al. 1997, Tervo and Moilanen 2003) and in the corneatrigeminal 

nerve-brainstem-facial nerve-lacrimal gland reflex arc (Battat et al. 2001, 

Benitez-del-Castillo et al. 2001, Linna et al. 2000b, Wilson and Ambrosio 2001). 

PRK injures the epithelial nerve ends, epithelial and subepithelial plexuses, and 

anterior stromal nerves. Histological (Tervo et al. 1994, Trabucchi et al. 1994) and CM 

studies (Erie et al. 2005, Tervo and Moilanen 2003) have assessed information on nerve 

regeneration after PRK. These findings showed regenerated fibres at one day post-PRK in 

histological sections, and visible by CM by seven days post-PRK. Corneal sensitivity 

correlated with the changes observed. Sensitivity begins to recover after one week and 

reached almost normal values three months later (Matsui et al. 2001, Perez-Santonja et al. 

1999). However, long-term morphological alterations were visible even one year later 

(Tervo et al. 1994) and subbasal nerve density examined by CM was not reached until two 

years after PRK (Erie et al. 2005, Moilanen et al. 2008). 

In LASIK, the lamellar incision cuts the bundles of nerve fibres of the superficial 

stroma and the subbasal nerve plexus. Yet postoperatively in the flap, the epithelial and 

basal epithelial/subepithelial nerves took a few days to disappear except for the hinge (Lee 

et al. 2002, Tervo and Moilanen 2003). Regeneration of anterior stromal, subbasal and 

epithelial fibres occurred approximately three months later although deep stromal nerves 

showed abnormal morphology five months after LASIK (Latvala et al. 1996, Linna et al. 

1998). Corneal sensitivity after LASIK measured by mechanical aesthesiometers reported 

a decrease of sensitivity one to two weeks after LASIK (Donnenfeld et al. 2004, Linna et 

al. 2000a) which recovered to normal level six to 12 months later. New noncontact 

aesthesiometers reported hypersensitivity one week post-LASIK followed by a decrease in 

sensitivity three to five months later. Near normal values has been reported two years after 

the procedure (Gallar et al. 2004, Tuisku et al. 2007). Post-LASIK corneal subbasal nerve 

density measured by CM showed a slower regeneration compared to PRK reaching nearly 

preoperative values five years after LASIK (Erie et al. 2005). An earlier study (Tuunanen 

et al. 1997) stressed the importance of corneal nerve density and nerve recovery to avoid 

haze. LASIK-induced neurotrophic epitheliopathy (LINE) is a term proposed by Wilson 

and Ambrosio (Wilson and Ambrosio 2001, Wilson 2001) to describe an entity in post- 

LASIK patients complaining of ocular discomfort resembling dry eye symptoms although 

corneal sensitivity and dry eye are normal (Tuisku et al. 2007). Transection of afferent 

sensory nerve fibres and aberrant regenerated corneal nerves are likely to be among the 

most important factors associated with this entity (Ambrosio et al. 2008). Some studies 

(Tuunanen et al. 1997, Wilson 2001, Tuisku et al. 2007) suggest that the modulation of 

corneal wound healing, post-operative anterior stromal scarring, or even symptoms 

showed a direct relation with corneal subbasal nerve plexus to maintain corneal healing 

and transparency. 

Several factors have been associated with more severe compromise of sensitivity after 

LASIK compared to PRK, including lamellar cut, thickness, (Nassaralla et al. 2005) 

orientation and width of the flap, (Donnenfeld et al. 2004) and ablation depth (Bragheeth 

and Dua 2005, De Paiva et al. 2006, Kim and Kim 1999, Shoja and Besharati 2007). Thin, 

nasally placed flaps, broader hinge and smaller ablations are associated with less 

compromise of corneal sensitivity. 

24

2.5 PREOPERATIVE ASSESSMENT OF REFRACTIVE 

SURGERY 

Corneal curvature by videokeratography needs to be measured. Pathology in corneal 

curvature is a contraindication to corneal refractive surgery, unless the procedure has a 

therapeutic aim. Different reported scales are available, yet the absolute and the 

normalized colour-scale are the most used. 

Pupil size under different light conditions, bright and dim, should be tested. Large 

pupil size under scotopic conditions has been associated with postoperative complaints of 

glare and halos (O'Brart et al. 1995, O'Brart et al. 1996, Rajan et al. 2006). Accordingly, 

the laser ablation zone should be 6 - 9 mm. Yet widening the ablation diameter increases 

the depth of ablation and thus the risk of post operative corneal ectasia (Rabinowitz 2006). 

Proper measure of central corneal thickness is crucial before refractive surgery. A 

residual corneal thickness between 300 and 250 µm should be left untouched in the 

posterior cornea after flap creation in LASIK patients to prevent the risk of postoperative 

ectasia (Randleman et al. 2003, Randleman et al. 2008, Wang et al. 1999). To date, the 

most commonly used method of measuring corneal thickness is ultrasound pachymetry 

(US). Some other optical techniques such as slit scanning elevation topography or hybrid 

slit-scanning topography, Scheimpflug imaging, or optical coherence tomography (OCT) 

have gained popularity (Rabinowitz 2006). Yet some of these techniques report thicker 

corneas than US (Cairns and McGhee 2005). 

Wavefront (WF) techniques measure the complete refractive status of the eye. WF 

aberration is defined as a deviation between an ideal optical system and the WF that 

originates from the measured optical system (Maeda 2001). These aberrations are 

classified as low order aberrations (sphere, cylinder aberrations) than can be corrected by 

spectacles and the high order aberration (HOA) that cannot. It also gives reason to suspect 

early corneal pathologies, such as keratoconus. In terms of vision, HOA can blur the 

quality of vision having a greater effect in scotopic conditions being a potential source of 

reduced image quality (Wang et al. 2003). Postoperative results after wavefront 

customized corneal ablations have shown excellent results (Kim et al. 2004, Kohnen et al. 

2004, Mastropasqua et al. 2004, Phusitphoykai et al. 2003). However, the superior results 

of customized ablations vs. traditional corrections are still a matter of discussion. 

Dry eye is one of the most common complications after laser refractive surgery (De 

Paiva et al. 2006, Lui et al. 2003, Quinto et al. 2008). Tear production usually decreases 

after refractive surgery (Ozdamar et al. 1999, Siganos et al. 2000). Preoperative dry eye 

condition is a major risk factor for more severe or symptomatic dry eye after surgery. 

Lower tear function is a factor for postoperative dry eye, and thus tear production and 

quality should be assessed prior to surgery. Surface ablations present a lower risk of 

developing dry eye (Lee et al. 2000) than intrastromal ablations (Albietz et al. 2004, Battat 

et al. 2001, Toda et al. 2001). PRK and LASIK seem to generate a tear deficient dry eye 

which is mediated by neural- mechanisms, with a recovery rate more delayed after LASIK 

than after PRK (Ang et al. 2001, Lee et al. 2000). Postoperative dry eye symptoms after 

LASIK have been suggested to be secondary to a neurotrophic epitheliopathy rather than a 

true dry eye (Ambrosio et al. 2008, Wilson 2001) probably as a consequence to aberrantly 

25

egenerate corneal nerves. Direct connections between postoperative dry eye symptoms 

and deep ablations have been suggested (Tuisku et al.). Patients should be informed of the 

possibility of developing chronic dry eye symptoms after laser refractive surgery, 

especially after deep ablations by LASIK. 

2.6 VISUAL ACUITY AND REFRACTIVE RESULTS AFTER 

EXCIMER LASER SURGERY 

In general the results of excimer laser corneal surgery are good, although measured 

parameters after refractive surgery differ in most publications, making direct comparisons 

difficult. Since the end of the 1990s standard guidelines for reporting outcomes after 

refractive surgery have been proposed by the editorial staffs of the Journal of Cataract 

and Refractive Surgery and the Journal of Refractive Surgery (Koch et al. 1998, Waring 

2000). Since then, most studies have reported results based on range groups of manifest 

refraction of spherical equivalent (MRSE) corrections and treatment modalities or laser 

platforms. The guidelines recommended assessing the efficacy, safety and stability of 

postoperative outcomes. 

The efficacy of refractive surgery is assessed by determining the proportion of eyes 

achieving a postoperative UCVA ≤0.0 (logMAR scale) or ≥20/20 (Snellen scale), which 

corresponds to the statistical mean visual acuity of the population, and/or the proportion of 

eyes achieving a UCVA ≤0.5 (logMAR scale) or ≥20/40 (Snellen scale), which 

corresponds to the threshold to measure the functional visual ability to drive in some 

Western countries, and the percentage of eyes with MRSE within ±1.00 diopters (D) or 

±0.50 D of the attempted correction. 

The safety of refractive surgery is determined by the percentage of patients with 

postoperative loss of 2 or more lines of BCVA after surgery, and also by the incidence of 

surgical and postoperative complications. 

The stability of refractive surgery is determined by the mean change in MRSE over a 

certain interval of time. 

2.6.1 PRK outcomes 

Published data on postoperative outcomes of PRK with at least one-year follow-up 

(Amano and Shimizu 1995, Chan et al. 1995, Goes 1996, Haw and Manche 2000, 

Keskinbora 2000, McCarty et al. 1996a, Nagy et al. 2001, Snibson et al. 1995, Spadea et 

al. 1998, Stevens et al. 2002, Tuunanen and Tervo 1998, Waring et al. 1995) and reviews 

(American Academy of Ophthalmology 1999, Ang et al. 2009, Reynolds et al. 2010, 

Sakimoto et al. 2006, Seiler and McDonnell 1995, Stein 2000, Steinert and Bafna 1998) 

report good efficacy, safety and stability. More recently, studies with at least five years of 

follow-up (Alio et al. 2008a, Alio et al. 2008b, Bricola et al. 2009, Honda et al. 2004, Kim 

et al. 1997, Koshimizu et al. 2010, Pietila et al. 2004, Rajan et al. 2004, Shojaei et al. 

26

2009, Stephenson et al. 1998) have demonstrated that these results persist over time (Table 

1). 

Most studies with short follow-up reported a postoperative UCVA ≥20/50 (logMAR 

0.4) in more that 80% of eyes. This value in long-term follow-up studies continues, yet 

attempted corrections (over 6 D) tend to decline in efficacy (Alio et al. 2008a, Alio et al. 

2008b). Predictability of MRSE within ± 1.00 D after one to three years postoperatively 

has been reported in ~ 70% of eyes (Bricola et al. 2009, Honda et al. 2004, Kim et al. 

1997, Koshimizu et al. 2010, Pietila et al. 2004, Rajan et al. 2004, Shojaei et al. 2009, 

Stephenson et al. 1998). In long-term follow-up studies predictability of MRSE within ± 

1.00 D varies between 34 to 91%. These differences can be explained by the inclusion 

criteria used, the postoperative goal, the amount of correction attempted, and even the 

parameters reported to have been used in the studies. This is the case, for instance, in 

Rajan et al. (Rajan et al. 2004), who reported a variation of MRSE within ± 1.00 D in 75% 

and 22% of eyes who underwent an attempted correction of -2 D and -7 D respectively. 

Yet long-term follow-up studies including and reporting correction less that -7.5 D 

without subgroups (Alio et al. 2008a, O'Connor et al. 2006, Pietila et al. 2004) (325 eyes) 

reported MRSE within ±1.00 D in more than 75% of the eyes at last follow-up round. On 

average, the postoperative loss of 2 or more lines of BCVA seems to be less than 4% 

(Steinert and Bafna 1998). This percentage has been reported to increase in corrections 

over 6 D (Alio et al. 2008b). Corneal postoperative haze, that could explain loss of lines of 

BCVA, has been reported to have cleared within 12 months in low correction and within 

24 months in moderate –high corrections (Fagerholm 2000, Moilanen et al. 2003). Some 

of the losses of BCVA in long-term studies were reported to be secondary to ocular 

pathologies instead of postoperative complications. PRK studies have previously 

demonstrated that stability tends to be reached in the first 6-12 months (Klyce and Smolek 

1993, Kremer and Dufek 1995, Pallikaris and Siganos 1994). A positive correlation has 

been found between regression and high myopic attempted correction (Rajan et al. 2004, 

Seiler and McDonnell 1995, Steinert and Bafna 1998, Stephenson et al. 1998), and inverse 

correlation with age (Rajan et al. 2004, Stephenson et al. 1998). The highest myopic 

regression reported in PRK studies was 1.60 D (Amano and Shimizu 1995). In long-term 

studies no significant difference was found in change of MRSE at one, six, and 12 year 

follow-up (Rajan et al. 2004). However, a slight but continuous myopic regression has 

been reported in all other long-term follow-up studies (Alio et al. 2008a, Alio et al. 2008b, 

Bricola et al. 2009, Honda et al. 2004, Kim et al. 1997, Koshimizu et al. 2010, Pietila et al. 

2004, Shojaei et al. 2009, Stephenson et al. 1998). 

27

Table 1 Postoperative outcomes of myopic long-term PRK studies 

Sample 

Size 

(Eyes) 

Male/ 

Female 

N 

Mean Age 

(Range) (Y) 

Follow-up 

Period (Y) 

Range of Pre- 

operative myopic 

MRSE 

28 

UCVA ≥ 

20/40 (%) 

MRSE Within 

±1.0 D (%) 

Loss of 2 or 

More Lines of 

BCVA (%) 

Mean Myopic 

Regression (D) 

Pietila et al. 2004 69 30/39 31 (19−54) 8 ≤6.0 78.3 78.3 0 0.4 

O'Connor et al. 

2006 

Honda et al. 2004 15 7/1 

58 18/21 32 (20−54) 12 1.8–7.3 91.3 81.1 0 0.6 

29 

(20 -42) 

5 3.0 – 9.0 100 NR NR 0.9 

Kim et al. 1997 201 NR NR 5 2.3–12.5 NR NR NR NR 

Koshimizu et al. 

2010 

42 13/16 

Alio et al. 2008a 225 72/66 

Alio et al. 2008d 267 89/192 

Rajan et al. 2004 118 NR 

Shojaei et al. 

2009 

Stephenson et al. 

1998 

33.4 

(21-60) 

30.1 

(17-66) 

32.1 

(8 - 66) 

46 

(34-70) 

10 2.5 -14.1 81 55 0 0.5 

10 1.0-5.9 77 75 3.1 0.2 

10 6.0-17.8 63 58 11.6 0.8 

12 2.0 -7.0 NA 34 1.4 

0.3 (30-40 Y) 

0.1 (40- 50 Y) 

0.2 (50- 60 Y) 

194 69/38 33.4 (20-58) 8 4.7 -14.5 73.1 79.3 2

2.6.2 LASIK outcomes 

Although LASIK is the most common laser refractive surgery currently performed in the 

world, long-term studies are scarce. LASIK short-term studies (Bahar et al. 2007, 

Kawesch and Kezirian 2000, Lindbohm et al. 2009, Lyle and Jin 2001, Magallanes et al. 

2001, Maldonado-Bas and Onnis 1998, Neeracher et al. 2004, Rashad 1999, Salchow et al. 

1998, Sugar et al. 2002) have shown that the procedure is effective and predictable in 

terms of obtaining good UCVA and that it is also safe with minimal loss of visual acuity. 

In terms of efficacy, short-term follow-up studies have reported that about 95% of eyes 

reached UCVA ≥20/50 (logMAR 0.4) when attempted myopic correction was less than ≤7 

D. However, this value tends to decline when attempted corrections are higher (Ang et al. 

2009, Sakimoto et al. 2006). Predictability of MRSE within ± 1.00 D was reported in 

about 95% of eyes with attempted correction less than 6 D, and this decreased to 80-85% 

with higher corrections (Sakimoto et al. 2006). Safety after LASIK with loss of 2 or more 

lines of BCVA has been reported to be ~ one % for low-moderate and high corrections. 

Regression up to 1.00 D in high corrections has been found post-LASIK (Kawesch and 

Kezirian 2000). 

Long-term studies (Table 2) with a follow-up longer than five years (Alio et al. 2008c, 

Alio et al. 2008d, Kato et al. 2008, Kymionis et al. 2007, Liu et al. 2008, O'Doherty et al. 

2006, Sekundo et al. 2003) after LASIK have focused on high corrections, with modest 

results. One of these reports (Alio et al. 2008d) have studied postoperative outcomes in 

eyes with less than 10 D corrections and reported that 90% of eyes were within UCVA 

≥20/50 and MRSE within ±1.00 D in 75% of eyes at 10 years. Loss of lines of BCVA 

seems to be around three %, but its rose to a very alarming 27% when high corrections 

were analysed (Kymionis et al. 2007). 

Stability at long-term is reached at around 3 months after surgery. A faster regression 

in the first two years followed by a slower rate of regression has been reported (Alio et al. 

2008d, Liu et al. 2008, O'Doherty et al. 2006). 

2.6.3 Comparison of myopic outcomes after PRK and LASIK 

Several studies have compared PRK and LASIK outcomes at least one year after surgery 

(el Danasoury et al. 1999, El-Maghraby et al. 1999, Helmy et al. 1996, Wang et al. 1997). 

In low-to-moderate attempted corrections (≤6. 00 D) efficacy and safety were similar, yet 

stability was reported to be better after LASIK than after PRK. In corrections over 6.00 D 

efficacy, safety and stability were superior in LASIK. In a recent editorial Waring GO 

(Waring 2008) compared the long-term results of PRK and LASIK (Waring 2008) closer 

to today’s criteria (≤ than 6.00 and 10.00 D for PRK and LASIK respectively) and 

concluded that PRK showed more regression and loss of lines of BCVA than LASIK. 

29

Table 2 Postoperative outcomes of myopic long-term LASIK studies 

O'Doherty et al. 

2006 

Alio et al. 

2008c 

Alio et al. 

2008d 

Sample Size 

(Eyes) 

Male/ 

Female N 

Mean Age 

(Range) 

(Y) 

Follow-up 

Period (Y) 

30 

Range of 

Pre- 

operative 

MRSE (D) 

UCVA 

≥20/50 (%) 

MRSE 

Within ±1.0 

D (%) 

Loss of 2 

or more 

Lines of 

BCVA 

(%) 

Mean 

Myopic 

Regression 

90 26/23 39 (NR) 5 1.5– 13.0 89 83 0 0,5 

196 52/66 

97 33/36 

32.9 

(18 -58) 

33.2 

(17 - 57) 

10 10 - 24 40 42 5 1.61 

10 < 10 90 73 3 0.91 

Kato et al. 2008 779 221/181 34.6 (NR) 5 0.7- 14.5 NR 90 1.3 NR 

Sekundo et al. 

2003 

Kymionis et al. 

2007 

33 NR 

11 2/5 

Liu et al. 2008 104 60/44 

• NR: Not reported 

39.9 

(28 - 59) 

41.7 

(34 -50) 

NR 

(22– 41) 

6 5.3 - 17.5 33 46 15 0.6 

11 10.0 -19.0 46 55 27 NR 

7 3.3-15.2 100 90 1 0 

(D)

2.7 PRK AND LASIK COMPLICATIONS 

Excimer laser refractive surgery complications, although not frequent, do occur. 

Complications may arise intraoperatively or during the postoperative period (Filatov et al. 

1997, Ghadhfan et al. 2007, Melki and Azar 2001, Stein 2000). Both procedures, PRK and 

LASIK, have postoperative over-undercorrections that need enhancement (Hersh et al. 

1998, Pop and Payette 2000). Some patients may develop glare, halos, monocular 

diplopia, changes in contrast sensitivity, and dry eye (Hersh et al. 1997, Hersh et al. 2000, 

Seiler and McDonnell 1995). Furthermore, long-term studies have demonstrated a 

postoperative regression (Hersh et al. 1998, Pop and Payette 2000). Intraoperative 

complications are more frequent after LASIK than after PRK, and are related to the 

intralamellar flap creation (Gimbel et al. 1998, Tham and Maloney 2000). Postoperative 

complications after LASIK include flap striae and folds, dislodging of the flap, interface 

debris, epithelial ingrowth, diffuse lamellar keratitis, and corneal infections (Davis et al. 

2000, Gimbel et al. 1998, Melki and Azar 2001). The most common intraoperative 

complications after PRK include decentration and central islands (Alio et al. 1998, 

Krueger et al. 1996, Seiler and McDonnell 1995). Postoperative complications after PRK 

are related to epithelial debridment and include pain, delayed epithelial healing, infection, 

and corneal scarring/haze (Alio et al. 1998, Stein 2000). 

Under and overcorrections and regression 

The most common complications after laser refractive surgery are under- and over 

corrections, with different prevalence among published studies (Alio et al. 2008a, Alio et 

al. 2008b, Alio et al. 2008c, Alio et al. 2008d, Bricola et al. 2009, Honda et al. 2004, Kato 

et al. 2008, Kim et al. 1997, Koshimizu et al. 2010, Kymionis et al. 2007, Liu et al. 2008, 

O'Doherty et al. 2006, Pietila et al. 2004, Rajan et al. 2004, Sekundo et al. 2003, Shojaei et 

al. 2009, Stephenson et al. 1998). In general after PRK, eyes tend to be slightly 

overcorrected soon after the operation, but the refraction stabilizes three to six months 

after surgery. Regression after PRK has been attributed to the differential changes in 

corneal thickness related to epithelial hyperplasia (Gauthier et al. 1996) and stromal 

remodelling (Moller-Pedersen et al. 2000) and may even continue up to five to ten years 

after PRK (Alio et al. 2008a, Alio et al. 2008b, Kim et al. 1997). Resynthesis of ECM by 

activated fibroblasts and altered keratocytes (Moller-Pedersen et al. 2000) appears to 

compensate the photoablated tissue at the anterior stroma leading to corneal re-steepening. 

Regression after LASIK seems to be secondary to an increase in the central epithelial 

hyperplasia leading to an increase in central thickness of the cornea (Chayet et al. 1998, 

Moilanen et al. 2008). A faster regression in the first two years followed by a slower rate 

of regression even ten years after LASIK has been reported (Alio et al. 2008d, Liu et al. 

2008, O'Doherty et al. 2006). Various preoperative ocular factors, such as refraction, 

keratometric values, size of optic zone and age have been associated with LASIK 

regression (Chen et al. 2007). 

31

Glare, halos, and contrast sensitivity 

Many studies have reported glare, halos, and impaired contrast sensitivity after laser 

refractive surgery, especially for correction of high myopia (Ambrosio et al. 1994, 

Holladay et al. 1999, Mutyala et al. 2000, Vetrugno et al. 2000). These complaints have 

been associated with large pupils and small ablation zones with abrupt transition areas. 

Increase of ablation zones and transition edges zones have alleviated most of the 

complaints, but not in all cases. Visual effect of glare, halos and reduction in contrast 

sensitivity may also arise from changes in the shape and corneal aberration structure 

induced by the laser (Holladay et al. 1999). Postoperatively the cornea becomes oblate 

(flat in the centre with steepening at the periphery) increasing the incidence of 

postoperative HOA (Endl et al. 2001, Holladay et al. 1999, Martinez et al. 1998, Oshika et 

al. 2006, Perez-Santonja et al. 1998). 

Decentration 

Although current active eye-tracking systems have reduced the incidence of decentration 

misalignment of the laser over the patient’s entrance pupil or eye movement may result in 

decentration. According to earlier reports (Cavanaugh et al. 1993, Wilson et al. 1991), 

ablations centred on the entrance pupil centre are more accurate than those centred on the 

corneal vertex. Eccentric ablation may induce irregular astigmatism, glare, monocular 

diplopia, decreased contrast sensitivity, or even impaired visual acuity. 

Central islands 

Central islands can occur after either PRK or LASIK. Central islands are characterized by 

circular or oval area of greater topographic power within an area of reduced corneal 

power, usually localized centrally. Compared to LASIK, PRK is more prone to this 

complication (Krueger et al. 1996), but most of them tend to resolve spontaneously within 

6 months (McGhee and Bryce 1996). LASIK, by contrast shows a small incidence of 

central island, however at 6 months may persist in a relatively high percentage of cases 

(Kang et al. 2000). The hypothesis about the nature of central islands includes different 

levels of corneal hydration in the centre and the periphery of the ablated zone (Dougherty 

et al. 1994, Oshika et al. 1998), or blockage of the laser beam by the ejected vortex plume 

and particulate debris generated during surgery (Noack et al. 1997). Nowadays, with the 

development of technology, the incidence of central islands is low. 

Pain 

Pain has been one of the major complaints post-PRK, and also one of the greatest 

advantages of LASIK over PRK. Pain usually intensifies in the first 24 hours after PRK 

followed by less intense discomfort abating as re-epitelization progresses, yet it may 

persist for weeks or months after surgery (McCarty et al. 1996b, Stein et al. 1994). Gallar 

et al. (Gallar et al. 2007) showed that post-PRK pain may be attributable to the direct 

injury of the nerve and the subsequent enhanced spontaneous activity developed by injured 

nerve fibres. Less importantly, the release of endogenous mediators may contribute to the 

maintenance of ongoing activity at the cut nerve fibres of the injured area. 

32

Dry eye 

Dry eye is one of the most common complications after refractive surgery (Hong and Kim 

1997, Sugar et al. 2002), being more often reported after LASIK than after PRK (De Paiva 

et al. 2006). Impairment in the ocular surface-lacrimal gland unit seems to be the origin. It 

is believed that transection of corneal nerves by the microkeratome is the main cause, 

besides the nerve damage caused by the excimer laser. Other possible causes have been 

attributed to alterations in the distribution of the tear film secondary to changes in the 

corneal shape and the relation with the ocular surface to the upper lid. In addition, it seems 

that post-LASIK dry eye represents a neurotrophic neuropathy most probably secondary to 

aberrantly regenerated corneal nerves rather than a real dry eye syndrome (De Paiva et al. 

2006). 

Scarring 

Postoperative superficial stromal opacification (haze) is a common finding after PRK. 

Haze appears to be the effect of an enhanced cellular reflection by activated keratocytes 

(Moller-Pedersen et al. 2000) and the subsequent synthesis of ECM (Moller-Pedersen et 

al. 1998). 

Haze after PRK begins during the first month postoperatively, peaks between the second 

and third months (Corbett et al. 1996), and decreases by six months to one year. Longterm 

follow-up studies have shown that induced haze may continue to disappear even after 

the first postoperative year (Rajan et al. 2004, Stephenson et al. 1998). Haze after LASIK 

is uncommon, and seems to be confined to the flap edges. 

Flap striae and interface debris 

Flap striae are classified into macro- and microstriae. Macrostriae are easily detected by 

retroilumination as parallel straight lines and are the results of flap dislocation. Microfolds 

are more common (Vesaluoma et al. 2000a), and seem to be related to the flap setting. The 

impact of microstriae on visual performance appears to be minimal, especially when they 

lie outside the pupil axis. Nevertheless, if they lie over the pupil or macrostriae coexist, 

they may induce higher-order aberrations (Pallikaris et al. 2002). In this case lifting the 

flap as soon as possible is indicated (Ambrosio and Wilson 2001, Linna et al. 2000b, 

Sugar et al. 2002). The presence of particles in the interface after LASIK is common, even 

with aggressive irrigation. An in vivo confocal microscope study revealed interface 

debrids in 100% of eyes 3 days after LASIK, which then decrease over time (Vesaluoma 

et al. 2000a). The particles presumably include cells, cell fragments (apoptotic bodies), 

debris, salt and metallic and plastic particles (Ivarsen et al. 2004, Perez-Gomez and Efron 

2003). Strangely enough, the use of FS has not decreased the incidence of interface debris 

after flap creation (Ramirez et al. 2007). 

Button hole 

Button hole, free caps, or incomplete flaps may be the result of either inadequate suction, 

excessively steep cornea (K>47 D), or a damaged blade. Other possible aetiologies 

include small eyes and deep eye sockets. A buttonhole occurs when the microkeratome 

blade runs more superficial than intended (Davis et al. 2000, Melki and Azar 2001). The 

33

formation of an epithelial defect allows epithelial–stromal interaction and facilitates scar 

formation (Li and Tseng 1995, Wilson 2001). As a result, these corneas show a variable 

degree of subepithelial haze and irregular astigmatism. 

Epithelial ingrowth 

Epithelial cells may grow in the flap interface after LASIK. Usually the cells are located at 

the periphery, at the flap edge, and do not progress toward the centre of the cornea (Davis 

et al. 2000, Melki and Azar 2001). The condition may also lead to flap melt (Alio et al. 

2000, Holland et al. 2000, Vesaluoma et al. 2000b), when the cells block the diffusion of 

aqueous humour and compromise flap nutrition. The areas involved in epithelial 

ingrowths show keratocyte activation, which is probably associated with the expression of 

proteolytic enzyme cascades (Ambrosio and Wilson 2001) which may also contribute to 

the melting of the flap. The epithelial tissue under the flap needs to be removed if the melt 

progresses (Ambrosio and Wilson 2001, Holland et al. 2000, Sugar et al. 2002). 

Corneal infections and inflammation 

Incidence of microbial keratitis has been reported only after LASIK and occurred in 0- 

0.16% of eyes (Lin and Maloney 1999). The pathogen in post-LASIK keratitis was most 

often staphylococcus aureus (Quiros et al. 1999, Rubinfeld and Negvesky 2001, Solomon 

et al. 2007). Other bacterial pathogens and fungal species have, however, been reported 

(Hamam et al. 2006, Moshirfar et al. 2007, Pache et al. 2003). The presence of bacterial 

ulcer on the LASIK flap is also rare (Chung et al. 2000, Lindbohm et al. 2005, Quiros et 

al. 1999, Rubinfeld and Negvesky 2001). The usual approach includes treatment with 

topical antibiotics and, if necessary, by lifting the flap and cleaning and rinsing the wound 

surfaces, or occasionally, in case of serious melt, by removal of the flap. DLK is a 

syndrome characterized by the appearance of diffuse white opacities at the LASIK flap 

interface in an inflamed cornea in the first week after refractive correction (Smith and 

Maloney 1998). The presence of a fine granular infiltrate in the interface periphery that 

looks like dust is the initial presentation. In 2000, Linebarger (Linebarger et al. 2000) 

proposed a classification based on the density and location of the corneal infiltrate. It can 

vary in severity from a mild self-limiting condition to severe inflammation. The aetiology 

of DLK is likely to be multifactorial (Johnson et al. 2001), being higher after flap creation 

by a FS than after flap creation with a mechanical microkeratome (Moshirfar et. al 2010). 

34

3 AIMS OF THE STUDY 

The general purpose of this study was to investigate the long-term safety, efficacy, and 

stability of excimer laser refractive surgery performed for myopia and/or astigmatism. To 

achieve this aim, we divided our study into five parts: 

1. The aim of Study I was to investigate the long-term results of PRK. 

Differences between the two most common laser delivery systems used in 

excimer laser were also evaluated. 

2. In Study II, we investigated the long-term results, subjective parameters, and 

late sequels of LASIK. 

3. Study III aimed to reveal possible differences and complications when 

moderate-to-high astigmatism was corrected with PRK or LASIK. 

4. The purpose of Study IV was to demonstrate the presence of irregular 

astigmatism, which may depend exclusively upon the corneal epithelium. 

5. The aim of Study V was to evaluate the role of corneal nerve recovery in 

corneal wound healing in eyes previously treated by LASIK and enhanced 

by PRK. 

35

4 PATIENTS AND METHODS 

4.1 PATIENTS 

The studies were carried out according to the tenets of the Helsinki Declaration and 

approved by the Ethical Review Committee of the Helsinki University Eye Hospital. 

Studies I, III, IV, V were retrospective studies, patients included in Study II attended a 

postoperative control seven to eight years after surgery. All patients and controls gave 

informed consent to their information being used in clinical studies. The patient 

demographics included in studies I –V is given in Table 3. 

Table 3 Preoperative demographic of patients enrolled in Studies I-V 

Study 

I 

Study 

II 

Study 

III 

Study 

IV 

Study 

V 

Patients 

n 

Eyes 

n 

Female/ 

Male 

Eye 

n 

Patients 

age 

(mean ± 

SD) 

• d: Day:; m: Month; y: Year 

36 

Laser 

procedure 

Mean 

MRSE 

Follow-up 

(range) 

46 61 24/37 28.5 ± 6.5 PRK -4.3 ± 1.5 8.3 -12. 2 y 

21 38 20/18 30 ± 6.8 LASIK -6.8 ± 1.7 6.7 – 8.2 y 

60 74 51/23 34.8 ± 9.7 PRK/ LASIK -5.4 ± 2.4 1 y 

9 11 5/6 47.2 ± 8.9 PTK/PRK -1.9 ± 1.9 15 -1704 d 

7 7 6/1 35 ± 10 PRK -6.5 ± 3.2 7 -29 m

4.2 PROTOCOLS 

The patients included in study I, II and III were recruited from a private clinic, 

Silmäkeskus Laser, in Helsinki, Finland. The patients included in Study IV and V 

belonged to a group of patients referred to Helsinki University Eye Hospital by other 

hospitals throughout the country or by private ophthalmologists. 

All patients were examined preoperatively and at the follow-up time stipulated in each 

study. UCVA, BCVA (logMAR scale), manifest refraction, corneal pachymetry, and VK 

were performed before excimer laser treatment. Exclusion criteria were 

immunocompromised patients, patients with uncontrolled uveitis, blepharitis, or any 

condition apart from their corneal pathology that could affect corneal healing. 

Postoperative control in all the studies included biomicroscopy, UCVA, BCVA, and 

manifest refraction. Study II additionally included a questionnaire to measure patient 

satisfaction after LASIK and a wavefront analysis. Study III included non-vector and 

vector analysis as described by Eydelman et al. (Eydelman et al. 2006) at each visit. In 

Study IV we studied pre- and postoperative VK. 

4.3 METHODS 

4.3.1 PRK/LASIK preoperative therapy 

The pre-postoperative medical therapy included either Ofloxacin (Exocin ® , Allergan, 

Irvine, CA, USA) or Levofloxacin (Oftaquix ® , Santen, Tampere, Finland) ophthalmic 

drops started the night before excimer laser and continued for a week 4 times a day. A 

drop of ketorolac tromethamine ophthalmic solution (Acular ® , Allergan, Irvine, CA, USA) 

or alternatively diclofenac sodium 0.1% (Voltaren ® Ophtha, Novartis, Basel, Switzerland) 

was used before the procedure. All patients received 25 mgs of oral diclofenac sodium 

(Voltaren ® , Novartis, Basel, Switzerland) 30 minutes before the operation.Oral diazepam 

(5–10 mg; Diapam ® , Orion, Helsinki, Finland) was prescribed for the first postoperative 

night. Prior to surgery the eyes were anaesthetized with topical 0.4% oxibuprocaine 

hydrochloride (Oftan Obucain ® ; Santen, Tampere, Finland). 

4.3.2 PTK procedure 

After scraping of the whole corneal epithelium except 0.5 – 1.0 mm from the limbus, PTK 

was performed on the debridement area. The PTK procedure was performed with a 6 mm 

central ring, 2 µm depth and 3 mm overlapping peripheral rings (6 – 8) covering the whole 

cornea. No masking agents were used. 

37

4.3.3 PRK procedure 

Laser ablation diameter was between 5.0 and 6.5 mm. The laser delivery system and 

software are described in detail in each study. Mechanical debridment of the epithelium 

with a Beaver eye blade (Becton Dickinson, Franklin Lakes, NJ, USA) was performed on 

the eyes included in Studies I, III and IV. Transepithelial ablation was performed on all 

eyes included in Study IV. Epithelial ablation was performed with a 6-mm central ring, 2- 

µm depth, and 3-mm overlapping peripheral rings (six to eight) covering the whole cornea 

with the same laser used for the PRK treatment. 

4.3.4 LASIK procedure 

The flap was created using a Hansatome microkeratome (Bausch and Lomb Surgical, Inc., 

San Dimas, CA). A superior hinge technique without suture was used (intended 

parameters were: thickness 160 µm, diameter 8.5 or 9.5 mm). Laser ablations data are 

given in each study. A balanced salt solution (BSS, Alcon Laboratories Inc., Fort Worth, 

TX, USA) was used to irrigate the cornea before and after the flap formation and after 

photoablation. 

4.3.5 PTK/PRK postoperative therapy 

Immediately after the procedure a soft contact lens (CL) was placed over the cornea for 

three days. After removal of the CL, chloramphenicol ointment (Oftan Chlora ® , Santen, 

Tampere, Finland) was applied three times daily for three days and, subsequently, for 

three nights. Fluoromethalone 0.1% drops (Liquifilm-FML ® , 1 mg/ml. Allergan Inc., 

Irvine, CA) starting on the fourth postoperative day, three times a day for the first two 

weeks, reduced to twice daily for the next two months and the tapered off by the three 

month. Carbomer eye gel (Viscotears ® , Novartis, Bagel, Switzerland) for at least one 

month was also used. Diclofenac sodium (25 mg) 2 – 3 times a day for the first days was 

used to alleviate postoperative pain. Mitomycin C was not used. 

4.3.6 LASIK postoperative therapy 

After the operation a soft CL was placed over the cornea for the first night and topical 

Ofloxacin (Exocin ® , Allergan, Irvine, CA, USA) twice a day was initiated. 

Fluoromethalone 0.1% drops twice a day (Liquifilm-FML ® , 1 mg/ml. Allergan Inc., 

Irvine, CA) were initiated once the CL was removed and continued for one week. In 

addition artificial tears (Oculac ® , povidone) were used for three months. 

38

4.3.7 Study subjects 

4.3.7.1 Study I. Longer-term PRK results 

The study included 61 PRK patients undergoing myopic or myopic astigmatism 

correction. Inclusion criteria for this study were preoperative myopic spherical refractive 

correction between -1.25 and -7.00 diopter (D) and myopic astigmatism lower than -2.50 

D. UCVA, BCVA, and manifest refraction at preoperative and at three months and at least 

eight years were collected. Twenty-seven excimer laser ablations were done with a broad 

beam laser (VISX (VISX Star VISX; Santa Ana, CA, USA) equipped with 2.5 software)) 

and 34 eyes with a scanning-slit laser (Nidek (NIDEK EC-5000, Nidek Technologies, 

Gamagory, Japan)).To ensure that the sample size was enough to detect significant 

differences between both delivery systems a retrospective power analysis was performed. 

4.3.7.2 Study II. Longer-term LASIK results 

The charts of 101 patients who underwent LASIK between 1999 and 2000 in a private 

clinic were located. These patients were invited to a free-of-charge ophthalmological 

examination seven to eight years after the surgery. Twenty-one patients (38 eyes) attended 

the follow-up. Laser ablations were done with the excimer laser (VISX Star (36 eyes) and 

Star2 (2 eyes), VISX; Santa Ana, CA, USA) equipped with 2.5 or 3.1 software. 

Preoperative examination included ophthalmological examination, UCVA, BSCVA, 

manifest refraction, US and VK. At each control UCVA, BCVA, and manifest refraction 

were assessed. At the last follow-up an additional questionnaire was adeministered and 

WF analysis (version 2.0 software; iTrace Technologies, Houston, Tex, USA) was 

performed. 

4.3.7.3 Study III. Correction of regular astigmatism 

A retrospective study that included 44 eyes treated with PRK and 30 eyes with LASIK. 

The inclusion criterion for this study was astigmatism >2.0 D. PRK treatments were 

performed with NIDEK EC-5000 (18 eyes), Visx 20/20 (5 eyes), Visx Star (4 eyes), Visx 

Star S2 (14 eyes) and Visx Star S4 (3 eyes). LASIK treatments were performed with Visx 

20/20 (1), Star (1), Star S2 (22) and Star S4 (6). Follow-up included a visit at six and 

twelve months. Non-vector and vector analyses were performed at each visit. Vector 

analysis estimates the surgically induced refraction correction (SIRC), the error vector 

(EV), the axis shift (AS), the normalized error vector (NEV), the error ratio (ER), the 

correction ratio (CR), the error of magnitude (EM), the error of angle (EA) and the 

treatment error vector (TEV). Briefly, the SIRC vector is the vector difference between the 

pre- and postoperative astigmatism correction vectors, and corresponds to the correction 

39

achieved. The EV is the vector difference between the intended refraction correction 

(IRC) and the SIRC. NEV is equal to EV, in magnitude, but it is rotated to allow easy 

visualization in the graphs. AS corresponds to the angular difference between the post- 

and preoperative manifest cylinder axes. ER is the proportion of the intended correction 

that was unsuccessfully treated. CR is the ratio of the correction magnitude achieved to the 

required correction. EM corresponds to the arithmetical difference in the magnitudes 

between SIRC and IRC, zero being the ideal result. EA measures whether the treatment 

was applied at the correct axis and TEV represents the magnitude of EM and the angle of 

EA containing both aspects of treatment error. 

4.3.7.4 Study IV. Correction of irregular astigmatism 

In Study IV, 11 eyes of 9 patients referred to the Helsinki Eye Hospital with diagnose of 

map-dot-fingerprint dystrophy and irregular astigmatism that did not respond to medical 

therapy were included. Our goal in this study was to call attention to the presence of 

irregular astigmatism, which may depend exclusively upon the corneal epithelium. Pre- 

and postoperative examination included ophthalmological examination, UCVA, BSCVA, 

manifest refraction and VK. Irregular astigmatism was assessed by VK according to the 

classification of Bogan et al. (Bogan et al. 1990) Irregular astigmatism was classified into 

two groups based on the possibility to define steep or flattened areas in the central and 

peripheral zones of the VK. The central zone was defined as an area of 3 mm. Group 1 had 

a VK with easily identifiable steep or flat areas and was divided into five basic types: 

Central elevation, central flat area, eccentric elevation, eccentric flat area and mixed. 

Group 2 had irregular astigmatism without pattern. 

4.3.7.5 Study V. PRK enhancement 

Seven eyes of seven patients who had had previous LASIK for myopia were retreated at 

least 2 years later by PRK. Inclusion criteria for PRK were flap-related complications 

during initial LASIK or strong adherences of the flap that prevented flap-lift retreatment. 

All eyes received transepithelial PTK/PRK using the Visx S4 excimer laser (Visx Co, 

Sunnyvale CA, USA). PRK treatment was limited to the flap thickness in order to preserve 

the residual stroma. On follow-up visits complete eye examination was performed. The 

postoperative corneal haze was graded subjectively during slit-lamp examination using the 

clinical grading scale (0+ to 4+) by Fantes (Fantes et al. 1990). 

4.3.8 Statistical methods 

In Studies I and III statistical analysis of paired outcomes was performed with the Mann- 

Whitney test for nonparametric comparison and one-way analysis of variance for repeated 

measures with the Bonferroni multiple comparison adjustment. The Kruskal-Wallis test 

40

with the post hoc Dunn multiple comparison was used to test for equality between the 

broad-beam group and the scanning-slit group (GraphPad Prism, version 4.03 for 

Windows, GraphPad Software). In Study II, statistical calculations were performed with 

Statview (version 5.0.1; SAS Institute Inc, Cary, NC) using analysis of variance with 

Bonferroni adjustment for repeated measures and non-paired t test. 

In Study IV, pre- and postoperative levels of BSCVA were compared with Wilcoxon 

signed rank t test (SPSS version 6.0; SPSS, Chicago, Ill). A P value less than 0.05 was 

considered statistically significant. 

41

5 RESULTS 

5.1 STUDY I AND II (PRK and LASIK long-term follow-up) 

Studies I and II measured the long-term postoperative results after PRK and LASIK. 

Details on patients demographics are given in Table 4. 

Table 4 Patients’ preoperative characteristic before PRK and LASIK 

Demographics PRK VISX PRK Nidek LASIK VISX 

Number of eyes 27 34 38 

Mean follow-up 10.3±0.7 9.8±0.4 7.5 ± 0.4 

Mean age (y ± SD) 28±5 28 ± 9 30 ± 6.8 

Men/Women 12/15 12/22 20/18 

Right/left eye 14/13 18/16 20/18 

Sphere (D ± SD) -4.3 ± 1.7 -3.9 ± 1.5 -6.5 ± 1.7 

Range of myopic 

Sphere(D) 

1.25 - 7 1.25 - 7 3.25 - 11 

Cyl (D ± SD) -0.4 ± 0.4 -0.5 ± 0.6 -0.63 ± 0.5 

Range of myopic 

cylinder 

0- 1.5 0 -2.5 0 - 2.3 

MRSE (D ± SD) -4.5±1.6 -4.2±1.6 -6.8 ± 1.7 

UCVA (mean ± SD) 2.8 ± 0.6 2.7 ± 0.7 2.9 ± 0.7 

BCVA (mean ± SD) -0.1±0.1 0.0±0.0 0.0 ± 0.1 

Efficacy: 

PRK 

UCVA ≤0.0 was achieved postoperatively in 74% and 62% of the eyes at three months, 

and at last follow-up these values were 55% and 65% after VISX and Nidek, respectively. 

UCVA ≤0.5 was achieved postoperatively in 100% of the eyes at three months and at last 

follow-up in both PRK groups. MRSE within ±0.5 D was found in 85% and 59% at three 

months after VISX and Nidek, respectively. At the last follow-up MRSE within ±0.5 D 

was found in 48% of the VISX treated eyes and 73% of the Nidek treated eyes. Ninetythree 

percent of VISX eyes and 85% of the Nidek eyes were within ±1.0 D of MRSE at 

three months and 85% (both groups) were within ±1.0 D at last follow-up. 

42

LASIK 

UCVA ≤0.0 was achieved postoperatively in 55% of the eyes at two months, 54% at two 

years, and 29% at the last follow-up (seven to eight years). UCVA ≤0.5 was achieved 

postoperatively in 100% of the eyes at two months, 97% at two years, and 87% at the last 

follow-up. This decrease in UCVA was statistically significant. At two months 75% of the 

eyes were within ±0.5 D and 83% of the eyes were within ±1.0 D of the MRSE. After two 

years these values were 63% and 83% respectively. At seven to eight years 34% of the 

eyes were within ±0.5 D and 42% were within ±1.0 D of the MRSE. 

PRK VISX vs. LASIK VISX 

Intended correction was significantly higher in LASIK eyes that in PRK eyes (p

Safety 

PRK 

In terms of loss/gain of visual acuity, 59% of the eyes in the VISX group at three months 

maintained the preoperative BCVA, 30% gained one line, and 11% lost one line. At the 

last follow-up 56% showed no changes in lines of BCVA and 22% showed increase of one 

line and four % two lines; 19% lost one line. In the Nidek group, 68% of the eyes at three 

months maintained the preoperative BCVA, 24% gained one line, six % gained two lines, 

and three % lost one line. At the last follow-up 71% showed no changes in BCVA and 

15% showed an increase of one line and three % two lines; 12% lost one line. There was 

no difference between groups in terms of gain or loss of BCVA. 

At the last follow-up, the mean BCVA was 0.0±0.1 (range 0.0 – -0.2) for both VISX 

and Nidek groups. Compared to preoperative BCVA, no significant differences were 

found at three months or at last follow-up in either group or between groups (p>0.05). 

Postoperatively, in the VISX group BCVA ≤0.0 was obtained in 96%, and 100% of the 

eyes at three months and at last follow-up respectively. In the Nidek group BCVA ≤0.0 

was obtained in 100% at three months and in 97% of the eyes at last follow-up. 

LASIK 

After two years 57% showed no changes in pre-LASIK BCVA and 32% showed an 

increase of one to two lines. Six % lost one line and six % lost to two lines. At last followup 

42% of the eyes preserved the pre-LASIK BCVA, 34% gained one line and 18% lost 

one line and five % lost two lines. Postoperatively, at two years the mean BCVA was 0.0 

± 0.0 (range 0.0 - -0.2), and at the last follow-up was 0.0 ± 0.0 (range -0.1 - 0.2). 

PRK VISX vs. LASIK VISX 

BCVA ≤0.0 was obtained in 89% of the eyes after LASIK and in 100% of the eyes after 

PRK at the last follow-up. No significant differences were found between LASIK and 

PRK (p>0.05). Safety results at last follow-up after PRK and LASIK are given in Table 6. 

44

Table 6 Safety postoperative values after PRK (VISX and Nidek) and LASIK (VISX) 

BCVA ≤0.0 

loss of 2 or more 

lines of BCVA 

Stability 

PRK 

PRK VISX PRK Nidek LASIK VISX 

100% 

45 

97% 

89% 

0% 0% 5% 

Three months after PRK mean MRSE was +0.1 D for VISX and +0.5 for Nidek. At last 

follow-up it changed to -0.7 D after VISX and -0.4 D after Nidek. Similar myopic 

regression was observed for both VISX and Nidek. In order to study the rate of regression 

we used the mean MRSE achieved at three months and compared that to mean MRSE 

achieved at last visit. We found that MRSE regressed by -0.09 D per year. 

LASIK 

In LASIK patients at first follow-up visit (2 months after procedure) mean MRSE was - 

0.41 D, then at two years -0.57 D, and at seven to eight years continued to decrease to - 

1.38 D. Change in MRSE was not statistically significant up to two years, whereas at last 

follow-up MRSE was significantly smaller compared to MRSE at two months (p

VISX PRK VS. VISX LASIK 

Postoperative stability seems to be slightly better after PRK than after LASIK. Although, 

preoperative Spherical Equivalent (SphEq) and Intended SphEq correction were statiscally 

higher in eyes treated by LASIK than in eyes treated by PRK. 

Figure 1 Stability values after PRK and LASIK 

Patient satisfaction after LASIK 

A questionnaire that included 8 questions related to postoperative satisfaction was 

distributed at last follow-up visit in the LASIK study. Patients were instructed to answer 

“yes” or “no” to the questionnaire. Response rate to the questionnaire was 86%. All 

respondent reported that they would have LASIK surgery again and that they considered 

that LASIK surgery had improved their quality of life substantially. Eighty-nine % were 

very satisfied with the surgery but only 55% were currently happy with their refractive 

status. Eleven % complained of visual performance in daylight and 39% complained of 

problems in dim light. Thirty-three % reported experiencing “tired eyes” in the past last 

month and 33% reported dry eye. Fifty-seven % did not wear corrective spectacles, 16% 

wore them occasionally, and 27% used spectacles for distance vision every day. 

46

5.2 STUDIES III AND IV. Regular and irregular astigmatism 

5.2.1 Regular astigmatism 

In study III we evaluated the postoperative outcomes of moderate-to-high astigmatism in 

eyes treated by PRK and LASIK by non-vector and vector analyses. 

Table 7 Patients’ preoperative characteristics before PRK and LASIK 

Demographics PRK LASIK 

Number of eyes 44 30 

Follow-up (months) 6 and 12 6 and 12 

Mean age (y ± SD) 36±10 33 ± 9 

Men/Women 13/23 6/18 

Right/left eye 25/19 14/16 

Sphere (D ± SD) -3.6 ± 2.3 -5.2 ± 2.4 

Range of myopic Sphere (D) 0.25 - 8.25 0 - 10 

Cylinder (D ± SD) -2.4 ± 0.5 -2.4 ± 0.4 

Range of myopic Cylinder (D) 0 - 1.5 2.0 – 3.5 

MRSE (D ± SD) -4.9 ±2.3 -6.5 ± 1.4 

UCVA (mean ± SD) 1.8 ± 0.7 2 ± 0.6 

BCVA (mean ± SD) 0.0±0.1 0.0 ± 0.0 

5.2.1.1 Non-vector results 

PRK vs. LASIK 

Efficacy 

Postoperatively, UCVA was significantly better at twelve months for LASIK compared to 

PRK eyes (p=0.03). Comparison of postoperative outcomes of MRSE between PRK and 

LASIK at six and twelve months was not statistically significant (p>0.05). The 

percentages values of UCVA and MRSE after moderate-to-high astigmatism correction at 

last follow-up are given in Table 8. 

47

Table 8 Efficacy postoperative values after PRK (VISX and Nidek) and LASIK (VISX) 

Safety 

PRK LASIK 

UCVA ≤0.0 29% 57% 

UCVA ≤0.5 100% 100% 

MRSE ±0.50 D 57% 80% 

MRSE ±1.00 D 80% 87% 

In terms of loss of lines of BCVA at the end of the follow-up nine and three % of the eyes 

after PRK and LASIK respectively lost two or more lines of BCVA. Comparative analysis 

at 12 months showed a higher incidence of eyes that gained one or more lines of BCVA 

after LASIK (66%) than after PRK (23%). Twenty-three and 10% of eyes lost one or more 

lines of BCVA after PRK and LASIK respectively. Comparison of postoperative 

outcomes of MRSE between PRK and LASIK at six and twelve months was not 

statistically significant (p>0.05). No eye in either group showed an increase in 

astigmatism >2.0 D compared to preoperative values. 

Table 9 Safety non-vector postoperative values after PRK and LASIK for correction of moderateto-high 

astigmatism 

BCVA ≤0.0 

loss of 2 or more lines of 

BCVA 

PRK VISX LASIK VISX 

81% 

48 

89% 

11% 3%

Stability 

PRK 

Mean MRSE at six months after PRK, was 0.2 ± 1.1 D (range 3.0 ― -5.0) and at twelve 

months it was 0.1 ± 1.4 D (range 3.0 ― -6.0). Stability analysis showed that between six 

and twelve months, 14% of eyes showed no changes in MRSE after PRK. A change less 

than 0.5 D was found in 66% of eyes, and a change >1.0 D was found in 14% of eyes after 

PRK. 

LASIK 

After LASIK, mean MRSE at six months was -0.3 ± 0.8 D (range 1.25 ― -2.5) and at 

twelve months MRSE was -0.5 ± 0.8 D (range 1 ― -2.5). Stability analysis showed that 

between six and twelve months, 13% of eyes showed no changes in MRSE after LASIK. 

A change less than 0.5 D was found in 83% of eyes after LASIK, all eyes were less than 

1.0 D of change after LASIK. 

PRK vs. LASIK 

Comparison of postoperative outcomes of MRSE and defocus between PRK and LASIK 

at six and twelve months were not statistically significant (p>0.05). 

5.2.1.2 Vector analysis 

Vector analysis was performed at the corneal plane. The mean intended refractive 

correction (IRC) was 2.4±0.5 and 2.4±0.4 D for PRK and LASIK respectively (Fig. 2). 

49

4 

3 

2 

1 

0 

1 

2 

3 

4 

Intended Refractive Correction 

50 

LASIK 

PRK 

EV showed no significant differences between PRK and LASIK (Fig. 3). 

4 

3 

2 

1 

0 

1 

2 

3 

4 

Error Vector 

Figure 2 Vector intended refraction 

correction scatterplot of PRK and LASIK 

showing similar values preoperatively 

between both procedures 

Figure 3 Error vector scatterplot 

showed a concentric cluster points 

around of the origin. 

LASIK 

PRK 

Yet, NEV graph showed that LASIK outcomes were more accurate than those for PRK 

(Fig. 4).

4 

3 

2 

1 

0 

1 

2 

3 

4 

Normalized Error Vector 

51 

LASIK 

PRK 

TEV showed that PRK had more under- and overcorrection than LASIK (Fig. 5). 

4 

3 

2 

1 

0 

1 

2 

3 

4 

Treatment Error Vector 

Figure 4 Normalized error vector 

scatterplot showing greater number of 

undercorrections (points at the right 

side of the vertical axis) and 

overcorrections (points at the left side 

of the vertical axis) after PRK than 

after LASIK. 

Figure 5 Treatment error vector 

scatterplot shows a greater number of 

points close to the origin point after 

LASIK than after PRK. 

PRK 

LASIK 

At 12 months, SIRC was 2.2±0.6 D for PRK and 2.3±0.5 D for LASIK, with a success 

index of astigmatism correction of 76% and 81% for PRK and LASIK respectively. In line 

with this result a small difference in correction ratio was found between PRK and LASIK. 

ER showed no significant differences between PRK and LASIK. EM at 12 months followup 

after PRK was 0.1±0.05 and after LASIK was 0.02±0.5. Statistically we found no 

differences between these parameters.

Table 10 Vector stability of cylinder at 6 and 12 months follow-up 

Magnitude of 

vector change in 

cylinder 

Eyes with ≤ 1.00 D 

of vector change 

Eyes with ≤ 0.5 D 

of vector change 

Mean magnitude ± 

SD of vector 

change between 

visits 

PRK LASIK 

6 months to 12 months 6 months to 12 months 

n/N % % CI n/N % % CI 

43/44 98 [88 -100] 30/30 100 [88 - 100] 

35/44 80 [65 - 90] 25/30 83.3 [65 - 94] 

0.3 ± 0.3 0.3± 0.2 

95% CI 0.10 0.08 

No significant differences were found in angle stability of the cylinder axis after PRK and 

LASIK, yet PRK showed a higher incidence of eyes within ≤ 15º of stability at 6 and 12 

months. Analysis of vector cylinder stability, SIRC, EM, EV, CR, ER between PRK and 

LASIK at 6 and 12 months showed no statistically significant differences (p>0.05). The 

values of vector stability of cylinder at 6 and 12 months are given in Table 10. 

5.2.2 Irregular astigmatism 

In Study IV we evaluated the postoperative outcomes in eyes with irregular astigmatism 

secondary to recurrent corneal erosion due to map-dot-fingerprint dystrophy treated by 

PTK. 


UCVA ≤0.0 was achieved postoperatively in four (4/11) eyes at last follow-up, the same 

number of eyes achieved UCVA ≤0.5 at last follow-up. MRSE within ±0.50 D was found 

in four eyes, and five eyes were within ±1.00 D of MRSE at last follow-up. 

52

Safety 

Nine eyes out of eleven gained lines of BCVA (one eye gained two lines, three eyes 

gained three lines, two eyes gained four lines and three eyes gained more than five lines). 

Two eyes showed no changes. The mean preoperative BCVA in the eye to be operated on 

was -0.18 ± 0.14 on a logarithm of the minimal angle of resolution (log MAR) scale. The 

mean postoperative BCVA was 0.04 ± 0.04 (log MAR). This increase in BCVA was 

statistically significant. 

Irregular astigmatism and VK 

All preoperative VK showed irregular astigmatism. However, postoperatively, all eyes 

showed a regular pattern. No correlation was found between the pre- and postoperative 

VK patterns. 

5.3 STUDY V. PRK after LASIK 

In study V, the mean time interval between the primary LASIK and the PRK enhancement 

was 45±13 months (range 27 to 61 months), and the mean follow-up time after PRK was 

14±10 months (range 7 to 29 months). Prior to LASIK the mean preoperative BCVA in 

log MAR scale was 0.0±0.0. The initial mean preoperative MRSE of the refractive error 

was -6.5±3.2 diopters (D, range -2 to -9.25). 


UCVA ≤0.0 was achieved postoperatively in three (3/7) eyes at last follow-up, seven (7/7) 

eyes achieved UCVA ≤0.5 at last follow-up. MRSE within ±0.50 D was found in five 

eyes, and six eyes were within ±1.00 D of MRSE at last follow-up. 

Safety 

No eye lost lines of BCVA. One eye gained three lines, one eye gained two lines, four 

eyes gained one line, and one eye showed no change. The mean preoperative BCVA in the 

eye to be operated on was -0.18 ± 0.14 on a log MAR scale. The mean postoperative 

BCVA was 0.04 ± 0.04 (log MAR). This increase in BCVA was statistically significant. 

53

6 DISCUSSION 

No other medical subspeciality has advanced as much as excimer laser in such a short 

period of time refractive surgery. Despite the large number of excimer laser refractive 

procedures performed around the world long-term follow-up studies have been scarce. 

Until 2007, the time when this project was started, just only three studies with a follow-up 

over 10 years had been published (Kymionis et al. 2007, O'Connor et al. 2006, Rajan et al. 

2004). The lack of uniform parameters between studies made it difficult to compare results 

or detect the possible changes in efficacy, safety, or stability after excimer laser surgery. 

Furthermore, the claims made in the marketing of new methods and 

equipment/instruments lack strong back-up. The rapid technological progress during the 

course of this study might actually be a drawback since most of the lasers used in this 

study have undergone evolution, and new ablation profiles and nomograms are now 

available. 

STUDIES I AND II. PRK/LASIK follow-up 

PRK 

Follow-up studies after PRK include 12-year (Rajan et al. 2004) and 14-year (Bricola et al. 

2009) follow-up, both of them performed using the Summit UV200 excimer laser, a BB 

system. These studies reported PRK to be a safe procedure with stability achieved between 

three months to one year after the procedure and maintained in follow-up. Two others 

studies (Alio et al. 2008a, Shojaei et al. 2009) have reported at least eight-year long–term 

postoperative outcomes after PRK with the same laser delivery systems as in our report, 

yet neither of the studies compared different excimer laser systems. 

In terms of efficacy, we found a better result in postoperative UCVA at last follow-up 

compared to earlier long-term studies with the same laser delivery system (Alio et al. 

2008a, Shojaei et al. 2009). Our postoperative BCVA results were slightly better than 

other long-term results (Alio et al. 2008a, Bricola et al. 2009, O'Connor et al. 2006, Rajan 

et al. 2004) These results in UCVA and BCVA were independent of the delivery system 

used. 

Compared to earlier studies, after eight years of follow-up after treatment (Shojaei et 

al. 2009) in a subgroup of moderate correction (≤6.0 D) 69% of eyes with a SS laser were 

within ±0.5 D, and 83% were within ±1.0 D of emmetropia at last follow-up. After 10 

years of follow-up after treatment with a BB laser (Alio et al. 2008a) eyes with myopia 

±1.00 D of the intended correction in both groups. No significant differences were found 

postoperatively between groups. 

Similar results were found in lines of BCVA gained or lost when we compared 

delivery systems, given good safety in long-term follow-up. 

Long-term studies (Alio et al. 2008a, Shojaei et al. 2009) reported that MRSE after SS 

(Shojaei et al. 2009) stabilized at 2 years, yet after BB (Alio et al. 2008a) seems to 

stabilize after five years. We found a similar myopic regression for both lasers procedures 

and the amount of regression in our study was similar to that in other long-term studies 

(Honda et al. 2004, Rajan et al. 2004). 

LASIK 

Although LASIK is the most common laser refractive surgery currently performed in the 

world (Sandoval et al. 2005) there are only four studies reporting follow-up longer than 

five years at the time when this study was conducted (Condon et al. 2007, Kymionis et al. 

2007, O'Doherty et al. 2006, Sekundo et al. 2003) and three of them focused on results 

after high myopic corrections (Condon et al. 2007, Kymionis et al. 2007, Sekundo et al. 

2003) and just one of them (O'Doherty et al. 2006) included all levels of myopia with an 

intended correction close to emmetropia. Two other studies (Alio et al. 2008c, Alio et al. 

2008d) with ten-year follow-up were published after our results were published, and one 

of them (Alio et al. 2008c) focused on high myopia results. 

The maximum FDA approved limit of correction for treating eyes by LASIK varies 

from one laser to another, but it is close to -12 D. We included MRSE between -3.9 and - 

11.5 D (mean -6.9 D); in our study, 74% of eyes were within ±0.5 D and 83% within ±1.0 

D at two years. At last follow-up seven to eight years postoperatively, however, 34% of 

eyes were within ±0.5 D and 42% were within ±1.0 D. These results show that although 

refractive results after LASIK are relatively good short-term; they tend to decline over 

time. Compared to earlier studies (Alio et al. 2008d, O'Doherty et al. 2006) our results 

showed a smaller percentage of eyes within ±0.5 D or ±1.0 D at last follow-up. This 

finding was also evident in the percentage of eyes achieving UCVA ≥0.0 at last follow-up. 

Congruent with these results, myopic regression of the MRSE was noticed in our study. At 

two months an undercorrection of -0.41 D was found; the follow-up study showed a 

minimal myopic regression to -0.6 D at two years, which continued to regress to -1.4 D 

by the last visit. This trend toward myopic regression was noted in all eyes, but was more 

pronounced in eyes with preoperative MRSE >6.0 D, and also in subjects

In terms of safety, at two years every third eye gained lines of visual acuity whereas ~ 

one in ten eyes lost lines. Compared to two years post-operatively, the number of eyes that 

gained one or more lines of visual acuity slightly increased at last follow-up visit, yet the 

number of eyes losing lines of visual acuity doubled from two years to seven to eight 

years. This may be related to subclinical opacities in the lens or secondary to higher order 

aberrations. As in other studies (Kymionis et al. 2007, O'Doherty et al. 2006) patient 

satisfaction was extremely high with 100% stating that they would have LASIK surgery 

again. 

PRK VISX vs. LASIK VISX in moderate myopia 

The advantages of LASIK over PRK are faster visual recovery and less pain. However, 

PRK entails lower risk of operative and post-operative complications. The long-term 

outcomes of moderate myopic correction treated by PRK or LASIK with the VISX laser 

used in our studies showed no significant differences in terms of efficacy, predictability or 

stability. A recent study (Alio et al. 2009) compared postoperative outcomes after PRK 

and LASIK using the VISX 20/20 and showed that both procedures were safe with 

slightly better efficacy and predictability after LASIK than after PRK, yet the range of 

correction –6 to -10 D included in that report exceeded the accepted ranges of correction 

nowadays used in PRK. In light of our results we suggest that the range of correction of 

myopic eyes should not exceed 6.0 D with PRK. 

STUDIES III AND IV. Regular and irregular astigmatism 

Regular astigmatism 

Earlier reports have found that PRK and LASIK results in a similar proportion of eyes 

postoperative with UCVA ≤ 0.3, yet a greater proportion of eyes with UCVA ≤ 0.0 has 

been reported found after LASIK than after PRK (El-Maghraby et al. 1999, Steinert and 

Hersh 1998, Van Gelder et al. 2002). Our findings showed that compared to PRK LASIK 

yielded not only better results in UCVA ≤ 0.0 but also in terms of UCVA ≤ 0.3 at six and 

twelve months postoperatively when high astigmatism corrections were compared. LASIK 

was found to be superior to PRK in terms of BCVA and also gained more lines of BCVA 

compared to PRK. Loss of two or more lines of BCVA was reported more frequently in 

PRK than in LASIK. This difference may result from the more aggressive wound healing 

and haze development after PRK. 

Earlier studies have reported almost identical results in MRSE after PRK and LASIK 

(el Danasoury et al. 1999, El-Maghraby et al. 1999, Steinert and Hersh 1998). Neither did 

we observe any significant differences between PRK and LASIK in terms of MRSE. The 

efficacy in correcting astigmatism was slightly superior in the LASIK group. PRK showed 

56

a tendency to overcorrection in MRSE compared to LASIK. PRK typically showed a 

regression between 0.5 and 3.0 D in MRSE at one to twelve months. (Hersh et al. 1997, 

Kim et al. 1997) It appears that the PRK nomogram is planned to induce overcorrection to 

compensate this regression. A spherical overcorrection has been reported with the Nidek 

EC 5000 (SS) (Huang et al. 1999) after elliptical ablation for astigmatism, yet no 

differences were found here between BB and SS excimer lasers. Vector analysis in our 

study found no significant differences between PRK and LASIK. 

Analysis of the stability of the cylinder by either non-vector or vector analysis 

revealed no difference between PRK and LASIK. This may reflect the accuracy of the 

nomogram, which was the same in both procedures. Both procedures showed 

undercorrection of intended astigmatism correction regardless of the technique. 

Furthermore, no differences were found secondary to misalignment, and accordingly it 

seems that the forces created by the suction ring, or the flap creation in LASIK do not 

interfere with the treatment. Our results are comparable to those of other studies (el 

Danasoury et al. 1999, Fraunfelder and Wilson 2001, Helmy et al. 1996, Hersh et al. 1998, 

Pop and Payette 2000) reporting accuracy and efficacy of astigmatic correction using 

various types of excimer laser (Stojanovic and Nitter 2001) or even wave front based 

nomograms (Partal and Manche 2006). 

Irregular astigmatism 

A variable epithelial thickness may contribute to or generate a morphologically irregular 

anterior corneal surface that may be result in irregular corneal astigmatism (Rosenberg et 

al. 2000). This is the case of anterior basement membrane dystrophy, such as Recurrent 

Corneal Erosion Syndrome (RCES) Map-dot-fingerprint (MDF). This corneal dystrophy 

has been suggested to arise from abnormal adhesion between the epithelium and the 

basement membrane-Bowman's layer complex (Brown and Bron 1976, Werblin et al. 

1981) generating a morphologically unstable irregular anterior corneal surface. MDF may 

be present in as many as 15% of general population (Cavanaugh et al. 1999, Werblin et al. 

1981) although it may not be associated with biomicroscopically observable changes at the 

time of examination (Rosenberg et al. 2000). 

In general refractive surgery has been used to correct spherical and cylindrical 

components of refractive defects. The standard preoperative examinations performed 

before laser refractive procedures cannot show the anatomical location of the tissue in the 

optical system of the eye that generates the optical irregularity. Preoperative assessment 

included the use of VK, and in cases of irregular astigmatism also WF technology 

enabling customized corneal photoablations in patients. (Arbelaez 2001, Doane and Slade 

2003, Waheed and Krueger 2003) Unfortunately, these methods do not distinguish in 

which corneal layer(s) the elevation prevails. In our study we showed the presence of 

irregular astigmatism that depends exclusively upon the corneal epithelium. The main 

clinical finding of this study is that if we assume that the astigmatism is due to epithelial 

irregularity and a PRK/LASIK customed correction is performed based on WF measures 

57

taken from an intact cornea, irregular astigmatism may be caused rather than treated by 

WF excimer laser. 

STUDY V. PRK enhancement 

Several studies have focused on using PRK enhancements after prior LASIK surgery. Yet 

the development of haze has been the most frequent limitation (Astudillo and Ortiz 1999, 

Carones et al. 2001, Gimbel and Stoll 2001, Jain et al. 2002, Muller et al. 2005, Shaikh et 

al. 2005). CM (Moilanen et al. 2003, Tervo and Moilanen 2003) and histopathological 

studies (Dawson et al. 2005) have shown differences between corneal wound healing after 

PRK and LASIK, the direct innervation of individual keratocytes by nerve bundles at the 

central stroma (Muller et al. 1996, Muller et al. 2003), and the changes in density of 

corneal subbasal nerve after photoablative procedures (Erie et al. 2005, Lee et al. 2002, 

Tervo and Moilanen 2003). This nerve density after PRK improves significantly even after 

one year, and reaches near normal mean values at two years. Nerve density after LASIK, 

however, recovers more slowly and normal nerve density is not reached until five years 

postoperatively (Erie et al. 2005). CM studies have shown that two years after LASIK the 

subbasal nerves density reach ~ 60% of the preoperative values (Erie et al. 2005, Moilanen 

et al. 2008). Similar values have been reported to be reached one year after PRK (Erie et 

al. 2005). Accordingly, it is feasible to suggest that LASIK enhancements after PRK are 

probably safe one year after the primary operation, whereas PRK enhancements after 

primary LASIK should be performed over two years after the primary operation. 

One previous report (Carones et al. 2001) advised against PRK after LASIK reporting 

severe haze three to ten months after the enhancement. In that study the re-treatments were 

performed between six and 15 months after LASIK when the active stage of corneal 

wound healing was supposed to be finished but the recovery of corneal sensory nerve 

innervation was still below 50% (Erie et al. 2005, Moilanen et al. 2003, Tervo and 

Moilanen 2003). Earlier studies (Muller et al. 2005, Weisenthal et al. 2003) have 

alternatively used prophylactic mitomycin C after transepithelial PTK/PRK to prevent 

haze formation in eyes with flap complications. In those studies the enhancements were 

performed between two weeks and five years after the flap complication. Shaikh et al. 

(Shaikh et al. 2005) reported good results after performing PRK enhancement in eyes with 

flap complications and/or previous LASIK treatment and stressed the importance of time 

interval between refractive procedures to minimize the keratocyte activity. 

58

7 SUMMARY AND CONCLUSIONS 

The present study evaluated the postoperative outcomes of excimer laser refractive 

surgery in myopic and myopic astigmatism correction. We also compared the results of 

moderate-to high astigmatism correction by PRK and LASIK. Furthermore, we 

demonstrated the presence of irregular astigmatism that depends exclusively on the 

corneal epithelial cells, and suggest that corneal sensory nerve recovery may have a 

substantial effect on corneal wound healing. Our results demonstrate the following: 

1. The long-term follow-up after PRK/LASIK demonstrated that outcomes of moderate 

myopic correction are safe and efficient. 

2. In the long-term the laser delivery system does not seem to play a major role in the 

safety and efficiency after PRK. 

3. We found an amount of regression after PRK similar to that reported in other longterm 

studies. Yet, when delivery systems were compared, we found that myopic 

regression favored the initial overcorrection achieved by the SS type laser. 

4. LASIK refractive outcomes are relatively good in the short terms, but tend to decline 

over time. The incidence of myopic regression was more pronounced when the 

intended correction was >6.0 D and in patients aged 2.0 D was associated with a greater risk of 

decrease in BCVA after PRK. 

11. Irregular astigmatism was proven to depend exclusively on the corneal epithelium. 

12. The standard preoperative examinations performed before laser refractive surgery 

cannot detect the anatomical location of the defect in the eye’s optical system that 

causes optical irregularity. 

13. Corneal sensory nerve recovery may have an important role in the modulation of 

corneal wound healing and post-operative anterior stromal scarring. PRK 

enhancement may be an option in eyes with previous LASIK after a sufficient time 

interval of at least two years. 

14. Our results strengthen the importance of intact corneal subbasal nerve plexus to 

maintain corneal transparency and also highlight their importance in corneal wound 

healing. 

59

8 ACKNOWLEDGEMENTS 

This work was carried out at the Department of Ophthalmology of the Helsinki University 

Central Hospital, Finland, during the years 2005–2010. I wish to express my sincere 

gratitude to the present and past heads of our Department, Professor Tero Kivelä, Dr 

Raimo Uusitalo, and Adjunct Professor Erna Kentala, for providing excellent research 

facilities and building a fruitful atmosphere for clinical work and research. 

My deepest gratitude, respect, and friendship are owed to my supervisors’ Professor Timo 

Tervo and Adjunct Professor Juha H. Holopainen, without them this thesis would not have 

been completed. 

Timo’s guidance, patience, respect, and expertise during this process have been invaluable. 

I will be always amazed at his creativity, speed of thoughts, and capacity to leap from one 

idea to another. Timo’s support in very single aspect of this thesis and even more 

important in every aspect not related to this thesis has been incredible. I can say I always 

have found an open door to discuss my problems and disinterested help to solve them. 

When I started this “journey” in the research world I never imagined the extraordinary 

changes in my life, these changes would have been more “traumatic” without Juha´s 

support and patience with somebody who had no idea what he was doing. Juha is one of 

the most gifted persons I have met, his dedication, interest in learning and teaching, plus 

his inspiring guidance and commitment to almost everything are truly remarkable. Juha’s 

example and dedication in research is admirable and I am really grateful to be able to call 

him my friend. 

I would like to thank my reviewers, Professor Charlotta Zetterstrøm (Ullevål University 

Hospital, Norway) and Adjunct Professor Olavi Pärssinen (University of Turku) for their 

constructive and careful review of this thesis. 

I thank Virginia Mattila MA for her revision of the English language of this thesis. 

I wish to thank my colleagues from the Cornea group Jukka Moilanen, Ilpo Tuisku, Petri 

Järventausta and Elisa Vuori. I also want to thank the investigators of other groups, who 

lived with me the lonely hours in front of the computer screen, sharing laughs, frustrations 

but fortunately most of the time joy, Seppo Tuomaala, Ranaa Al Jamal, Sanna Seitsonen, 

Ilkka Puusaari, Päivi Toivonen, Emma Kujala, and Mamunur Rashid. 

During these years it has been my great pleasure to collaborate with a number of people. 

Among them I would like to give my thanks to Professor Juana Gallar and Adjunct 

Professor M.Carmen Acosta and their group from the Instituto de Neurociencias de 

Alicante, Universidad Miguel Hernández-CSIC, Spain for their friendship, 

professionalism and help. 

60

I am grateful to Ms. Elina Haapaniemi, Ms. Sirkka Elomaa, Ms. Marja Ikonen, and Ms. 

Kaisa Kalander for their assistance and friendship. I cordially thank all of my colleagues 

and friends at the Helsinki University Eye Hospital. 

I am deeply grateful with my parents-in-law, Kristina “Pippe” and Jarl-Olof “Jaffe” 

Floman for their help and love to me and my family, and their help with the everyday 

situations. 

This work is dedicated to my family, especially to my wonderful parents Jose and Ilda, 

who have been always supporting me and encouraging me to follow my dreams and 

teaching me to give the best of myself. Bendición. Special gratitude to my brothers 

Wlamyr and Willmar and their families for always being there, being the best friends in the 

world. 

I owe my deepest thanks to my wife Mikaela for her everlasting love and her capacity for 

keeping me moving, picking up the pieces when the frustration overcame me 

(unfortunately too often), dealing with my bad moods, and most importantly, for 

reminding me by her example what is really important in life. Finally to the motor of my 

life, my three “nightmares” Ricardo, Daniela and Manuela for making me smile, laugh 

and learn. 

I would like to thank God that this project, which started with a dream, has become more 

than a reality, a new life. 

This study was financially supported by Center for International Mobility CIMO, Clinical 

Research Fund of the Helsinki University Central Hospital, the Research Foundation of 

the Orion Corporation, the Finnish Eye Foundation, the Finnish Eye and Tissue Bank 

Foundation, the Nissin Foundation, the Mary and Georg C. Ehrnrooths Foundation, the 

Oskar Öflundi Foundation, The Friends of the Blind Foundation 

The reprints are reproduced by permissions of the copyright holders. 

61

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