Acta Ophthalmologica

Thesis
http://www.actaophthalmologica.com

PhD Thesis

Past and Present of Corneal Refractive Surgery

A Retrospective Study of Long-term Results after Photorefractive Keratectomy,
and a Prospective Study of Refractive Lenticule Extraction

Anders Højslet Vestergaard

Faculty of Health Science,
University of Southern Denmark and Department of Ophthalmology,
Odense University Hospital, Denmark
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ACTA OPHTHALMOLOGICA 2014

This thesis was submitted for evaluation to The Faculty of Health Science, University of Southern Denmark, in November 2013, and
was defended on February 28th, 2014.

Members of the evaluation committee:

Professor, DMSci, MD Walter Sekundo, Philipps University of Marburg, Germany.
Associate Professor, DMSci, MD Carsten Edmund, University of Copenhagen and Glostrup Hospital, Denmark.
Associate Professor, PhD, MD Janus Laust Thomsen, Research Unit of General Practice, Institute of Public Health, University of
Southern Denmark, Odense, Denmark.

Supervisors:
Associate Professor, PhD, DMSci, MD Jakob Grauslund, University of Southern Denmark and Department of Ophthalmology, Odense
University Hospital, Odense, Denmark.
Associate Professor, PhD, MD Anders R. Ivarsen, Aarhus University and Department of Ophthalmology, Aarhus University Hospital,
Denmark.
Professor, PhD, DMSci, MD Jesper Ø. Hjortdal, Aarhus University and Department of Ophthalmology, Aarhus University Hospital,
Denmark.
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Contents

PREFACE I SUMMARY OF RESULTS 9

LIST OF PUBLICATIONS II Photorefractive keratectomy (Paper I) 9
Predictability and stability 9
LIST OF ABBREVIATIONS III Efficacy and safety 10
ABSTRACT 1 Satisfaction evaluation 10
INTRODUCTION 1 Refractive lenticule extrcation (Paper II, III,
and IV) 10
Myopia 1
Predictability and stability 10
Corneal refractive surgery in the past 1
Efficacy, safety, and contrast sensitivity 10
The excimer laser 2
Whole-eye and corneal higher-order
The femtosecond laser 2
aberrations 11
Photorefractive keratectomy 2
Subbasal nerve alterations, corneal
Long-term outcomes of PRK 3 sensation, and tear film parameters 11
Laser-assisted in situ keratomileusis 3 Corneal pachymetry 11
Outcomes after LASIK 3 Corneal hysteresis and corneal resistance
Refractive lenticule extraction 3 factor 11
Outcomes after ReLEx flex and Satisfaction evaluation 11
ReLEx smile 4
DISCUSSION 11
OBJECTIVES 4 Long-term outcomes of PRK (Paper I) 11
PATIENTS AND METHODS 4 Limitations 13
Photorefractive keratectomy (Paper I) 4 Evaluation of ReLEx flex and ReLEx smile
Study population 4 (Paper II, II, and IV) 13
Excimer laser procedure 4 Flap vs. cap - the similarities 13
Examination procedure 4 Flap vs. cap - the differences 15
Refractive lenticule extraction Limitations 15
(Paper II, III, and IV) 5 CONCLUSIONS AND PERSPECTIVES 15
Study design 5
Femtosecond laser surgical procedures 5 RESUMÉ PÅ DANSK 16
Standard and additional examination REFERENCES 18
procedures 5
Visual acuity and refraction (Paper II) 6
Contrast sensitivity (Paper II) 6
Wavefront error (Paper II) 6
In vivo confocal microscopy (Paper III) 7
Central corneal esthesiometry (Paper III) 7
Non-invasive and invasive tear film
evaluation (Paper III) 7
Central corneal sublayer pachymetry
(Paper IV) 8
Corneal biomechanics (Paper IV) 8
Satisfaction (Paper II) 9
Statistical design and analysis 9

Cover image: Schematic illustration of femtosecond laser-based refractive lenticule extraction.

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ACTA OPHTHALMOLOGICA 2014

Preface
This PhD thesis is based on research performed at the Departments of Ophthalmology at both Odense and Aarhus University Hospitals,
Denmark, in the period from 2010 to 2013.

This thesis is a result of inspiration and guidance from many sources. First of all I would like to thank Anne Katrin Sjølie and Jesper
Hjortdal, for giving me the opportunity to do research in corneal refractive surgery with home base in Odense, thereby balancing family
and work interests. I wish to thank Anne Katrin Sjølie for her support and continuous motivation in all aspects, despite my choice of
subject, and even when illness struck her. I am very sorry that she is no longer among us. She is truly missed. I wish to thank Jesper
Hjortdal for introducing me to the amazing world of corneal and refractive surgery, and for his continuous support and trust in me to do
all kinds of interesting research projects. I wish to thank Anders Ivarsen for his invaluable help and constructive criticism of my work, and
this project has benefited from his high level of academic skills. Anders has also provided me with great-tasting cake recipes, and
especially Snickers cakes were consumed in huge quantities during this PhD project. I wish to thank Jakob Grauslund for his continuous
support of this project, and especially for wanting to take over the responsibility as main supervisor when Anne Katrin passed away. I have
enjoyed and learned a lot from our many conversations at our office, including those concerning football results. Overall, I would like to
express my gratitude to all four of my supervisors for their invaluable help and commitment to the project. You always had time to answer
my queries professionally, rapidly, and with around-the-clock replies landing in my email inbox. You are an inspiration in terms of
research, medical skills, and communication. It has been a privilege working with all of you, and I hope to continue our collaboration in
the future.

I wish to thank Niels Lyhne and Kresten Work for support and detailed information about the retrospective study, which could not have
been performed without your help.
I would also like to thank optometrists Henrik, Nicolaj, Jens Christian, and Christina for their great flexibility when planning and
performing patient examinations at all times of the day. The prospective study could not have been performed without your communicative
skills and help.
I wish to thank Kelvin Kamp Mortensen and Toke Bek for the opportunity and privilege of doing research, at their Departments of
Ophthalmology at both Odense and Aarhus University Hospitals.
I wish to thank Hanne Olsen Julian for helping me with patient examinations in Copenhagen, and Sven Asp in Aarhus.
I am also very happy to have worked, travelled, winter bathed, and eaten tons of chocolate with all my colleagues at the PhD office in
Odense, Karen, Rebecca, Kristian, Malin, Christina, and Ulrik, and from Aarhus, Esben and Iben. Thank you for all your help and fruitful
discussions.
My warmest thanks also go to my family for their endless support. A special thank-you goes to my two beautiful girls at home - my wife,
Stine, and daughter Ida. You mean the world to me.

The work was supported by generous donations from: Odense University Hospitals PhD Research Grant, Fight for Sight Denmark,
Bagenkop Nielsens Myopia Foundation, The Synoptik Foundation, The A. P. Møller Foundation for the Advancement of Medical Science,
The Danish Society of Ophthalmology, Institute of Clinical Research at the University of Southern Denmark, Alcon and Novartis travel
grants, The A. J. Andersen and Wife Foundation, The Hans and Nora Buchards Foundation, The Henry and Astrid Møllers Foundation,
University of Southern Denmark.

Anders Højslet Vestergaard

Odense, November 2013
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ACTA OPHTHALMOLOGICA 2014

List of publications
This thesis is based on a review and the following original papers:

I A. Vestergaard, J. Hjortdal, A. Ivarsen, K. Work, J. Grauslund, A. K. Sjølie (2013). Long-term outcomes of photorefractive
keratectomy for low to high myopia: 13 to 19 years of follow-up. Journal of Refractive Surgery, 29:312–319.

II A. Vestergaard, J. Grauslund, A. Ivarsen, J. Hjortdal. Efficacy, safety, predictability, contrast sensitivity and aberrations after
femtosecond laser lenticule extraction. Journal of Cataract & Refractive Surgery Accepted for publication 31 July 2013.

III A. Vestergaard, K. Grønbech, J. Grauslund, A. Ivarsen, J. Hjortdal (2013). Subbasal nerve morphology, corneal sensation, and tear
film evaluation after refractive femtosecond laser lenticule extraction. Graefe’s Archive for Clinical and Experimental
Ophthalmology, [Epub ahead of print].

IV A. Vestergaard, J. Grauslund, A. Ivarsen, J. Hjortdal (2013). Central corneal sublayer pachymetry and biomechanical properties
after refractive femtosecond laser lenticule extraction. Journal of Refractive Surgery Accepted for publication 24 October 2013.
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ACTA OPHTHALMOLOGICA 2014

List of abbreviations
AS-OCT: Anterior segment optical coherence tomography
CCT: Central corneal thickness
CDVA: Corrected distance visual acuity
CE: Conformité Européenne
CH: Corneal hysteresis
CRF: Corneal resistance factor
CS: Contrast sensitivity
D: Diopter
ET: Epithelial thickness
ETDRS: Early Treatment Diabetic Retinopathy Study
FDA: Food and Drug Administration (U.S.)
FLEX: Femtosecond lenticule extraction (ReLEx flex)
FSL: Femtosecond laser
HOAs: Higher-order aberrations
ICC: Intraclass correlation coefficient
IVCM: In vivo confocal microscopy
LASIK: Laser-assisted in situ keratomileusis (or laser in situ keratomileusis)
logCS: Logarithm of contrast sensitivity
logMAR: Logarithm of the minimum angle of resolution
Nd:YAG: Neodymium-doped yttrium aluminium garnet
NI-BUT: Non-invasive tear film break-up time
OCT: Optical coherence tomography
OLCR: Optical low coherence reflectometry
ORA: Ocular response analyzer
PRK: Photorefractive keratectomy
ReLEx: Refractive lenticule extraction
RK: Radial keratotomy
RSB: Residual stromal bed
SD: Standard deviation
SE: Spherical equivalent
SMILE: Small-incision lenticule extraction (ReLEx smile)
TBUT: Tear film break-up time
TMH: Tear meniscus height
UDVA: Uncorrected distance visual acuity
 Acta Ophthalmologica 2014

PhD Thesis

Past and present of corneal refractive surgery

A retrospective study of long-term results after photorefractive
keratectomy and a prospective study of refractive lenticule
extraction
Anders Højslet Vestergaard1,2
1
Faculty of Health Science, University of Southern Denmark, Odense, Denmark
2
Department of Ophthalmology, Odense University Hospital, Odense, Denmark

ABSTRACT
Surgical correction of refractive errors is becoming increasingly popular. In the 1990s, the excimer laser revolutionized the field of
corneal refractive surgery with PRK and LASIK, and lately refractive lenticule extraction (ReLEx) of intracorneal tissue, using only a
femtosecond laser, has become possible. Two new procedures were developed, ReLEx flex (FLEX) and ReLEx smile (SMILE).
Until this thesis, only a few long-term studies of PRK with a relatively limited number of patients had been published; therefore, this
thesis intended to retrospectively evaluate long-term outcomes after PRK for all degrees of myopia for a large number of patients.
Furthermore, a prospective contralateral eye study comparing FLEX and SMILE, when treating high to moderate degrees of myopia,
had not been performed prior to this study. This was the second aim of this thesis.
In the first study, results from 160 PRK patients (289 eyes) were presented. Preoperative spherical equivalent ranged from 1.25 to
20.25 D, with 78% having low myopia (< 6 D). Average follow-up time was 16 years (range 13–19 years), making this the longest
published follow-up study on PRK patients. Outcomes from eyes with low myopia were generally superior to outcomes from eyes with
high myopia, at final follow-up. Seventy-two percent were within 1.00 D of target refraction, as compared to 47% of eyes with high
myopia. However, results from a subgroup of unilateral treated PRK patients indicated that refraction at final follow-up was affected by
myopic progression. Fifty percent of eyes with low myopia had uncorrected 20/20 distance visual acuity or better, as compared to 22% of
eyes with high myopia. Haze did not occur if attempted corrections were < 4 D, and only eyes with high myopia lost two lines or more of
CDVA (corrected distance visual acuity). Eighty-one per cent were satisfied or very satisfied with their surgery.
Conclusion: The results support the continued use of the excimer laser for corneal surface ablation as a treatment option for correction
of low degrees of myopia, and as the treatment of choice for subgroups of refractive patients (thin corneas, etc.). The results also highlight
that treatment of higher degrees of myopia with standard PRK should only be done today under special circumstances, due to low
refractive predictability, and high risk of corneal haze. Technological advances since then should be taken into account when comparing
these results with contemporary techniques.
In the second study, 35 patients were randomized to receive FLEX in one eye and SMILE in the other. Preoperative spherical
equivalent refraction ranged from 6 to 10 D with low degrees of astigmatism. A total of 34 patients completed the 6 month follow-up
period. Refractive and visual outcomes were very similar for the two methods, as well as tear film measurements and changes in corneal
biomechanics. Ninety-seven percent were within 1.00 D of target refraction, no eyes lost two lines or more of CDVA, and contrast
sensitivity was unaffected after both procedures. The changes in higher-order aberrations were also very similar. There were also no
differences in tear film parameters 6 months after surgery, although less postoperative foreign body sensation was reported within the
first week after surgery in SMILE eyes. Corneal sublayer pachymetry measurements demonstrated equally increased epithelial thickness
6 months after surgery. Contrary to expectations, it was not possible to measure the theoretical biomechanical advantages of a small
corneal incision in SMILE as compared to a corneal flap in FLEX. The main differences between FLEX and SMILE were found when
the corneal nerves and intraoperative complications were evaluated. Thus, corneal sensitivity was better preserved and corneal nerve
morphology was less affected after SMILE, but intraoperative complications occurred more frequently, although without visual sequela.
Finally, 97% were satisfied or very satisfied with both their surgeries.
Conclusion: The results support the continued use of both FLEX and SMILE for treatment of up to high degrees of myopia. Overall,
refractive and visual results for both procedures were good and similar, but from a biological point of view, the less invasive SMILE
technique is more attractive, as demonstrated in this study, despite being slightly more surgically demanding than FLEX.

Acta Ophthalmol.
ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

doi: 10.1111/aos.12385
This thesis was submitted for evaluation to The Faculty of Health Science, University of
Southern Denmark, in November 2013 and was defended on 28 February 2014.

1
Acta Ophthalmologica 2014
Introduction
Myopia
In refractive eye disorders, the balance
between eye length and the overall
refractive power of the cornea and the
crystalline lens is disturbed. In myopia,
distant objects are focused in front of
the retina, while only near objects are
seen clearly (Fig. 1). Myopia can be
classified as either physiologic or path-
ologic with the dioptric power of the
eye being less than or greater than
6.00 D. Myopia is usually caused by
axial elongation, and in pathologic
myopia, the excessive dimensions of
the eye can result in retinal degenera-
tive changes and lead to complications
including reduced visual acuity.
Myopia is the most common eye
disorder worldwide, affecting up to
more than 80% in some Asian popula-
tions (Pan et al. 2012; Lee et al. 2013).
In 2004, the estimated prevalence of
myopia among 18-year-old Danish con-
scripts was 12.8% ( 0.50 D or more in
spherical equivalent, SE), including
0.3% with higher degrees of myopia
( 6.50 D or more; Jacobsen et al.
2007). The prevalence and progression
are affected by many variables such as
ethnicity, sex, familial disposition, age
of onset, the degree of myopia, educa-
tion level, near reading activities, as well
as outdoor activities (Lee et al. 2013).
Stability of myopia is not considered to
occur before the age of 21 and may even
progress further during adulthood or
occur as adult-onset myopia (Azar et al.
2013, p. 88). These are important con-
founding factors when analysing short-
and especially long-term outcomes of
refractive surgery.
In Denmark, refractive eye surgery
is covered by national healthcare for
subgroups of refractive errors, includ-
ing patients with more than 6 D of
myopia in both eyes.
Fig. 1. Schematic illustration of myopia (Top-
rak).
2
Corneal refractive surgery in the past et al. 1994; McDonnell et al. 1996;
Rapuano et al. 2013, p. 43–45). Many
Refractive errors have traditionally
other corneal refractive procedures were
been corrected by spectacles and
also attempted, such as thermal collagen
contact lenses. Despite their long-stand-
shrinkage and epikeratoplasty, but
ing use, there are some disadvantages in
these are now mostly abandoned. Oth-
both forms of optical correction.
ers are still in use, such as arcuate
Increased light scatter, image magnifi-
keratotomy and corneal inlays.
cation/minification, discomfort and
In the early 1980s, the excimer laser
inconvenience are some of the issues
was introduced in refractive surgery,
with glasses. And contact lenses may
accompanied from 2001 by the femto-
irritate the ocular surface with increased
second laser (FSL). Both lasers have
risk of corneal scratches and infections.
revolutionized the field of corneal
As the cornea is readily accessible for
refractive surgery.
surgery and accounts for approximately
two-thirds of the eye’s optical power,
most surgical efforts have concentrated The excimer laser
on changing the corneal focusing power.
The word excimer is derived from
The principles of corneal refractive
excited dimer, to describe an ener-
surgery date back to the 19th century.
gized molecule with two components.
Snellen first studied astigmatic changes
Laser is short for light amplification
after cataract surgery, and Schioetz
by stimulated emission of radiation, a
performed the first penetrating corneal
technique derived from microwave
incision in 1885 to treat high postcat-
amplifying devices (masers) in the late
aract surgery astigmatism (Snellen
1950s (McAlinden 2012). The excimer
1869; Schiotz 1885). In the 1940s and
laser is an ultraviolet laser combining
1950s, Sato introduced anterior and
a noble gas (Argon) with a reactive
posterior keratotomy as treatment for
halogen gas (Fluoride). It emits pho-
myopia and astigmatism (Sato 1950;
tons at a wavelength of 193 nm,
Sato et al. 1953). The central part of
which can break the peptide back-
the cornea was flattened by up to 80
bone and vaporize corneal collagen
anterior or posterior incisions, but
molecules in a process called ablative
success was limited as the technique
photodecomposition. This was first
damaged the endothelium. Barraquer
described and introduced in refractive
then pioneered modern refractive sur-
surgery by Trokel et al. (1983). The
gery with the invention of keratomileu-
laser has high corneal absorption and
sis (from Greek: keras meaning horn,
low tissue penetration and can ablate
here applied to the cornea, and smileusis
corneal tissue without significantly
meaning carving or chiselling) and the
heating or damaging the adjacent
microkeratome over 50 years ago.
tissue because of the short pulse
These were milestones in lamellar surgi-
duration.
cal techniques, but they required
The excimer laser energy can gen-
improvements in both accuracy and
erally be delivered with three different
ease to be implemented in daily clinical
types of lasers. Broad-beam lasers
use (Barraquer 1996; Krachmer et al.
were used in the first-generation laser
2011, p. 1831). In the 1970s and 1980s,
platforms. They used a full laser beam
Fyodorov & Durnev (1979), in the
with internal masks or diaphragms for
former USSR, refined the Sato tech-
customized ablations, but the ablation
nique to only anterior corneal incisions
plume sometimes resulted in untreated
placed centrifugally with a metal blade.
areas, so-called central islands (Lin
Up to 32 corneal cuts were performed in
1994; Levin et al. 1995). Scanning-slit
a technique called radial keratotomy
lasers used a smaller slit-shaped laser
(RK). This was later modified to the less
beam capable of rotation and were
invasive mini-RK technique using 4–8
able to treat larger-diameter ablation
cuts and was mainly performed in
zones. Today, most modern excimer
patients with low degrees of myopia
lasers are flying-spot lasers (Fiore
(Lindstrom 1995). Progressive flatten-
et al. 2001) with eye trackers (Lin
ing of the cornea, diurnal fluctuation of
et al. 2008), allowing for more
vision postsurgery and the invention of
complex treatments such as topogra-
laser-based techniques were some of the
phy or wavefront-guided treatments.
reasons that RK today is largely con-
They use small circular laser spots at
sidered an obsolete procedure (Waring
high frequency and sufficiently spaced

to avoid thermal effects. Overall, laser
pulse frequency, energy and duration
are important parameters to avoid
slow treatment, thermal effects and
variation in the laser ablation effect.
The amount of laser energy per unit of
area needed for corneal photoablation
is approximately 50 mJ/cm2, and
subthreshold fluence can cause irregu-
lar and incomplete ablation. Further-
more, corneal hydration affects
ablation rate, hence, dehydration
increases ablation rate and vice versa
(McAlinden 2012).
The femtosecond laser
The FSL is a solid-state Nd:Glass
laser source, similar to an Nd:YAG
laser. It uses ultra-fast (10 15 seconds)
focused pulses at near-infrared wave-
lengths to create photo disruption at
their focal point. The laser pulse
generates a high-intensity electric field
causing the formation of a mixture of
free electrons and ions that consti-
tutes the plasma state. The plasma
then expands rapidly and displaces
the surrounding tissue. The vaporized
tissue forms a cavitation bubble in
the focal volume of the laser beam,
and when the laser bubbles fuse,
cutting is completed. The process is
called laser-induced optical break-
down, and the result is high-precision
tissue cleavage with minimum collat-
eral damage (Stern et al. 1989; Rat-
kay-Traub et al. 2001). The
technological evolution has resulted
in a gradual increase in laser firing
frequency from the original 6 to
500 kHz that is used today, for faster
and smoother corneal cuts (Hjortdal
et al. 2012a,b). Different FSL plat-
forms differ in pulse energy and fre-
quency, applanation surface (flat or
curved), laser delivery (raster or spiral
pattern) and mobility (Kymionis et al.
2012). The FSL’s primary application
has been as a replacement for the
microkeratome in laser-assisted in situ
keratomileusis (LASIK), offering
increased precision in flap creation
(Lee et al. 2009). The FSL is also used
for corneal intrastromal ring implan-
tation to treat presbyopia and ectatic
corneal diseases such as keratoconus.
Other applications include astigmatic
keratotomy, lamellar cutting during
corneal transplantation and cataract
surgery (Alio et al. 2006a,b; Abbey
et al. 2009; Buzzonetti et al. 2009;
Hoffart et al. 2009; Kymionis et al.
2009; Pinero et al. 2009; Ruiz et al.
2009; Bouzoukis et al. 2012; Hjortdal
et al. 2012a,b; Baradaran-Rafii &
Eslani 2013; Roberts et al. 2013).
Photorefractive keratectomy
Photorefractive keratectomy (PRK)
was the first excimer laser technique
for the treatment of refractive errors.
Seiler performed the first corneal abla-
tion in a live patient in 1985, and
McDonald treated the first human
sighted eye in 1988 after extensive
preclinical investigation (Seiler et al.
1987, 1988; Reinstein et al. 2012a,b).
The PRK procedure involves removal
of the central corneal epithelium, most
commonly performed mechanically
after brief alcohol application to
loosen the epithelium. The denuded
anterior stroma is then reshaped by the
excimer laser, with either central cor-
neal flattening, steepening or a torical
pattern when treating myopia, hyper-
opia or astigmatism, respectively. Due
to significant postoperative pain, rela-
tively slow visual recovery and haze
development, especially when treating
high myopia (Ehlers & Hjortdal 1992;
Gartry et al. 1992; Rosman et al.
2010), the intrastromal LASIK proce-
dure was invented (Pallikaris et al.
1990). LASIK virtually eliminated the
previously mentioned drawbacks, but
instead flap-related complications
developed, as well as a higher risk of
corneal ectasia. Surface ablation of the
cornea is therefore, by some, still
considered the overall safest procedure
for treatment of low to moderate
myopia (Lee et al. 2001; Rao et al.
2004; Ghadhfan et al. 2007; Hodge
et al. 2011). It is still performed today,
especially in corneas with superficial
scarring, epithelial dystrophies or
recurrent erosions, in thin corneas,
after penetrating keratoplasty and for
keratorefractive retreatments. The
introduction of mitomycin C and
modern surface ablation techniques
has also increased the range of treat-
ment and lowered the risk of haze and
regression after PRK (Carones et al.
2002; Bedei et al. 2006; Shalaby et al.
2009; Teus et al. 2009; Hofmeister
et al. 2013).
Long-term outcomes of PRK
Only a few studies with a follow-up
time of more than 10 years have been
Acta Ophthalmologica 2014
published. Studies were often with a
limited number of patients and with
dropout rates ranging from roughly 1/
3 to 2/3 of the original cohorts (Rajan
et al. 2004; O’Connor et al. 2006;
Bricola et al. 2009; Guerin et al.
2012). Most long-term studies of
PRK reported 55–81% of eyes being
within 1.00 D of attempted refrac-
tion, depending on the refractive cor-
rection, and with refractive stability
within 1 year after surgery (Rajan
et al. 2004; O’Connor et al. 2006; Alio
et al. 2008a,b; Koshimizu et al. 2010;
Guerin et al. 2012). Apart from night-
time visual disturbances and haze
development, complications after
treatment of low to moderate degrees
of myopia were few. Also, patient
satisfaction was often reported to be
high, with most patients stating that
they would undergo the procedure
again (Rajan et al. 2004; Guerin et al.
2012).
Laser-assisted in situ keratomileusis
The term LASIK was first used in
1990 by Pallikaris, in which a micro-
keratome was used to cut a hinged
corneal flap, followed by excimer
ablation of the stromal bed and flap
repositioning (Pallikaris et al. 1990,
1991). LASIK has now become the
most common elective surgical proce-
dure in the world, presumably because
it is an almost painless surgical pro-
cedure with fast visual recovery, as
compared to PRK (Reinstein et al.
2012a,b). These advantages have been
documented in several reviews com-
paring PRK and LASIK, but they
have also underlined that accuracy
and safety were very similar in the
two techniques for treatment of low
to moderate myopia and when con-
temporary techniques such as wave-
front-guided treatments and FSL flap
creation were used (Shortt & Allan
2006; Ang et al. 2009; Shortt et al.
2013). Nonetheless, the deeper corneal
cut in LASIK has made careful
preoperative screening of patients
even more important, to minimize
the risk of the rare but feared
complication of ectasia (Randleman
et al. 2003).
Outcomes after LASIK
There is relative high uniformity in
outcomes between the different com-
mercial laser systems available, but
3
Acta Ophthalmologica 2014
outcomes vary depending on the
degree of refractive error corrected
(Ang et al. 2013; Rosman et al. 2013).
In recent studies, including by far
the largest study to date of LASIK
(more than 10 000 eyes), 3-month
results demonstrated high refractive
predictability and safety. Thus, 95–
100% were within 1.00 D of target
refraction, <1% lost two lines or
more of corrected distance visual
acuity (CDVA) and complications
such as epithelial ingrowth and diffuse
lamellar keratitis were rare (Ang et al.
2013; Rosman et al. 2013; Tomita
et al. 2013). As with PRK, not many
long-term studies exist, and outcomes
are typically reported to be inferior to
short-term results, especially concern-
ing predictability. For example, two
long-term studies reported 78–88%
being within 1.00 D of target refrac-
tion 10–13 years after LASIK (Alio
et al. 2009; Dirani et al. 2010).
Refractive lenticule extraction
Picosecond laser keratomileusis, with
removal of a stromal lenticule from
under a corneal flap, was first
reported in a case study in the late
1990s, and the first clinical results of
femtosecond laser intrastromal cutting
were published in 2003 (Krueger et al.
1998; Ratkay-Traub et al. 2003).
However, it was the VisuMax FSL
(Carl Zeiss Meditec, Jena, Germany)
that paved the way for refractive
Fig. 2. Schematic illustration of femtosecond laser-based refractive lenticule extraction,
with or without a flap. Front view of the eye and anterior segment OCT side view of the
cornea.
4
lenticule extraction (ReLEx), that
is, intrastromal keratomileusis without
the use of excimer laser or microk-
eratomes. Two new procedures were
developed, ReLEx flex (FLEX) and
ReLEx smile (SMILE), as first
described by Sekundo et al. (2008,
2011). Here, a refractive lenticule is
cut within the corneal stroma, and a
subsequent surface cut allows access
to dissection and manual removal of
the lenticule (Fig. 2). In FLEX, a
LASIK-like flap is used to access the
stromal lenticule (Sekundo et al. 2008;
Blum & Sekundo 2010; Kamiya et al.
2012, 2013; Gertnere et al. 2013;
Vestergaard et al. 2013). In SMILE,
only one or two small incisions are
made, minimizing the trauma to the
corneal surface (Sekundo et al. 2011;
Shah & Shah 2011; Shah et al. 2011;
Hjortdal et al. 2012a,b; Tay et al.
2012; Vestergaard et al. 2012a,b,
2013). Theoretically, this should
reduce corneal denervation, postoper-
ative dry eye and epithelial ingrowth,
as well as enhance biomechanical
stability and stability in case of eye
trauma, as compared to flap-related
procedures. However, this has not yet
been studied comprehensively.
The two procedures are Conformit
e
Europ
eenne (CE) marked, and FDA
(U.S. Food and Drug Administration)
studies are currently ongoing. The
ReLEx software became commercially
available in 2011, but software for
treatment of hyperopia has not yet
been released. The range for treatment
of refractive errors with ReLEx ranges
from 0.50 to 10.00 D sphere and up
to 5.00 D in cylinder (as described by
the manufacturer).
Outcomes after ReLEx flex and ReLEx
smile
Until now (September 2013), <30
prospective or retrospective clinical
human eye studies have been pub-
lished concerning treatment of myo-
pia with FLEX or SMILE and only
one study concerning treatment of
hyperopia. Also, prior to the begin-
ning of this study, no contralateral
eye studies directly comparing FLEX
and SMILE had been published. Pre-
vious studies have showed that both
techniques seem predictable, efficient
and safe when treating both low and
high degrees of myopia, despite vari-
ations in baseline characteristics.
Mean refractive residual error up to
1 year after both techniques were
reported close to emmetropia ranged
between 0.25 D (Sekundo et al.
2011; Shah & Shah 2011; Shah et al.
2011; Hjortdal et al. 2012a,b; Kamiya
et al. 2012; Tay et al. 2012; Vesterg-
aard et al. 2012a,b; Gertnere et al.
2013; Kamiya et al. 2013; Vestergaard
et al. 2013). Dry eye, decentration,
microstriae, interface scatter, interface
irregularities, higher-order aberrations
and abrasions have been reported as
reasons for postoperative loss of
visual acuity, but in most cases with
restoration to preoperative values
over time (Blum et al. 2010; Sekundo
et al. 2011; Shah & Shah 2011;
Hjortdal et al. 2012a,b; Kamiya et al.
2012a,b; Vestergaard et al. 2012a,b;
Blum et al. 2013; Ivarsen et al. 2013;
Vestergaard et al. 2013).
Objectives
The aims of this thesis were as follows:
1 To retrospectively evaluate long-
term outcomes after PRK for all
degrees of myopia for a large number
of patients.
2 To prospectively investigate and
compare treatment of moderate to high
degrees of myopia and low degrees of
astigmatism, with ReLEx flex and Re-
LEx smile surgery in a paired eye
study, concerning the following:
• Efficacy, predictability, safety,
contrast sensitivity, wavefront

aberrations and patient satisfac-
tion up to 6 months after surgery.
• Changes in sub-basal nerve mor-
phology, corneal sensation, tear
film evaluation and dry eye sen-
sation from before surgery to
6 months after surgery.
• Changes in central corneal sub-
layer pachymetry and biome-
chanical properties from before
surgery to 6 months after surgery.
Null hypothesis (when performing
significance tests): no difference in out-
comes when comparing ReLEx flex
and ReLEx smile.
Working hypotheses: no difference
in visual and refractive outcomes;
superiority in corneal nerve and tear
film-related parameters as well as
biomechanical properties after a small
incision compared to a flap-like
incision.
Patients and methods
Photorefractive keratectomy (Paper I)
Study population
Since 1992, PRK for treatment of myo-
pia has been performed at the Depart-
ment of Ophthalmology, Odense
University Hospital, Denmark. In this
retrospective long-term follow-up
study, 751 patient charts from 1992 to
1998 were reviewed, and pre- and initial
postsurgery data were collected. The
inclusion criteria for PRK patients in
this study were as follows: age between
19 and 30 years at time of surgery of the
first eye, stable myopia for at least
1 year before surgery and CDVA of
20/40 or better on the Snellen chart.
Exclusion criteria were all other ocular
conditions except myopia with or with-
out astigmatism. Pregnant or breast-
feeding women were also excluded.
None of the patients had worn contact
lenses within 2 weeks (soft lenses) or
4 weeks (hard lenses) prior to assess-
ment. Of the 751 patients, 365 fulfilled
the specified inclusion and exclusion
criteria, and a total of 276 patients were
invited to a final follow-up examination.
The remaining patients had either died,
moved abroad or were under ‘research
protection’ (n = 73), which meant that
they were not allowed to be contacted.
Excimer laser procedure
All patients had been treated by the
same surgeon and with the same broad-
beam laser (SVS Apex laser system;
Summit Technology, Inc., Waltham,
MA, USA), without the use of an eye
tracker. They had received either single
zone, multizone or a combined spherical
and torical ablation. There had been no
use of topical mitomycin C, and the
epithelium had been removed with a
Beaver blade without the use of alcohol.
Postoperative treatment included
chloramphenicol drops or ointment
three times a day for 1 week, dexameth-
asone drops three times a day for a
minimum of 3 months, homatropine or
cyclopentholate three times a day
for 1 week, systemic non-steroidal
anti-inflammatory drugs and
benzodiazepines for the first three nights
(manufacturers unknown).
Examination procedure
At baseline and initial follow-up:
The surgeon had performed both
pre- and postsurgery examinations and
had followed the patients for
6 months. In cases with complications,
the patients had often been followed
for several years. In these initial exam-
inations, patients had undergone a
standard eye examination, including
measurement of manifest visual acuity
and subjective refraction using a
custom clip-on trial frame with glasses
and a standard Snellen chart, Gold-
mann applanation tonometry, slit-lamp
examination, corneal haze grading and
fundoscopy. Objective keratometry,
topography, central corneal thickness
(CCT) or axial length had not been
assessed.
At final follow-up:
In 2011, the final examinations were
performed 13–19 years after PRK
treatment. The patients underwent a
thorough eye examination including
history of eye diseases, visual acuity,
refraction, slit-lamp examination,
fundoscopy, Pentacam HR tomog-
raphy (Oculus, Wetzlar, Germany),
Goldmann applanation tonometry and
patient satisfaction.
Manifest visual acuity and refraction
were measured with a custom clip-on
trial frame with glasses and the Jackson
cross-cylinder using an Early Treat-
ment Diabetic Retinopathy Study (ET-
DRS) chart. Refraction was done with
guidance from an auto-refractor (RK-2
auto ref-keratometer; Canon, Tokyo,
Japan). All measurements were per-
formed in the same examination room
with carefully controlled lighting.
Acta Ophthalmologica 2014
Corneal haze was assessed according
to the Fantes classification: Grade 0,
totally clear cornea, no opacity seen by
any method of slit-lamp microscopic
examination; Grade 0.5, a trace or a
faint corneal haze seen only by indirect
broad tangential illumination; Grade 1,
haze of minimal density seen with
difficulty with direct and diffuse illumi-
nation; Grade 2, a mild haze easily
visible with direct focal slit illumina-
tion; Grade 3, a moderately dense
opacity that obscures the iris details;
Grade 4, a severely dense opacity that
completely obscures the detail of intra-
ocular structures (Fantes et al. 1990).
Patient satisfaction was evaluated with
a question based on a visual analog
scale from 0 to 10 anchored at each end
by adjectival descriptors. In writing,
the patients were asked at follow-up:
‘Are you satisfied with your laser sur-
gery for nearsightedness?’ on a scale
from 0 to 10, and a linear score was
derived. Also, results were divided into
four subgroups (0–2.5: very dissatis-
fied, >2.5 to 5: dissatisfied, >5 to 7.5:
satisfied, >7.5 to 10: very satisfied) and
correlated with spectacle independence.
Refractive lenticule extraction (Papers
II–IV)
Study design
In this study, 35 patients (70 eyes) were
included in a prospective, single-
masked, paired eye study registered
at www.clinicaltrials.gov (identifier:
NCT01673503). All patients were
selected from the group of approxi-
mately 1000 patients with moderate to
high myopia or anisometropia who are
referred to The Department of Oph-
thalmology, Aarhus University Hospi-
tal every year for refractive surgery.
The inclusion period lasted from May
2011 to August 2012. Inclusion criteria
were as follows: age 25–45 years, stable
myopia for at least 1 year, a CDVA of
20/25 or better, spherical equivalent
refraction from 6 to 10 D with less
than a 2 D difference between the two
eyes and refractive astigmatism of
<2 D. Patients were told to discontinue
using soft contact lenses for 2 days
prior to assessment. Usage of hard
contact lenses, CCT <480 lm, a calcu-
lated postoperative residual stromal
bed (RSB) of <250 lm and all other
ocular conditions meant exclusion
from surgery. Pregnancy and breast-
feeding were also exclusion criteria.
5
Acta Ophthalmologica 2014
Patients were randomized after ocular
dominance (using the hole in the hand
method) to receive FLEX in one eye
and SMILE in the other eye for treat-
ment of moderate to high myopia, with
an equal number of dominant eyes in
each group. Randomization was
revealed after the final 6 months
examination.
Femtosecond laser surgical procedures
A VisuMax 500-kHz FSL was used for
both the FLEX and the SMILE treat-
ments. The desired refractive change
was entered directly into the laser, and
the patient was positioned under the
curved contact glass and asked to fixate
a blinking target. Topical anaesthesia
was applied at 5 and 1 min before
surgery using two drops of 0.8% oxy-
buprocaine tetrachloride (Bausch and
Lomb, Berlin, Germany). A lid specu-
lum was inserted, and when appropri-
ate centration (centre of pupil) was
observed, suction was applied to the
contact glass. Surgery was performed
bilaterally and with the same laser
settings for both eyes. The laser cut
energy index ranged from 25 to 34
(corresponding to approximately
125–170 mJ), and spot spacing ranged
from 2.5 to 4.5 lm. The laser first
created the back of the intrastromal
lenticule, with photo disruption from
the periphery to the centre of the
cornea. Then, the lenticule front was
created with an anterior lamellar cut
from the centre to the periphery. The
lenticule front cut was extended
towards the surface to create a corneal
flap (approximately 330°) in FLEX and
a 40–60° small incision in SMILE.
Lenticule diameter was 6.0–6.5 mm,
and the flap/cap diameter ranged from
7.9 to 8.0 mm in FLEX and was
7.3 mm in SMILE. Intended cap thick-
ness was 100–120 lm. The flap hinge
was superiorly placed in all FLEX
procedures, as well as the small incision
in all SMILE procedures. After laser
treatment, a thin blunt spatula was
used to break the remaining tissue
bridges and loosen the stromal lenti-
cule, which afterwards was grasped
with a pair of forceps and removed
(Fig. 3). The corneal stromal pocket
was then flushed with saline. All
patients received one drop of chloram-
phenicol and one drop of diclofenac
(Voltaren Ophtha; Novartis Health-
care, Copenhagen, Denmark) at the
end of the procedure. Postoperative
6
(A)
Fig. 3. Images of femtosecond laser lenticule cutting and removal from the surgeon’s perspective.
(A) ReLEx flex and (B) ReLEx smile.
treatment comprised Fluorometholone
(Flurolon; Allergan Pharmaceuticals,
County Mayo, Ireland) and chloram-
phenicol eye drops four times daily for
1 week, followed by two times a day in
the second week. The patients were
also encouraged to use lubricating
drops as needed to improve comfort
and facilitate surface repair.
Standard and additional examination
procedures
All patients underwent a thorough eye
examination before undergoing refrac-
tive eye surgery. This included visual
acuity and refraction, auto-refraction,
intraocular pressure and keratometric
measurements (NIDEK TONOREF II,
Gamagori, Japan), pupil size (NIDEK
pupillometer, Gamagori, Japan), slit-
lamp examination and fundoscopy.
Regular topographic patterns of both
the corneal front and back were
confirmed with a Pentacam-HR
Scheimpflug camera (Oculus, Wetzlar,
Germany). This included usage of the
Belin/Ambr
osio enhanced ectasia mod-
ule to exclude subclinical keratoconus.
Furthermore, CCT was measured by
optical low coherence reflectometry
(OLCR; Haag-Streit, K€ oniz, Switzer-
land). The patients were then re-exam-
ined immediately after surgery and
after 1 day, 1 and 3 months. The
patients were also recommended to
(B)
visit their private ophthalmologist
after 1 week and to contact the Depart-
ment of Ophthalmology in case of
complications.
For patients included in the ReLEx
study, two extra visits were required,
one before and one 6 months after
surgery. Here, the additional measure-
ments were performed, as elaborated
below. The non-invasive additional
measurements were performed at first
(tear film osmolarity, contrast sensitiv-
ity and all imaging techniques) and
ending with the most invasive tech-
niques (Schirmer’s test, ocular response
analyzer, tear film break-up time, es-
thesiometry and confocal microscopy).
Visual acuity and refraction (Paper II)
All measurements were performed in
two identical examination rooms with
carefully controlled lighting. Specially
trained optometrists determined the
manifest visual acuity and subjective
refraction using phoropters and
ETDRS charts. Cycloplegic refraction
was also determined to assess absolute
refraction.
Contrast sensitivity (Paper II)
Contrast sensitivity (CS) was measured
using the Freiburg acuity and contrast
test (FrACT), in which the examiner
operated the directional keypad (with
eight possible directions) according to

Fig. 4. Schematic illustration of stimuli and responses when assessing contrast sensitivity with the
Freiburg acuity and contrast test (FrACT).
the patients’ verbal responses (Wese-
mann 2002; Dennis et al. 2004; Buhren
et al. 2006; Bach 2007). The test was
performed monocularly with an undi-
lated pupil and optimal spherical and
cylindrical correction. The system used
a forced choice test with a Landolt C
optotype of 1.1 logMAR (equivalent to
Snellen 0.08). During the test, the
Landolt ring was rotated around eight
different positions, and the patients
indicated the location of the gap
(Fig. 4). Depending on the patient’s
answer (correct or incorrect), the pro-
gramme used a ‘Best PEST’ (parameter
estimation by sequential testing) adap-
tive threshold estimation and maxi-
mum-likelihood algorithm for the
calculation of contrast threshold mea-
sured in Weber contrast units (Dennis
et al. 2004; Buhren et al. 2006; Nielsen
& Hjortdal 2012). To reduce variability,
the test was repeated for each eye. The
average value of the two measurements
for each eye represented the reciprocal
of the CS. The logarithm of CS values
(logCS) was used for statistical analysis
(Dennis et al. 2004; Nielsen & Hjortdal
2012). Patients were allowed to
respond to each trial at their own pace,
and time was given to allow retinal
photoreceptor adaptation. Standard-
ized and carefully controlled lighting
was also used during contrast sensitiv-
ity measurements, as described in detail
in Paper II. In addition to the clinical
measurements, the patients were asked
to subjectively compare overall visual
quality between the FLEX and the
SMILE eye.
Wavefront error (Paper II)
Total higher-order aberrations
(HOAs), spherical aberration, coma
and trefoil were analysed and com-
pared. Whole-eye wavefront aberra-
tions were measured using the
WASCA Analyzer (Carl Zeiss Meditec,
Jena, Germany). Only measurements
of eyes with pupil size 5 mm or more
were included (n = 30 for FLEX and
n = 29 for SMILE eyes). Total (ante-
rior + posterior) corneal wavefront
error (RMS, root mean square, lm)
was calculated from the Pentacam
tomography data (Oculus, Wetzlar,
Germany) over the 5-mm central cor-
neal zone and decomposed into Zer-
nike polynomials up to the 8th order,
as previously described (Vestergaard
et al. 2012a,b, 2013). All measurements
were performed under standard scotopic
light settings.
In vivo confocal microscopy (Paper III)
The confocal microscope uses point
illumination and pinholes in the optical
path to reject out of focus light and
generate high-resolution images (Min-
sky 1988; Jalbert et al. 2003). In vivo
Fig. 5. Schematic drawing of central corneal confocal microscopy with imaging of the sub-basal
nerves and nerve tracing using NeuronJ (pink).
Acta Ophthalmologica 2014
laser scanning confocal microscopy
(IVCM) of the central cornea was
performed using the Rostock Cornea
Module (RCM) of the Heidelberg
Retina Tomograph (Heidelberg Engi-
neering GmbH, Heidelberg, Germany).
The RCM is an attachment to the lens
system combined with a motorized z-
axis drive that allow easy and stepless
movement of the focal plane while
image capturing. The microscope lens
is an immersion lens (Olympus, Ham-
burg, Germany), with 963 magnifica-
tion, and a contact objective covered
by a sterile single-use Tomo-Cap (Hei-
delberg Engineering, GmbH). The
images comprised 384 9 384 pixels
and covered an area of 400 9
400 lm. Transversal digital resolution
was approximately 2 lm, and longitu-
dinal digital resolution was approxi-
mately 4 lm (Heidelberg Engineering).
Before IVCM examination, patient
eyes received a drop of topical anaes-
thetic (Minims tetracaine hydrochlo-
ride 0.5%, Chauvin Pharmaceuticals
Ltd., London, UK). One drop of gel
tear substitute (Viscotears, Alcon,
Camberley, UK) was instilled on the
Tomo-Cap. Images of sub-basal nerves
of the central cornea were acquired by
focusing the microscope beneath the
basal epithelium (Fig. 5) while the
patient was looking at a fixed light
source. Real-time imaging was used by
the examiner to optimize manual align-
ment between the central part of the
cornea and the microscope. Four rep-
resentative and complete images of the
central corneal sub-basal nerve plexus,
from the layer immediately at or pos-
terior to the basal epithelial layer, were
selected from each eye both before and
6 months after surgery for analysis.
7
Acta Ophthalmologica 2014
Nerves were quantified by the semi-
automated tracing program NeuronJ
(Fig. 5; Meijering). IVCM images were
graded and regraded by a masked
observer concerning nerve density,
which was defined as the total length
of visible nerves within a frame
(expressed in mm/mm2; Labbe et al.
2012). Another masked observer
graded and regraded confocal images
concerning tortuosity and number of
nerve segments, including all small
branches, observed within a frame
(number/mm2). Tortuosity was classi-
fied according to a previously validated
scale (Oliveira-Soto & Efron 2001;
Labbe et al. 2012).
Central corneal esthesiometry (Paper III)
Central corneal sensation was mea-
sured using the Cochet–Bonnet (CB)
esthesiometer (Luneau, Paris, France),
which consists of a nylon monofila-
ment (0.12 mm wide, 60 mm long).
The instrument was advanced perpen-
dicularly to the corneal surface until
contact was made, with the patient
positioned at the slit lamp. Starting
from 6 cm, the filament length was
gradually reduced with 5 mm intervals
until a positive patient response (sen-
sation of the filament on the cornea)
was obtained and recorded. A bend in
the filament indicated corneal contact,
and ‘dummy runs’ were used to avoid
false-positive responses. The mean
value of four measurements was calcu-
lated and represented central corneal
sensitivity.
Non-invasive and invasive tear film evaluation
(Paper III)
Different techniques, in the described
order, were used to measure potential
changes in the tear film and ocular
surface symptoms. A time interval of
10 min between measurements was
used to minimize test results interfer-
ing with each other, and the most
invasive techniques were used at the
end.
Patients were asked ‘Do you suffer
from dry eyes, on a scale from 0 to
10 where 0 means not at all and 10
means very dry eyes?’, and they had
to respond on a visual analogue scale
(VAS). Patients were asked about dry
eye symptoms in general, and with
and without contact lenses. Also,
they had to discriminate if any dis-
comfort was worse in one eye or in
the other.
8
The Tearlab System (TearLab
Osmolarity System; TearLab Corp.,
San Diego, CA, USA) was used to
measure tear film osmolarity by analy-
sing the electrical impedance of a 50
nanoliter sample from the inferior
lateral meniscus of each eye immedi-
ately after blinking. The instrument was
calibrated (within 1 mOsms/l) before
each examination. The result ‘Below
Range’ was noted as 275 mOsms/l after
retesting had confirmed the result.
Imaging with the Oculus Kerato-
graph (Oculus, Wetzlar, Germany) was
used for non-invasive tear film break-
up time (NI-BUT). The Keratograph
illumination system consists of 200 red
LEDs (wavelength 653 nm) with low
heat emission to reduce thermal alter-
ations of the tear film. Measurements
were performed in a dark room. A
Placido disc ring pattern was projected
onto the cornea. The patient was asked
to blink twice and afterwards to keep
his or her eyes open as long as possible.
Irregularities in the reflected image
indicated tear film instability and
break-up. From the real-time images,
both the time to first break-up and the
average break-up time were measured
automatically using the integrated dig-
ital imaging software.
Anterior segment optical coherence
tomography (AS-OCT) imaging with
the Heidelberg Spectralis Anterior Seg-
ment Module (Heidelberg Engineering
GmbH) was used to measure tear
meniscus height (TMH; Fig. 6). Two
vertical line scans centred at the infe-
rior tear meniscus were obtained.
Patients were asked to look straight
ahead at a fixation light and were
allowed to blink spontaneously. Images
were captured immediately after blinking.
Subsequently, the images were magni-
fied to 400%, and one masked observer
measured TMH using the integrated
Fig. 6. Heidelberg Spectralis anterior segment OCT images of the tear meniscus. Tear meniscus
height (TMH) is measured from the lower eyelid to the cornea.
system software. The mean value of
two measurements was recorded as the
TMH. The Spectralis AS-OCT has a
digital resolution of 3.9 lm axially
911 lm laterally (user manual for
Heidelberg SPECTRALIS software version
5.7).
Schirmer’s test (Schirmer tear test
strips, Haag-Strait, UK) without an-
aesthethic was used to measure reflex
tearing.
Tear film break-up time (TBUT) was
measured using fluorescein strips and
one drop of isotonic saline instilled in
the lower conjunctival fornix. The time
from blinking until the first break or
dry spot appeared was recorded man-
ually with a stopwatch. TBUT was
calculated as the mean of four consec-
utive measurements. Room tempera-
ture and lighting were kept stable
during all examinations.
Central corneal sublayer pachymetry
(Paper IV)
AS-OCT (Heidelberg Engineering
GmbH) was also used to measure
central corneal parameters (Fig. 6).
High-resolution, horizontal line scans
centred at the pupil were obtained.
Afterwards, the images were analysed
using the integrated system software.
Centred on the light reflex, the images
were magnified to 800%, and one
masked observer measured different
corneal parameters perpendicular to
the anterior surface, pre- and 6 months
postsurgery: CCT (the distance bet-
ween the epithelial surface and the
endothelium-anterior chamber inter-
face), central epithelial thickness (ET,
from the epithelial surface to
Bowman’s membrane), central flap/
cap thickness (from the epithelial sur-
face to the laser cut interface) and
central RSB thickness (from the laser
cut interface to the endothelium-ante-

Fig. 7. Central corneal thickness measurements (orange line) postsurgery.
rior chamber interface). The mean
value of two measurements for each
parameter was used to minimize mea-
surement error (Fig. 7).
Corneal biomechanics (Paper IV)
An ocular response analyzer (ORA
version 2.04; Reichert Ophthalmic
Instruments, Depew, NY, USA) was
used to assess corneal hysteresis (CH)
and corneal resistance factor (CRF), to
characterize changes in corneal biome-
chanics. The system automatically gen-
erated an average result for each eye
based on four ORA measurements.
Only measurements with reliable wave-
form scores (>3.5) were included (Lam
et al. 2010). Furthermore, all measure-
ments were obtained quickly to avoid
tear film alterations affecting the
results. The system uses bidirectional
applanation through brief air pulses to
rapidly deform the cornea inwards and
outwards, measuring intraocular pres-
sure twice (Fig. 8). An electro-optical
system monitors the central 3 mm cur-
vature of the cornea throughout the
deformation process during the 20
millisecond measurement. The CH is
calculated as the difference between the
Fig. 8. The ocular response analyzer. Illustration of inward and outward applanation and
measurement of corneal hysteresis (Technologies R)
two pressure values at the two appla-
nation points and is an indicator of
corneal tissue viscous damping. The
CRF is also derived from this response
and calculated using a linear function
of the two pressures and a proprietary
algorithm. It is believed to be a mea-
surement of the overall corneal resis-
tance, or total viscoelastic properties,
of the cornea during measurement
(Luce 2005; Gatinel et al. 2007; Ortiz
et al. 2007).
Satisfaction (Paper II)
Finally, patient satisfaction was evalu-
ated in writing in the same way as
described in Paper I. Also, all patients
were verbally asked about patient sat-
isfaction (very satisfied, satisfied, dis-
satisfied, very dissatisfied) and whether
they felt any differences between the
two eyes. Finally, they were questioned
about the presence of night vision
disturbances, and whether they would
recommend laser surgery.
Statistical design and analysis
Before the PRK study, it was presumed
that approximately 400 patients would
Acta Ophthalmologica 2014
fulfil the inclusion and exclusion crite-
ria and that approximately 200 patients
would attend a final follow-up exami-
nation, thereby providing sufficient
statistical power for data analyses.
Before the ReLEx study, it was
presumed that approximately 30–50
patients could be recruited to partici-
pate in the study within a year. This
was based on previous research experi-
ence with refractive patients, in which
recruitment to paired eye studies and
especially completion of all follow-up
examinations proved difficult. There-
fore, only two additional visits were
planned, to avoid patient dropout of
the study due to multiple visits and
exhausting examinations. A prestudy
sample size calculation was performed
in SIGMAPLOT (Version 12; Systat
Software Inc., San Jose, CA, USA) to
estimate the minimum number of
patients required for statistically useful
results. However, since there were more
than 30 different outcome parameters
and some with yet unknown mean
values and standard deviations for
FLEX and SMILE, a general sample
size calculation was performed instead
of one calculation for each parameter.
This revealed that at least 29 patients
were needed to obtain a statistical
power of 70% in case of normal
distribution, significance level = 5%
and an expected difference in means
between the two equal-sized groups =
0.20 with standard deviation = 0.30.
As expected, recruitment turned out
to be difficult, and post hoc statistics
were therefore also performed to eval-
uate the statistical power of the study.
The sample size in the ReLEx study
offered 92% statistical power at 5%
level to detect a difference in mean
refraction of 0.25 D from before to
6 months after surgery, when the
expected standard deviation of the
mean difference was 0.30 D. For visual
acuity, it offered 77% statistical power
(significance level = 5%, detectable dif-
ference = 2 letters on the chart, with
SD = 3 letters). Therefore, the actual
number of patients included should in
general be sufficient to detect changes
between FLEX and SMILE. Outcomes
and statistical power are described in
detail in Papers II–IV.
In both the PRK study and the
ReLEx study, all measured data were
collected and entered into the patients’
journal and in an anonymous form into
a standardized study spread sheet in
9
Acta Ophthalmologica 2014
Microsoft Excel 2007 (Microsoft, Red-
mond, WA, USA). Statistical analyses
were performed using Microsoft Excel
2007, Systat SIGMAPLOT 12 and STATA
Intercooled software version 11.0
(StataCorp, College Station, TX,
USA). Statistical analysis of visual
acuity was based on logMAR units
(Holladay 2004). Student’s t-test and
paired Student’s t-test were used to
compare normally distributed data.
Mann–Whitney rank sum test and
Wilcoxon signed rank test were used
for non-normally distributed data. The
Kolmogorov–Smirnov test was used to
test for normal distribution. The Pear-
son correlation coefficient (r) was used
for correlation analyses, and Fisher’s
exact test for proportions. The p < 0.05
was considered statistically significant.
The coefficient of variation was calcu-
lated as the standard deviation divided
by the mean value of measurements. All
values were given as mean  SD.
In the PRK study, only results from
one randomly chosen eye of each
patient were used in the statistical
analyses, unless otherwise stated. Eyes
were randomly chosen using the ran-
dom number generator in Excel 2007.
However, concerning safety and com-
plications, results from both eyes were
also stated, to avoid masking of impor-
tant events, complications, etc. due to
the halving of data for statistical
correlations.
In the ReLEx study, reliability/in-
tragrader agreement was evaluated by
regrading 20% of IVCM and AS-OCT
images again, randomly chosen and
calculated using STATA. Intraclass cor-
relation coefficient (ICC) was used for
continuous variables, and weighted
kappa for ordinal variables.
Summary of results
Photorefractive keratectomy (Paper I)
One hundred and sixty-four patients
(59%, 293 eyes) completed the last
follow-up examination 13–19 years
after their PRK procedure. Average
follow-up time was 16 years. Four of
the 164 patients had undergone re-
treatment when attending the follow-
up examination and were excluded
from the data analyses, giving a total
of 160 eyes for analyses (one from each
patient). Mean preoperative SE was
4.84  2.95 D (range 1.25 to
20.25 D), and 78% had low myopia
10
(below 6 D). The maximum degree of
myopic correction was 15 D, and
especially eyes with high degrees of
myopia were deliberately undercorrect-
ed. A subgroup of 35 patients had
undergone unilateral PRK, and of
these, 21 patients still had an untreated
eye when attending final follow-up.
The two reasons for unilateral treat-
ment were emmetropia/minimal refrac-
tive error or dissatisfaction with the
surgical result of the first eye.
Predictability and stability
Mean refraction was close to emmetr-
opia both 3 and 6 months postsurgery,
but with a wide range (see Paper I –
Table 2). At the final follow-up, mean
difference in achieved versus attempted
refraction was 1.00  1.56 D, with
no eyes ending up with more than
1.00 D of hyperopia (see Paper I –
Table 2; Fig. 1). Predictability was
highly related to the degree of myopia
corrected, with 72% of eyes with low
myopia being within 1.00 D of target
refraction, as compared to 47% of eyes
with high myopia ( 6 D or more).
There was no statistically significant
difference when comparing refractive
predictability in single zone versus
multizone ablation, nor when exclud-
ing eyes with cataract.
Unilaterally treated PRK patients
were on average 1.57  1.99 D from
attempted refraction. Myopic progres-
sion was noted in their untreated eyes,
with a mean difference of 1.22 
1.06 D from baseline refraction (see
Paper I – Table 3).
Efficacy and safety
UDVA of 20/20 or better at final
follow-up was obtained in significantly
more eyes with low myopia (50%) than
eyes with high myopia (22%). Further-
more, 79% of all eyes fulfilled vision
requirements for driving without spec-
tacles (20/40 or better, see Paper I –
Fig. 5). Ninety-nine percentage of all
eyes had CDVA of 20/40 or better both
6 months after surgery and at final
follow-up. Two percent of eyes with
high myopia and no eyes with low
myopia had lost two lines or more of
CDVA at final follow-up. Eight per-
centage had gained two lines (see
Paper I – Fig. 6). The results were very
similar when including both eyes of all
patients in the analysis (n = 289 eyes).
Fourteen percent had haze at the last
follow-up visit (12% when including
both eyes), and half of these had only
clinically insignificant trace haze
(grade 0.5). The degree of haze was
correlated with the attempted refrac-
tive correction, and haze did not occur
in eyes with attempted corrections of
less than 4 D. The degree of haze
also diminished from 6 months to final
follow-up.
At final follow-up, concomitant eye
diseases for all 289 eyes included cat-
aract (2%), myopic macular atrophy
(3%) and glaucoma (1%). None of the
27 patients who had received intraocular
pressure-lowering drops after PRK was
diagnosed with glaucoma at follow-up.
Also, no signs of postoperative corneal
ectasia were noted.
Satisfaction evaluation
Patient satisfaction was relatively high,
with 81% being satisfied or very satis-
fied, and a mean satisfaction score at
last follow-up of 7.4  2.9 (range
0–10). Satisfaction was highly corre-
lated with spectacle independence.
Refractive lenticule extraction (Papers II–
IV)
Thirty-four patients completed the
6 months follow-up period. Baseline
characteristics for FLEX and SMILE
eyes are presented in Table 1. There
were no statistically significant differ-
ences at baseline.
Predictability and stability
Refractive predictability was high and
with refractive stability from 1 month
postsurgery (see Paper II – Table 2,
Figs 3–6). In FLEX eyes, achieved
refraction was 0.04  0.38 D (range
1.25 to +0.75 D) from the attempted
refraction after 6 months, and in
SMILE eyes, it was 0.09  0.39 D
(range 1.13 to +0.50 D). In both eyes,
97% were within 1.00 D of target
refraction, and 88% were within
0.50 D. There were no statistically
significant differences between FLEX
and SMILE results at any time-points.
Efficacy, safety, and contrast sensitivity
Results concerning visual acuity are
presented in Table 2. There were no
statistically significant differences at
any time-points between FLEX and
SMILE eyes. Furthermore, when mea-
sured and asked 6 months after surgery,
patients had no change in CS and also
no difference between their two eyes.
 Acta Ophthalmologica 2014

Table 1. Baseline characteristics. (range 0–8) to 0.8  1.1 (range 0–4).

No. of eyes
Gender (% male)
Right eye dominant (%)
Age (Years)
Mean  SD
Range
Spherical equivalent (D)
Mean  SD
Range
Intraocular pressure (mmHg)
Mean  SD
Range
Average keratometry (D)
Mean  SD
Range
Central corneal thickness (lm)
Mean  SD
Range
Three intraoperative complications
occurred in three different SMILE
eyes: suction loss with uncomplicated
reattachment and treatment, a small
peripheral inferotemporal perforation
with the spatula and a small corneal
abrasion. At slit-lamp examination
at day 1 after surgery, there were
neither signs of the abrasion nor the
perforation. No enhancement proce-
dures were performed.
Whole-eye and corneal higher-order aber-
rations
In both groups, a statistically signifi-
cant induction of most HOAs was
found, except for whole-eye trefoil in
both groups and corneal trefoil in
FLEX eyes. Furthermore, corneal
spherical aberration decreased in both
eyes, although only statistically signif-
icant in FLEX eyes (see Paper II –
Table 3). When comparing FLEX and
SMILE eyes, there were no statistically
Seventy-four percent indicated that
FLEX SMILE
postoperative dryness and foreign body
34 sensation were more pronounced in the
32 FLEX eye within the first day to 1 week
67 after surgery, as compared to 9% with
more symptoms in the SMILE eye. The
35  7 rest felt no difference.
25 to 45
Corneal pachymetry
7.59  0.97 7.56  1.11
6.00 to 9.75 6.00 to 9.88 Intragrader agreement was very high
(≥98%) for CCT and RSB measure-
16  3 16  3 ments and was moderately high
10 to 24 11 to 24 (≥75%) for ET and flap/cap thickness.
Furthermore, AS-OCT measurements
43.37  1.52 43.43  1.47 of changes in CCT were correlated with
40.74 to 46.88 40.79 to 46.72 OLCR measurements (r = 0.62 in
FLEX eyes, r = 0.75 in SMILE eyes).
546  29 544  31
490 to 613 484 to 618 Six months after surgery, the mean
decrease in CCT was 105 lm in FLEX
eyes and 106 lm in SMILE eyes. Mean
central ET increase was 6–7 lm after
significant differences in HOAs neither both procedures, but with no statisti-
at baseline nor after 6 months, nor cally significant difference between the
when comparing the induced change in two techniques. The increase was not
aberrations. correlated with the amount of corneal
tissue removed. When the increase in
Sub-basal nerve alterations, corneal sen- ET was subtracted, there was no sta-
sation and tear film parameters tistically significant difference between
Results are presented in Table 3. expected and measured mean flap/cap
Intragrader agreement for all three thickness in either FLEX or SMILE
morphology parameters was around eyes and also with no difference
90%. Corneal nerve density and num- between the two techniques. Likewise,
ber of nerve segments were reduced in there was no difference in mean RSB
both FLEX and SMILE eyes 6 months thickness 6 months after surgery, and
after surgery, but significantly more in no eyes had a RSB of <250 lm. See
FLEX eyes. Corneal sensation was also Paper IV for details.
significantly reduced in FLEX eyes, but
not in SMILE eyes. Correlations are Corneal hysteresis and CRF
described in detail in Paper III. When comparing FLEX and SMILE,
There were no statistically significant there was no statistically significant
differences when comparing the changes difference in the induced change in
in FLEX and SMILE tear film param- neither CH nor CRF from before to
eters from before to 6 months after 6 months after surgery. CH was
surgery. Nonetheless, mean dry eye reduced by approximately 3 mmHg
VAS score improved from 2.3  2.5 and CRF by approximately 4.5 mmHg

Table 2. Results after 1, 3 and 6 months.

FLEX SMILE FLEX SMILE FLEX SMILE

1 month 3 months 6 months

UDVA ≥ 20/40* (%) 100 100 97 97 100 100

UDVA ≥ 20/20* (%) 43 59 55 60 55 60
CDVA (logMAR) 0.04  0.08 0.06  0.08 0.06  0.06 0.08  0.08 0.06  0.08 0.08  0.08
(0.16 to 0.14) (0.16 to 0.16) (0.12 to 0.20) (0.14 to 0.18) (0.12 to 0.20) (0.12 to 0.20)
Change in CDVA (%)
Lost 1 line 12 9 3 3 3 3
Unchanged 82 76 85 71 79 76
Gained 1 line 3 15 12 26 18 21

* Only eyes with emmetropia as their target refraction were included (FLEX: n = 31; SMILE: n = 30).

11
Acta Ophthalmologica 2014
Table 3. Results from evaluation of sub-basal nerve parameters, central corneal esthesiometry and tear film measurements presented as mean  SD.
Three of the 34 patients could not complete in vivo confocal microscopy due to discomfort during examination and pronounced blinking.
Corneal nerve morphology (n = 31)
Density (mm/mm2)
Number (/mm2)
Tortuosity (grade)
Corneal sensation (n = 34)
Cochet–Bonnet esthesiometry (cm)
Tear film evaluation (n = 34)
Osmolarity (mOsms/l)
Keratograph, first break-up (seconds)
Keratograph, average break-up (seconds)
Schirmer’s test (mm)
Tear meniscus height (lm)
Tear film break-up time (seconds)
A statistically significant difference between FLEX and SMILE of *p < 0.05 and **p < 0.01.
after both procedures. Also, CH and
CRF were highly correlated with CCT,
but not with patient age. See Paper IV
for details.
Satisfaction evaluation
Ninety-seven percent were satisfied or
very satisfied in both groups 6 months
after surgery. Mean VAS satisfaction
score was >9 after both procedures
(range 4.5–10). Questionnaire and ver-
bal responses were identical. One
patient scored 4.5 on the VAS for both
eyes because spectacles were sometimes
still needed due to remaining astigma-
tism. Four patients had slightly more
night vision disturbances (halos and/or
glare) in both eyes than before surgery.
All patients would recommend laser
surgery for nearsightedness to a friend
or a family member.
Discussion
Refractive eye surgery has become
increasingly popular within the last
two decades. Evaluation of both short-
and long-term results is therefore of
utmost importance to monitor predict-
ability, efficacy and safety, as with all
surgical procedures. However, lasers
and refractive techniques evolve rap-
idly, and this should be taken into
account when evaluating results and
comparing different techniques.
Long-term outcomes of PRK (Paper I)
This study evaluated results from the
longest follow-up of patients having
undergone PRK for myopia and also
with more patients included than in
12
FLEX SMILE FLEX
Before surgery 6 months after surgery
19.0  5.5 17.6  5.3 4.8  3.9
80.3  25.8 78.3  19.4 32.7  22.4
1.6  0.5 1.7  0.5 1.5  0.6
5.9  0.2 5.9  0.2 5.5  0.5
293.4  10.4 293.4  9.3 294.2  10.2
6.1  3.6 6.0  2.7 4.4  2.6
10.3  4.4 10.0  3.8 8.1  4.0
18.8  11.1 19.0  11.5 17.6  10.8
313  113 280  91 294  104
13.2  6.2 13.6  6.3 7.3  4.5
most other long-term studies (160
patients, 289 eyes). It underlines that
even ‘early PRK treatments’, without
mitomycin C, without eye tracker and
without high-frequency flying-spot ex-
cimer lasers, can still produce reason-
able results, especially when limiting
treatment to patients with lower
degrees of myopia. Results were not
comparable to short-term results after
contemporary surface ablation tech-
niques or intrastromal procedures such
as LASIK or ReLEx (Shah & Shah
2011; Hjortdal et al. 2012a,b; Costa
et al. 2013; Hofmeister et al. 2013;
Shortt et al. 2013). However, our
results were comparable to other
long-term prospective and retrospec-
tive results 12–16 years after PRK,
despite differences in study design,
including patient age, the degree of
myopia, size of optical zones, follow-up
rates, etc. (Rajan et al. 2004; O’Connor
et al. 2006; Bricola et al. 2009; Guerin
et al. 2012).
Apart from this study, the longest
follow-up of PRK patients was
reported by Guerin in a prospective
16-year study (Guerin et al. 2012).
Here, data were presented from 23 of
the initial 80 patients treated for myo-
pic astigmatism up to 7.25 D, with
5 mm ablation zones by a Summit
excimer laser. Outcomes were very
similar to the findings in our study,
when treatments of low to moderate
degrees of myopia with similar optical
zones were compared. Our retrospec-
tive results thereby support the results
of the prospective study by Guerin, but
with a significantly higher number of
patients included and a higher percent-
SMILE FLEX SMILE
Difference (pre to post)
8.4  7.0* 14.2  6.2 9.2  7.8*
53.8  37.5** 47.6  30.4 24.5  36.2*
1.6  0.5 0.1  0.9 0.1  0.7
5.8  0.3** 0.4  0.5 0.1  0.3**
293.6  9.4 0.8  12.1 0.1  12.1
5.6  4.9 1.8  4.0 0.4  5.1
8.8  4.3 2.2  5.0 1.2  5.6
18.8  12.2 1.3  10.6 0.2  7.4
282  89 28  93 2  63
8.8  3.3* 5.8  6.7 4.8  7.2
age of patients attending final follow-
up. The same was the case when
comparing our results with 12- to 14-
year follow-up studies of PRK with the
Summit excimer laser (Rajan et al.
2004; O’Connor et al. 2006; Bricola
et al. 2009). Again, these studies
involved relatively few patients and
with the well-known problem of low
participant rates at long-term follow-
up examinations after refractive sur-
gery, but closer to the 59% follow-up
rate reported in Paper I.
In our study, refractive predictability
was inferior when correcting high myo-
pia as compared to low myopia, as
reported ever since the introduction of
the PRK technique (Gartry et al.
1992). This included a higher risk of
both under and over correction in
highly myopic eyes, as previously
described (Koshimizu et al. 2010). Pre-
dictability was lower at final follow-up
than after 6 months, indicating refrac-
tive instability. Previous studies have
reported refractive stability occurring
4 months to 2 years after treatment,
depending on the refractive correction,
and then maintained for up to 16 years
after surgery (Gartry et al. 1992; Rajan
et al. 2004; O’Connor et al. 2006;
Bricola et al. 2009). Front surface cor-
neal power has also been reported to
stabilize within 1 year after PRK, in
contrast to LASIK (Ivarsen & Hjortdal
2012). However, regression of the abla-
tive effect as well as myopic progres-
sion can still occur (Alio et al. 2008a,
b). In our study, the average change in
refraction from 6 months to final fol-
low-up was approximately 1 D. Epi-
thelial hyperplasia, corneal steepening,

change in axial length, lenticular scle-
rosis and many other factors have
been reported as reasons for refractive
instability (Pietila et al. 1998; Loh-
mann et al. 1999; Koshimizu et al.
2010; Backhouse et al. 2012). How-
ever, our results from unilaterally
treated eyes indicated that the change
in refraction primarily was due to
myopic progression. This was in
accordance with most previous stud-
ies, but is of course speculative, since
the ‘control group of untreated eyes’
was not perfectly matched to the
entire cohort. Also, we had no base-
line values, and pre- and postsurgical
axial length measurements and kera-
tometry would have been helpful in
analysing just how much of the
change in SE over time was due to
natural myopic progression, especially
because the patients were relatively
young at the time of surgery.
The safety of the PRK procedure
was generally high, especially for treat-
ment of low myopia, and when avoid-
ing excessive corrections (especially
more than 10 D). No late adverse
events were noticed up to 19 years
after PRK. The main reasons for loss
of two lines or more of CDVA were
pronounced corneal haze and myopic
macular degeneration and were only
seen in eyes with high myopia. Our
result of haze in 12% of all eyes was
comparable to other long-term studies
and also supports previous reports of
haze being related to the amount of
ablated tissue (Gartry et al. 1992).
Today, modern surface ablation
profiles have reduced the incidence of
haze, even when treating moderate to
high degrees of myopia and even
without the use of mitomycin C (Hof-
meister et al. 2013). Also, the majority
of eyes had received relatively small
5 mm ablation zones, as compared to
the ≥6 mm optical zones used today.
Ablation depth was therefore presum-
ably low, and it could be speculated
that this reduced the risk of develop-
ment of ectasia (and haze), despite the
fact that a small percentage of eyes
were treated for values not consider-
able for surface ablation today. In
contrast, small optical zones can
increase the risk of regression and
night vision disturbances such as glare
and halos (O’Brart et al. 1995). This
was also an issue among patients in
this study. Here, approximately 10%
reported of problems with halos during
daytime, and 40–50% had halos or
glare during night-time (Vestergaard
et al. 2012a,b, 2013).
Despite these visual disturbances,
patient satisfaction was relatively high,
although not comparable to the ≥90%
patient satisfaction rate reported after
LASIK and ReLEx (Ang et al. 2009;
Vestergaard et al. 2012a,b; Tomita
et al. 2013; Vestergaard et al. 2013).
In general, patient satisfaction can be
evaluated in many different ways, with
numerous types of more and less val-
idated questionnaires and is reported in
most studies when evaluating safety
(Freitas et al. 1995; McGhee et al.
1996; Papas & Schultz 1997; Terwee
et al. 2007; Ang et al. 2009; Blum et al.
2010; Sekundo et al. 2011; Vestergaard
et al. 2012a,b, 2013). In both the PRK
study and the ReLEx study, patient
satisfaction was evaluated at final fol-
low-up examination with a question
taken from a translated version of a
questionnaire for PRK patients
(McGhee et al. 1996). The VAS score
question had also previously been used
to test patient satisfaction in a similar
group of PRK patients at Odense
University Hospital and without
reports of conceptual or interpretive
difficulties (Kvaraciejute & Lyhne
2006). Since this was a relatively new
type of surgery at the time, all patients
had been informed about the known
risks that there was no guarantee of
spectacle independence and that long-
term outcomes were unknown. There-
fore, patient satisfaction in this study
should be evaluated under these terms.
Since the most important reason for
undergoing refractive surgery in most
patients is to improve unaided vision
and avoid the necessity of using spec-
tacles, it was not surprising that satis-
faction scores were highly related to
spectacle independence (McGhee et al.
1996).
Limitations
First of all, this was a retrospective
study with the risk of different kinds of
bias, especially selection bias. This
applied to both the entire cohort and
the group of unilaterally treated
patients and especially when data from
these groups were compared. Perhaps,
patients who attended follow-up were
less satisfied and had more complica-
tions after PRK than the entire cohort
– or vice versa. To accommodate this,
worst/best case scenarios can be calcu-
Acta Ophthalmologica 2014
lated to analyse the range of possible
outcomes if all patients had partici-
pated. We also noted some occupa-
tional selection bias in terms of a
predominance of policemen and sol-
diers in the cohort. Nonetheless, all
social classes were presumably repre-
sented, since all refractive eye surgery
was covered by Danish national
healthcare in the 1990s. Furthermore,
our age inclusion criteria induced selec-
tion bias and risk of including patients
with not yet stabile refraction, but
young patients were chosen to mini-
mize age-related eye diseases affecting
outcomes. However, cycloplegic eye
drops had not been used, as a pseud-
omyopic component had not been
noticed presurgery.
It is also important to remember
that outcomes only represent a single
treatment performed 13–19 years ago,
since retreatments were excluded.
Results also incorporate the learning
curve of the surgeon. Furthermore,
data were based on a now outdated
broad-beam laser and treatment algo-
rithms and cannot be directly com-
pared with contemporary techniques.
Evaluation of ReLEx flex and ReLEx
smile (Papers II–IV)
All FSL-based refractive surgery has
led to renewed interest in lamellar
refractive surgery. In just a few years,
FLEX and SMILE have become estab-
lished refractive procedures for treat-
ment of myopia and myopic
astigmatism and alternatives to excimer
laser treatments. Some of the empirical
and theoretical advantages, as com-
pared to an excimer-based treatment,
include the following:
• No need for fluence testing.
• No smell of burned corneal tissue.
• Potentially less variation in corneal
hydration and tissue removal,
because the refractive cut is per-
formed before the stroma is exposed
to ambient changes (Kim & Jo 2001;
Patel et al. 2008; Vestergaard et al.
2012a,b, 2013).
• The possibility to perform minimal
invasive stromal tissue removal with
the SMILE technique and also to
cryopreserve the refractive lenticule,
which perhaps later on can be used
for lamellar surgery (Mohamed-Nor-
iega et al. 2011; Angunawela et al.
2012).
13
Acta Ophthalmologica 2014
Some potential disadvantages
include the following:
• No use of eye tracker and no com-
pensation for cyclotorsion, which
can prove an issue when correcting
high degrees of astigmatism.
• Treatment of hyperopia is not yet
possible with commercially available
software.
• SMILE is more surgically demand-
ing than flap-based procedures. Len-
ticule tissue remnants and corneal
irregularities can occur in cases
involving difficulties with lenticule
removal, in both ReLEx procedures
(Vestergaard et al. 2012a,b; Dong &
Zhou 2013; Vestergaard et al. 2013).
Thorough loosening, starting at the
anterior side of the intrastromal
lenticule, is therefore essential to
avoid the lenticule becoming stuck
on the flap/cap.
• Currently, retreatments are more
easily performed in FS-LASIK (and
FLEX) by flap-lifting. In FLEX, a
subsequent excimer procedure is usu-
ally performed, while in SMILE, it
still remains to be established how
enhancements are best performed.
PRK, LASIK, a new SMILE proce-
dure, or laser-based opening of the
cap with subsequent photoablation
are possible options (Hjortdal et al.
2012a,b; Riau et al. 2013).
Flap versus cap – the similarities
In this study, safety, refractive predict-
ability and stability were high and not
related to the degree of refractive
correction, as previously described
(Hjortdal et al. 2012a,b). Most FLEX
and SMILE results were almost iden-
tical and in accordance with previous
published results after both procedures,
as well as after FS-LASIK (Sekundo
et al. 2008; Blum et al. 2010; Blum &
Sekundo 2010; Sekundo et al. 2011;
Shah et al. 2011; Ang et al. 2012;
Hjortdal et al. 2012a,b; Kamiya et al.
2012; Vestergaard et al. 2012a,b; Ang
et al. 2013; Gertnere et al. 2013;
Kamiya et al. 2013; Rosman et al.
2013; Shortt et al. 2013; Tomita et al.
2013; Vestergaard et al. 2013; Wei &
Wang 2013). High similarity between
refractive and visual outcomes in
FLEX and SMILE was also expected
due to the fact that the refractive cut
was obtained in the same way and with
the same laser settings for each patient.
An exception was the flap/cap diame-
14
ter, which was slightly larger in FLEX
eyes, but smaller than the 8–9.5 mm
flap cut diameter used in most LASIK
procedures. The difference in flap/cap
size did not seem to negatively affect
outcomes or cause optical distur-
bances. Neither did treatment of a
few eyes with slightly larger mesopic
pupil size than lenticule diameter. Fur-
thermore, results in our study were not
affected by early postoperative inter-
face scatter and delay in visual recov-
ery, as reported in early ReLEx studies
(Sekundo et al. 2008; Vestergaard
et al. 2012a,b, 2013). Optimization of
laser settings, including the use of the
spiral-in/spiral-out scanning trajectory
instead of vice versa, is reported to have
solved this issue (Shah & Shah 2011).
Second-order spherocylindrical
errors account for the majority of the
focus errors in the human eye. How-
ever, 3rd, 4th and other HOAs, as well
as changes in CS, can negatively affect
visual acuity (Kohnen 2001; McLeod
2001; Buhren et al. 2006; Gatinel et al.
2010; Ivarsen & Hjortdal 2012).
Despite there being only a few publi-
cations, the changes in HOAs and CS
were previously reported to be equal to
or slightly better after FLEX and
SMILE than compared to FS-LASIK
procedures, especially concerning
spherical aberration (Sekundo et al.
2011; Shah et al. 2011; Kamiya et al.
2012; Vestergaard et al. 2012a,b; Gert-
nere et al. 2013; Kamiya et al. 2013;
Tomita et al. 2013; Vestergaard et al.
2013). In this study, we found very
similar results in FLEX and SMILE
eyes. The relatively high increase in
coma could in some part be related to
the slight decentration that was
observed in three eyes (Kamiya et al.
2012, 2013), but coma is often reported
to increase after both procedures (Shah
et al. 2011; Gertnere et al. 2013), in
contrast to the more favourable
change in spherical aberration (Sekun-
do et al. 2008, 2011; Gertnere et al.
2013). Both topography-derived cor-
neal aberrations and whole-eye-derived
aberrations (by Hartmann-Shack aber-
rometry) were evaluated for optimal
assessment of changes in HOAs, espe-
cially since the impact of corneal
wavefront changes after refractive sur-
gery have been reported to be compen-
sated to some degree by internal optics
(Gatinel et al. 2010). Low repeatability
of wavefront aberrations calculated
from Pentacam corneal topography
has also been reported and should be
taken into account when evaluating the
results (Shankar et al. 2008). For
assessment of CS, we chose the FrACT
because it was relative easy and fast to
use, and because it has good repeat-
ability irrespective of background lumi-
nance and glare sources (Buhren et al.
2006). The large Landolt C optotype
was composed of a mixture of low to
medium spatial frequencies (as can be
determined by Fourier analysis).
Therefore, CS was not assessed per
spatial frequency by sine-wave gratings
as in other contrast tests (Bondarko &
Danilova 1997; Bach 2013; Gertnere
et al. 2013; Richman et al. 2013).
Dry eye and tear film instability are
common problems after refractive pro-
cedures (Pflugfelder et al. 2000; Levin-
son et al. 2008; Mian et al. 2009; Golas
& Manche 2011; Labbe et al. 2012;
Murakami & Manche 2012). The
mechanisms for dry eye symptoms are
proposed to be multifactorial, and
lately, osmolarity was included in the
definition of dry eye disease (Lemp &
Foulks 2007; Mian et al. 2009; Hong
et al. 2013). TBUT, Schirmer’s test and
grading of subjective symptoms are the
most widely adopted examination
methods, but recently, non-laboratory
testing of osmolarity became possible.
In some studies, osmolarity is reported
as a procedure with higher sensitivity
and less variability than other dry eye
tests (Sullivan et al. 2012a, 2014).
However, a lack of association between
signs and symptoms is commonly seen,
and tear film alterations were therefore
evaluated in several ways in this study
(Nichols et al. 2004; Johnson 2009;
Sullivan et al. 2012, 2014). A reduction
in superficial punctuate staining and
dry eye symptoms has previously been
reported in SMILE compared to
FLEX eyes (Sekundo et al. 2011), but
in our study, we found no differences
between FLEX and SMILE eyes
6 months after surgery. Furthermore,
none of the tests significantly corre-
lated with the patients’ subjective dry
eye sensation. This was in correspon-
dence with previous studies of FS-
LASIK, in which dry eye symptoms
reverted to preoperative levels within
6 months after surgery, and this was
probably also the case in our study
(Mian et al. 2009; Golas & Manche
2011). A study design with measure-
ments at earlier time-points would
presumably have made detection of

differences more easy. This conclusion
was supported by the finding of less
subjective dry eye symptoms in SMILE
eyes within the first few days after
surgery.
Precision in corneal cutting is of
utmost importance to avoid both in-
traoperative complications and long-
term corneal changes such as ectasia.
For assessment of flap/cap cut preci-
sion, corneal pachymetry can be per-
formed by several different techniques,
with different strengths and limitations.
For instance, the light reflection from
the AS-OCT can cause image blurring
and make central corneal measure-
ments difficult, and the placement of
the marker can always be questioned.
In this study, we chose not to include
the tear film in pachymetry measure-
ments to avoid tear film changes affect-
ing the other sublayer measurements.
Fortunately, CCT results measured by
AS-OCT were highly correlated with
automatic CCT measurements by
OLCR, which indicated reliability and
accuracy of measurements. However,
results were not directly comparable
due to differences in wavelengths and
refractive indices (Ivarsen et al. 2009a,
b). Only central corneal perpendicular
measurements were performed on the
AS-OCT images, as peripheral mea-
surements are more sensitive to mea-
surement error due to misalignment
and also as both the VisuMax FSL and
AS-OCT images captured were centred
on the visual axis and not on the
corneal centre. High-precision lenti-
cule/flap/cap-cutting was also found
after both procedures, with no indica-
tions of corneal oedema or microdis-
tortions affecting outcomes (Tay et al.
2012; Ozgurhan et al. 2013; Yao et al.
2013). The increased ET is within
previously reported results after myo-
pic LASIK or PRK and is expected to
be stable over time (Patel et al. 2007;
Ivarsen et al. 2009a,b; Reinstein et al.
2012a,b).
Corneal biomechanics is another
way to evaluate safety and investigate
corneal changes. Most of the corneal
tensile strength is located in the ante-
rior part of the cornea owing to a more
interwoven collagen fibre arrangement
(Abahussin et al. 2009). Reduction in
CH and CRF after refractive surgery
has been interpreted as biomechanical
weakening of the cornea and has been
reported after both surface ablation
techniques and flap-based intrastromal
procedures (Pepose et al. 2007; Kirwan
& O’Keefe 2008; Shah & Laiquzzaman
2009; Shah et al. 2009). However,
results have been ambiguous. In some
studies, the flap creation itself has been
related to a decrease in CH and CRF,
while in other studies, no difference was
found between surface ablation proce-
dures and LASIK, and it was mainly
the tissue removal which accounted for
the induced changes (Gatinel et al.
2007; Kirwan & O’Keefe 2008; Uzbek
et al. 2011). Also, a large measurement
overlap in ORA parameters in normal
and keratoconic corneas has been
reported (Fontes et al. 2011). In our
study, we found reduction in CH and
CRF after both FLEX and SMILE
6 months after surgery but were unable
to measure the theoretical biomechan-
ical advantage of a small incision.
Nonetheless, this was comparable to
previous results from a paired eye
study comparing SMILE and FS-
LASIK (Agca et al. 2013). This
unmeasurable change could be a result
of changes in both viscous and elastic
properties, thereby masking potential
differences not fully characterized by
CH and CRF (Uzbek et al. 2011). New
approaches can hopefully increase sen-
sitivity and specificity in detecting
abnormal corneal changes. This
includes the new ORA software, with
advanced keratoconus/ectasia screen-
ing based on waveform characteristics
and, also, the newly developed Corvis
ST, which combines non-contact to-
nometry with high-speed Scheimpflug
imaging.
Finally, patient satisfaction rates
were equal and comparable to FS-
LASIK results (Ang et al. 2009; Tomi-
ta et al. 2013). Furthermore, there was
no difference in results when satisfac-
tion was evaluated verbally during
examination or afterwards in writing,
that is, no indication of examinator
biased outcome.
Flap versus cap – the differences
All types of keratorefractive surgery
disrupt the integrity of corneal nerves,
and in this study, the main differences
in outcomes after FLEX and SMILE
were found when confocal microscopy
and corneal esthesiometry were per-
formed. IVCM has shown high con-
cordance with observations made in
histological studies, and images of the
hyper-reflective corneal nerves in the
sub-basal plexus are relatively easily
Acta Ophthalmologica 2014
defined and captured (Oliveira-Soto &
Efron 2001). However, the small field
of view makes detection of the same
area difficult. Therefore, as in this
study, results from several images of
the central cornea are usually used to
increase accuracy and approximation
of mean corneal nerve parameters
(Vagenas et al. 2012). Also, numerous
software tools can be used for nerve
quantification. NeuronJ was chosen as
it was an easy-to-use freeware pro-
gram, with semi-automatic nerve trac-
ing, and as it is one of the most used
and cited techniques for this purpose
(Meijering 2010).
Previous studies have reported
reduced sub-basal nerve density for
up to 5 years after LASIK, and abnor-
malities of stromal nerves have been
identified up to 40 years after penetrat-
ing keratoplasty (Erie et al. 2005; Nie-
derer et al. 2007). Recovery of corneal
sensation after intrastromal refractive
surgery is usually reported to occur
within 6–12 months, although it may
take longer (Kumano et al. 2003;
Perez-Gomez & Efron 2003; Feng et al.
2013; Wei & Wang 2013). Results in
this study demonstrated less reduction
in sub-basal nerve density and the total
number of nerves and nerve branches,
in favour of SMILE. In addition, mean
corneal sensation in SMILE eyes was
not significantly different from base-
line, in contrast to reduced sensitivity
after FLEX. Intuitively, these findings
were also expected due to the smaller
corneal cut in SMILE. Our results
thereby support previous non-paired
findings, including findings at earlier
time-points, of SMILE compared to
FLEX and FS-LASIK (Solomatin
et al. 2013; Wei & Wang 2013). Our
measured baseline values of nerve fibre
density and the degree of tortuosity
were also in accordance with previous
results, which along with high intra-
grader reliability helped validate the
morphological measurements (Labbe
et al. 2012). In contrast, we found a
significantly higher number of nerve
segments, presumably because all small
branches were included in this outcome
parameter and not only long nerve
fibres within the image. Control mea-
surements of corneal sensation with
non-contact gas esthesiometers would
have been interesting to analyse, as
they have been reported to be more
reliable than CB esthesiometry
(Benitez-Del-Castillo et al. 2007).
15
Acta Ophthalmologica 2014
Unfortunately, this was not possible.
Furthermore, when performing CB
esthesiometry, it is important to
remember the degree of subjectivity
when performing the measurement and
that it only stimulates the mechanosen-
sitive nerve fibres.
Finally, intraoperative complica-
tions were more frequent after the
SMILE procedure, but did not affect
visual or refractive outcomes. This is in
accordance with findings from as yet
unpublished data of more than 1500
SMILE surgeries and underlines that
SMILE is technically more demanding
than FLEX and FS-LASIK (Ivarsen
et al. 2013).
Limitations
Several compromises were made in this
study. Especially measurements at ear-
lier time-points for all outcome param-
eters would have been interesting to
analyse, but was not practically possi-
ble. A trade-off between the number of
measurements at each visit and exam-
ination time was made to ensure
patient participation and avoid patient
dropouts. In addition, measurements
were not always repeated as many
times as suggested in the literature,
due to the risk of patient exhaustion.
Also, IVCM examination was not pos-
sible in three patients due to discom-
fort, and the Keratograph was not able
to measure NI-BUT in two patients.
However, these patients did not seem
to differ from the rest when comparing
outcomes. More patients included
would have enhanced the study’s abil-
ity to detect small differences, but post
hoc power analyses revealed acceptable
statistical power for the main outcome
parameters. The contralateral design
was chosen to minimize variability and
selection bias, but subjective outcomes
reported could be biased by difficulties
of distinguishing symptoms from one
or both eyes. Also, despite relatively
high reliability, there will always be an
aspect of subjectivity in some of the
measurements and image analyses. A
longer time period between tear film
evaluation tests would also have min-
imized potential test interactions.
Finally, the study should have been
double-masked to avoid physician-
related bias. This was not entirely
possible as it was relatively easy to
identify the FLEX and the SMILE eye
by slit-lamp examination. A great
effort was made not to perform exam-
16
inations that would reveal randomiza-
tion to the physician, before the end of
the examination.
Conclusions and
perspectives
The main findings of this thesis were as
follows:
For Paper I:
• The longest published follow-up
study of PRK (up to 19 years) with
results supportive of findings in other
long-term studies.
• Refractive predictability was rela-
tively high for treatment of low
degrees of myopia, as well as safety
and patient satisfaction, despite the
use of a now outdated broad-beam
laser.
• Results from treatment of high
degrees of myopia were inferior to
results from low degrees of myopia
in all aspects, and especially when
compared to short-term results from
contemporary intrastromal-based
techniques.
• Results from a subgroup of unilat-
erally treated PRK patients indicated
that refraction in the entire cohort of
patients was not stable over time but
was particularly affected by myopic
progression.
• Haze diminished over time and
rarely occurred when treating low
degrees of myopia.
• No late adverse events were noticed
13–19 years after PRK.
The results therefore support the
continued use of the excimer laser for
corneal surface ablation as a treatment
option for correction of low degrees of
myopia and the treatment of choice for
subgroups of refractive patients, as
previously mentioned. This could also
include retreatment of SMILE-treated
eyes, until the optimal approach to
retreatment has been determined.
Another application could be a combi-
nation of excimer surface ablation and
cross-linking for treatment of ectatic
corneas, although long-term refractive
effects and safety issues of this combi-
nation are unknown.
Our results also highlight that treat-
ment of higher degrees of myopia with
standard PRK should only be done
today under special circumstances, due
to low refractive predictability and
high risk of corneal haze. Technologi-
cal advances since then should be taken
into account when comparing these
results with contemporary lasers and
advanced ablation profiles. However,
the findings of this study should pro-
vide reassurance to both patients and
refractive surgeons concerning long-
term outcomes after surface ablation
for low degrees of myopia.
For Papers II–IV:
• The first paired eye study of the two
all FSL-based techniques, FLEX and
SMILE.
• Both procedures had good refractive
and visual outcomes up to 6 months
after surgery when treating eyes with
moderate to high myopia and low
degrees of astigmatism.
• Results were comparable to previous
publications of the two ReLEx pro-
cedures and also with modern exci-
mer-based techniques.
• Refractive predictability, safety, effi-
cacy, contrast sensitivity, wavefront
aberrations and patient satisfaction
were almost identical, regardless of
treatment.
• Intraoperative complications were
without visual or refractive sequela,
but occurred more frequently after
the SMILE procedure. No postoper-
ative adverse events were noted.
• Corneal nerve morphology was less
affected, and corneal sensitivity was
better preserved, after a small inci-
sion in SMILE compared to a flap-
like incision in FLEX.
• Reduced subjective dryness and for-
eign body sensation were reported
within the first week after surgery in
SMILE eyes as compared to FLEX
eyes, but 6 months after surgery, there
were no differences in objective or
subjective ocular surface symptoms.
• Corneal sublayer pachymetry dem-
onstrated equally increased epithelial
thickness of approximately 15%
as well as high-precision flap/
cap-cutting.
• A similar reduction in both viscous
and total viscoelastic properties was
found. Hence, the theoretical biome-
chanical advantages of a small cor-
neal incision compared to a corneal
flap could not be identified by the
ocular response analyzer in this
study, 6 months after surgery.
Our results support the continued
use of both FLEX and SMILE for
treatment of up to high degrees of

myopia. Overall, refractive and visual
results for both procedures were good
and similar, but from a biological point
of view, the small incision in SMILE is
more attractive, as demonstrated in
this study, and despite the fact that
we were not able to quantify any
biomechanical advantages of a small
corneal incision. Newly developed
techniques for visualization and mea-
surement of corneal deformation can
hopefully shed further light on the
biomechanical changes. Nevertheless,
a SMILE-treated eye is still expected to
be less vulnerable to ectasia, and in
case of eye trauma, than an eye treated
with a flap-based procedure, due to
better preservation of the anterior
lamellae. The SMILE procedure also
has the potential to supersede excimer
surface ablation as the treatment of
choice when treating refractive errors
in soldiers, athletes and others with
high risk of eye trauma and when fast
visual recovery/low pain is desired. On
the other hand, the SMILE technique
proved slightly more surgically
demanding than FLEX and without
the option of simple flap-lift for
enhancement. And despite no need for
retreatments in this study, the optimal
way to perform enhancement proce-
dures after SMILE has yet to be
determined. Therefore, the FLEX pro-
cedure may still remain important to
master in years to come.
Nonetheless, the future seems to
point in the direction of SMILE treat-
ments for all types of refractive errors.
The lack of a transition zone and the
concave shape of the lenticule with
thicker edges can, however, prove a
challenge when treating hyperopia. In
addition, optimal centration of the
treatment zone is even more important
when treating hyperopic eyes. Insertion
of cryopreserved viable tissue, from an
extracted stromal lenticule into corneal
pockets created by the FS laser, has
been suggested as an alternative way to
correct refractive errors and can per-
haps even be used to treat ectatic
corneas. Aspheric stromal lenticule
cutting and eye rotational compensa-
tion by the VisuMax laser are also
some of the issues currently being
investigated to optimize refractive
results. As with any new technology,
unexpected hurdles can appear along
the way, and further studies need to be
performed to fully understand these
new techniques. In particular, long-
term results and biomechanical effects
need to be evaluated, along with treat-
ment of hyperopia and higher degrees
of astigmatism. However, initial data
seem to indicate that all femtosecond
laser-based refractive surgery, using
refractive lenticule extraction, and
especially without a flap, is a new
complementary or perhaps even supe-
rior technique, as compared to excimer
laser-based LASIK and surface
ablation techniques.
Resum
e p
a dansk
Kirurgisk behandling af øjets bry-
dningsfejl er tiltagende populært. I
1990erne revolutionerede excimer la-
seren refraktionskirurgien vha. PRK
og LASIK, og indenfor de senere  ar er
femtosekund laser behandling med
udskæring og ekstraktion af en corneal
vævslinse (ReLEx) blevet muligt.
Indtil nu er der kun publiceret f a samt ved m
langtidsstudier af PRK og med relativt
f
a patienter. Form alet med denne af-
handling var derfor at evaluere langt-
idsresultater efter PRK-behandling for
alle grader af myopi og for et højt antal
patienter. Endvidere var der ikke tid-
ligere blevet udført et prospektivt kon-
tralateralt studie der direkte
sammenlignede de to ReLEx-proced-
urer, FLEX og SMILE, mht. behan-
dling af høje til moderate grader af
myopi. Dette var det andet form al med
afhandlingen.
I det første studie blev resultater fra
160 PRK-patienter (289 øjne) præsent-
eret. Præoperativ sfærisk ækvivalent
varierede fra 1.25 til 20.25 D, og
78% havde lav grad af myopi (mindre
end 6 D). Gennemsnitlig
opfølgningstid var 16  ar (spændvidde
13 til 19  ar). Ved den afsluttende
undersøgelse var resultater fra lavmy-
ope øjne generelt set bedre end fra
højmyope øjne. 72% var indenfor
1.00 D af m alrefraktionen, sammen-
lignet med 47% af de højmyope øjne.
Dog indikerede resultater fra unilater-
alt behandlede PRK-patienter at re-
fraktionen ved den afsluttende
undersøgelse var p avirket af myopipro-
gression. 50% af lavmyope øjne s a 20/
20 eller bedre ukorrigeret p a afstand,
sammenlignet med 22% af de højmy-
ope øjne. Der var ingen tilfælde af
hornhinde-slør (‘haze’) ved korrektion-
er pa under 4 D, og kun højmyope
øjne havde mistet to eller flere linjer af
bedst-korrigeret afstandssyn. 81% var
Acta Ophthalmologica 2014
tilfredse eller meget tilfredse med deres
operation.
Vores resultater understøtter der-
med konklusionerne i andre langtids-
studier, men nu med data op til 19  ar
efter behandling. Resultaterne er bas-
eret pa en forældet laser, men støtter
alligevel fortsat brugen af excimer
laser til overfladebehandling af hornh-
inden, dog hovedsageligt som en
behandlingsmulighed til lavmyopi og
andre subgrupper af refraktionskirurg-
iske patienter.
I det andet studie blev 35 patienter
randomiseret til behandling med FLEX
pa det ene øje og SMILE p a det andet
og fulgt i 6 m aneder. Præoperativ
sfærisk ækvivalent varierede fra 6 til
10 D og med lav grad af astigma-
tisme. I alt gennemførte 34 patienter
opfølgningsperioden p a 6 m aneder.
Refraktive og synsmæssige resultater
var meget ens ved FLEX og SMILE,
alinger p a t
arefilmen og
ændringer i hornhindens biomekanik.
97% var indenfor 1.00 D af m alref-
raktionen, ingen øjne havde mistet to
eller flere linjer af bedst-korrigeret af-
standssyn og kontrast synet var uæn-
dret efter begge procedurer. Ændringer
af højere-ordens aberrationer var ogs a
meget ens. Der var heller ingen forsk-
elle i t arefilmsparametre 6 m aneder
efter behandling, selvom postoperativ
fremmedlegemefornemmelse i den før-
ste uge var mindre i SMILE øjne.
Tykkelsesm alinger af hornhindens
forskellige lag viste høj præcision af
udskæringerne, men forøget epiteltykk-
else 6 m aneder efter begge procedurer.
Modsat forventningerne, var vi ikke i
stand til at m ale den teoretiske biom-
ekaniske fordel ved et lille snit i hornh-
inden ved SMILE ift. udskæring af en
flap ved FLEX. De væsentligste forsk-
elle mellem FLEX og SMILE blev
fundet ved evaluering af hornhindens
nerveforhold og operationskomplika-
tioner. S aledes var hornhindens
sensitivitet bedre bevaret og nervemorf-
ologien mindre p avirket efter SMILE,
men intraoperative komplikationer
var hyppigere, dog uden synsse-
quelae. Slutteligt angav 97% at være
tilfredse eller meget tilfredse med begge
operationer.
Resultaterne var sammenlignelige
med tidligere ReLEx studier og mod-
erne excimer-baserede teknikker, men
dette studie tilføjer nu en direkte sam-
menligning af FLEX og SMILE. Vores
resultater understøtter dermed brugen
17
Acta Ophthalmologica 2014
af b
ade FLEX og SMILE til behan-
dling af op til høje grader af myopi.
Dog synes SMILE at være førstevalg til
bevarelse af hornhindens integritet ved
at undga udskæring af en flap.
Conflicts of interest
None.
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Correspondence:
Anders Højslet Vestergaard, MD
Department of Ophthalmology
Odense University Hospital
Sdr. Boulevard 29
5000 Odense C
Denmark
Tel: +45 65413196
Fax: +45 66126387
Email: anders.vestergaard@rsyd.dk
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