Professional Documents
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Editor
Corneal
Transplantation
123
Corneal Transplantation
Jesper Hjortdal
Editor
Corneal Transplantation
Editor
Jesper Hjortdal
Department of Ophthalmology
Aarhus University Hospital
Aarhus
Denmark
Corneal transplantation has been performed for more than 100 years. Until 15
years ago the state-of-the art type of transplantation was penetrating kerato-
plasty, but since the start of this millennium, newly designed surgical tech-
niques have developed considerably. Today, the vast majority of keratoplasty
procedures are performed as delicate lamellar procedures either assisted with
fine microkeratomes or femtosecond lasers or using skilled surgical dissec-
tion procedures.
These advancements have helped patients undergoing keratoplasty to have
a much faster visual recovery and a more stable eye with less risk of rejection
episodes.
Besides covering updated chapters on penetrating keratoplasty, and ante-
rior and posterior lamellar procedures, this textbook also gives a thorough
overview of the history of corneal transplantation and a detailed presentation
of the microstructural components of the cornea essential to keratoplasty pro-
cedures. Corneal banking has changed over recent years as graft preparation
for anterior and posterior lamellar keratoplasty now often is performed within
the bank. Chapters have been devoted to description of graft registries, which
are an indispensable source of information of daily practices and outcomes,
and to economical evaluations of keratoplasty procedures. The optical conse-
quences of a keratoplasty procedure, especially in relation to simultaneous or
later cataract surgery, are discussed in addition to current methods for reduc-
ing post-keratoplasty astigmatism. Economic considerations on cost and ben-
efit of medical treatment and surgical procedures are today an integrated part
of the health system in many countries, and a chapter covers these aspects of
corneal transplantation.
This textbook is aimed at presenting an updated review of the new tech-
niques and to assist fellows and corneal surgeons in their advice and selection
of patients for the best surgical procedure considering benefits and risks.
v
Contents
vii
viii Contents
ix
x Contributors
Abstract
The concept of corneal transplantation is very old. However, it took
many centuries before this miraculous operation could be performed with
some success in both animals and humans. Knowledge of the history of
keratoplasty is obligatory for a better understanding of modern corneal
transplantation.
In the second half of the twentieth century, penetrating keratoplasty
became the gold standard in corneal transplantation. Good results became
more or less routine, due to a better knowledge of indications for treat-
ment, a better understanding and hence prevention and treatment of
allograft rejection and improvements in eye banking, operating micro-
scopes, instruments and suture materials.
The recent two decades have once more seen a paradigm shift towards
the selective replacement of only the diseased layers of the cornea. This
has resulted in a rapid rise in the popularity of (deep) anterior lamellar and
endothelial keratoplasty.
Keywords
History of keratoplasty Corneal transplantation Penetrating kerato-
plasty Deep anterior lamellar keratoplasty (DALK) Endothelial
keratoplasty (EK)
History of Keratoplasty
G. van Rij, MD, PhD, FEBOphth (*) In ancient times, cosmetical treatment of corneal
Department of Ophthalmology, scars had been performed by means of a tattoo-
Erasmus Medical Center, Rotterdam, like coloration of the scar. Lampblack or soot was
The Netherlands
e-mail: g.vanrij@kpnmail.n used in old Egypt (1500 BC), and copper sul-
phate reduced with nutgall was applied to achieve
B.T.H. van Dooren, MD, PhD
Department of Ophthalmology, reasonable cosmesis by Galenus (131200 AD).
Amphia Hospital, Breda, The Netherlands In the eighteenth century, superficial removal of
scars was widely performed by surgeons in not introduced until 1846, chloroform anaesthe-
France and Germany [1]. The idea of removing sia in 1847 and topical cocaine anaesthesia in
scars from the cornea using a trephine was first 1858. His patient initially received more light in
proposed by Erasmus Darwin (the grandfather of his eye, but the cornea opacified and absorbed
Charles Darwin) in 1796 [2]. In 1789 Pellier De over a 2-week period [10]. The experiments on
Quengsy introduced his ideas on treating corneal corneal transplantation in humans and animals
opacification with what would now be called ker- conducted by Power, described in 1872, suffered
atoprosthesis, i.e. the replacement of opaque cor- the same fate [11].
neal tissue by man-made material. His concept Success in heterografting remained elusive
entailed an artificial cornea made from glass until the first successful lamellar heterograft in a
framed in silver [3]. Attempts in the second half human by Von Hippel. A leucoma corneae was
of the nineteenth century to actually treat patients excised from a young girls eye with Descemets
with artificial corneas, among others by von membrane and endothelium remaining, and a
Hippel and by Nussbaum, were not successful [4, rabbit cornea was transplanted into the wound
5]. The artificial cornea concept was in fact not bed. This procedure was performed in 1886 and
developed into a useful technique until 1963, was described in 1888 as the first in a series of 8
when among others Strampelli published on suc- lamellar operations, of which 4 were successful
cessful clinical application of keratoprostheses. [4]. Von Hippel performed anterior lamellar kera-
In Strampellis case, this was the osteo-odonto- toplasty because he felt that corneal transparency
keratoprosthesis, in which the optical element depended on the integrity of the corneal endothe-
was embedded in a biocompatible carrier made lium and Descemets membrane. Therefore, he
out of the patients own tooth and jawbone [1, 6]. abandoned full-thickness corneal grafts.
Recently the application of keratoprostheses It was not until 1905 that the first successful
made of artificial materials has increased, with penetrating homologous corneal graft was per-
variable results in patient groups with significant formed in a human patient. The Moravian oph-
high-risk eyes [7]. thalmologist Eduard Konrad Zirm transplanted a
The first widely known experiments with full- donor cornea obtained from an enucleated eye of
thickness tissue corneal transplantations in ani- a young boy into the eye of a 45-year-old labourer,
mals, conducted in 1818, either heterologous suffering from corneal scars caused by a chemi-
(between species a.k.a. xenografting) or homolo- cal lye injury. Zirm used general anaesthesia
gous (within species), are attributed to Reisinger. (chloroform) and strict asepsis [12].
He also introduced the term keratoplasty for Shortly thereafter, the concept of auto-
corneal transplantation [8]. Wars at the end of the keratoplasty or homograft was initiated. In this
eighteenth and the beginning of the nineteenth concept the donor cornea was harvested from the
centuries made corneal blindness from smallpox, patient itself: from the fellow, blind eye, as
venereal disease and Egyptian ophthalmia (tra- described by Plange [1], or as a rotational graft in
choma) prevalent. With this background, Bigger which a small corneal scar can be rotated out of
performed the first successful corneal transplan- the visual axis in the diseased eye, as described
tation in animals. In 1837, during his captivity in by Kraupa [5].
Egypt by Sahara Bedouins, he performed a Allografting, in which the donor cornea is har-
homograft on his captors pet gazelle which had vested from another individual of the same spe-
been blinded by a corneal wound [9]. cies, is currently the most commonly practised
Heterologous transplantations of animal tissue form of corneal transplantation. However, it took
into humans were then attempted. In 1838, the quite some time after Zirm, before reproducible
New York ophthalmologist and general practitio- results with penetrating corneal allografts were
ner Richard Sharp Kissam transplanted a pigs obtained. First the operative technique and donor
cornea into a human patient. Kissam operated tissue preservation and preparation had to be fur-
without any anaesthesia. Ether anaesthesia was ther developed and standardised. Much work in
1 The History of Corneal Transplantation 3
this respect was done and published in the 1920s button of diseased cornea is replaced by full-
and 1930s by Elschnig from Tsjechia, Filatov thickness corneal donor tissue. A successful out-
from Russia, Tudor Thomas in the UK and come after a penetrating keratoplasty is a clear
Castroviejo in the USA [1318]. Improvements graft with low astigmatism, providing a good
in lamellar transplant technique were achieved by visual acuity. Irregular and high regular astigma-
the French ophthalmologists Paufique et al. [19] tism are the most frequent visual acuity impair-
and Switzerlands Franceschetti [20], from the ing complications after penetrating keratoplasty.
1930s through the 1950s, leading to a temporar- At present there are three forms of penetrating
ily renewed popularity of this treatment keratoplasty: traditional penetrating keratoplasty;
modality. anterior mushroom keratoplasty, with a wider
The biggest hazard to a successful penetrating anterior than posterior diameter; and top-hat (or
corneal graft is allograft rejection. Paufique posterior mushroom) keratoplasty, with a wider
described the concept of maladie du greffon, posterior than anterior diameter. A top-hat kera-
i.e. opacification of a previously clear cornea, toplasty is indicated in patients with both endo-
which he attributed to sensitisation to the donor thelial failure and secondary stromal opacities.
by the recipient [19]. This seminal concept of Anterior mushroom keratoplasty has better astig-
immunological rejection of the donor graft was matic properties and can be applied in patients
proven by Maumenee in 1951 [21]. Much impor- with relatively healthy endothelium [26, 27].
tant work in the field of corneal allograft rejec- Femtosecond lasers have recently been
tion was done by Khodadoust and Silverstein applied to more reproducibly fashion several
[22, 23]. The use of corticosteroids realised a types of (mushroom and other) shaped corneal
breakthrough in the treatment and prevention of incisions in both donor and recipient corneas
corneal transplant rejection and opacification. [28].
This concurred with the introduction of antibiot- The graft survival in all types of PK is good in
ics, the introduction of the operation microscope, low-risk cases, with a success rate of 80 % or
the development of microsurgical techniques and more of having a clear graft after 10 years. The
of newer suture materials that ensued. Other cornea enjoys a relative immune privilege being
important developments included the better avascular tissue, and furthermore immunosup-
understanding of endothelial physiology and of pressive treatment can be directly applied in high
donor cornea preservation. US-based ophthal- concentrations using eye drops. Therefore, HLA
mologists and scientists such as Paton, Troutman, matching of donor tissue to recipient status is
Maurice, McCarey and Kaufman played impor- usually not performed in low-risk cases, and still
tant roles in these developments [24, 25]. All good graft survival rates are obtained. Allograft
these developments led to a substantial improve- rejection however is still one of the major causes
ment in the popularity of penetrating keratoplasty of corneal transplant failure in PK [29]. When a
and hence in the number of cases operated with cornea becomes vascularised, the risk for corneal
this technique. graft rejection is elevated. High-risk cases include
repeat transplantations, especially after previous
allograft rejection, and corneas with extensive
Recent and Current Developments deep blood (and lymph) vessel ingrowth [29, 30].
in Penetrating and Lamellar Other important reasons for graft failure in PK
Keratoplasty are (secondary) glaucoma, ocular surface prob-
lems and late endothelial failure [29]. The concept
Penetrating Keratoplasty of late endothelial failure is an intriguing prob-
lem. After PK, grafts lose endothelial cells at a
In the past, penetrating keratoplasty was consid- faster than physiological rate, even in the absence
ered the gold standard in corneal transplantation. of overt endothelial allograft rejection. The exact
In penetrating keratoplasty (PK), a full-thickness cause for the elevated endothelial cell loss rate
4 G. van Rij and B.T.H. van Dooren
needs yet to be determined. Hypothetically it may membrane could reproducibly be bared. In this
arise from prolonged cell redistribution onto the technique an air bubble is used to dissect through
recipient cornea or from chronic pro-apoptotic the corneal stroma and to split the stroma from
changes in the anterior chamber [3133]. Descemets membrane. A nearly full-thickness
donor cornea, devoid of donor endothelium, is
sutured in. Visual results after deep ALK with the
Anterior Lamellar Keratoplasty big-bubble technique proved to be as good as or
even better than PK [38]. Injecting viscoelastic
In anterior lamellar keratoplasty (ALK), only the material into the deep stroma can also be used to
diseased epithelium, Bowmans membrane and bare Descemets membrane [39].
(anterior) corneal stroma are removed and trans- Microkeratome and femtosecond laser-
planted, leaving the unaffected but vulnerable assisted approaches towards ALK have recently
endothelium of the patient in place. Indications gained some interest. Especially with the micro-
for ALK include many cases of keratoconus, epi- keratome, both the recipient and donor lamellar
thelial and (anterior) stromal corneal dystrophies interfaces can be cut very smoothly. For selected
and partial-thickness post-infective (i.e. non- cases, the results are promising [40].
active, of herpetic and non-herpetic origin) and
non-infective (e.g. traumatic) corneal scars.
In the 1960s and 1970s, the frequency with Endothelial Keratoplasty
which anterior lamellar keratoplasty was per-
formed sank inversely with the increase in PKs Endothelial keratoplasty (EK) is a treatment con-
success and hence popularity. This was mainly cept aimed at replacing only the diseased endo-
caused by ALKs disappointing visual results. A thelium and posterior corneal layers, which have
large part of these poor results stem from the irreg- caused corneal clouding through oedema.
ular scattering of light (diffraction) at the recipient- Disorders that may be treated with EK include
donor wound interface. The need for a very smooth endothelial dystrophies, especially Fuchs endo-
recipient and host surface at the wound interface, thelial dystrophy, iridocorneal endothelial (ICE)
which was to be obtained more readily at a deeper syndrome and pseudophakic bullous keratopathy.
corneal plane, was recognised early on. However, The main advantage of this concept is an
to attain this goal required both surgical skills and untouched anterior corneal curvature, resulting in
time [34]. Yet, the advantages of ALK over PK in much less suture-induced high and irregular
suitable indications remained tempting. There astigmatism, as can be seen after PK. Other
were less complications to be expected, as ALK suture- and full-thickness wound-related compli-
was not truly an intraocular surgery. There was no cations such as infections and wound dehiscence
risk of postoperative endothelial rejection and can also be avoided.
probably less risk of late endothelial failure and Barraquer was the first to publish on the
open globe after traumatic wound dehiscence. concept of selective transplantation of an
In spite of this, comparative studies from the endothelium-containing posterior corneal
late 1970s kept on showing that visual results lamella for the treatment of corneal oedema.
were better after PK than after ALK for keratoco- In 1951 he reported for the first time on such a
nus one of the most apt indications for ALK design, which involved the (manual) cutting of a
[3436]. However, good visual results were actu- hinged anterior lamellar corneal flap, followed
ally shown to be obtainable, when the lamellar by the excision and replacement of a deep corneal
dissection could be made at or just above the stroma lamella including the endothelium [41].
level of Descemets membrane which presented a In 1964 he reported on the first results obtained
natural, very smooth optical interface [37]. It with this technique in two patients, who obtained
was not until the introduction of the big-bubble clear grafts and good visual acuities. In 1983 he
technique by Anwar, however, that Descemets introduced the motor-driven microkeratome in
1 The History of Corneal Transplantation 5
EK for the cutting of the anterior flap in both particularly remarkable because the posterior
donor and recipient and reported a good result in donor disc was not kept in place by sutures. The
one patient [42]. pressure of an air bubble in the anterior chamber
Apparently unaware of Barraquers work, helps to keep the disc in place in the first postop-
Tillet published a report in 1956 on the selective erative hours. The supposed mechanism that
transplantation of a posterior donor corneal maintains good donor disc apposition thereafter
lamella with endothelium, performed success- might be the mere pumping action of the endo-
fully in a patient with Fuchs endothelial dystro- thelial cells. Other postulated appositional mech-
phy, in 1954. The posterior recipient disc had anisms include the inherent adhesive quality of
been excised after a manual lamellar dissection bare stromal surfaces and fibrils, assisted by the
through a 180 superior corneal incision. The intraocular pressure [54, 55]. In 1999 and 2000,
half-thickness donor posterior disc was posi- the first encouraging results in the first seven
tioned onto the posterior surface of the recipients patients in Melles series were reported, with all
anterior cornea and fixated with silk sutures. The transplants attached and all corneas clear [56,
graft remained clear for at least 1 year. However, 57]. In the next few years, technical improve-
the visual results were disappointing because of a ments included the use of a smaller incision com-
poorly controlled glaucoma [43]. bined with the insertion into the anterior chamber
In the late 1970s, the concept of selective of a folded donor disc. Later, Descemets mem-
endothelial transplantation gained new interest, brane stripping or descemetorhexis, instead of
when experimental models were developed for the previously used deep lamellar cross-corneal
the transplantation of cultured human and heter- dissection of the recipient corneal disc, was intro-
ologous corneal endothelial cells. Experiments duced [58].
were performed with seeding the endothelial Terry introduced PLK in the USA with slight
cells on animal and human donor corneas, modifications under the name deep lamellar
Descemets membranes, amnion membranes and endothelial keratoplasty (DLEK) and reported on
artificial carrier devices [44]. Experiments on large series of patients operated successfully with
bioengineered corneal constructs with cultured this technique [59, 60]. Price adopted the tech-
human corneal endothelial cells have continued nique involving the descemetorhexis. He named
into the present time [45]. Although progress has this technique Descemets stripping with endo-
been made, none of these techniques has reached thelial keratoplasty (DSEK) or Descemets strip-
the clinical phase yet. ping automated endothelial keratoplasty
The microkeratome-assisted approach towards (DSAEK) when a microkeratome was used to cut
EK, as conceptualised by Barraquer, was revived the donor cornea. This reproducible technique
in the 1990s. A number of patients were operated provided excellent results regarding visual acu-
with these techniques. These attempts however ity, speed of visual recovery, astigmatism and
suffered from very unpredictable refractive out- postoperative refractive error and showed a low
comes [4650]. A quite different approach for donor disc detachment rate [60, 61]. Midterm
EK, more in line with the technique described by donor endothelial cell survival after EK seems
Tillet, was initiated by Ko et al. in 1993. They comparable or even favourable to PK, and graft
used a technique of EK in a rabbit model, in survival is also very comparable [62]. DSAEK
which the posterior lamella was introduced has currently become the most often used tech-
through a superior limbal incision and sutured nique for EK worldwide. Not only EK rates but
against the recipient corneal surface [51]. also comprehensive corneal transplant rates have
In 1997 and 1998, Melles reported on a model gone up since DSAEKs introduction [63].
for EK or posterior lamellar keratoplasty (PLK): Recent improvements in DSAEK include the use
the transplantation of a posterior corneal lamella of thinner and pre-cut (i.e. microkeratome dissec-
with endothelium through a 9 mm corneoscleral tion in eye banks instead of in the OR) donor
tunnel incision [52, 53]. This technique was lamellae [64, 65].
6 G. van Rij and B.T.H. van Dooren
In Descemets membrane endothelial kerato- 12. Zirm E. Eine erfolgreiche totale Keraoplastik. Albrecht
Von Graefes Arch Ophthalmol. 1906;54:58093.
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lar keratoplasty (ELK). Invest Ophthalmol Vis Sci. Audit Study 8). Trends in the indications for corneal
1998;39:S76. graft surgery in the United Kingdom: 1999 through
48. Ehlers N, Ehlers H, Hjortdal J, Moller-Pedersen 2009. Arch Ophthalmol. 2012;130:6218.
T. Grafting of the posterior cornea. Description of a 64. Busin M, Madi S, Santorum P, Scorcia V, Beltz
new technique with 12-months clinical results. Acta J. Ultrathin Descemets stripping automated endo-
Ophthalmol Scand. 2000;78:5436. thelial keratoplasty with the microkeratome double-
49. Busin M, Arffa RC, Sebastiani A. Endokeratoplasty pass technique: two-year outcome. Ophthalmology.
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Ophthalmology. 2000;107:207782. J. Comparison of organ cultured precut corneas
8 G. van Rij and B.T.H. van Dooren
versus surgeon-cut corneas for Descemets strip- 69. Cursiefen C, Kruse FE. DMEK: Descemet mem-
ping automated endothelial keratoplasty. Cell brane endothelial keratoplasty. Ophthalmologe.
Tissue Bank. 2014 Dec;15(4):573-8. doi: 10.1007/ 2010;107:3706.
s10561-014-9429-x. 70. Heinzelmann S, Maier D, Boehringer D, Auw-Haedrich
66. Melles GR, Ong TS, Ververs B, Van der Wees C, Reinhard T. Visual outcome and histological find-
J. Descemet membrane endothelial keratoplasty ings following femtosecond laser-assisted versus
(DMEK). Cornea. 2006;25:98790. microkeratome-assisted DSAEK. Graefes Arch Clin
67. Ham L, Dapena I, Van Luijk C, et al. Descemet mem- Exp Ophthalmol. 2013;251:197981.
brane endothelial keratoplasty (DMEK) for Fuchs 71. Van den Biggelaar FJ, Cheng YY, Nuijts RMMJ,
endothelial dystrophy; review of the First 50 consecu- Schouten JS, Wijdh RJ, Pels E, Van Cleynenbreugel
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68. Price MO, Giebel AW, Fairchild KM, Price FW. evaluation of endothelial keratoplasty techniques and
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spective multicenter study of visual and refractive Ophthalmol. 2012;154:27281.
outcomes and endothelial survival. Ophthalmology.
2009;116:23618.
Anatomy and Physiology:
Considerations in Relation 2
to Transplantation
Ursula Schltzer-Schrehardt
and Friedrich E. Kruse
Abstract
Over the past decade, corneal transplantation has evolved rapidly from
full-thickness penetrating keratoplasty toward partial-thickness or lamel-
lar keratoplasty. Lamellar corneal surgery is in continuous evolution,
which requires an understanding of the structural, biomechanical, and his-
tological characteristics of corneal layers involved. In this chapter, we
describe the anatomy and physiology of the human cornea in order to pro-
vide the structural basis for understanding the newly developed tech-
niques. The chapter provides detailed information on morphological,
histological, ultrastructural, and physiological characteristics of the five
anatomical corneal layers, i.e., epithelium, Bowmans layer, corneal
stroma consisting of regularly arranged collagen fibrils interspersed with
keratocytes, Descemets membrane, and endothelial cells, in relation to
corneal transplantation. In particular, it outlines regional and age-related
differences in structure, biomechanical properties, mechanisms of wound
healing and restoration of corneal transparency, causes of stromal haze,
cleavage planes and interface characteristics in lamellar transplantation
techniques, and reasons for graft failure. Patterns of corneal innervation
and the molecular mechanisms of antiangiogenic and immune privileges,
which determine the success of allogeneic corneal transplantation, are
described in addition.
Keywords
Epithelium Bowmans layer Stroma Descemets membrane
Endothelium Anatomy Histology Electron microscopy Corneal
innervation Immune privilege
foreign bodies and pathogens, and contributes, Gross Anatomy and Physiology
together with the tear film, two-thirds of the eyes
refractive power. It is nourished and provided In adults, the cornea has a horizontal diameter of
with oxygen anteriorly by tears and posteriorly 11.012.0 mm, a vertical diameter of 10.0
by the aqueous humor. It has to maintain the 11.0 mm, and a thickness of approximately 500
intraocular pressure and to withstand the forces 550 m at the center, which gradually increases
applied by the extraocular muscles during eye to 600800 m toward the periphery [18]. The
movement. Corneal shape and curvature, which cornea has an aspheric anterior surface being
are relevant for refraction, are achieved by the steeper in the center and flatter in the periphery.
specific arrangement of collagen lamellae in the Average refractive power is 43.25 diopters, aver-
stroma, and corneal transparency, which is criti- age radius of curvature is 7.8 mm, and the corneal
cally important for vision, is the result of many index of refraction is 1.376. It is composed of five
factors including avascularity of the corneal tis- anatomical layers, i.e., corneal epithelium,
sue, the integrity of the corneal epithelium, and Bowmans layer, corneal stroma, Descemets
the regular arrangement of the extracellular and membrane, and corneal endothelium (Fig. 2.1a).
cellular components of the stroma, which in turn Besides these conventional layers of the cornea,
depends on the state of hydration regulated by the an additional pre-Descemets stromal layer has
corneal endothelium [18]. been recently described [19], which has, how-
Corneal transplantation remains the mainstay ever, been subsequently disproved by a multi-
treatment for patients with corneal blindness. The center study [66].
success of allogeneic corneal transplantation Confocal microscopy with the Heidelberg
benefits from the immunologically privileged retina tomograph (HRT) II and Rostock Cornea
state of the cornea [55]. Penetrating keratoplasty Module can be used for in vivo imaging of all
(PKP) has been the gold standard for corneal anatomical layers and corneal cell types includ-
transplantation for almost a century. Over the ing nerve plexi and immune cells (Fig. 2.2).
past decade, corneal transplantation has evolved
rapidly from full-thickness PKP toward partial-
thickness or lamellar keratoplasty to only remove Corneal Epithelium
and replace damaged or diseased layers of the
cornea allowing more rapid visual rehabilitation The epithelial surface of the cornea represents the
and reduced rates of rejection [4, 63, 69]. Current physical barrier to the outer environment and an
developments in lamellar keratoplasty include integral part of the smooth tear filmcornea inter-
deep anterior lamellar keratoplasty (DALK) for face that is critical for the refractive power of the
anterior corneal disorders [3], such as keratoco- eye. It is responsible for protecting the eye against
nus or stromal scars, as well as Descemets strip- loss of fluid and invasion of foreign bodies and
ping (automated) endothelial keratoplasty pathogens and for absorbing oxygen and nutri-
(DSEK, DSAEK) and Descemets membrane ents from the tear film.
endothelial keratoplasty (DMEK) for posterior The corneal surface is covered by a stratified,
corneal disorders, such as Fuchs corneal endo- nonkeratinizing, squamous epithelium, about
thelial dystrophy [47, 61]. Lamellar corneal sur- 50 m in thickness, comprising 57 cell layers
gery is in continuous evolution, which requires collectively. It can be structured into three layers,
an understanding of the structural, biomechani- the superficial or squamous cell layer, the supra-
cal, and histological characteristics of corneal basal wing cell layer, and the basal columnar cell
layers involved. In this chapter, we describe the layer (Fig. 2.1b) [18, 60]. Desmosomes promote
anatomy and physiology of the human cornea in strong adhesion between cells of all epithelial
order to provide the structural basis for the subse- layers. The superficial layer is formed by 23 lay-
quent chapters on corneal transplantation ers of flat polygonal cells, which form intercel-
techniques. lular tight junctions to provide an effective barrier
2 Anatomy and Physiology: Considerations in Relation to Transplantation 11
Fig. 2.1 Light (a) and transmission electron (bh) micro- fibrils. (f) Descemets membrane (DM), the basement
graphs of anatomical corneal layers. (a) Semithin cross membrane of the corneal endothelium, being composed of
section of the cornea showing three cellular layers, i.e., interfacial matrix (IFM), anterior banded layer (ABL), and
epithelium, stroma with keratocytes, and endothelium. (b) posterior nonbanded layer (PNBL). (g) Bowmans-like
Corneal epithelium showing three layers, the superficial layer (BL), a meshwork of randomly arranged collagen
or squamous cell layer, the suprabasal wing cell layer, and fibrils at the interface between Descemets membrane and
the basal columnar cell layer resting on Bowmans layer. stroma. (h) Connecting collagen fibrils (arrows) project-
(c) Anchoring complexes formed by hemidesmosomes ing from Bowmans-like layer into the interfacial matrix
(arrows) and anchoring fibrils (arrowheads) mediating zone (IFM) of Descemets membrane (magnification
attachment of basal epithelial cells to basement membrane bars = 100 m in a; 15 m in b and d; 5 m in f; and
(BM) and Bowmans layer. (d) Bowmans layer represent- 0.5 m in c, e, h) (e, g Reproduced from Schltzer-
ing the most anterior portion of the corneal stroma. (e) Schrehardt et al. [66], and h Reproduced from Schltzer-
Interface (dotted line) between Bowmans layer and cor- Schrehardt et al. [64], with permission from Elsevier)
neal stroma showing differing arrangement of collagen
12 U. Schltzer-Schrehardt and F.E. Kruse
and numerous surface microvilli, which increase spreading of the tear film with each eyelid blink
the cellular surface area and enhance oxygen and [26, 70]. The tear film also supplies immunologi-
nutrient uptake from the tear film. The microvillar cal and growth factors that are critical for epithe-
glycocalyx coat interacts with and helps to stabi- lial health, proliferation, and repair, and defects
lize the pre-corneal tear film, which is composed in tear film, e.g., in neurotrophic keratopathy
of three layers: a superficial lipid layer to provide after corneal surgery, can cause epithelial wound
protection from evaporation, an aqueous layer healing problems and surface inflammation. The
providing nutrients and oxygen supply to the cor- wing cell layer is formed by 23 layers of wing-
neal epithelium, and a basal mucin layer, which shaped cells which have laterally interdigitated
interacts closely with the epithelial cell glycoca- cell membranes with numerous desmosomes
lyx to allow lubrication of the ocular surface and (Fig. 2.2a). The basal layer consists of a single
2 Anatomy and Physiology: Considerations in Relation to Transplantation 13
layer of columnar cells (Fig. 2.2b), which are known as limbal stem cell deficiency [1]. In these
attached to the underlying basement membrane cases, epithelium of conjunctival phenotype may
by hemidesmosomes (Fig. 2.1c). The epithelial replace the corneal surface. Transplantation of
basement membrane has a critical role in corneal limbal autografts or allografts [35] and ex vivo
wound healing, because defects in this delicate expanded limbal epithelial stem cells are estab-
layer allow penetration of growth factors from lished therapeutic strategies to regenerate the
the epithelium into the stroma [71]. Corneal epi- damaged corneal surface [67].
thelial adhesion to Bowmans layer is maintained The corneal epithelium responds to injury in
by an anchoring complex including anchoring three phases, i.e., migration, proliferation, and
fibrils (type VII collagen) and anchoring plaques differentiation with reattachment to the basement
(type VI collagen) (Fig. 2.1c) [25]. Abnormalities membrane [80]. Following injury, cells adjacent
in these anchoring complexes may result clini- to an epithelial defect migrate to cover the wound
cally in recurrent corneal erosions or nonhealing within few hours. Following wound closure,
epithelial defects. basal epithelial and limbal stem cells proliferate
Besides epithelial cells, there are numerous and differentiate to repopulate the epithelium. In
nerve endings in between the cells (Fig. 2.2c), the final phase, hemidesmosomes replace focal
which exert important trophic influences on the contacts in order to anchor the basal epithelial
corneal epithelium and which have been esti- cells tightly to the basement membrane and
mated to amount to a density of 7000 nociceptors stroma. If the basement membrane remained
per mm2, which is 400 times more than in the intact, a tight adhesion is established in only a
skin [52]. Mechanical stress to these nerves, such few days. If the basement membrane was dam-
as in bullous keratopathy, can therefore cause tre- aged, its repair can take up to 6 weeks. During
mendous pain. Furthermore, resident MHC class this time, the epithelial attachment to the newly
II-expressing cells, i.e., CD11c+-dendritic cells deposited basement membrane tends to be unsta-
and CD207+-Langerhans cells, were identified in ble and weak, and the regenerated epithelium is
the human basal epithelium and anterior stroma very susceptible to damage. Following PKP, re-
(Fig. 2.2d), which are capable of rapidly mobiliz- epithelialization is usually observed within 1
ing to the site of epithelial trauma and viral infec- week, although morphological abnormalities,
tion within the cornea [37]. The corneal detected by specular microscopy, may persist up
epithelium itself exerts strong anti-inflammatory to 6 months postoperatively [74]. Corneal grafts
and antiangiogenic properties, and transplanta- showed some recovery of the subbasal nerve
tion of donor corneas without the epithelium, plexus, at least in the graft periphery, but not
e.g., after abrasion, leads to increased postopera- complete recovery of function [68].
tive inflammation and neovascularization [17].
Corneal epithelial cells routinely undergo
apoptosis and desquamation from the surface. Bowmans Layer
This process results in complete turnover of the
corneal epithelial layer every 57 days as deeper Bowmans layer represents the most anterior,
cells replace the desquamating superficial cells in acellular portion of the corneal stroma (Fig. 2.1d).
an orderly, apically directed fashion. Two popu- It is approximately 812 m thick and structur-
lations of cells, the basal epithelial cells and lim- ally composed of randomly oriented collagen
bal stem cells, help renew the epithelial surface fibrils, 2025 nm in diameter, consisting of col-
[7]. The epithelial stem cells and their progeni- lagen types I, III, V, and VI (Fig. 2.1e) [77]. Its
tors are located at the bottom of the palisades of thickness has been reported to decline with age
Vogt at the corneoscleral limbus [15]. Depletion by 0.06 m per year, thus losing one-third of its
of this stem cell reservoir, e.g., after chemical thickness between 20 and 80 years of age [23].
burns, can cause severe ocular surface disease Unmyelinated nerve axons penetrate Bowmans
and significant visual deterioration, a condition layer to terminate within the epithelium. The
14 U. Schltzer-Schrehardt and F.E. Kruse
functional role of Bowmans layer is not com- with adjacent lamellae being oriented at right
pletely known, but it is believed to serve as a bar- angles, although there are organizational differ-
rier that protects corneal stroma and nerves from ences in the collagen bundles between anterior
traumatic injury. In addition, it has been sug- and posterior stroma [45]. In the anterior third of
gested to ensure epithelial anchorage to the cor- the stroma, lamellae are oriented more obliquely,
neal stroma and helps to maintain the shape and mediating a tighter cohesive strength and rigid-
tensile strength of the cornea. Bowmans layer ity, which appears particularly important in main-
also functions as an important UV shield protect- taining corneal curvature [51], whereas in the
ing the inner eye and a nearly insurmountable posterior two-thirds, lamellae run in parallel to
barrier against the invasion of epithelial tumors the corneal surface. These differences in stromal
into the corneal stroma [60]. collagen organization may also explain why the
When disrupted, Bowmans layer does not anterior stroma resists changes to stromal hydra-
regenerate but forms a scar. Therefore, diseases tion much better [46] and why surgical dissec-
or surgical procedures leading to defects in tion in a particular plane is easier in the posterior
Bowmans layer increase the risk for corneal rup- depths of the stroma, e.g., in DALK. Moreover,
tures and ectasias. On the other hand, sutures the peripheral stroma is thicker than the central
have to extend through Bowmans layer to ensure stroma, and the collagen fibrils may change direc-
tight and effective suturing [17]. tion to form a circumferentially oriented network,
which is thought to be pivotal in maintaining cor-
neal stability and curvature, as they approach the
Corneal Stroma limbus [45]. Any disturbance of this fine-tuned
arrangement, either by deposition of abnormal
The stroma is the thickest layer of the cornea extracellular matrix, e.g., deposition of muco-
measuring approximately 500 m in width and polysaccharides in macular corneal dystrophy,
represents a dense avascular connective tissue of or the irregular arrangement of collagen fibrils in
remarkable and unique regularity. It is composed stromal scars, can cause corneal opacity.
of regularly arranged bundles of collagen fibrils The collagen lamellae are interspersed with
embedded in a glycosaminoglycan-rich extracel- flattened stellate keratocytes, which are inter-
lular matrix, which are interspersed with flattened connected by gap junctions and arranged in a
fibroblast-like cells termed keratocytes [18]. circular, corkscrew pattern forming a coherent
Collagen organization in the stroma is crucial to network (Fig. 2.2e) [50, 59]. The density of kera-
corneal functions such as light transmission and tocytes in the anterior stroma is 20,00024,000
maintenance of corneal curvature, tensile strength, cells/mm2 and the density decreases posteri-
and rigidity [27]. The individual collagen fibrils, orly. Keratocytes are metabolically active cells
being mainly composed of collagen types I and involved in synthesis and turnover of extracellu-
V, are extremely uniform in diameter measur- lar matrix components, i.e., collagen molecules
ing about 2530 nm [38, 44] and are organized and glycosaminoglycans. They contain water-
into approximately 250300 2 m thick sheets or soluble proteins, corneal crystallins, which
lamellae. Regular spacing of fibrils within these appear to be responsible for reducing backscatter
lamellae is maintained by interactions of colla- of light from the keratocytes and for maintaining
gens with proteoglycans forming bridges between corneal transparency [32]. In addition, sensory
the fibrils [53]. The major proteoglycans of the nerve fibers are present in the anterior stroma,
stroma are keratan sulfate proteoglycans, such as which are cut during PKP leading to a mild neu-
keratocan and lumican, and chondroitin/dermatan rotrophic keratopathy [68], and MHC class II
sulfate proteoglycans, such as decorin [27, 48], antigen-presenting cells, which seem to migrate
which also regulate stromal hydration by means out of the cornea during organ preservation,
of their ability to bind water molecules. The col- thereby explaining the reduced rates of immune
lagenous lamellae form a highly organized ply, rejections of longer organ-cultured grafts [17].
2 Anatomy and Physiology: Considerations in Relation to Transplantation 15
Following injury to the stroma, e.g., in PKP, three-center study provided evidence that there is
keratocytes adjacent to the wound undergo apop- no distinctive acellular pre-Descemets stromal
tosis [71, 78, 80]. About 24 h after wounding, the zone justifying the term layer apart from a thin
remaining keratocytes begin to proliferate and (0.51.0 m) intermediary Bowmans-like
transform into activated fibroblasts, which zone of randomly arranged collagen fibers at the
migrate into the wound region and produce extra- Descemets membranestromal interface
cellular matrix components, a process that may (Fig. 2.1g). The collagen fibers of this intermedi-
last up to 1 week. Inflammatory cells, including ary layer partly extend into Descemets mem-
monocytes, granulocytes, and lymphocytes, infil- brane serving a connecting function (Fig. 2.1h).
trate the stroma from the limbal blood vessels. Stromal keratocytes were found to approach
Fibroblasts transform into myofibroblasts, which Descemets membrane up to 1.5 m (mean
contract the wound and secrete extracellular 4.97 2.19 m) in the central regions and up to
matrix, a process which may last up to 1 month. 4.5 m (mean 9.77 2.90 m) in the peripheral
Deposition of large amounts of disorganized regions of the cornea. The intrastromal cleavage
extracellular matrix may lead to loss of corneal plane after pneumodissection, which seemed to
transparency causing stromal haze. Matrix occur at multiple stromal levels along rows of
remodeling by repopulating keratocytes thereby keratocytes offering the least resistance to
restoring transparency is the last phase of stromal mechanical forces, was obviously determined by
wound healing and can last for years [71]. In pen- the variable distances of keratocytes to
etrating or lamellar keratoplasty, a rather com- Descemets membrane. Consistently, the residual
plete wound healing response is usually noted at stromal sheet separated by air injection into the
donor-recipient interfaces. However, abnormal stroma varied in thickness from 4.5 to 27.5 m,
collagen fiber size and arrangement, indicating being usually thinnest in the central and thickest
incomplete stromal wound remodeling and per- in the peripheral portions of the bubble (Fig. 2.3d).
sistence of fibrotic scar tissue, have been observed This phenomenon has been well documented as
within the graft margin after PKP [11]. Similarly, residual stroma in previous studies, providing
the presence of fibrocellular tissue, probably evidence that the big-bubble technique in DALK
derived from myofibroblasts, has been found in is not consistently a Descemet-baring technique
the grafthost interface in about 20 % of corneas [31, 36, 43].
after DSAEK failure [79]. Therefore, stroma-to-
stroma interface haze may occur in DALK or
DSAEK and can degrade visual acuity, even if Descemets Membrane
the microkeratome or femtosecond laser is used
to achieve a smooth resection [4]. Descemets membrane represents the thickened
Recently, the existence of a novel, previously (1012 m), specialized basement membrane of
unrecognized layer of the pre-Descemets cor- the corneal endothelium consisting of collagen
neal stroma, which can be separated by air injec- types IV, VIII, and XVIII and non-collagenous
tion into the stroma during DALK using components including fibronectin, laminin, nido-
big-bubble technique, has been reported [19]. gen, and perlecan as well as dermatan, keratan,
This distinct layer was reported to measure about heparan, and chondroitin sulfate proteoglycans
10 m in width and was characterized to lack any [64]. Apart from providing structural integ-
keratocytes and to show a pronounced immunos- rity of the cornea, Descemets membrane has
taining for collagen types III, IV, and VI [20]. been suggested to play a role in several impor-
However, the description of this hypothesized tant physiological processes including corneal
new anatomic layer was critically commented on hydration, endothelial cell differentiation and
in the literature and eventually refuted by a proliferation, and maintenance of the corneal
detailed ultrastructural reinvestigation of the curvature. It is composed of an anterior banded
human corneal stroma [66]. The findings of this (fetal) layer, approx. 3 m in thickness, and a
16 U. Schltzer-Schrehardt and F.E. Kruse
posterior nonbanded (postnatal) layer that gradu- thickened fusion site, known as Schwalbes line,
ally thickens with age reaching up to 10 m in is a gonioscopic landmark that defines the end of
elderly individuals (Fig. 2.1f) [33, 54]. In the Descemets membrane and the beginning of the
periphery, Descemets membrane forms wart- trabecular meshwork.
like excrescences (Hassall-Henle warts) and Descemets membrane is attached to the
merges into the trabecular meshwork beams. The corneal stroma by a narrow (about 1 m thick)
Fig. 2.3 Light (D) and transmission electron (ac, eg) are shown in higher magnification on the left illustrating
micrographs showing cleavage planes in lamellar kerato- the stromal sheet forming the bubble wall of variable
plasty and usability of Descemets membrane ultrastruc- thickness with remnants of keratocytes (arrow). (eg)
ture as indicator of endothelial function. (a, b) Ultrastructural analysis of Descemets membrane show-
Physiological cleavage plane between the posterior stro- ing normal structure (e), abnormal collagen inclusions
mal collagen lamellae (a) and interfacial matrix zone (arrows) within posterior nonbanded layer (PNBL) (f),
(IFM) of Descemets membrane in DMEK. (c) Lamellar and a posterior collagenous layer (PCL) deposited onto a
splitting of Descemets membrane between anterior normal Descemets membrane (g) (IFM interfacial matrix,
banded layer (ABL) and posterior nonbanded layer ABL anterior banded layer; magnification bars = 2 mm in
(PNBL) (arrow) of a donor cornea with unsuccessful d; 2.5 m in c, e, f, g; and 1 m in a and b) (a, c, e repro-
stripping due to strong adhesion of Descemets membrane duced from Schltzer-Schrehardt et al. [65], and c repro-
to the corneal stroma (dotted line). (d) Semithin section of duced from Schltzer-Schrehardt et al. [66], with
a donor cornea showing big-bubble formation after air permission from Elsevier)
injection into the corneal stroma; the boxed areas (1, 2, 3)
2 Anatomy and Physiology: Considerations in Relation to Transplantation 17
anterior chamber more difficult. Thus, corneas cells, which form a hexagonal honeycomb-like
from donors older than 55 years of age are prefer- mosaic when viewed from the posterior surface
ably used for DMEK graft preparation [41]. The (Fig. 2.2f), are 56 m in height and 1820 m in
exact reasons why grafts adhere to the recipient diameter. Some cells have apical cilia, which
bed are not known. Physical, biochemical, and play a role in morphogenesis and repair of the
physiological mechanisms such as endothelial endothelial monolayer [8]. Their lateral surfaces
pump function have been proposed. It has been are highly interdigitated and possess apical junc-
shown that the use of organ-cultured grafts tional complexes comprising both gap and tight
exhibiting modified biochemical properties and a junctions forming a leaky barrier and allowing
larger removal of Descemets membrane of the paracellular movement of fluid and substances
host promote graft adhesion [42, 73]. from the aqueous into the cornea. The basal sur-
Although intraoperative manipulation may be face of the endothelium contains hemidesmo-
a frequent cause of primary graft failure, the somes that promote adhesion to Descemets
majority of failed DMEK grafts revealed ultra- membrane. The endothelial layer is responsible
structural signs of preoperative endothelial dys- for dehydration of the cornea and maintenance of
function, i.e., inclusions of abnormal collagenous corneal transparency by pumping water out of the
material within Descemets membrane proper corneal stroma [24]. The dehydration process is
[14]. Due to its continued appositional growth described by the pump-leak hypothesis, in
with age [54], Descemets membrane provides a which leakage of solutes and nutrients from
lifelong record of pathological events and endo- aqueous humor to superficial layers of the cornea
thelial function [33], and any deposition of is counteracted by pumping water in the opposite
abnormal extracellular material is indicative of direction. This passive bulk fluid movement is
previous stress or damage to the endothelial cells fueled by the energy-requiring processes of trans-
(Fig. 2.3e, f). Thus, a preexisting subclinical cor- porting ions to generate the osmotic gradient.
neal endothelial dysfunction, as indicated by The most important ion transport systems are the
abnormal inclusions within Descemets mem- membrane-bound Na,K-ATPase and the intracel-
brane, may have contributed to primary DMEK lular carbonic anhydrase, producing a net flux of
failure [14]. In contrast, a posterior fibrous layer, ions from the stroma to the aqueous humor [9].
mainly consisting of collagen types I and IV and The number of endothelial cells decreases
fibronectin, may be produced and deposited on with age, trauma, inflammation, surgery, and dis-
the posterior surface of an otherwise normal ease processes such as Fuchs endothelial dystro-
Descemets membrane by attenuated endothelial phy. Endothelial cell density at birth is
cells that underwent transdifferentiation into approximately 35004000 cells/mm2, decreasing
(myo)fibroblast-like cells (Fig. 2.3g) [75]. The gradually at an average rate of 0.6 % per year to
formation of an abnormal posterior collagenous 2500 cells/mm2 at age 50 and 2000 cells/mm2 at
layer is the result of a final common pathway fol- age 80 [6]. Endothelial cells of the human cornea
lowing endothelial dysfunction and damage, have a low proliferative capacity and lost cells are
including intra- or postoperative trauma, and has replaced by spreading of adjacent cells resulting
been also reported to contribute to failed lamellar in an increase in cell size (polymegathism) and
and penetrating grafts [28, 39]. an increase in variation of cell shape (pleomor-
phism). With increasing cell loss, the pump and
barrier functions of the endothelium may be
Corneal Endothelium compromised. A density lower than 500 cells/
mm2 may lead to endothelial decompensation
The innermost layer of the cornea, the corneal and corneal edema with concomitant loss of
endothelium, is a single layer of cuboidal cells, transparency. Endothelial cell loss following pen-
which have a critical role in maintaining corneal etrating and lamellar keratoplasty has been
hydration and thus transparency (Fig. 2.1f). The reported to average about 70 % in PKP, about
2 Anatomy and Physiology: Considerations in Relation to Transplantation 19
50 % in DSEK, and about 40 % in DMEK at 5 retina tomograph (HRT) II and Rostock Cornea
years [21]. However, remaining endothelial cells Module, show morphological alterations associ-
can also migrate along a density gradient and ated with a reduction in central corneal sensation
cover denuded areas [30]. early after DMEK [12]. However, a complete
In contrast to the in vivo situation, human recovery of corneal nerve density and function
endothelial cells retain their proliferative capac- up to preoperative values occurs within 410
ity in vitro and can proliferate in response to months. In contrast, subbasal nerve density does
growth stimulation factors [34]. Thus, the use of not recover to normal values throughout 30 years
ex vivo cultured human corneal endothelial cells after PKP [57].
may represent a potential future alternative to
full-thickness or lamellar keratoplasty in the
replacement of defective corneal endothelium. Corneal Immune Privilege
Preclinical studies applying corneal endothelial
cell therapy are giving promising results [29, 56, Since corneal avascularity is an essential factor
58, 62]. for corneal transparency, the cornea has devel-
oped strategies to maintain avascularity, a phe-
nomenon termed corneal antiangiogenic
Corneal Innervation privilege [5, 17]. Several antiangiogenic factors
have been shown to contribute to corneal avascu-
The cornea is densely innervated by unmyelin- larity, including pigment epithelium-derived fac-
ated sensory nerve fibers derived from the tri- tor (PEDF), thrombospondins, and receptors
geminal nerve, mainly via the long ciliary nerves. binding and inactivating angiogenic growth fac-
About 70 main nerve bundles enter the peripheral tors like vascular endothelial growth factor
cornea in a radial manner and move centrally in (VEGF). The strong expression of VEGF recep-
the anterior one-third of the stroma. They divide tor 3 on the corneal epithelium, which is nor-
into smaller branches and penetrate Bowmans mally expressed on vascular endothelial cells,
layer to form the subepithelial or subbasal nerve seems to be especially potent.
plexus at the interface between Bowmans layer The cornea has also developed strategies to
and the corneal epithelium (Fig. 2.2c). Individual minimize inflammatory reactions, a phenomenon
fibers penetrate all epithelial layers and termi- termed corneal immune privilege. The success
nate in the superficial layers. It is estimated that of allogeneic corneal transplantation benefits
there are approx. 7000 nociceptors per mm2 in from this property, which is attributed to multiple
the human corneal epithelium [52]. The den- anatomical, physiological, and immunoregula-
sity of nerve endings per unit area is 400 times tory factors [55]. For instance, absence of blood
higher than in the skin, making the cornea one and lymph vessels in the graft bed is essential for
of the most densely innervated tissues in the graft survival. Thus, the molecular mechanisms
body. In conformity with the density of nerve of immune privilege are similar to those mediat-
endings, corneal sensitivity increases from the ing avascularity, e.g., thrombospondin-1 is
limbus to the central cornea. Corneal nerves involved in both processes. Corneal epithelial
release neuropeptides, such as substance P and and stromal cells secrete soluble factors, includ-
calcitonin gene-related peptide (CGRP), which ing VEGFR-2 and endostatin, which inhibit lym-
have important trophic functions on the corneal phangiogenesis and hemangiogenesis, thereby
epithelium and stimulate epithelial wound heal- maintaining immune privilege [2]. The corneal
ing [22]. Loss of corneal sensory innervation can endothelium also expresses membrane-bound
lead to neurotrophic keratopathy, involving epi- molecules, such as Fas ligand (FasL), which
thelial defects, poor wound healing, and ulcers defend against immune effector cells including T
[10]. Corneal nerves, which can be visualized cells and components of the complement cas-
using confocal microscopy with the Heidelberg cade. Another mechanism contributing to the
20 U. Schltzer-Schrehardt and F.E. Kruse
success of allogeneic corneal transplantation is patterning and repair of corneal endothelium. Proc
Natl Acad Sci U S A. 2011;108:281924.
anterior chamber associated immune deviation
9. Bonanno JA. Molecular mechanisms underlying the
(ACAID), which is defined as the systemic corneal endothelial pump. Exp Eye Res. 2012;95:27.
downregulation of an immune response against 10. Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic
antigens injected into the anterior chamber of the keratitis. Eye (Lond). 2003;17:98995.
11. Boote C, Dooley EP, Gardner SJ, Kamma-Lorger CS,
eye [55]. As a consequence, immune reactions
Hayes S, Nielsen K, Hjortdal J, Sorensen T, Terrill NJ,
against, e.g., donor endothelial antigens are less Meek KM. Quantification of collagen ultrastructure
destructive. after penetrating keratoplasty implications for cor-
Nevertheless, the central corneal stroma and neal biomechanics. PLoS One. 2013;8, e68166.
12. Bucher F, Hos D, Matthaei M, Steven P, Cursiefen C,
epithelium are endowed with significant numbers
Heindl LM. Corneal nerve alterations after descemet
of resident MHC class II-negative inflammatory membrane endothelial keratoplasty: an in vivo confo-
and antigen-presenting cells, including dendritic cal microscopy study. Cornea. 2014;33:11349.
cells and epithelial Langerhans cells as well as 13. Chen ES, Shamie N, Terry MA, Phillips PM, Wilson
DJ. Retention of host embryonic descemet mem-
macrophages. These cells become activated and
brane in endothelial keratoplasty. Cornea. 2009;28:
increase in numbers after contact lens use and 3513.
inflammation (Fig. 2.2d), causing higher injection 14. Cirkovic A, Schltzer-Schrehardt U, Weller JM,
rates in inflamed high-risk recipient beds [16]. Kruse FE, Tourtas T. Clinical and ultrastructural char-
acteristics of graft failure in DMEK: 1-year results
after repeat DMEK. Cornea. 2015;34:117.
15. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker
RM. Existence of slow-cycling limbal epithelial basal
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Developments in Corneal Banking
3
Diego Ponzin, Gianni Salvalaio, Alessandro Ruzza,
Mohit Parekh, and Stefano Ferrari
Abstract
Eye banks are currently advancing to decrease the unnecessary manipula-
tion of tissues in the operating theatre and reduce the high surgical skill or
risk quotient for surgeries like EK or ALK. Development in the tissue stor-
age techniques, surgical devices for advanced and selective surgery, modi-
fication and manipulation of the tissues, and designing new methodologies
for ocular health care are now becoming a part of the eye bank activities.
Apart from the research and development, eye banks are now taking a lead
in standardizing and validating new procedures also for the clinics. Precut
and preloaded tissues may potentially reduce the overall intervention costs
and surgery time and enhance the surgical outcomes in the future. Synthetic
media are being evaluated for corneal storage at 3137 C (organ culture) to
replace serum. Manufacturing of surgical devices using three-dimensional
(3D) printing may further enhance the capabilities of the eye banks. Thus,
we envision that eye banks are growing not only in the field of procuring the
tissues for transplantation but also in the field of research and development.
Keywords
Eye bank Lamellar keratoplasty Corneal storage 3D printing and
surgical device
Introduction
lamellar keratoplasty) or the posterior corneal risk of transmission). Making the criteria for
stroma with the Descemet membrane-endothe- donor screening a little more stringent for pene-
lium complex (posterior lamellar/endothelial trating than for lamellar grafts.
keratoplasty). The field of endothelial kerato- Diseases with the potential of transmission
plasty (EK) has showed a dramatic impact in cur- by corneal transplantation comprise infections
rent eye banking and corneal transplantation with (local and/or systemic), hematologic malignan-
increasing number of EK procedures every year cies, prion diseases, and corneal disorders, the
[1]. The speed of adoption of this new form of latter being more related to quality than to safety
selective tissue replacement has been astonish- issues. Metastatic neoplasia does not exclude
ing, and most eye banks are now pre-cutting, pre- from donation and transplantation. The European
bubbling, and pre-stripping tissues for DSAEK, Eye Bank Association (EEBA) [4] and the Eye
DMEK, and DALK. Bank Association of America (EBAA) [5] have
established Minimum Medical Standards and
Medical Standards, respectively (details can be
Role of Eye Banks found at www.europeaneyebanks.org or www.
restoresight.org). The contraindications com-
Eye banks recover, evaluate, and preserve donor prise a group of systemic disorders (including
corneas and other ocular tissues for surgical use. the death of unknown cause), intrinsic eye dis-
If the next of kin of the donor consents, then the eases, and prior intraocular or anterior segment
tissues could also be used for research purposes surgery.
to better understand the fundamentals of the As set by the European Directives, the sero-
human eye and develop strategies or drugs as logical screening for HBV, HCV, HIV, and syphi-
potential treatment measures. Tissue removal and lis must be performed for every tissue that has
tissue processing in an eye bank should be car- been donated. Besides the search for antibodies
ried out under strict aseptic techniques. The mor- of antigens, some nations require the execution of
phologic and functional status of the endothelium nucleic acid testing (NAT), a molecular technique
is the most important indicator of donor corneal developed to shorten the window period (the time
suitability for transplantation. Corneal lenticules between the infection and when a positive anti-
can be prepared by eye bank technicians who body/antigen can be revealed). Because of the
have demonstrated proficiency in sectioning the window period, also the behaviors that may have
cornea. For keratolimbal allografts, the donor put the donors at risk, such as intravenous drug
limbal epithelium must be protected from trauma use, must be evaluated.
and desiccation, and a conjunctival rim of Postmortem blood can be obtained from direct
34 mm should be left [2]. Donor sclera is pre- heart puncture or accessible blood vessels, within
pared from ocular tissue following excision of 24 h from death.
the corneoscleral button or from the donor globes. Despite the low incidence, transmissible spon-
Recent advances in the fields of eye banking, giform encephalopathies, such as Creutzfeldt-
ophthalmology, and regenerative medicine are chal- Jakob disease, have been transmitted via corneal
lenging the traditional activities of eye banks [3]. transplantation. The disease is progressive and
fatal. For this reason, any donor who died with
neurological symptoms, or degenerative neuro-
Screening of Donors logical conditions, are excluded from donation.
There has not been any report of a systemic
Transplantation of human cornea involves poten- malignancy transmission following keratoplasty.
tial risks of transmission of host disease to recipi- A single case of ocular retinoblastoma transmis-
ent. In order to ensure safety, a set of sion has been reported in 1939 and has justified
contraindication has been established, after retro- the exclusion of donors with systemic lymphop-
spective discoveries of transmission of disease, roliferative disorders, documented ocular malig-
or on a cautionary basis (theoretical or significant nancies, and retinoblastoma.
3 Developments in Corneal Banking 25
It is important to document The source of by PBS is used to prevent corneal toxicity. Then,
information which includes pathologist, medical a preparation of the operative area using sterile
records, attending medical and nursing staff, gauze moistened in the iodine solution should
family members or other relevant persons close be performed, starting at the medial canthus of
to the deceased, family doctor, postmortem the upper closed eyelid and moving out, around
report. and below the lid, over the bridge of the nose, in
Early-stage anterior and posterior membrane an ever-widening circular pattern. The donor is
dystrophies and keratoconus may escape detec- then draped to create a sterile field at the opera-
tion. A thorough tissue evaluation in the eye bank tive site.
may minimize these events. The upper eyelid of the donors right eye is
Age criteria for cornea donors are not well gently opened with sterile gauze, and the closed
defined and vary between eye banks and surgeons. lid speculum is inserted, taking care that the cor-
The small diameter, thinness, and elasticity of nea is left untouched. The conjunctiva is grasped
the cornea excised from an infant eye may cause with the forceps, near the lateral edge of the cor-
technical problem for the surgeon. In general, nea at the limbus, and cut using the microsurgery
the diagnosis of the recipient and the surgeons scissors, continuing 360 all the way around the
experience are more important than donor age in cornea, removing the conjunctiva as far as possi-
determining the long-term graft clarity. ble. Closed, straight scissors are inserted under
Ocular tissues should be recovered as soon as the conjunctiva, and a blunt dissection is per-
possible after death. A short postmortem interval formed by gently opening the blades. This will
warrants a higher yield of suitable corneas and separate any adhesions between the conjunctiva
limits endothelial loss during storage. and the anterior globe. The conjunctival remains
The donors eyelids should be kept wet and are carefully scrapped using a scalpel blade from
closed until the retrieval. Elevating the donors the limbus.
head prevents pooling of blood in the head and
decreases the incidence of bleeding and swelling
in the eye region following enucleation. Enucleation
In Situ Corneoscleral Rim Excision PBS, where they are left until the corneal excision
is performed. This procedure has been reported to
Without perforating the choroid, a scleral incision reduce the percentage of contaminated eyes.
is performed using a scalpel, approximately 4 mm
from, and parallel to, the limbus. The incision is
extended 360 with microsurgery scissors, taking Tissue Evaluation
care to remain at least 4 mm from the limbus and
avoid perforating the underlying uveal tissue. The morphological and functional status of the
The removal is completed using one pair of endothelium is a key factor for the success of cor-
small forceps to hold the scleral rim and a second neal grafting and therefore the most important
set of forceps, to push the ciliary body choroid indicator of donor cornea quality. As there is no
downward and away from the corneoscleral but- direct functional test that can be used, the cornea
ton. The remaining adhesions can now be gently must be evaluated by morphological parameters
separated from the corneoscleral button, avoiding [5, 6]. A cornea suitable for transplantation is
distortion of the cornea shape with excessive required to display some essential biological
traction. The posterior chamber of the donor eye characteristics which include, a noninterrupted
must be examined to check the presence of the epithelial layer, a stroma free of opacities,
natural crystalline lens. absence of folds of he stroma and a viable and
regular endothelium with a cell density above
20002200 cells/mm2 [depending on the eye
Donor Reconstruction bank criteria].
Corneas from eligible donors with local eye
After enucleation, a moistened piece of gauze, disease affecting the corneal endothelium, or
rolled into a ball of the approximate dimensions previous ocular surgery that does not compro-
of the globe, can be placed in the socket and cov- mise the corneal stroma, can be used for lamellar
ered with a plastic eye cap, or a plastic prosthesis (anterior, posterior) or patch grafts.
can be applied. The conjunctival remains are In general, the slit lamp biomicroscopy of the
used for overall covering. anterior segment (enucleation) or the slit lamp
The eyelids will be closed and gently manipu- examination of the cornea (In situ excision) is
lated to restore the donors appearance. It is rec- combined with specular microscopy (mostly in
ommended to ask the mortuary staff to check the the USA) or with light microscopy [6].
conditions of the donor later.
puterized microscopes. Endothelial density can or injuries during tissue manipulation. Apart
be estimated by a calibrated reticule or calculated from the intercellular borders and cell count,
by built-in software. polymorphism (pleomorphism and polymegath-
ism) are also observed for determining the suit-
ability of the tissues for grafting.
Light Microscopy
Fig. 3.1 Human corneal endothelium. (a) Regular pattern thelium with large area of trypan blue-positive cells
of the corneal endothelium without any trypan blue- determining necrotic cells or total cell loss
positive cells and (b) completely damaged corneal endo-
28 D. Ponzin et al.
It is still a point of debate whether the clinical the removal of the epithelium, to determine which
outcome after grafting corneas stored by hypo- microkeratome head to use to obtain a final graft.
thermic or organ culture techniques is the same,
although few studies comparing the effect of the
storage methods on outcome demonstrate similar Resection of Cornea with a Swinging
graft survival and postoperative decline in endo- Microkeratome
thelial cell density [1215]. Irrespective of the
storage method used, inspection of the endothe- The corneal epithelium must be gently removed
lium after a prolonged storage is essential to pre- before preparation, or left in place. In the former
vent transplantation of poor quality corneas. case, the subsequent swelling of the stroma dur-
ing preservation can be limited. Two points are
marked on the midperiphery of the cornea using a
Tissue Processing for Specic sterile gentian violet or trypan blue marker to assist
Surgical Purposes with re-aligning the cap back onto the remaining
stromal bed after the cut has been made.
Eye Bank Preparation of Corneal The microkeratome head is rotated manually
Tissue for Lamellar Keratoplasty across the cornea. Once the sectioning is com-
pleted, the free cap is removed from the micro-
Donor selection criteria for corneas used in keratome head and repositioned onto the corneal
lamellar keratoplasty are the same as for pene- bed, taking care of re-aligning the marks. A
trating keratoplasty with a few exceptions. wexel sponge spear is used to smooth out any
Corneas with prior laser photoablation surgery or bubbles between the cap and the graft bed.
noninfectious anterior stromal scars may be suit- Once lamellar keratectomy has been com-
able for posterior keratoplasty, but corneas with pleted, the cornea should be re-evaluated by slit
previous intraocular surgery scars are not recom- lamp biomicroscopy and specular/light micros-
mended for use since the cornea may rupture copy to confirm that the tissue is suitable for the
under infusion pressure while on the artificial intended use [19].
anterior chamber [1618].
A 34 mm scleral rim is needed for corneas
used in lamellar keratoplasty procedures to Storage of Corneal Lenticules
ensure an adequate seal on the artificial chamber for Lamellar Keratoplasty
of the automated microkeratome.
An automated microkeratome system consists Anterior corneal lenticules can be either dehy-
of a control unit, an artificial chamber, microkera- drated or freeze-dried and stored at 26 C
tome turbine, and heads. The control unit should be according to the eye banks validation protocol.
set up in close proximity to the laminar flow cabi- Alternatively, anterior/posterior lenticules can
net. The cornea is placed using tissue forceps cen- be placed in a cornea viewing chamber filled with
trally onto the artificial anterior chamber which has preservation media (hypothermic storage) or in
been moistened by activating the irrigation system, the transport medium (organ culture).
and the chamber is locked into place. The cornea is
pressurized by infusing PBS through the irrigation
system. A tonometer lens is placed on the corneal The Preparation of Donor Sclera
surface to confirm that a minimum of 65 mmHg
has been established inside the artificial chamber The donor sclera is used in allografts for a variety
through the infusion of PBS. In case of anterior len- of procedures, most commonly to enclose orbital
ticules, the graft desired thickness is obtained by the implants for reconstruction of anophthalmic cavi-
correspondent microkeratome head. For posterior ties, reconstruct eyelids, cover tubes used in glau-
lenticules, a pachymetry reading is obtained after coma surgery, repair scleral thinning, and correct
30 D. Ponzin et al.
lid retraction and cicatricial entropion and tumor oncogenes; therefore, technically it would be
excision. Selection criteria are the same as cited safer to develop and integrate a totally synthetic-/
for penetrating keratoplasty, except that tissue with animal-free media in the routine eye banking pro-
local eye disease affecting the corneal endothelium cedures [20, 21].
is acceptable for use. Being a vascularized tissue,
malignancies are applied as additional contraindi-
cation. Postmortem interval may be extended. Precut and Preloaded Tissues
Donor sclera is prepared from remaining ocu- for Descemet Stripping Automated
lar tissue following excision of the corneoscleral Endothelial Keratoplasty
button or from donor globes which have been dis-
qualified before corneoscleral rim excision. Since Donor tissues for Descemet stripping automated
conjunctival tissue is an excellent carrier for endothelial keratoplasty (DSAEK) can be pre-
microbes, remnants of muscles and conjunctiva pared by the eye banks where the cornea is cut
must be removed. using a microkeratome and the entire tissue is
The intraocular material is removed by using delivered to the surgeon as a precut lenticule. The
forceps, iris scissors, sterile gauze, or cotton- anterior cap of the cornea can still be left attached
tipped applicators. The sclera is finally rinsed in to the scleral rim by its peripheral edge for ease
PBS, reshaped to its original spherical form, pre- of transportation and to lower any potential endo-
served dehydrated in ethanol (70 % or higher thelial cell damage [2224].
concentration) or glycerol, fixed in formalin, If the tissue is prepared by the surgeon in the
freeze-dried, or frozen. operating theater and if it fails due to irregular cut
or perforation in some cases, then the surgery has
to be postponed or an extra cornea has to be kept
Future Aspects in Eye Banking ready for replacement which increases the tissue
wastage in general. Hence a pre-cut or a pre-
Synthetic Medium for Corneal loaded tissue (as described further) may be
Preservation helpful.
Fig. 3.2 Device layout. (a) Computer-generated image of tissue culture media, (d) the computer-aided design
storage glide, (b) the working model of the glide printed (CAD) image of the device with the penholder that was
using a 3D printer with the lenticule, (c) the preservation stamped using 3D printer, and (e) final working prototype
container where the glide is fixed and filled with 50 ml of of a 3D printed glide
extraction of the glide easier with the handle dur- the preservation media with dextran, and all the
ing the surgery as shown in Fig. 3.2. grafts are ready to be delivered within 4 days
from the preparation.
References
Pre-stripping the Tissues 1. Parekh M, Salvalaio G, Ruzza A et al. Posterior lamel-
for Descemet Membrane Endothelial lar graft preparation. A prospective review from an
Keratoplasty eye bank on current and future aspects. J Ophthalmol.
2013;2013:769860
2. Croasdale CR, Schwartz GS, Malling JV. Keratolimbal
Stripping, unlike the bubble separation tech- allograft: recommendation for tissue procurement and
nique, is performed by peeling the Descemet preparation by eye banks, and standard surgical tech-
membrane and the endothelium away from the nique. Cornea. 1999;18(1):528.
3. Mohit P, Stefano F, Diego P. Eye Banking: an over-
stroma leaving a hinge at the end of the lenticule. view. In. Mohit P, Stefano F, Diego P. Eye Banking:
This allows the preservation of pre-separated Changing face of corneal transplantation. Nova
endothelial grafts in the eye bank further shipped Biomedical; 2015. p. 118.
to the surgeons. This technique has showed mini- 4. European Eye Bank Association. Agreements on min-
imum standards. http://www.europeaneyebanks.org.
mum mortality rate as compared to the other cur- 5. Eye Bank Association of America. Medical Standards.
rently performed techniques. http://www.restoresight.org.
6. Wiffen SJ, Nelson LR, Ali AF, Bourne WM.
Thus, preloaded, pre-bubbled, or pre-stripped Morphologic assessment of corneal endothelium by
tissues can be prepared in the eye bank and specular microscopy in evaluation of donor corneas
shipped to the surgery to ensure a validated graft for transplantation. Cornea. 1995;14(6):55461.
7. Pels L, Schuchard Y. Organ culture in the Netherlands.
by the eye bank for surgery. Preservation and endothelial evaluation, chapter 46.
In: Brightbill FS, editor. Corneal surgery. Theory,
Conclusions technique and tissue. 2nd ed. St. Louis: Mosby
Thus, we envision that eye bank is growing Elsevier Publisher; 1993. p. 62232.
8. Komuro K, Hodge DO, Gores GJ, Bourne WM. Cell
not only in the field of procuring the tissues death during corneal storage at 4C. Invest Ophthalmol
for transplantation but also in the field of Vis Sci. 1999;40(12):282732.
3 Developments in Corneal Banking 33
9. Pels E, Beele H, Claerhout I. Eye bank issues: 20. Parekh M, Ferrari S, Salvalaio G, Ponzin D. Synthetic
II. Preservation techniques: warm versus cold storage. versus Serum based medium for corneal preservation
Int Ophthalmol. 2008;28(3):15563. in organ culture: a comparative study between two dif-
10. Borderie VM, Laroche L. Microbiologic study of ferent media. Eur J Ophthalmol. 2015;25(2):96100.
organ-cultured donor corneas. Transplantation. 21. Camposampiero D, Tiso R, Zanetti E, Ruzza A, Bruni
1998;66(1):1203. A, Ponzin D. Cornea preservation in culture with bovine
11. Zanetti E, Mucignat G, Camposampiero D, Frigo serum or chicken ovalbumin. Cornea. 2003;22(3):2548.
AC, Bruni A, Ponzin D. Bacterial contamination of 22. Ide T, Yoo SH, Kymionis GD, et al. Descemet strip-
human organ-cultured corneas. Cornea. 2005;24(5): ping automated endothelial keratoplasty. Effect of
6037. anterior lamellar corneal tissue-on/-off storage con-
12. Chu W. The past twenty-five years in eye banking. dition on Descemet-stripping automated endothelial
Cornea. 2000;19(5):75465. keratoplasty donor tissue. Cornea. 2008;27(7):7547.
13. Frueh BE, Bhnke M. Prospective, randomized clini- 23. Rose L, Briceno CA, Start WJ, et al. Assessment
cal evaluation of Optisol vs organ culture corneal stor- of eye bank prepared posterior lamellar corneal tis-
age media. Arch Ophthalmol. 2000;118(6):75760. sue for endothelial keratoplasty. Ophthalmology.
14. Armitage WJ, Easty DL. Factors influencing the suit- 2008;115(2):27986.
ability of organ-cultured corneas for transplantation. 24. Terry MA. Precut tissue for Descemet stripping auto-
Invest Ophthalmol Vis Sci. 1997;38(1):1624. mated endothelial keratoplasty: complications are
15. Rijneveld WJ, Remeijer L, van Rij G, Beekhuis H, from technique, not tissue. Cornea. 2008;27(6):6279.
Pels E. Prospective clinical evaluation of McCarey 25. Busin M, Scorcia V, Patel AK, Salvalaio G, Ponzin
Kaufman and organ culture cornea preservation D. Pneumatic dissection and storage of donor endo-
media: 14-Year Follow-up. Cornea. 2008;27(9): thelial tissue for Descemets membrane endothelial
9961000. keratoplasty: a novel technique. Ophthalmology.
16. Wiffen SJ, Weston BC, Maguire LJ, Bourne 2010;117(8):151720.
WM. The value of routine donor corneal rim cul- 26. Parekh M, Ruzza A, Salvalaio G, et al. Descemet
tures in penetrating keratoplasty. Arch Ophthalmol. membrane endothelial keratoplasty tissue prepara-
1997;115(6):71924. tion from donor corneas using a standardized sub-
17. Wilhelmus KR, Stulting D, Sugar J, Khan MM. Primary merged hydro-separation method. Am J Ophthalmol.
corneal graft failure. A national reporting system. 2014;158(2):27785.
Arch Ophthalmol. 1995;113(12):1497502. 27. Ruzza A, Parekh M, Salvalaio G, Ferrari S,
18. Kim T, Palay DA, Lynn M. Donor factors associated Camposampiero D, Ponzin D. Bubble technique for
with epithelial defects after penetrating keratoplasty. DMEK tissue preparation in the eye bank: air or liq-
Cornea. 1996;15(5):4516. uid? Acta Ophthalmol. 2015;93(2):e12934
19. Salvalaio G, Fasolo A, Bruni A, Frigo AC, Favaro 28. Ferrari S, Barbaro V, Di Iorio E, Fasolo A, Ponzin
E, Ponzin D. Improved preparation and preservation D. Advances in corneal surgery and cell therapy: chal-
of human keratoplasty lenticules. Ophthalmic Res. lenges and perspectives for the eye banks. Expert Rev
2003;35(6):30158. Ophthalmol. 2009;4(3):31729.
Endothelial Keratoplasty
4
Ovette F. Villavicencio, Marianne O. Price,
and Francis W. Price Jr.
Abstract
Full-thickness corneal transplant was for many years the only surgical
option for corneal endothelial diseases. With the advantages of better
visual potential, shorter recovery times, and lower rejection risk, endothe-
lial keratoplasty (EK) has now superseded penetrating keratoplasty (PK)
for these conditions. This revolutionary change was initiated by the insight
of Gerrit Melles that partial-thickness grafts could stick to the back of the
cornea without sutures. Progressive surgical refinement and advances in
instrumentation by many surgeons have led to widespread adoption.
Currently, Descemets stripping endothelial keratoplasty (DSEK/DSAEK)
is the most popular surgical procedure for corneal endothelial dysfunction.
Descemets membrane endothelial keratoplasty (DMEK) has emerged as
an alternative to DSEK offering improved vision, shorter recovery time,
and reduced rates of immunologic graft rejections. Compared to DSEK,
DMEK selectively replaces bare endothelium and Descemets membrane
without a stromal scaffold. This chapter focuses on the evolution of EK,
techniques, outcomes, and complications.
Keywords
Endothelial keratoplasty Penetrating keratoplasty DLEK DSEK
DSAEK DMEK
Not all branches in an evolutionary history are approach for endothelial diseases at several
successful. Several alternative or hybrid tech- centers.
niques were developed in an attempt to overcome The wide range of endothelial disorders can
the surgical challenges with DMEK. One usually be managed with the different EK tech-
approach involved delivering the Descemets niques, and penetrating keratoplasty is rarely
membrane with a small peripheral 360 skirt of required. Table 4.1 summarizes the varied indi-
posterior stroma, instead of an entire layer of cations that can be treated with EK as well as
donor stroma. This was termed DMEK with stro- the important considerations. For example, with
mal rim (DMEK-S) when performed manually or the appropriate techniques and sufficient ante-
Descemets membrane automated endothelial rior chamber room, EK can be performed in
keratoplasty (DMAEK) when a microkeratome eyes with glaucoma tubes, synechiae, and iris
was used to perform the lamellar dissection step abnormalities.
[21, 22]. Another approach employed stromal
support along one side and was called sickle
DMEK. These procedures combined the visual Surgical Techniques
advantages of DMEK with the tissue insertion
and positioning ease of DSEK, but the donor tis- DLEK
sue was prepared by pneumatic (big bubble) dis-
section, which was more challenging and resulted As noted above, DLEK was never widely adopted
in a higher rate of tissue loss than the direct peel- because of its technical difficulty and unpredict-
ing method typically used to prepare DMEK tis- able visual recovery. Although not ideal, DLEK
sue (these techniques will be described in greater was the first successful EK procedure. It certainly
detail below). had several advantages over PK because it uti-
Another approach to improving visual out- lized a smaller incision and maintained the recip-
comes was to create a thinner donor lenticule ients anterior corneal surface. Visual recovery
with the microkeratome, a technique called ultra- was similar to PK and the suture-related compli-
thin DSAEK [23, 24]. In many cases, this tech- cations seen with PK were prevented.
nique is also associated with increased tissue
wastage [25]. Ultrathin DSAEK approaches the
advantages of DMEK but may increase the risk DSEK
of endothelial damage. Also tissue manipulation
becomes more challenging as the DSAEK tissue In DSEK, the endothelium, Descemets mem-
becomes ultrathin. Concomitantly, refinements in brane, and deep stromal tissue are delivered to
the surgical steps of DMEK along with compel- the posterior surface of the cornea after removing
ling evidence of its excellent visual results and the recipients dysfunctional Descemets mem-
low rejection rates have made it the preferred brane and endothelium. The procedure comprises
38 O.F. Villavicencio et al.
three steps: (a) preparation of a posterior lamellar tissue-cutting block and trephined to the
graft, (b) removal of the host Descemets mem- desired diameter (usually 89 mm) from the
brane and dysfunctional endothelium, and (c) endothelial side. Methods of lamellar dissec-
insertion of the graft into the anterior chamber tion include:
and positioning using air tamponade. Manual dissection (Fig. 4.1, first row) An
initial 45-mm curvilinear incision is
(a) Donor preparation: The donor cornea is made at the limbus to a depth of approxi-
mounted on an artificial anterior chamber for mately 300350 m with a guarded dia-
lamellar dissection. Then it is placed on a mond/Bevers blade. Short and long
Fig. 4.1 Donor tissue preparation: equipment and meth- enlarged with more air to separate the Descemets mem-
ods. First row (L-R) Descemets stripping endothelial brane (DM) from the posterior stroma. Fourth row (L-R)
keratoplasty (DSEK): manual dissectors (DORC, Descemets membrane endothelial keratoplasty (DMEK)
Netherlands); Barron disposable artificial anterior cham- graft preparation: peripherally scored DM is separated
ber (Katena Products); manual dissection with donor cor- from underlying stromal tissue circumferentially using a
nea mounted on artificial anterior chamber. Second row microfinger; DM is peeled in four quadrants leaving it
(L-R) Descemets stripping automated endothelial kerato- attached at the center; final peel to free the center of the
plasty (DSAEK): microkeratome (Moria); reusable artifi- tissue; scrolled donor Descemets membrane and endo-
cial anterior chamber (Moria); microkeratome-assisted thelium. Fifth row (L-R) DMEK graft insertion: trypan
donor dissection; microkeratome (Gebauer, Germany). blue is being used to stain the DM scroll to improve visu-
Third row (L-R) Descemets membrane automated endo- alization; the stained DM scroll; the tissue is being loaded
thelial keratoplasty (DMAEK) graft preparation: air is into the cartridge of an intraocular lens inserter; the DM
injected via a needle inserted through the peripheral scroll within the inserter
scleral rim; this creates a big bubble; the big bubble is
4 Endothelial Keratoplasty 39
curved dissecting blades are used to graft diameter or slightly smaller. DM strip-
extend the lamellar dissection 360 to ping is necessary in Fuchs endothelial
reach to the limbus. dystrophy to remove the guttae; however,
Microkeratome dissection (Fig. 4.1, second this step may be optional in conditions where
row) The donor dissection plane is cre- the DM is optically clear and devoid of any
ated with a microkeratome. The micro- structural alterations, such as in failed PK
keratome head depth can be selected and pseudophakic corneal edema [2830].
according to the desired plane of lamellar (c) Graft insertion and positioning: The graft
dissection (usually 250400 m). was initially inserted through a 5-mm inci-
Microkeratome dissection produces a sion using forceps; however, a number of
smoother and more regular dissection glides and inserters have been developed to
plane compared with manual dissection. facilitate this process and help minimize
Numerous eye banks have purchased damage to the tissue during insertion. The
microkeratomes and provide pre-dis- incision size has also been decreased in many
sected tissue. The most commonly used cases down to 3.4 mm with curled donors.
microkeratome (Moria, Antony, France) Currently used donor insertion instruments
cuts deeper in the periphery than centrally, include:
and this somewhat compensates for the Forceps The donor tissue is folded into a
normally increased thickness of the cor- 60/40 configuration (with the endothe-
nea in the periphery compared with the lium facing inward and protected with a
center, usually resulting in a fairly planar small amount of viscoelastic) and inserted
posterior donor button. into the anterior chamber using atraumatic
Femtosecond (FS) laser dissection (FS- non-coapting forceps (Ex. Charlie II,
DSEK) The feasibility of using a femto- Goosey, Kelman forceps) [3, 6, 7].
second laser to create lamellar cuts has Sheets glide This method can be helpful in
been assessed in multiple studies. So far eyes with a shallow anterior chamber and
all have had suboptimal visual results predisposed to iris prolapse. The anterior
because the laser does not produce as chamber is maintained using an anterior
smooth a dissection plane in the soft pos- chamber (AC) maintainer. A Sheets intra-
terior stroma as it does when producing a ocular lens (IOL) glide is inserted halfway
flap in the anterior stroma for laser refrac- into the chamber, which serves to keep the
tive surgery. In addition, irregularities are iris from prolapsing out of the wound. The
induced in the posterior stroma when the donor graft is placed onto the glide with
donor tissue is applanated against a solid the endothelial side facing downward and
laser interface. Finally, the anterior cor- protected with a generous amount of
neal surface is usually used as a reference cohesive viscoelastic. An intraocular for-
surface for the cut causing the peripheral ceps is inserted through the site opposite
graft to be variably thicker than the center, to the main incision. The donor edge is
depending upon the thickness gradient in grasped with the forceps and pulled inside
the donor cornea. The latter limitation the anterior chamber (pull-through
could potentially be addressed with method) [31]. Alternatively, the graft may
appropriately sophisticated imaging tech- be inserted through the main incision
nology and laser software [26, 27]. So far, using a Sinskey hook or small-gauge nee-
no one has been able to demonstrate that dle (push-in method) without the use of an
this much more expensive approach anterior chamber maintainer.
results in any tangible benefits. Busin glide (Fig. 4.2, first row second)
(b) Stripping of the host Descemets membrane This reusable funnel glide (Moria, Inc.,
(Fig. 4.2, first row first): The host DM is Antony, France) curls the graft into a
removed within an area corresponding to the cylindrical shape as it is pulled through the
40 O.F. Villavicencio et al.
Fig. 4.2 Recipient preparation, graft insertion, and posi- ade. Third row (L-R): DMEK graft insertion; short bursts
tioning. First row (L-R): Descemets membrane scoring; of balanced salt solution unfold the scrolled tissue; partial
loading a DSEK graft into a Busin glide (Moria); pull- unfold achieved. Fourth row (L-R): unwrapping the
through method of graft insertion using a Busin glide and scrolled DMEK donor tissue over a posterior air bubble
intraocular forceps. Second row (L-R): loading a DSEK (the air bubble helps anchor the graft in the correct posi-
graft into an EndoSerter (Ocular Systems, Winston- tion); final air injection to press the donor tissue against
Salem, NC); graft insertion with EndoSerter; air tampon- the recipient cornea
glide to minimize endothelial trauma dur- arm of the suture is passed through the
ing insertion [32]. The leading edge of the periphery of the donor lenticule, entering
graft is grasped and pulled into the anterior from the endothelial side and exiting from
chamber with an intraocular forceps intro- the stromal side. Both sutures are then
duced through an incision opposite to the passed through the incision, across the
main incision (Fig 4.2 first row - third). anterior chamber, and out through the cor-
Suture pull-through In this method [33], a nea 1 mm peripheral to the edge of
10-0 prolene suture is passed through a stripped DM. The donor lenticule is gen-
5-mm main incision and across the ante- tly folded in half with the suture at the
rior chamber to exit through the cornea leading edge, and the anterior lip of the
approximately 1 mm beyond the edge of incision is lifted as both ends of the suture
stripped DM. The donor endothelium is are pulled to guide the graft into the eye.
coated with viscoelastic, and the second The graft unfolds as the AC is filled with
4 Endothelial Keratoplasty 41
air, and it is secured by tying off the refined technique modifications like totally
suture, which helps minimize the risk of freeing up the scored peripheral Descemets
graft dislocation. membrane before stripping, results have
Injectors/Inserters (Fig. 4.2, second row greatly improved. The donor corneoscleral
first and second) Several single-use rim is submerged with the endothelial side
devices have been designed to deliver the up in a viewing chamber filled with corneal
graft with minimal endothelial trauma storage solution, or it can be placed on a cut-
[34, 35]. Adoption has been limited by the ting block. The DM is lightly scored 12 mm
cost and the good results surgeons have inside the trabecular meshwork using a
obtained with the other methods described Y-hook, because peripheral DM is the area
above. most likely to tear during edge lift due to adhe-
sions. Trypan blue staining improves visual-
After the graft is inserted, it is positioned and ization of the scored edge, which is then lifted
attached to the host posterior stroma using an air circumferentially with a microfinger (Moria,
bubble (Fig. 4.2, second row third). Complete Inc.). Radial tears are identified and removed
air fill in the anterior chamber is maintained for prior to edge lift with the microfinger because
1012 min, followed by a partial air-fluid these tears can extend centrally. The edge of
exchange to avoid risk of raised intraocular pres- the DM is grasped with a Tubingen forceps
sure (IOP) secondary to pupillary block. (Ambler Surgical), while fixation of the lim-
Alternatively, a prophylactic inferior iridectomy bus is achieved with 0.5-mm forceps. DM is
may be made prior to graft insertion to prevent partially peeled in four quadrants, leaving the
pupillary block because of air, and a 90 % air fill center part attached (corridor method) a
can be left in the eye as long as the iridectomy is technique which decreases tension during
not covered by air. Postoperatively, supine posi- the peel by decreasing the width of the peel
tioning is maintained for 1530 min or longer. zone [41]. The membrane is floated back into
position and the donor is trephined lightly
into stroma. The donor is placed back in the
DMEK viewing chamber for a final peel to detach
DM centrally. The detached DM spontane-
DMEK involves harvesting of donor DM and ously forms a scroll with the endothelium on
endothelium followed by insertion, unfolding, the outside. The DM scroll is placed either
and positioning in the proper orientation. Just as in the storage medium or used immediately
in DSEK, the central host DM is removed before for transplantation. The DM thickens with
inserting the donor tissue. However while the age; thus grafts from older donors generally
DSEK grafts will easily stick to retained areas of scroll less tightly, which makes graft unwrap-
the host Descemets membrane and endothelium, ping easier during surgery. Therefore, donor
DMEK grafts stick much better to bare stroma. tissue over 40 years of age is preferable for
DMEK. As with DSEK, DMEK donor tis-
(a) Donor preparation (Fig. 4.1, fourth row): sue can be prepared several days before the
Donor DM can be isolated by direct peeling surgical procedure [42]. Other variations of
[36] or by injection of air to create a big bub- donor stripping have been reported by Kruse
ble [37]. Direct peeling has a higher success [43] and Jardine [44], with the latter tech-
rate with less endothelial cell loss [38]. Giebel nique leaving one side of the donor attached
and Price described a direct peeling method so that the tissue can be laid back in place for
called submerged cornea using backgrounds endothelial cell density assessment by the eye
away (SCUBA) that has a success rate of bank.
almost 99 % [39, 40]. Earlier reports had A newer method for detaching the
lower success rates, but with experience and Descemets membrane with air has been
42 O.F. Villavicencio et al.
termed PDEK [45]. The developer claims injected under the donor to secure the orientation
that this method detaches Duas [46] layer [40]. The recipient corneal surface is stroked to
along with the Descemets membrane and center and unfold the graft completely, followed
endothelium, allowing use of younger donors by air fill in the anterior chamber. The patients
and reportedly easier unfolding of the tissue are advised to keep supine position for 60 min to
[45]. However, donor diameters are limited allow for donor adherence.
to about 77.5 mm because of the diameter
of Duas layer.
(b) Graft insertion, unfolding, and positioning: Hybrid Techniques
The DM scroll can be loaded into a glass
pipette or IOL cartridge and injector and Hybrid techniques have been developed to com-
inserted through a 2.43-mm wide corneal bine the optical outcomes of DMEK with the
incision. Various types of IOL cartridges are easier handling of DSEK. Studeny described
suitable for graft delivery including Carl transplantation of a posterior corneal lamella
Zeiss inserters (Jena, Germany) and Viscoject consisting of endothelium and DM centrally with
(Medicel AG, Wolfhalden, Switzerland) a stromal supporting rim (DMEK-S), and
(Fig. 4.1, fifth row). A variety of new glass McCauley et al. described a partially automated
tubes have also been used including the variation (DMAEK) [21, 22]. The bare central
Straiko modified Jones tube for DMEK endothelium and DM provide excellent optical
(Gunther Weiss, Portland, Oregon). Graft outcomes, comparable with those of successful
adhesion is reported to be better with use of a DMEK patients, while the stromal rim provides
closed system without any addition of visco- support to the fragile and thin central portion of
elastic [47]. the donor. This helps to maintain donor shape and
orientation while preventing scrolling, allowing
Several graft unfolding maneuvers are avail- for easier delivery into the anterior chamber
able (Fig. 4.2, third and fourth row). Dapena while maintaining correct orientation. The donor
et al. [48] described a standardized no-touch tissue is dissected as in DSEK using either hand
technique for DMEK transplants. A glass injector dissection or a microkeratome. The Descemets
is used to deliver the DMEK roll into the anterior membrane is then detached from the posterior
chamber with the endothelium facing the cornea. stroma using a big bubble technique (Fig. 4.1,
A small air bubble is delivered between the dou- third row). Rapid big bubble formation can cause
ble rolls to unfold the graft. After unfolding, the rupture of DM. More importantly, the bubbles
air bubble is removed, and an air bubble under- can sometimes develop in the periphery of the
neath the graft (between iris and graft) is injected cornea, instead of the center. Peripheral bubbles
for graft fixation [48]. Liarakos et al. [49] are thinner and tend to rupture and break easily. If
described 4 standard (standardized no-touch a peripheral bubble forms, the donor tissue can
DMEK, Dirisamer technique, Dapena maneuver, no longer be used for the hybrid technique, but an
and single sliding cannula maneuver) and 3 aux- attempt can be made to convert the tissue for use
iliary techniques (flushing, manual centration, with DMEK. The DMEK-S or DMAEK donor
and bubble bumping) for unfolding the graft in tissue is inserted into the eye using the pull-
the anterior chamber depending upon the orienta- through technique with the aid of a Busin glide,
tion and how tightly the DM is curled. Essentially, and air is injected to attach the donor to the recip-
the DM scroll in the anterior chamber is opened ient stroma. Donor insertion and positioning is
using short quick bursts of BSS. A portable slit easier than DMEK because the tissue unfolds
beam or optical coherence tomography attach- spontaneously because of the added rigidity
ment on the operating microscope can be used to afforded by the skirt of stromal tissue. Both cen-
confirm the graft orientation [50]. After the scroll ters developing the hybrid techniques have dis-
is partially unwrapped, a small air bubble is continued their use because of increased donor
4 Endothelial Keratoplasty 43
loss relative to DMEK and increased need for because the DM graft is delicate and requires
reinjection of air to promote donor adherence. more manipulation to position the graft in com-
Nevertheless, hybrid donor tissue can still be parison to DSEK. When deciding about the type
ordered from eye banks as precut tissue options. of EK, the potential advantages of a given proce-
dure need to be weighed against the technical
ease in an individual case-based scenario.
Ultrathin DSAEK
Some surgeons have reported better visual acuity Aphakic Eyes with Complete
and faster visual recovery with thinner endothe- or Partial Aniridia
lial grafts [24]. Busin et al. described a
microkeratome-assisted double-pass method for In eyes with aphakia with complete or partial
obtaining ultrathin posterior lamellar grafts aniridia, a potential concern is intraoperative or
(<100 ) [23]. The first pass is done with a 300- postoperative graft detachment, which may result
or 350-m microkeratome head to debulk the in graft dislocation into the posterior segment.
cornea. The thickness of the residual bed deter- Several options are available to manage this situ-
mines the selection of the microkeratome head ation depending upon the extent of iris abnormal-
for the second pass, which is necessarily made ity [17]. A DSEK pull-through technique with or
going the opposite direction to help avoid perfo- without a suture is typically used. If forceps are
ration, because the blade penetrates deepest at the used to pull the tissue in, a fixation suture can be
beginning of the pass. Nomograms which take used to secure the donor once air fills the anterior
into account donor thickness, corneal storage chamber and the donor is in position [33]. A pos-
medium, pressurization of the artificial anterior terior chamber IOL (sulcus/scleral fixated) with
chamber, and cutting speed have been devised to or without iris reconstruction/pupilloplasty can
help select the appropriate microkeratome head be planned simultaneously or a few weeks before
size to obtain thin EK donor tissue with either an EK procedure. In eyes with large iris defects,
single- or double-pass techniques [24]. Some eye the host DM stripping should be avoided or per-
banks reportedly prepare ultrathin DSAEK by formed cautiously to prevent the fragments from
varying the pressure inside the artificial anterior falling into the posterior segment. Furthermore,
chamber to control the depth of cut. The risk of in aphakic eyes, the air bubble used to promote
tissue loss from perforation is higher with ultra- graft adhesion may migrate to the posterior seg-
thin grafts compared with standard DSEK grafts. ment intra- or postoperatively, leading to shallow
anterior chambers and iridocorneal touch.
Prolonged air tamponade and proper head
Surgical Considerations with Ocular positioning may be additional measures to pro-
Comorbidities mote graft adhesion.
In aniridic eyes with an artificial iris implant,
EK is most straightforward in an eye with a nor- the graft can slide between the edge of the implant
mal anterior segment and a stable posterior and the wall of the eye and fall into the posterior
chamber IOL. Because of the well-known advan- segment. To prevent this from happening, air
tages of DSEK over PK, the indications for EK should be injected under the graft before it is
have expanded to eyes with anterior segment released from the insertion forceps, and a tempo-
complexity such as those with pupillary abnor- rary fixation suture should be used to hold the
malities, peripheral anterior synechiae, glaucoma- graft in place [17]. Alternatively, the graft can be
filtering procedures, glaucoma tube shunts, prior inserted with a suture pull-through technique,
PK, or anterior chamber IOL. While DSEK can and the pulling sutures can be used to affix the
be attempted successfully in all mentioned condi- graft until adherence is confirmed in the postop-
tions, the decision for DMEK is more reserved erative period [33].
44 O.F. Villavicencio et al.
to the irregularity at the graft-host junction that maintainer during the surgery helps in main-
may interfere with the graft attachment process. taining the anterior chamber during the DSEK
Particularly with DMEK, an uneven posterior pro- surgery.
file of a previous failed PK can make positioning
of the donor DM and endothelium more difficult,
and reinjection of air to promote graft attachment Surgical Outcomes
is required more often than it is in virgin eyes.
One of the most remarkable findings in a Visual Acuity
series of 60 eyes with DSEK after failed PK was
that neither neovascularization nor the number of When compared with PK, the visual recovery is
previous graft failures increased the risk of graft remarkably rapid, occurring within a few weeks
failure. The only preoperative characteristic asso- of EK, and mean visual outcomes continue to
ciated with increased risk of graft failure was pre- improve for up to several years afterward,
vious filtration surgery, either trabeculectomy or although delayed improvement is more common
aqueous shunt [56]. in DSEK than DMEK. The average Snellen cor-
rected distance visual acuity (CDVA) reported
after DSEK has ranged from 20/30 to 20/60 in
Iridocorneal Endothelial (ICE) different studies, with variable follow-up periods
Syndrome [18, 59]. Several factors may interfere with com-
plete visual recovery: graft folds, thickness irreg-
These eyes may have a very shallow anterior ularity, centration, interface haze, and residual
chamber because of broad peripheral synechiae anterior abnormalities in the host cornea [60].
[14]. In addition they may have undergone a DMEK virtually eliminates any thickness
prior glaucoma-filtering surgery/drainage surgery variation or folding of tissue to conform to the
for IOP control. Extensive synechiolysis may back surface of the recipient cornea, thereby
be required for deepening the anterior chamber. resulting in better and faster visual recovery with
Postoperatively, frequent follow-up and aggressive fewer higher order aberrations from the posterior
control of IOP are needed for graft survival [57]. surface of the cornea [61]. Most patients achieve
20/25 or better vision within several weeks with
DMEK [39, 40]. Like DMEK, DMAEK also pro-
Pediatric Endothelial Keratoplasty vides superior visual recovery with high rates of
20/25 or better vision [24]. The relationship
DSEK can be more challenging in pediatric eyes between DSEK graft thicknesses and visual acu-
as compared with adults. The main reasons for ity has been debated [62, 63]. While some believe
performing EK in pediatric eyes are for failed that thinner grafts are associated with better
graft, congenital hereditary endothelial dystro- vision, others have failed to establish this associ-
phy (CHED), and pseudophakic corneal edema. ation. Thinner, well-centered, and planar grafts
Surgical challenges involve insertion and unfold- may induce fewer higher order optical aberra-
ing of the donor tissue in the small anterior cham- tions and contribute to superior visual results.
ber of a child, avoiding trauma to the crystalline Busin et al. have reported excellent visual out-
lens, postoperative positioning requirements, and comes with ultrathin DSAEK [23].
anesthesia issues [58]. CHED eyes in particular
are difficult because of poor visibility. These
young eyes have very thin DM, which can be dif- Refractive Results
ficult to strip. Pediatric eyes can have a positive
vitreous pressure, which can make the surgical DSEK does not significantly alter anterior cor-
maneuvers difficult. Discussing with the anesthe- neal topography, but tends to cause a mean hyper-
tist the need for hypotensive anesthesia during opic shift of 0.751.5 D through changes in the
graft insertion and the use of an anterior chamber posterior corneal curvature [64]. Because of the
46 O.F. Villavicencio et al.
nonplanar configuration of the DSEK donor len- compared with 53 % for DSEK and 70 % for
ticule, which is typically thinnest in the middle, a PKP. They also found that a single air reinjection,
minus lens is introduced on the posterior corneal which is sometimes required in DMEK to pro-
surface. Also, the increase in the thickness of the mote graft adherence, did not greatly affect endo-
cornea caused by implanting additional stroma thelial cell density [76].
leads to a decrease in the radius of curvature of
the posterior surface. The resulting hyperopic
shift should be taken into consideration when Graft Survival
planning a triple procedure to better achieve the
target refraction. Although DMEK does not The reported graft survival rates through 1 year
increase the corneal thickness or introduce a with DSEK range from 55 to 100 % in various
minus lens effect, it also results in a mean hyper- studies [18, 71, 77]. This wide range reflects dif-
opic shift of 0.250.50 D that is attributed to the ferences in sample size, indications for endothe-
resolution of the corneal edema after restoration lial keratoplasty, associated comorbid conditions,
of the endothelial function [65, 66]. and varying rates of iatrogenic graft failure due to
the surgeons initial learning curve. Price et al.
reported a 5-year survival rate of 95 % for Fuchs
Endothelial Cell Loss endothelial dystrophy and 76 % for pseudopha-
kic and aphakic corneal edema [70]. Prior glau-
The endothelial cell loss reported after DSEK is coma surgery was the most significant risk factor
1835 % at 6 months, 3136 % at 1 year, 3141 % for early graft failure [71]. With this risk factor
at 2 years, 44 % at 3 years, and 54 % at 5 years taken into account, the 5-year DSEK survival rate
[34, 6772]. Compared with the 5-year cell loss was comparable to 5-year PK survival rates at the
experienced with PK procedures performed in same center [70]. The reports on 1-year survival
the Cornea Donor Study for similar indications, rates after DMEK are encouraging, and longer
the cell loss at 5 years may be lower with DSEK term follow-up is awaited.
[71]. Hence, despite the higher initial endothelial
cell loss experienced with DSEK compared with
PK, the rate of subsequent cell loss appears to be Complications
less with DSEK for reasons that have not been
fully elucidated. Early Postoperative Intraocular
There are few reports so far on long-term Pressure Elevation
endothelial cell loss after DMEK because the
technique is relatively new. In a report by Tourtas Elevated IOP can occur as a result of pupillary
et al., the mean endothelial cell loss at 6 months block by the injected air required to promote graft
after DMEK and DSAEK was comparable [73]. attachment. The pupillary block may be relieved
In another comparative study between DMEK with pupillary dilation or partial anterior cham-
and DSAEK, there was no difference in the endo- ber decompression. Air may migrate to the pos-
thelial cell loss at 1 year [74]. Baydoun et al. [75] terior chamber in an eye with a floppy/abnormal
reported endothelial cell density (ECD) for eyes iris or tone or even to the posterior segment in an
that underwent DMEK. They report decreases in eye with an open posterior lens capsule leading to
ECD by 35 % at 6 months, 38 % at 12 months, an appositional angle closure, iridocorneal touch,
43 % at 24 months, 47 % at 36 months, 52 % at and raised IOP. This may be managed by remov-
48 months, and 55 % at 60 months compared to ing the air from the anterior segment and allow-
preoperative values [75]. Feng et al. compared ing the iris to drop back into place or by having
the 5-year endothelial cell loss after DMEK to the patient properly positioned with head facing
reported rates for DSEK and PKP [76]. The down. Eyes with large residual air bubbles should
median 5-year cell loss was 39 % with DMEK always be checked a few hours after surgery.
4 Endothelial Keratoplasty 47
Graft Detachment (Fig. 4.3, First Row) graft detachments will often seal down sponta-
neously without any intervention. Total DSEK
The reported graft detachment rates after DSEK graft detachments can be managed by reinject-
vary from 0 to 82 % [18, 77, 78]. Although the pre- ing air (called rebubbling). Spontaneous reat-
cise mechanism of graft adhesion is unknown, it tachments of totally detached DSEK grafts have
is probably an interplay of three factors: mechan- been reported but are unpredictable and may be
ical, biochemical, and physiological. Achieving a decentered.
complete air fill in the anterior chamber helps in As with DSEK, graft detachment is one of the
the initial mechanical apposition of the graft to most frequent complications with DMEK. Partial
the stroma, followed by the physiological effect graft detachments are less likely to spontane-
of the endothelial pump [78]. Graft detachments ously resolve with DMEK than DSEK. In con-
are more common in situations where it is either trast to DSEK, where residual DM may not affect
difficult to achieve an air fill for a required time graft adhesion, remnants of host DM in the
interval or to maintain a firm eye, such as eyes stripped bed can definitely interfere with the
with vitrectomy, aphakia, glaucoma-filtering sur- adhesion of a DMEK graft. Also, the elastic
gery, or repeated squeezing or eye rubbing on the forces of the DM scroll need to be overcome for
part of the patient. Strategies described to reduce a firm adhesion of the DMEK graft, whereas the
the risk of graft detachments include: scraping of donor posterior stromal tissue helps keep the
the peripheral host stromal bed, mid-peripheral graft uncurled with DSEK. In an early report by
venting incisions, good wound integrity, pro- Guerra et al., the rebubbling rate was 62 % in a
longed air tamponade, and supine positioning, prospective series of eyes undergoing DMEK
especially in high-risk situations. Partial DSEK [40]. In this study, the graft insertions were done
Fig. 4.3 Postoperative complications. First row (L-R) epithelial downgrowth at the interface originating from
first and second panels: DMEK partial detachments; third the edge of the DSEK graft. Third row (L-R) rejection epi-
panel: complete detachment (DM scroll shown in the sodes in DSEK, DMAEK, and DMEK, each showing
anterior chamber). Second row (L-R) folds in DSEK graft; fresh keratic precipitates without noticeable corneal
interface haze with DSEK; late DSEK graft failure; edema
48 O.F. Villavicencio et al.
with an injector that required a viscoelastic plug. keratic precipitates, Khodadoust line, redness,
With the modifications in the insertion techniques and anterior uveitis.
that avoided the viscoelastic use, the rebubbling
rates dropped to 15 % [79]. Some surgeons are
less likely to intervene with partial DMEK graft Glaucoma
detachments and thus may have relatively low
rebubbling rates. Because of the required air bubble for graft
adherence, acute pupillary block glaucoma after
EK is a relevant complication affecting long-
Primary Graft Failure term visual rehabilitation. The reported rates
of acute glaucoma after DSEK range from 0 to
Primary graft failure is a potential complication 54 % [77, 87]. A previous history of glaucoma
following any type of keratoplasty procedure. or ocular hypertension is a significant risk factor
The incidence of primary graft failure after PK for development of raised IOP after DSEK [87].
ranges from 0.3 to 2 % [78]. The reported rates of In DMEK, the longer air bubble time and higher
primary graft failure after DSEK have ranged rate of air reinjection pose an increased risk of
from 0 to 29 %, suggesting that iatrogenic endo- acute glaucoma. However, Melles et al. found
thelial trauma may be a factor [18, 8083]. The that, compared with PK and DSEK/DSAEK,
rate of primary graft failure after DMEK was DMEK was not associated with an increased risk
89 % in early studies that included the surgeons of uncontrolled glaucoma [88].
initial learning curve [40, 74]. With modifications Topical corticosteroids are used for the pre-
and refinements in some of the surgical steps and vention and treatment of corneal graft rejection.
increased surgeon experience, both DSEK and However, long-term topical corticosteroids lead
DMEK have become more predictable with more to elevated IOP and cataracts. Since immuno-
consistent results [80]. logic rejection rates are lower in DMEK due to
the donor graft only consisting of DM and bare
endothelium, Price et al. studied different corti-
Immunologic Rejection (Fig. 4.3, costeroid strengths after DMEK [89]. They found
Third Row) that the difference between the rejection rates
between the prednisolone acetate 1 % and fluoro-
The rate of rejection after DSEK has varied metholone 0.1 % arms was statistically insignifi-
widely in small series from 0 to 46 % with the cant. They conclude that decreasing postoperative
mean rate of approximately 10 % [18, 54, 77]. topical corticosteroid strength significantly
Hjortdal et al. [84] reported rejection rates of 5 % reduces the risk of IOP elevation without sub-
of patients during the first 2 years after DSAEK stantially increasing the risk of immunologic
for Fuchs. Rejection rates are lower in EK com- graft rejection episodes [89].
pared with PK because the use of corticosteroids
can be continued without much concern about
healing of the relatively small incision [85]. Epithelial Downgrowth (Fig. 4.3,
Additionally, less donor tissue is implanted in EK Second Row: Fourth)
versus PK and the reduced antigenic load could
be another favorable factor. A study by Anshu Decentration during trephination can lead to
et al. reported that DMEK eyes had 15 times incorporation of donor epithelium with a DSEK
lower risk of having an immunologic rejection donor lenticule, which may lead to epithelial
episode within the first 2 years than DSEK eyes downgrowth. Also, recipient epithelium can be
and 20 times lower risk than PK eyes [86]. introduced during the donor insertion or intro-
Allograft rejection in EK may present with duced through surface venting incisions if proper
4 Endothelial Keratoplasty 49
technique is not employed. Epithelial ingrowth investigations have been promising. Other
can be associated with graft failure. research is directed toward the identification of
genetic mutations involved in specific endothelial
cell diseases such as Fuchs endothelial dystrophy
Interface Abnormalities and customizing treatment [95]. It is possible that
many new medical modalities may emerge for
Donor graft interface or thickness irregularities the management of some of the endothelial
can occur with manual dissection or irregular diseases.
microkeratome cuts. No attempt is made to match
donor and recipient curvature, and a significant Conclusion
mismatch can result in folds and wrinkles in an DMEK, at this time, is the ideal selective
EK graft that may be visually significant (Fig. 4.3, transplant procedure for endothelial disorders
second row first) [60]. Another cause of inter- providing perfect anatomical replacement of
face abnormalities is incomplete removal of vis- the diseased endothelium. However, DSEK
coelastic after stripping DM (Fig. 4.3, second continues to remain the surgery of choice for
row second) [90]. This haze or reticulated- endothelial diseases associated with more
looking interface may take months to clear if the complex anterior segment pathologies.
viscoelastic is not removed. Removing it leads to Pharmacological modalities of treating endo-
immediate resolution of the interface haze. thelial diseases are an exciting breakthrough,
but at this point it is uncertain whether these
have potential to completely replace endothe-
Infections lial keratoplasty or serve as an adjunctive
treatment modality in the management of
EK techniques create an interface between the endothelial dysfunctions.
donor tissue and the recipient stroma in which
infectious agents can be introduced and get trapped
during the surgical intervention. There have been References
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Anterior Lamellar Surgery
5
Naoyuki Maeda
Abstract
Anterior lamellar keratoplasty (ALK) is classified into two categories:
superficial anterior lamellar keratoplasty (SALK) and deep anterior lamel-
lar keratoplasty (DALK).
Superficial anterior lamellar keratoplasty consists of an automated
lamellar therapeutic keratoplasty (ALTK) as an optical procedure for
the superficial stromal disorders and lamellar grafting as a therapeutic
procedure for corneal perforation, corneal thinning, or ocular surface
diseases.
Recently, DALK has been actively performed for the stromal patholo-
gies of the cornea with healthy corneal endothelium as a selective lamellar
keratoplasty for optical purposes. DALK is also performed as a therapeu-
tic procedure for serious corneal infection that does not respond to phar-
macological therapy.
The advantages of DALK over penetrating keratoplasty are the elimi-
nation of endothelial rejection and better ocular integrity. As a trade-off, a
steep learning curve, intraoperative complications such as corneal perfora-
tion and postoperative complications including double chamber, persistent
stromal folds, and insufficient visual recovery due to residual stromal
opacity may be found. To solve these problems in DALK, novel proce-
dures and new instruments are being developed.
Keywords
Deep anterior lamellar keratoplasty Automated lamellar therapeutic ker-
atoplasty Rejection reaction Selective lamellar keratoplasty Descemets
membrane Femtosecond laser Big bubble technique
Classication of Anterior Lamellar the corneal disorders that have stromal opacity
Keratoplasty from superficial to mid-stroma. Good indications
are the superficial stromal disorders such as lat-
For a long time, penetrating keratoplasty had tice corneal dystrophy, stromal scar after corneal
been conducted for the majority of corneal trans- infection, refractive surgery, or trauma [9, 42,
plantation cases. However, the advances in tech- 48]. If the depth of the stromal opacities is deeper
niques and technologies in eye surgery have than 100 m from the surface, ALTK rather than
enabled us to perform the selective lamellar kera- PTK is indicated.
toplasty on the eyes where corneal pathology is ALTK is less invasive than the conventional
limited to the anterior or posterior part [2, 4, 32, anterior lamellar keratoplasty. The procedure can
37, 44, 45]. be sutureless with topical anesthesia. The wound
Anterior lamellar keratoplasty has been per- quality by microkeratome [16] or femtosecond
formed for the tectonic purpose or optical purpose laser [5, 51] is less irregular than that by the man-
as shown in Fig. 5.1. For the optical purpose, auto- ual cut, and the femtosecond laser can minimize
mated lamellar therapeutic keratoplasty (ALTK) the disparity of the size between host and graft.
or deep anterior lamellar keratoplasty (DALK) is The shape of the donor by the microkeratome
indicated for the corneal stromal disorders. For the basically resembles the free-cap flap in
tectonic purpose, central, peripheral, or ectopic LASIK. The thickness profile of the graft is
lamellar keratoplasty is indicated for corneal per- meniscus shaped in the center, and the edge is
foration, corneal stromal thinning, immunologic tapered with an acute angle. Therefore, one needs
corneal diseases, and ocular surface disorder. to pay careful attention to wrinkles and disloca-
tion of the graft. In contrast, the graft made by
femtosecond laser has a planar shape in the cen-
Supercial Anterior Lamellar ter, and the edge has a side cut with an obtuse
Keratoplasty angle. Therefore, less dislocation of the graft and
better wound adaptation is expected.
Automated Lamellar Therapeutic On the other hand, femtosecond-assisted
Keratoplasty (ALTK) ALTK cannot be performed on eyes with dense
corneal opacity. In addition, one should recog-
Purpose and Indication nize that the shape of the stromal bed would be
The purpose of the automated lamellar therapeu- irregular if ALTK was performed on eyes with an
tic keratoplasty (ALTK) is visual recovery from irregular anterior surface.
Optical ALTK
SALK Central
Tectonic peripheral
ALK ectopic
Descemetic
Optical
DALK Pre-Descemetic
Fig. 5.1 Classification of Tectonic
anterior lamellar keratoplasty
5 Anterior Lamellar Surgery 55
For the annular or sector annular graft, mark- amblyopia should be conducted not only after
ing with large and small trephine blades is useful surgery but also before surgery.
for creating an identical incision at both host and
graft. Incision is made manually with a knife on Procedure
the mark. Then, the stroma inside the incisions is For limbal dermoid, the conjunctiva is removed
carefully dissected with lamellar spatulas. The from the surrounding area of the dermoid. The
donor is mounted at the artificial chamber or cautery of feeding vessels is helpful for avoiding
sutured to the base for improving handling during bleeding during excision of the tissue. The partial
the preparation. The same marking is made on cut with trephine followed by dissection under
the donor, and identical incisions are made fol- the dermoid is conducted. The slit illumination
lowed by the dissection in the same fashion. For during excision is useful for avoiding the corneal
advanced cases, free-hand corneoscleral graft perforation. Full-thickness graft can be used in
may be used. most of cases. If necessary, trimming at the pos-
After aligning the graft on the host, the graft is terior edge of the graft is effective for good adap-
sutured from the proximal side followed by the tation of the wound.
suture at the distal side alternately. The deep and In general, the recurrence of pterygium can be
short bite is preferred especially at the proximal treated with the combination of mitomycin C,
side. The soft contact lens will be placed for a amniotic membrane, and conjunctival autograft.
while to facilitate wound healing and to prevent However, massive proliferation of the conjunc-
the persistent epithelial defect. The appropriate tiva or thinning at the peripheral cornea and/or
use of general and topical steroid and immuno- sclera may require the additional use of a tectonic
suppressant is critical for inflammatory disorders. lamellar patch.
normal eyes, and there is a risk of wound dehis- complications such as the rupture of Descemets
cence associated with trauma or suture removal membrane and double chamber.
[18, 22]. The big bubble technique developed by Anwar
In addition, there is a trend toward mini- made DALK more popular [2]. This is because
mally invasive ophthalmic surgery nowadays. If one can expose the Descemets membrane more
patients had stromal pathologies of the cornea easily in less time than with layer-by-layer tech-
with healthy corneal endothelium, DALK, which niques. When the big bubble was not shown, the
replaces only pathological stroma and preserves visibility of corneal stroma was deteriorated, and
the corneal endothelium and Descemets mem- the layer-by-layer procedure became more diffi-
brane, will be less invasive and can be performed cult. For avoiding perforation with the needle and
as a closed surgery. Because corneal endothe- increasing the probability of big bubble forma-
lium is auto-tissue in DALK, endothelial rejec- tion, modified techniques such as the use of blunt
tion and prolonged used of topical steroid can be cannula and lamellar dissection before air injec-
avoided, and a stronger wound is advantageous tion were devised. As alternative techniques for
for earlier suture removal and less risk of wound exposing the Descemets membrane, many varia-
dehiscence. tions including hooking technique and visco-
Although the concept of selective lamellar delamination technique were introduced.
keratoplasty has been considered for a long time, Currently, DALK can be classified into two
sufficient dissection of stroma in DALK was categories: Descemetic DALK and pre-
technically very difficult and time consuming. Descemetic DALK (Fig. 5.2). In pre-Descemetic
Lamellar keratoplasty, which is currently termed DALK, the thin stroma layer still remains on the
anterior lamellar keratoplasty (ALK), had been Descemets membrane, so its surface is irregular.
mainly performed not for optical purposes but for On the other hand, in Descemetic DALK the
tectonic purposes. This is because manual dissec- Descemets membrane or pre-Descemetic layer
tion of the stroma has to be conducted for both is exposed, and the surface is shiny and smooth.
host and donor in ALK. As the lamellar graft and Indications for optical DALK are irreversible
stromal bed of the host tended to be irregular by stromal opacity with intact corneal endothelium
the manual dissection, visual recovery following and Descemets membrane. Therefore, keratoco-
ALK was suboptimal and inferior to that fol- nus, stromal corneal dystrophy, necrotizing kera-
lowing PK. Therefore, PK has been the primary titis in herpetic keratitis, old interstitial keratitis,
procedure even for eyes with healthy corneal stromal scar after trauma, or corneal infection are
endothelium. good indications for DALK. Also, keratectasia
The advances in surgical microscopes and following LASIK and extremely irregular cornea
instruments for stromal dissection made it possi- following radial keratotomy or other refractive
ble to perform layer-by-layer removal of patho- surgeries can be indications for DALK. On the
logical stroma. In addition, the visualization and other hand, if there is a history of acute hydrops
handling of the very thin corneal stroma were in keratoconic eye or damage to Descemets
remarkably improved by the air injection to the membrane for any reason, there will be a higher
stroma [3] or hydration of stroma [40]. With chance of rupture in Descemets membrane dur-
these techniques, surgeons can expose the ing big bubble technique.
Descemets membrane or reach the pre- Recently, therapeutic DALK for severe cor-
Descemetic layer and implant the full-thickness neal infection has been attempted [1, 41].
graft. This procedure was previously called deep
lamellar keratoplasty (DLK). As DLK also stands
for diffuse lamellar keratitis after LASIK, the Preoperative Evaluation
acronym DALK took the place of DLK.
These layer-by-layer techniques required spe- As DALK is basically the procedure that replaces
cific skills on the part of the surgeon and longer the pathological corneal stroma with a healthy
surgical time with unique intra- or postoperative one, all the other components, i.e., corneal
5 Anterior Lamellar Surgery 59
endothelium, Descemets membrane, and cor- the location and degree of the thinnest point and
neal epithelium should be determined as being in the thickness at the site of partial trephination, is
good condition before surgery. helpful.
Endothelial function can be estimated by the Similarly to PK, the assessment of cornel
combination of slit lamp examination, specular epithelium for ruling out limbal stem cell defi-
microscope, pachymetry, and OCT. The slit ciency is critical, and also the evaluation of
lamp findings such as stromal edema, subepi- the condition of the lid, lacrimal function, and
thelial edema, and folds in Descemets mem- function of the nasolacrimal duct is necessary.
brane are signs of endothelial dysfunction. The Glaucoma, ocular infection, and inflammation
endothelial cell density at the clear part of the of the anterior segment should be treated and
cornea is useful for estimating the corneal endo- stabilized before the surgery. Ocular comorbidi-
thelial count when the corneal pathology is in ties including cataract, vitreoretinal diseases,
an inactive stage. Pachymetry with ultrasound and neuro-ophthalmological disorders should be
or OCT is useful for quantitating the stromal evaluated.
edema. The cross-sectional images of the cor-
nea with the anterior segment OCT can show us
the information at the invisible area with slit Procedure
lamp because infrared light penetrates more
deeply than visible light. The folds in Descemets DALK can be performed under local or general
membrane or retro-corneal fibrosis may be anesthesia while soft eye is maintained during
identified with OCT in the invisible area with surgery. It is important to ready for the conver-
the slit lamp. The observation of Descemets sion to PK in all cases, even if the risk is low. For
membrane with the slit lamp examination and considering the risk of conversion to PK, the
OCT is also very important for excluding its pupil is usually constricted with miotic drug
damage due to acute corneal hydrops or perfo- before surgery. Partial thickness trephination is
rating corneal injury. performed on half to two-thirds of the corneal
For working out a surgical strategy, confirm- thickness at the area. Then, stromal dissection is
ing the thickness profile of the stroma, especially started with one of the following techniques.
60 N. Maeda
viscoelastic material, the donor will be placed on and can measure cross-sectional images in real
the recipient bed and sutured. time. Another OCT is the portable-type OCT
(iVue 1002: Optovue, USA) mounted on the
Identication of Stromal Thickness or arm [11]. In such cases, observation with the
Instrument Position operating microscope and measurement by OCT
One of the most difficult points in DALK is the are performed alternatively.
inability to visualize the residual stromal depth or
the distance between the instrument and Application of Femtosecond Laser
Descemets membrane under the operating Recently, the femtosecond laser has been applied
microscope. Coaxial illumination and oblique not only for the LASIK but also penetrating kera-
illumination are not useful for the purpose. toplasty, DSAEK, and astigmatic keratotomy [5].
Intraoperative findings are sometimes useful This trend is also true in DALK. Instead of partial
for estimating the depth. During the stroma dis- straight-edge trephination performed manually,
section, the lamellar structure at the superficial zigzag or mushroom configuration by femtosec-
stroma is compact and firm. On the other hand, ond laser is performed [31, 36]. The deep inci-
the posterior stroma is rough and soft. During the sion minimizes air escape into the peripheral
delamination with spatula, the radial folds from cornea during the big bubble technique and also
the tip of the spatula will appear if the tip is close is useful as the reference for manual stromal dis-
enough to Descemets membrane. section. In addition, non-straight wound configu-
The Melles technique utilizes the specular ration can facilitate the matching of anterior
light reflex at the posterior corneal surface [24]. surface between host and graft [31].
To enhance the specular light reflex, the aqueous
in the anterior chamber is replaced with air.
Between the blade tip and light reflex, the dark Clinical Outcome
band that indicates the unincised posterior cor-
neal tissue can be seen. Therefore, surgeons can Results
reach just anterior to the Descemets membrane The clinical outcomes after DALK from the
when the dark band disappears. experts showed similar results. Visual outcome in
A more direct method is the visualization of DALK using the big bubble technique is compa-
the cross section of the cornea with a slit illumi- rable to that in penetrating keratoplasty in patients
nator as we do in the office with a slit lamp. Slit with keratoconus [13]. There were no relevant
illuminators for vitreoretinal surgery (Zeiss) and differences between Descemetic DALK and pre-
the slit illuminator utilizing a very fine LED light Descemetic DALK in patients with keratoconus
for selective lamellar corneal surgery (MS-SI01, except for the faster visual recovery in Descemetic
Topcon, Japan) are commercially available and DALK [33]. The comparison among Descemetic
can be mounted on the operating microscope. DALK, pre-Descemetic DALK, and PK indi-
With slit illumination, the surgeon can recognize cated that visual acuity in Descemetic DALK is
the residual stromal thickness or the distance significantly better than that in pre-Descemetic
between the instrument and Descemets mem- DALK or PK [43]. Also, there were no significant
brane continuously during the maneuver. Also, a clinical outcomes between successful big bubble
handheld slit (510 L, Eidolon Optical LLC) can and failed big bubble followed by manual dissec-
be used not only for DALK but also for tion [7].
Descemets membrane endothelial keratoplasty A report by the American Academy of
(DMEK) [8]. Ophthalmology concluded that DALK is equiva-
Currently, anterior segment OCT is available lent to PK for the outcome measure of BSCVA,
for evaluating the information about the depth. particularly if the surgical technique yields mini-
One is the OCT exclusive for surgery by Zeiss, mal residual host stromal thickness on the basis
which is mounted in the operating microscope of level II evidence in 1 study and level III
5 Anterior Lamellar Surgery 63
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The Penetrating Keratoplasty
(PKP): A Century of Success 6
Berthold Seitz, Nora Szentmry,
Moatasem El-Husseiny, Arne Viestenz,
Achim Langenbucher, and Gottfried O.H. Naumann
Abstract
Besides routine postoperative follow-up, the prophylaxis of complications
in penetrating keratoplasty (PKP) includes special preoperative and intra-
operative aspects. Preoperative prophylaxis consists of the therapy of sys-
temic diseases and eyelid abnormalities, determining individual optimal
graft size, avoiding PKP in cases of uncontrolled intraocular pressure,
avoiding PKP in cases of acute corneal hydrops, pretreatment of vascular-
ized cornea, amniotic membrane transplantation before PKP in cases of
ulcerative keratitis, quality-controlled organ-cultured transplants, and pre-
operative counseling by the microsurgeon to ensure patient compliance.
Intraoperative prophylaxis consists of controlled arterial hypotension and
complete relaxation during general anesthesia and application of a
Flieringa ring in aphakic vitrectomized eyes. Precautions for intraopera-
tive prophylaxis of astigmatism must be followed. A measurable improve-
ment seems to be possible using the technique of nonmechanical
trephination of patient and donor from the epithelial side using the excimer
laser but not the femtosecond laser. Graft size should be adjusted individu-
ally (as large as possible, as small as necessary). Limbal centration
should be preferred over pupil centration (especially in keratoconus). In
addition to the situation-specific diagnosis and preoperative planning, the
critical selection of the donor tissue, and the minimally invasive
Keywords
Corneal transplantation Penetrating keratoplasty Trephination
technique Suture technique Astigmatism Immune reactions
Complications Excimer laser Femtosecond laser Prophylaxis
in higher topographic regularity, earlier of the technique 10 years ago the superiority of
visual rehabilitation, and less suture loosen- this high-price and difficult-to-maintain option
ing requiring only rarely suture has not been proven, yet!
replacement.
10. Intraoperative keratoscopy should be applied
after removal of lid specula and fixation Surgical Techniques
sutures.
The first successful total penetrating keratoplasty
Postoperatively Postoperatively, periodical (PKP) was performed by Eduard Zirm on
control examinations using fluorescein and blue December 9, 1905, in Olmtz, which today is
light are indispensable. All loose sutures have located in the Czech Republic. This means that
to be removed as early as possible. In cases of corneal transplantation is the oldest, most com-
herpetic eye disease, 2 400 mg of oral acyclo- mon, and most successful transplantation in
vir should be administered for at least 1 year. humans overall [85]. In the USA approximately
In cases of therapy-resistant epithelial defects, 45,000 keratoplasties are performed per year,
100 % autologous serum eye drops or amniotic with the equivalent figure being more than
membrane transplantation (patch technique) is 5.200 in Germany; in Homburg/Saar we per-
a valid option. Immune reactions must be diag- formed around 300 in 2014. In the year 2013,
nosed and treated immediately with high doses 43.5 % of all corneal transplants performed in
of corticosteroids (topically, intracamerally, Germany were of the posterior lamellar type,
systemically). with only 4.4 % being anterior lamellar grafts
and 52.1 % still being carried out as PKP. This
Results Prospective clinical studies have survey is based on the German Keratoplasty
shown that the technique of non-contact excimer Register, which since 2002 has been maintained
laser PKP improves donor and recipient decen- by the DOG-Sektion Kornea.
tration and reduces vertical tilt and horizontal With a better understanding of immunological
torsion of the graft in the recipient bed, thus transplant reactions and secondary glaucomas
resulting in significantly less all-sutures-out after PKP, the demands placed on microsurgeons
keratometric/topographic astigmatism, higher with regard to corneal transplantation have
regularity of the topography, and better visual increased. Today, a crystal-clear cornea after
acuity. Besides less blood-aqueous barrier PKP with high and/or irregular astigmatism,
breakdown during the early postoperative course especially in combination with high anisometro-
after PKP, excimer laser trephination does not pia, can no longer be considered successful in
induce cataract formation and does not impair normal-risk keratoplasty. With the increasing
the graft endothelium. Likewise, the rate of experience of the microsurgeon, the technique of
immunological graft rejections is not adversely keratoplasty goes far beyond the replacement of
affected by the excimer laser but by femtosec- two collagen disks and is crucial for the func-
ond laser trephination. In addition, trephination tional postoperative outcome.
of an instable cornea is facilitated using the non-
contact excimer laser.
Astigmatism and Keratoplasty
Conclusions Because of undisputed clinical
advantages, especially in eyes with keratoconus, Denition of Astigmatism after
excimer laser trephination with orientation teeth/ Keratoplasty
notches is still favored in Homburg/Saar in daily The cornea provides approximately two thirds of
practice. The femtosecond laser-assisted kerato- the refracting power of the human eye. Surgical
plasty technique has been very exciting but due to interventions on the cornea can therefore signifi-
major lack of all-suture-out data after introduction cantly affect the refractive power. Astigmatism
70 B. Seitz et al.
after PKP is often irregular, i.e., two or more Table 6.1 Classification of post-PKP astigmatism
meridians are separated from one another by an Early postoperatively with sutures in place:
angle which is not equal to 90. Two or more Symmetry of suture positions
Homogeneity of suture tension
steep hemi-meridians are not located opposite one
Late postoperatively persisting without sutures:
another. The same applies to the flat hemi-
Cut quality
meridians. In addition, the refracting power in Wound configuration (horizontal/vertical)
corresponding hemi-meridians may be different Symmetry of graft placement
[52]. Especially in the case of irregular astigma-
tism, patients accept only a smaller subjective cyl-
inder than the objective cylinder measured by The low quality of the trephination wound and
keratometry or topography analysis [58]. With geometric incongruities (horizontal and vertical)
high irregular astigmatism, it is only possible to require higher suture tension in order to guarantee
achieve good visual acuity with hard contact a watertight wound closure and pseudo-optimal
lenses. topography during the early postoperative phase.
In addition to the keratometry, topography Asymmetrical regional forces between the donor
analysis today is essential in order to determine and recipient can lead to inhomogeneous wound
the refracting power distribution over the entire healing processes. The removal of the sutures
graft. The refracting power and the individual axes results in the release of forces due to geometric
of the four hemi-meridians are supplemented by incongruities and inhomogeneous wound heal-
system-specific indices (e.g., SRI surface regu- ing. For this reason, horizontal, vertical, and
larity index or SAI surface asymmetry index topographic discrepancies between the donor and
of the TMS topography system) [30]. recipient intraoperatively appear to be responsible
for the increase in astigmatism after removal of
Causes of Astigmatism after the sutures. Thus, it is reasonable to conclude that
Keratoplasty in addition to wound healing, factors associated
Each individual step, from the selection of the directly or indirectly with the quality of the wound
donor, intraoperative trephination, and the suture geometry (quality of the cut, wound configuration
technique to the quality of the postoperative fol- (horizontal/vertical), symmetry of the graft fit)
low-up treatment, can be decisive not only for have a strong influence on long-term astigmatism
corneal transparency but also for the final refrac- after removal of the sutures [10, 11, 58].
tive outcome [20, 40, 45, 81, 82].
In addition to tissue-intrinsic factors in the
donor and recipient, early astigmatism with The main intraoperative determinants
sutures in place appears to depend strongly on (Table 6.2, Fig. 6.1) for high and/or irregu-
the suture placement technique and the lar astigmatism after suture removal are
approaches used for intra- and postoperative [42, 61, 63]:
suture adjustments (the signature of the micro-
surgeon) [42]. After suture removal the corneal Decentration (donor and/or recipient
curvature normally becomes more regular [58], trephination)
although the net astigmatism can significantly Vertical tilt (incongruent cut angle
increase [15, 36, 39, 46]. between donor and recipient)
We have to distinguish between the early post- Horizontal torsion (horizontal dis-
operative astigmatism with sutures in place and crepancy between the donor and recipi-
the late persisting astigmatism after suture ent form and/or asymmetrical graft
removal (Table 6.1). Concerning the pathomech- fit The second cardinal suture is
anism of the increase in astigmatism after suture crucial!)
removal, the following suggestions are made:
6 The Penetrating Keratoplasty (PKP): A Century of Success 71
Undercut at
endothelial level
Since the introduction of artificial anterior cham- all trephine systems results in openings which are
bers, microsurgeons have been able to carry larger than the nominal trephine size. Furthermore,
out donor trephination from the epithelial side, the diameter at the level of Descemets mem-
i.e., in the same direction as in the patient. If brane is greater, resulting in divergent cut angles
the pressure in the artificial anterior chamber [49, 82]. This can be explained at least in part by
is kept at its normal level (e.g., 22 mmHg), the bulging (ballooning) of the cornea in the tre-
advantages with respect to the congruence of phine opening due to the pressure exerted.
the cutting angles are self-evident [48].
Graft Size
In a quantitative study we were able to show that
the corneal diameter in keratoconus patients is
Central flattening
significantly greater than the diameter in Fuchs
patients (mean horizontal diameter of 11.8 mm in
keratoconus compared to 11.3 mm in patients
with Fuchs dystrophy [54]). In general, larger
graft dimensions have a favorable effect on the
optical qualities and endothelial cell count, while
Fig. 6.3 The combination of the donor cornea (conver- a low rate of immunological rejection and lower
gent cutting angle) trephined from the endothelial side risk of postoperative ocular hypertension are
and the mechanically trephined recipient cornea (diver- affected by a small graft.
gent cutting angle) causes a triangular deficit at the level
of Descemets membrane, which has to be compensated
for by suture tension. This can lead to central flattening,
vertical tilt, and irregular astigmatism The graft size should be determined on an
individual basis: as large as possible, but
as small as necessary.
Technical Details of PKP
General anesthesia has clear safety advan- For many eyes with keratoconus, an 8.0 mm
tages over local anesthesia, especially in diameter has proven to be a good preset for com-
young keratoconus patients. The arterial blood munication with the cornea bank (arcus lipoi-
pressure should be kept as low as possible des!), while for many eyes with Fuchs dystrophy
when the eye is open (controlled arterial not suitable for posterior lamellar keratoplasty, a
hypotension). 7.5 mm diameter is appropriate. Today, diameters
Typically, the pupil is constricted with pilo- from 5.5 to 7.0 mm are only very rarely needed
carpine in order to protect the lens of the pha- and are usually reserved for small eyes with spe-
kic eye. cial immunological implications.
Paracentesis at the limbus is recommended It has been assumed that a smaller graft is
before trephination. associated with higher astigmatism after kerato-
The head and limbus level must be horizontal plasty. In a more recent study, in which we com-
during trephination. pared 8.0, 7.5, and 7.0 mm grafts with each other,
A peripheral iridotomy at 12 oclock prevents we were able to show the following [58]:
pupillary block and therefore an acute glau-
coma attack. In case of keratoconus after the Smaller grafts are associated with a flatter
administration of atropine, this may appear as curvature.
a so-called Urrets-Zavalia syndrome with a Smaller grafts are associated with higher top-
persistent maximally dilated pupil due to an ographic irregularity.
iris sphincter necrosis [80]. Smaller grafts result in a higher proportion of
The correct position of the second cardinal non-measurable keratometry images.
suture is absolutely crucial for a correct graft Suture removal is associated with a positive
alignment. tendency toward regularization of the
Intraoperative keratoscopy should be applied topography.
after removal of the lid speculum and fixation It has not been possible to show a difference
sutures [6, 40, 42, 63]. with respect to the amount of net astigmatism
74 B. Seitz et al.
between smaller and larger grafts, neither for trephine systems or laser trephination in which
grafts with nor without suture. the donor is cut from the epithelial side. In the
case of keratoconus, it has been recommended
Recent studies show that the rate of chronic not to carry out donor oversizing.
endothelial cell loss after PKP depends on the
initial diagnosis [34, 47]. Endothelial migration
along a density gradient from the donor to the Undersizing of the graft for the purpose of
recipient ring is probably the main reason for this simultaneous correction of keratoconus-
phenomenon in pseudophakic bullous keratopa- intrinsic axial myopia will result in irregu-
thy. For this reason, eyes with bullous keratopa- lar astigmatism and is not recommended.
thy are probably better treated with a larger graft, The difficulty of achieving a watertight
not only in order to improve the optical quality wound closure requires excessive suture
but also to transplant as many endothelial cells as tension, with the consequence of irregular
possible. Nevertheless, the graft size must be astigmatism and a relative cornea plana.
determined individually by the microsurgeon for
each individual patient before recipient trephina-
tion in order to find the best compromise between
immunological purposes and optical quality. A Pupil or Limbal Centration?
slit lamp with a measuring device, such as the Centration is essential, both in terms of the
Haag-Streit slit lamp, can be helpful. Furthermore, immunological graft reaction and the astigma-
the removal of a vascularized pannus is recom- tism after keratoplasty [31, 32, 53, 81]. Typically,
mended (in contrast to vascularized stromal cor- an attempt is made to reach a compromise
neal scars) before trephination in order to achieve between limbus and pupil centration in nontrau-
a greater individually ideal graft diameter [52]. matized pupils. However, limbus centration is
In repeat PKP an attempt should be made to preferred especially in the case of keratoconus,
excise the old graft completely and recenter the scars after trauma, or irregular astigmatism due
trephination if the cornea is large enough and a to other causes. In such eyes, the center of the
host rim of about 1.5 mm is left [17, 73]. This is entrance pupil is in fact optically displaced from
especially of importance in eyes with high and/or the position of the actual anatomical pupil [33].
irregular astigmatism as the reason for repeat For example, the pupil in the typical keratoco-
grafting. nus eye tends to be optically displaced supero-
nasally due to the inferotemporal location of the
Graft Oversize cone.
In mechanical trephination the diameter of the We use a radial keratotomy marker with eight
recipient bed tends to be larger than the trephine lines in order to ensure limbal centration
diameter. In contrast, the diameter of the donor (Fig. 6.4). Additional central punctate marking
disk, which is punched from the endothelial side, can be helpful for certain trephine systems (e.g.,
tends to be smaller than the trephine diameter, Hessburg-Barron trephine, GTS after Krumeich).
which has a corresponding effect on the spherical
equivalent [21, 82]. For this reason, donor over- Keratoconus
sizing of 0.250.50 mm is usually carried out in In keratoconus, a large (typically 8.0 mm) central
this situation. This is performed on the one hand circular keratoplasty is indicated as soon as hard
to prevent the flattening of the graft and on the oxygen-permeable contact lenses are no longer
other hand to prevent narrowing of the iridocor- tolerated. If nonmechanical excimer laser trephi-
neal angle where there is a predisposition to sec- nation is used, corneas which are extremely steep
ondary glaucoma [24, 46]. In contrast, no before keratoplasty do not have worse prognosis
oversizing is required with the use of guided than those which are less deformed [84].
6 The Penetrating Keratoplasty (PKP): A Century of Success 75
Suture Technique
The type of trephination has a major impact on
the correct placement of the first four or eight
cardinal sutures [45, 63]. The main purposes of
these cardinal sutures include:
Fig. 6.5 In case of keratoconus it has been recommended applanation during trephination applies in femtosecond
not to use an obturator in order to avoid elliptical or laser application (Courtesy of Professor Herbert Kaufman)
pear-shaped excision shapes. The same principle of
76 B. Seitz et al.
a
Method of excimer laser trephination
Photoablation
Photoablation
Donor mask Recipient
mask
Donor Recipient
b c
Fig. 6.7 (a) Principle of excimer laser trephination in the before donor trephination with the excimer laser. (f)
donor and recipient (schematic sketch, sagittal view). (b) Side view of a very prominent keratoconus immediately
Donor mask (8.1 mm in diameter) with eight orientation before trephination. (g) During host trephination with the
teeth on the outside lying directly on the corneoscleral excimer laser, the metal recipient mask (8.0 mm in diame-
disk in the artificial anterior chamber. The laser is guided ter) is well centered around the cone without deformation.
along the outer edge. (c) Pseudo-ring-shaped automated The laser is guided along the inner edge of the mask. (h)
Schwind AMARIS excimer laser ablation profile along Schematic sagittal view of the cone protruding through the
the outer edge of a donor mask on a corneoscleral disk central hole of the metal recipient mask allowing a trephi-
in an artificial anterior chamber. (d) Donor trephination nation without deformation. (i) Exact positioning of the
immediately before penetration with smooth cut edges and second cardinal suture in penetrating excimer keratoplasty
orientation teeth (arrows; macroscopy). (e) Histology of through the use of a small tooth and a corresponding notch
straight, almost perpendicular incision edges immediately to prevent horizontal torsion (intraoperatively)
78 B. Seitz et al.
d e
h i
here also with regard to prion-caused optical quality of the graft than various suture
contagious diseases. techniques or methods of subsequent suture
adjustments, the technique of nonmechanical
Nonmechanical Excimer Laser corneal trephination has been developed and
Trephination (Fig. 6.7a, b) optimized in Erlangen since 1986 [41].
Under the hypothesis that the characteristics of Originally, the elliptical shape was proposed on
the wound bed are considerably more important the basis of the idea that an elliptical graft could
for the astigmatism after suture removal and the best be fitted to the natural elliptical human
6 The Penetrating Keratoplasty (PKP): A Century of Success 79
cornea, both from the optical and the immuno- pressure within the artificial anterior chamber is
logical perspective [28]. Prof. G.K. Lang pub- adjusted to approximately 22 mmHg using
lished details of the first two patients after Maklakoff tonometer [2].
elliptical keratoplasty in 1990 [29]. A total of 42 For recipient trephination which is performed
elliptical keratoplasties were performed in clinically with the manually or automated
humans from 1989 to 1991 [75]. Subsequently, guided laser beam, a corresponding recipient
this method was abandoned for optical reasons, mask is used (diameter 12.9 mm, central open-
because the need for simple interrupted sutures ing 5.58.5 mm, 8 orientation notches).
to prevent rotation of the graft in the recipient Before the start of trephination, centering rela-
bed and the need for asymmetrical suture tension tive to the limbus is achieved through the asso-
in these multiple interrupted sutures had ulti- ciation of the eight notches in the mask with the
mately not resulted in improved curvature, nei- eight linear marks of a blue-stained radial kera-
ther with nor without sutures [76]. Today, we still totomy marker which has been previously
use elliptical excimer laser keratoplasty for ellip- applied under microscopic control (Fig. 6.7fh).
tical ulcers with descemetoceles or penetration
for the purposes of keratoplasty chaud (a typi- Advantages of Nonmechanical Trephination
cal example of elliptical ulceration would be The main advantage of this excimer laser cutting
acanthamoeba keratitis) or pellucid marginal method, which is performed from the epithelial
degeneration with eccentric thinning of the cor- side in donor and recipient, is the avoidance of
nea at the bottom close to the limbus [27]. mechanical distortions during trephination
Since July 01, 1989, more than 4,000 eyes (Table 6.3). This results in smooth cut edges
have been successfully operated in Erlangen and which are congruent in both the donor and recipi-
Homburg/Saar with the MEL70 excimer laser ent, so that the vertical tilt is reduced [32].
made by Zeiss Meditec and, recently, with the Orientation teeth on the edge of the graft [4]
AMARIS excimer laser made by Schwind
(Fig. 6.7c).
Table 6.3 Advantages of nonmechanical trephination
with the 193 nm excimer laser along metal masks with
orientation teeth
With a share of approximately one third,
1. No trauma to intraocular tissues
keratoconus has always been by far the
2. Prevention of deformation and compression of the
most common indication for PKP with this tissue during trephination
non-contact excimer laser technique. 3. Reduction of horizontal torsion (orientation
teeth)
4. Reduction of vertical tilt (almost perfect
congruent incision edges)
Technique Before trephination, the limbus is 5. Improvement of recipient and donor centration
centered along the vertical helium-neon target 6. Possibility of harmonization of donor and
beam in the donor and patient in order to ensure a recipient topography
reproducible position to the laser beam and there- 7. Reduction of anterior chamber inflammation after
fore symmetrical cutting angles in the entire keratoplasty
circumference. 8. Reduction of astigmatism after suture removal
For donor trephination from the epithelial 9. Increase in the regularity of the topography of the
cornea
side, a round open metal mask (diameter 5.6
10. Significantly better spectacle-corrected visual
8.6 mm, central opening 3.0 mm for centering,
acuity
thickness 0.5 mm, weight 0.2 g, 8 orientation 11. Feasibility of trephination of an instable cornea
teeth) is placed on a corneoscleral disk (16 mm) (e.g., open eye, descemetocele, status post-radial
which is fixed in an artificial anterior chamber keratotomy, iatrogenic keratectasia after LASIK). Any
under microscopic control (Fig. 6.7be). The shape possible (e.g., elliptical)
80 B. Seitz et al.
and corresponding notches in the edge of the keratoconus) are avoided, so that a latent
recipient for undoubted symmetrical positioning watertight closure is often achieved after just
of the first eight cardinal sutures reduce the four cardinal sutures.
horizontal torsion (Fig. 6.7i). In this way it is During the subsequent suturing procedure, the
possible to improve the optical quality after anterior chamber remains largely stable as a
transplantation. Furthermore, donor and recipient rule.
centration is improved [31, 53]. These beneficial The final double-continuous suture only has to
influences on the main intraoperative determi- be tightened to a very slight extent in order to
nants of astigmatism after keratoplasty (Table 6.2) maintain an anterior-step-free wound adjust-
result in lower keratometric net astigmatism, ment and watertight wound closure even
higher topographic regularity, and improved after the removal of the eight cardinal sutures.
spectacle-corrected visual acuity after suture For this reason, additional interrupted sutures
removal [50, 51, 74]. with an unfavorable effect on the graft topog-
In addition to less disruption to the blood- raphy are needed only very rarely at the end of
aqueous barrier in the early phase after kerato- surgery.
plasty [26], the laser trephination does not result Furthermore, the so-called barrel-top forma-
either in increased cataract formation [5] or tion at the proximal ends of the sutures, which
higher endothelial cell loss of the graft [56]. In result in a relative cornea plana and, therefore,
addition, the frequencies of the immunological delayed optical rehabilitation, is largely
graft reaction [55] and secondary ocular hyper- avoided.
tension were comparable in both techniques [57]. After removal of the eyelid speculum and the
The use of metal masks allows an arbitrary treph- fixation sutures, the use of a Placido disk after
ination technique [75, 76]. Moreover, the use of intraoperative suture adjustment often pro-
the laser allows the trephination of an instable vides a round projection image.
cornea, such as in a perforated corneal ulcers (or
descemetoceles) or after radial keratotomy or in
iatrogenic keratectasia after laser in situ ker- Nonmechanical trephination using the
atomileusis LASIK [27, 59, 60]. 193 nm excimer laser along metal masks
has significantly improved the results of
Practical Considerations for the Microsurgeon penetrating keratoplasty after suture
The somewhat longer trephination time (around removal. The use of the excimer laser also
90 s with the Schwind laser) is largely compen- allows controlled trephination of instable
sated for by the practical advantages for the corneas, such as in perforated ulcers or iat-
microsurgeon during the subsequent course of rogenic keratectasia after LASIK.
the surgery [41, 42, 51, 60, 66, 74]:
we do not perforate the patients cornea. If the in 2005 in order to achieve a watertight wound
big bubble is successfully achieved and we can closure [8, 62].
bare Descemets membrane without perforat-
ing we terminate the operation as DALK. If this The Fundamental Problem
does not succeed to our satisfaction, the opera- of Femtosecond Laser Trephination
tion can be completed as excimer laser PKP with Over the last 10 years, femtosecond laser kerato-
all of the advantages described above without any plasty has caused a good deal of excitement. The
disadvantage for the patient. Primum nil advantages of femtosecond laser keratoplasty are
nocere. the arbitrary horizontal and vertical shapes,
including the top-hat, mushroom, zigzag,
Femtosecond Laser Trephination Christmas tree, octagon, decagon, dove-
for PKP tail, etc. [3, 16]. The fundamental problem of
The femtosecond laser (FSL) operates at a wave- every femtosecond laser trephination is that
length of about 1 m (infrared) and the excimer even with a curved interface a certain amount
laser at 193 nm (UV). The cornea is transparent of flattening of the cornea is necessary, which is
to the FSL. The excimer laser is absorbed by the associated with deformation. In advanced kerato-
cornea. The pulse duration of the excimer laser is conus in particular, this results in noncircular
a few nanoseconds, whereas that of the FSL is a excisions in the patients cornea and, therefore,
few 100 femtoseconds. The repetition rate of the horizontal torsion as the main intraoperative
excimer laser today reaches up to 1000 Hz and in determinant of high/irregular astigmatism after
the FSL within the range of several kHertz. The PKP [52].
energy density of the excimer laser fluctuates In regular trephination during keratoplasty,
between 150 and 400 mJ/cm2, and that of the FSL maximum intraocular pressure values of
between 1 and 10 J/cm2. The pulse size of the 135 mmHg are measured with the IntraLase,
excimer laser fluctuates between 0.6 and 6 mm, 65 mmHg with the VisuMAX, 205 mmHg with
whereas in the FSL it is a few micrometers. The the Femtec and 184 mmHg with the Femto LDV
tissue interaction of the excimer laser is based on in experimental use [83]. Furthermore, in
direct photoablation, while the tissue interaction advanced keratoconus in particular, applanation
of the FSL is plasma mediated. results in noncircular (often oval or pear-
shaped) apertures in the patients cornea and
therefore horizontal torsion as the main intraop-
The principal advantages of the femtosec- erative determinant of high/irregular astigmatism
ond laser use are that no masks are needed after PKP. The eight lines which are applied, for
and that no tissue loss and no thermal example, for the IntraLase femtosecond laser, in
effects occur. the donor and recipient cannot be brought into
alignment sometimes intraoperatively in the
treatment of keratoconus.
In contrast to the excimer laser, which only Some authors claimed that femtosecond laser
allows surface ablation, with the femtosecond PKP has advantages in the short-term follow-up
laser (a femtosecond corresponds to 1015 s), it is concerning refractive cylinder and visual acuity
also possible to cut the cornea within the stroma, [3, 14, 23, 35]. However, there is a large amount
so that actual three-dimensional cuts without of missing data with respect to the potential
opening the eye and without thermal damage are advantages of femtosecond laser keratoplasty
possible. With real 3-D sections, it may be pos- after complete suture removal. Only few groups
sible to achieve self-sealing wounds. Based on have published results pertaining to the situation
the publication by Massimo Busin in 2003, we after complete suture removal [7, 9]. After a
proposed the inverse mushroom (now com- mean follow-up of 14 5 months, the topographic
monly referred to as the top hat configuration) astigmatism without sutures in the mushroom
82 B. Seitz et al.
profile was 6.4 3.0 dpt, and in the top hat profile
5.8 4.6 dpt [7]. The degree of the astigmatism Keratometric or topographic astigma-
after femtosecond PKP is therefore comparable tism (not only refractive manifest
with that after motor trephination (now with- cylinder!)
drawn from the market [51, 74]). Moreover, in Measure of the topographic regularity
the mushroom profile, the rate of the postopera- (e.g., SRI (surface regularity index) or
tive immune reactions is significantly increased SAI (surface asymmetry index) of the
[79]. TMS system and ISV (index of surface
FSL keratoplasty has been very interesting, variance) or IVA (index of vertical
but no prospective randomized study has so far asymmetry) of the Pentacam), in each
been carried out in which both trephination pro- case before and after suture removal
cedures (FSL and excimer laser) for PKP in kera-
toconus and Fuchs dystrophy have been
compared to each other. Such a study has just Summary
been finished in Homburg/Saar [13]. With FSL-
PKP in keratoconus using a double-running Donor and recipient trephination should be per-
suture, we found more decentration, more vis formed with the same system from the epithelial
tergo, and more often the need of single sutures side. The horizontal position of the limbus plane
to achieve donor-host apposition without steps is essential. The graft size should be adapted indi-
and gaps. After suture removal, topographic vidually to the cornea size (as large as possible,
astigmatism after FSL trephination in keratoconus as small as necessary) and limbal centration pre-
(6.8 3.1 D) was significantly larger that after ferred to pupil centration in cases of doubt (espe-
excimer laser trephination (2.5 1.4 D). In addi- cially with keratoconus). Furthermore, excessive
tion, the surface regularity index (SRI) of the graft over- or undersizing should be avoided. At
TMS-5 system in keratoconus was significantly
unfavorable after FSL trephination (0.8 0.3)
Table 6.4 True benefits comparing excimer laser versus
than after excimer laser trephination (0.5 0.4).
femtosecond laser trephination practical considerations
Best spectacle corrected visual acuity after suture (+ + + = very favorable, = very unfavorable)
removal in keratoconus was 0.8 0.2 after
Cumbersome procedure +
excimer laser and 0.7 0.2 after FSL laser trephi-
Centration +++ +
nation [13]. Avoid deformation and compression +++
Certainly manifest cylinder is not appropri- of tissue during trephination
ate to compare the outcome of different trephina- High IOP during laser action +++
tion procedures for PKP [35]. In case of a highly Minimizing amount of completion of (+) ++
irregular surface, the manifest cylinder will be incision by scissors
zero although the benefit for the patient is nil Location of first 8 cardinal sutures +++ ++
[58]. True benefits of excimer laser versus femto- unequivocally given
second laser trephination for PKP are summa- Stable anterior chamber during ++ +++
suturing
rized in Table 6.4.
Feasibility of double-running suture +++ +++
No need for additional single sutures + + + +
Feasibility of trephination with +++
On principle, the minimal requirements for instable cornea
comparative studies on various trephina- Feasibility of trephination in repeat +++
tion techniques in PKP are: keratoplasty
Helpful for DALK ++ ++
Visual acuity with spectacle correction Potential for DSAEK (donor/ +
(not contact lens acuity!) and central recipient)
refracting power (But: suboptimal stromal surface quality!)
Immune reactions +
6 The Penetrating Keratoplasty (PKP): A Century of Success 83
the end of the operation, adjustment of the con- Prevention of early postoperative
tinuous cross-stitch suture should be carried out complications
using a Placido disk. Nonmechanical excimer laser Prevention of late complications after
trephination results in lower astigmatism, higher keratoplasty
topographic regularity, and better visual acuity
(especially in younger patients with keratoconus). Besides these aspects the adequate preopera-
In the case of an unstable cornea (e.g., after RK, iat- tive preparation and selection of donor tissue are
rogenic keratectasia after LASIK, descemetocele, of utmost importance for the outcome the PKP.
perforated ulcer), trephination by laser application
is possible. New keylock variants for the pos-
sible self-sealing fit of the donor disk in the recipi- Preoperative Prevention
ent bed were looming on the horizon 10 years ago of Complications
(future no-stitch keratoplasty) after introduction
of femtosecond laser application. However, recent Assessing Phototherapeutic
all-suture-out data demonstrate that the potential Keratectomy or Lamellar Techniques
superiority of this high price and difficult to main- as an Alternative
tain option cannot be proven! Thus, today the fem- At all events, an examination should be carried
tosecond laser application for PKP must be called out to determine whether superficial avascular
the excitement of yesterday. corneal opacities, e.g., in granular dystrophy or
Salzmanns nodular degeneration, cannot be
treated by means of excimer laser phototherapeu-
Conclusions tic keratectomy (PTK), so that corneal transplan-
tation can be avoided [12].
Today, the expectations with regard to the results Furthermore, consideration should also be
after PKP are limited not only to the achievement given in all cases today to whether anterior
of a clear graft. The only criterion that matters to (DALK) or posterior lamellar keratoplasty
the patient is good visual acuity, preferably with- (DSAEK or DMEK) is feasible in order to mini-
out contact lenses, but with a well-tolerated pair mize the risk of expulsive hemorrhage during the
of spectacles. For this reason, transplant micro- open-sky period of PKP [69].
surgeons should not only respect all options for
preventing high or irregular astigmatism after Recognizing and Treating Underlying
keratoplasty. Due to the fact that it is never pos- System Diseases and Eyelid
sible to foresee the refractive outcome in an indi- Abnormalities
vidual patient after keratoplasty, surgeons should As a matter of principle, systemic underlying dis-
also be familiar with the surgical procedures for eases, in which problems with the surface of the
correcting refraction errors after PKP (especially eye are very common, must be identified and
in high astigmatism) in order to achieve the best consistently treated before PKP. These include,
individual result for the patient. among others, neurodermitis, rosacea, primary
chronic polyarthritis, alcoholism, liver diseases,
and diabetes mellitus.
Prophylaxis and Management In cases of very severe neurodermitis, consid-
of Complications eration should be given as to whether cyclosporine
A oral can be administered at a dosage of 150 mg
Complications in keratoplasty can be divided up twice a day for 4 weeks before PKP. Conventional
into immunological and optical. eyelid margin hygiene and a dermatological con-
This chapter is structured as follows [67]: sultation are indispensable before PKP. Both drug
therapy for existing blepharitis and the surgical
Preoperative prevention of complications correction of eyelid malpositions (e.g., entropion
Prevention of intraoperative complications with trichiasis) must be carried out before PKP.
84 B. Seitz et al.
In cases of severe limbal stem cell insuffi- ulcerative keratitis. It is well known that the risk
ciency (such as in congenital aniridia), a limbal of immune reactions, epithelial healing disorders,
transplant might better be carried out before PKP and the rate of suture loosening are increased
[70]. after emergency keratoplasty. Here we prefer an
amniotic membrane transplantation AMT (typi-
No Keratoplasty if the Intraocular cally referred to as multi-graft sandwich) [64]
Pressure Is Not Controlled in order to achieve a reduction in the symptoms
of inflammation and the acceleration of epithelial
healing. Instead of emergency keratoplasty in the
General rule: Keratoplasty must not be highly inflamed eye, we plan elective kerato-
performed if the intraocular pressure is not plasty in the non-inflamed eye after 36 months.
controlled. This improves the graft prognosis, not least
because of the possibility of selecting an opti-
mum donor cornea [19].
A pressure of 20 mmHg under 3 topical anti-
glaucoma agents cannot be considered as con- Quality-Assured Grafts from Organ
trolled! Here it should be borne in mind that the Culture
validity of the indirect methods (including Quality-assured donor corneas from organ
Goldmann applanation tonometry) is doubtful. culture are widely used in Europe today. This
Despite a thickened cornea, the intraocular pres- includes not only microbiological and sero-
sure is often measured as being too low in bullous logical analyses of the donor blood and culture
keratopathy. Here, direct intracameral needle medium but also an examination of the corneas
pressure measurement can be an alternative using the slit lamp to detect scars, endothe-
approach [37]. Predisposing factors for second- lial damage, or other abnormalities. In accor-
ary ocular hypertension after keratoplasty are dance with the guidelines of the European Eye
preexisting glaucoma, pseudoexfoliation syn- Bank Association EEBA, only corneas with an
drome, aphakia, scars after a penetrating injury, endothelial cell density of at least 2,000 cells/
persistent anterior synechiae, and simultaneous mm2 as assessed by phase contrast micros-
artificial lens replacement, especially in the case copy are transplanted. Anterior-segment OCT
of anterior chamber lens removal and secondary methods are currently being developed which
scleral-fixated posterior chamber lens implanta- can ensure during the organ culture stage that
tion and simultaneous vitrectomy [24, 57]. the cornea concerned has not undergone any
refractive surgical intervention or suffers from
Pretreatment of Vascularized Corneas keratoconus.
In principle, anti-VEGF drugs can be applied
topically as drops or as a subconjunctival injec- Individually Optimized Graft Size
tion prior to keratoplasty in order to reduce cor- As a matter of principle, an individually opti-
neal neovascularizations. With a sizeable singular mized graft size should be selected for each kera-
vessel, which typically occurs with a vascular- toplasty. The graft size is determined
ized disciform corneal scar of herpetic origin, preoperatively for each individual, e.g., using a
fine-needle diathermy as first proposed by the slit lamp with a measuring device. Each graft
working group under Dua may be successful at should be as large as possible (for optical rea-
limiting intraoperative hemorrhaging [25]. sons) and as small as necessary (for immunologi-
cal reasons). In keratoconus, grafts of 8.08.5 mm
Amniotic Membrane Transplantation are ideal, whereas in the case of Fuchs dystro-
AMT Before Penetrating Keratoplasty phy with typically smaller and more elliptical
in Ulcerative Keratitis corneal dimensions, a 7.5 mm graft is often suit-
If possible, emergency keratoplasty ( chaud) able if this eye is not eligible for DMEK or
should not be carried out today in the case of DSAEK [54, 58, 63].
6 The Penetrating Keratoplasty (PKP): A Century of Success 85
No Keratoplasty in the Acute Stage The risk and symptoms of suture loosening
of Keratoconus The risk of epithelial defects with a risk of
PKP in the acute phase of keratoconus (the so- infection
called corneal hydrops) should be avoided Hypesthesia of the graft over several years
because postoperatively this often results in
suture loosening with corresponding adverse For this reason, glasses with side protection
consequences such as infectious infiltration and should be worn postoperatively for several
neovascularization. The fear of the doctor and months. The briefing before the operation
patient of perforation is largely unjustified in includes the instruction that if the patient experi-
acute keratoconus! Smoothing and hyperosmolar ences red eye, tears, pain, or blurred vision, he
drops are administered, with the PKP then being or she should immediately seek medical atten-
performed successfully between 3 and 6 months tion. This personal briefing by the surgeon on the
after wound healing and scar formation is com- evening before surgery and also before dismis-
plete [60]. Certainly, in these eyes with ruptured sion contributes toward ensuring patient compli-
Descemets membranes, DALK is not advisable ance and the long-term success of the operation!
(Fig. 6.8)!
result. General anesthesia has safety advantages topographic regularity, earlier visual rehabilita-
over local anesthesia, especially in young kerato- tion, and a lower rate of suture loosening [22]. All
conus patients. The arterial blood pressure should knots are buried in the stroma to avoid mechani-
be kept as low as possible when the eye is open cal irritation and the attraction of neovasculariza-
(controlled arterial hypotension with maxi- tion. We aim to produce deep lamellar
mum relaxation). In children, consideration pre-descemetal stitches. Typically, Descemets
should be given to the preoperative intravenous membrane should be pushed forward as a triangle
administration of acetazolamide and mannitol. In in front of the tip of the needle (wave of
every case the anesthetist should have been Descemets). In all diseases with defects in the
trained in the specific aspects of penetrating Bowmans layer or where there is a risk of melt-
keratoplasty before a large opening is made in the ing, we use multiple interrupted sutures (typi-
eye ball especially in children [68]. cally 24 in number), in order to avoid the need for
Typically, the pupil is constricted with pilocar- the postoperative replacement of sutures if some
pine in order to protect the lens of the phakic eye. become loose.
Horizontal positioning of the head and limbal Intraoperative keratoscopy using a handheld
plane is an indispensable precondition for the Placido disk with adjustment of the continuous
avoidance of decentration, vertical tilt, and sutures or replacement of too tight interrupted
horizontal torsion. Paracentesis at the limbus is sutures should be performed after the lid specu-
recommended before trephination. In aphakic lum and cardinal sutures have been removed [6].
vitrectomized eyes, the transconjunctival attach-
ment by suturing (e.g., with 8-0 Vicryl sutures) of Special Aspects in Case
a Flieringa ring to stabilize the open globe is rec- of Acanthamoeba Keratitis
ommended [43]. In cases of doubt, limbal centra- Approximately 1 week before PKP (in the sub-
tion should be preferred over pupil centration acute stage), photodynamic therapy (PDT) is a
(the optical displacement of the pupil must be potential method that is available today for an
taken into consideration, especially in keratoco- attempt to reduce the load of acanthamoeba.
nus). A peripheral iridotomy at 12 clock serves as Typically, the clinical application of PDT is per-
prophylaxis of a so-called Urrets-Zavalia syn- formed today as riboflavin/UVA cross-linking
drome [80] (Fig. 6.9). [77]. Simultaneously with excimer laser PKP,
As long as Bowmans layer is intact, a double- corneal cryocoagulation (freezing-thawing-
running cross-stitch suture according to freezing) is always performed intraoperatively
Hoffmann is preferred, since it results in higher (before the opening of the globe!) [78]. In cases
of elliptical corneal ulcers, we use elliptical
excimer laser trephination with the aid of a metal
mask [27, 75]. After acanthamoeba kerato-
plasty, we currently carry out treatment in the
form of dual therapy with Brolene and Lavasept,
tapering off for approximately 1 year.
Ophthalmology should be carried out in a spe- removed in the case of a double-running cross-
cialized cornea/keratoplasty outpatient service, stitch after 6 weeks without having to replace
every 3 months if possible, until the removal of sutures.
the last sutures. Standard aspects of keratoplasty If ocular hypertension is present during the
follow-up include: subsequent course after keratoplasty [57], we ini-
tially consider the steroid response, which occurs
History in about 15 % of patients. Postoperative pressure
Slit lamp biomicroscopy with fluorescein/blue increases must be treated aggressively with medi-
light cation (including carbachol in the case of pseu-
Subjective/objective refractometry dophakic eyes) or preferably with cyclodestructive
Sc/cc visual acuity methods (e.g., cyclophotocoagulation) because
Keratometry long-term hypotension often leads to an immune
Topography analysis reaction after a filtering operation. In terms of
Endothelial cell analysis (quantitative and drugs, we avoid prostaglandin analogues in
qualitative) underlying herpetic disease and topical acetazol-
Pachymetry amide if the endothelium is borderline.
Intraocular pressure For the treatment of surface problems, the
options available include not only unpreserved
Using fluorescein/blue light it is possible to artificial tears and soothing gels or ointments
accurately determine whether the suture is tight, (with/without a pressure bandage), vitamin A,
whether leakage is occurring (Seidel positive), and hyaluronic acid (without phosphate!) but
and whether erosion or an infiltrate is present. also the application of 100 % autologous serum
Furthermore, using the slit lamp at maximum drops. In persistent epithelial defects, single or
magnification, an examination is carried out with multilayer amniotic membrane transplantation,
respect to retrocorneal precipitates, cells/Tyndall temporary (lateral) tarsorrhaphy, or botulinum
in the anterior chamber, and the presence of a toxin injection may be indicated for the tempo-
focal epithelial or stromal edema of the graft as rary induction of ptosis (natural bandage).
an early sign of an immunological graft reaction. In cases of primary graft insufficiency (i.e.,
After 3 months we routinely carry out gonios- the graft is not clear at any time after PKP), the
copy in order to be sure that no anterior synechiae aim should be to replace the graft at an early
are present. stage, i.e., after not more than 6 weeks. Here, if
Typically, topical steroids (e.g., prednisolone the donor tissue has been documented as good at
acetate 1 % AT) are initially tapered 5 times a day the cornea bank and the surgical technique is
for 69 months. In aphakic or pseudophakic eyes, uncomplicated, it is always important to consider
we recommend one drop of prednisolone acetate a latent herpes simplex virus infection of the graft
lifelong [44]. as the cause [72].
We remove the first of the two running sutures In underlying herpetic disease, pretreatment is
after 1 year and the second running suture after carried out with topical/systemic acyclovir and
18 months. After epithelial closure following steroids. Postoperatively, systemic acyclovir is
suture removal, we resume use of the steroids prescribed for at least 1 year at a dosage of
over 6 weeks, tapering them from 5 times a day in 400 mg twice a day (initially 5 times 400 mg for
order to prevent immune reactions. Earlier suture 6 weeks), in zoster 800 mg twice a day for the
removal is carried out for every (!) loose suture, prevention of relapse [65, 66]. In vascularized
infiltrate, and progressive neovascularization herpetic scars, a combination therapy with 1 g of
along a suture, but not necessarily in subepithe- mycophenolate mofetil twice a day for one year
lial fibrosis or intra-epithelial pseudocyst forma- should be considered [38]. After keratoplasty, no
tion at the proximal suture ends [67]. Experience steroids should be administered without acyclo-
has shown that a loose, continuous suture can be vir protection. Long-term therapy with acyclovir
88 B. Seitz et al.
ointment once a day at night immediately along a density gradient from the graft to the host
before bedtime is considered. We always treat cornea [34, 47].
supposed graft reactions, in which the differential Even after several years, an immunological
diagnosis of herpes recurrence can hardly ever be graft reaction can occur [44, 79]. This may be
confirmed clinically, with a combination of topi- epithelial, stromal, or endothelial. Typical of the
cal/systemic steroids and acyclovir [65, 66]. so-called chronic stromal immune reaction are
nummuli-like, fine subepithelial infiltrates such
as in epidemic keratoconjunctivitis. However, in
Late Postoperative Complications the immune reaction these are restricted to the
transplant. The stromal immune reaction may
Predisposing factors for late suture loosening are also occur in a peracute manner in the form of a
defects in the Bowmans layer, stromal vascular- graft abscess without hypopyon. However, the
ization, underlying rheumatic disease, a single most common immunological graft reactions are
continuous suture, keratoplasty in children (26 endothelial, either acutely diffuse (here the graft
34 %) [68], and acute keratoconus (the so-called becomes completely cloudy) or chronically focal
corneal hydrops). (in these cases a so-called Khodadoust line
spreads from one edge of the graft typically
with the occurrence of neovascularization like
Each loose corneal suture must be removed wildfire over the whole graft to the opposite edge
as soon as possible. of the graft). In the case of an immune reaction,
the patient must be treated immediately with
local high doses of prednisolone acetate every
If a suture infiltrate is present, the suture is half hour. An intracameral Fortecortin injection
removed immediately and typically treated has proven successful. Typically, we also admin-
topically with antibiotics and systemically with ister systemic steroids (e.g., 250 mg of Solu-
steroids. Decortin H initially).
Predisposing factors for step formation in
addition to trauma are premature suture removal
(especially in elderly female patients with bul- The ophthalmologist in private practice
lous keratopathy). Here, the first suture should should arrange an immediate follow-up
never be removed before 1 year has passed. In appointment for a keratoplasty patient who
trauma, the steps typically appear to occur infero- calls in with problems.
nasally and after suture removal
inferotemporally.
Experience has shown that preexisting corneal
neovascularizations tend to regress on the host Conclusions for Clinical Practice
cornea in the case of underlying herpetic disease
with appropriate therapy after PKP. In contrast, In addition to the situation-specific diagnosis
new vessels typically grow again on the graft in and preoperative planning, the critical selec-
the host tissue in the case of limbal stem cell tion of the donor tissue, and the minimally
insufficiency [1]. invasive microsurgical technique, it is espe-
The so-called idiopathic endothelial cell loss cially the indication-dependent close-meshed
after PKP in keratoconus is significantly lower in follow-up which plays an important role in the
keratoconus than in Fuchs dystrophy and again long-term success of penetrating keratoplasty.
lower than in corneal endothelium epithelial In the follow-up process, the repeated
decompensation (the so-called bullous keratopa- emphatic sensitization of the patient to alarm-
thy). We attribute this to endothelial cell migration ing subjective symptoms and the informed
6 The Penetrating Keratoplasty (PKP): A Century of Success 89
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Immunology of Keratoplasty
7
Daniel Bhringer and Thomas Reinhard
Abstract
This is an overview of the current understanding of the pathomechanisms
in graft rejection after keratoplasty. We discuss the experimental data on
allorecognition and ACAID. We cover tissue typing of the human leuko-
cyte antigen system and selected minor antigens. We give an overview of
the clinical evidence in this field. The chapter ends with a recommendation
on the best clinical practices with respect to tissue typing in keratoplasty.
Keywords
ACAID Immune reaction Allorecognition HLA MHC Matching
HLAMatchmaker Antibody Minor antigens Histocompatibility
into the outer cell membrane of an APC. APCs restriction and has its roots in thymic T-cell
loaded in such a way migrate to the regional development [2].
lymph nodes or the spleen. Here, they can acti-
vate lurking donor-specific T lymphocytes Direct vs. Indirect Allorecognition
which clonally expand and fan out into the in the Clinical Setting
periphery [42]. Alternatively, the APCs stay Both anatomical properties and morphologic
within the anterior chamber. There, the specific appearance of graft rejections differ vastly
milieu of the aqueous humor the APCs favors between the rodent models and the human situa-
generation of allospecific regulatory T cells tion, e.g., the anterior chamber is much shallower
(Tregs). These Tregs are thought to be the major in mice than in humans. This brings the graft into
structural correlate of ACAID as they promote a closer proximity to the iris vasculature.
longlasting anergy against their specific anti- Furthermore, in humans the opacity from graft
gens [14]. Allospecific Tregs and effector lym- rejection is mostly due to stromal edema, whereas
phocytes are thought to constantly counteract in mice the opacity is due to cellular infiltrates.
each other until activated effector lymphocytes Therefore, the data from the mouse model are
eventually reach the graft. Here, they conduct an most likely not directly applicable to the clinical
inflammatory graft rejection by activating and situation. The direct pathway may thus still play
recruiting other players of the innate and a rather significant role in humans despite the
adaptive immune system [30]. negative evidence from animal models. In
humans, experimental insights into graft rejec-
Direct vs. Indirect Allorecognition tion are ruled out by ethical concerns. However,
in the Mouse Model organ culture and the recent rise of lamellar graft-
Current evidence suggests that donor antigens ing incidentally shed some light on allorecogni-
presented indirectly in the context of own tion in humans.
MHC are the major trigger for graft rejections in
a mouse keratoplasty model [21]. This mecha- Clinical Clues Toward Direct
nism (as detailed in the previous section) is Allorecognition
known as indirect allorecognition. In indirect Direct allorecognition has two premises: firstly
allorecognition, antigens are randomly picked APCs have to be located in the graft in the first
out of the donor tissue by means of lysosomal place. Secondly, APCs need to be able to migrate
fragmentation inside the APCs. However, the out of the graft and reach the lymphatic organs
corneal graft comprises only a small percentage intact. Both premises are actually supported by
of MHC molecules. This renders indirectly pre- histopathology and clinical observations [27].
sented donor MHC fragments subordinate for APCs have been demonstrated in the graft epithe-
stochastic reasons. Consequently, matching lium as well as in the graft stroma [4]. Tissue
MHC alleles (namely, HLA matching, HLA is density of APCs reduces during graft storage.
the name for MHC in humans) would be of lim- Interestingly, long storage intervals have been
ited value in preventing indirect allorecognition. reported to be protective toward immune reac-
Actually, MHC matching has been demonstrated tions [36]. This points toward graft APCs actively
ineffective in the mouse model [37]. migrating into the lymphatics and promoting
MHC matching would be of larger impact if alloreactions there. Furthermore, it came to a sur-
functioning donor-derived APCs could interact prise that immune reactions are only rarely
with recipient leukocytes directly. This is known observed after Descemet membrane endothelial
as direct allorecognition. Here, intact donor keratoplasty (DMEK) [1]. These grafts comprise
MHC class II molecules talk to T-cell receptors only of endothelium and Descemet membrane.
on recipient leukocytes. This crosstalk is postered Graft APCs are therefore not present. On the
by similarities between donor and recipient MHC other hand, the target antigens on the endothe-
overlap. This phenomenon is known as MHC lium do not differ much from penetrating kerato-
7 Immunology of Keratoplasty 95
plasty. Both observations are supporting the assays. These can detect up to 100 unique alleles
hypothesis that graft APCs play an important role at once. The HLA allele naming is somehow con-
in eliciting graft reactions in humans. fusing because broads and splits share the
same number range in the nomenclature. Higher
numbers had been sequentially assigned to the
Tissue Typing newly discovered alleles without removing the
broad equivalents. The polymerase chain reaction
Major Histocompatibility Antigens (PCR) enabled the typing of truly distinct alleles.
(HLA) The accuracy and precision of the molecular typ-
The HLA system plays an outstanding role in ing increased the number of known HLA alleles
eliciting graft rejections, i.e., when direct vastly. In the current star notation, each allele is
allorecognition is involved. This genetic complex a distinct colon segmented number [26]. However,
is located on chromosome six. The proteins from the lower resolution splits or the original broads
this complex are subdivided into three classes are still in clinical use and can be inferred from
[25]. Only class I and class II are directly relevant the star notation. For example, the HLA class II
to transplantation immunology, though. Class I broad antigen HLA DR3 can be split into DR17
molecules are located on the membrane of all and DR18. These in turn can be subdivided into
nucleated cells. They comprise of a heavy and a the alleles DRB1 03:02 and DRB1 03:03. The
light chain (b2 microglobuline). Class I mole- molecular methods are essential for typing cor-
cules can embed an antigen peptide of nine amino neal donors. These pose a special challenge to
acid residues. The major class I loci are A and serologic HLA typing because the blood sample
B. Further loci are C, E, F, G, K, and L. These are may be collected up to 72 h after onset of clini-
either strongly genetically linked to the A/B hap- cal death. This limits the detection of cell-bound
lotypes or not much polymorphic. For this rea- antigens by antibodies because the cell mem-
son, only the A and B loci are commonly branes suffer from incremental autolytic damage.
considered in HLA matching in solid organ trans- Therefore, some alleles are prone to be falsely not
plantation. Class II molecules are located mostly detected or to cross-react with other alleles. This
on the membrane of APCs. These present pep- has actually been an issue in the past [20].
tides of 1224 amino acid residues cleaved from
external antigens. The locus DR is of particular HLA Matching
importance to transplantation immunology. The HLA pool is highly variable in any given
Further important loci are DP, DR, DM, and DO. population. More than 100 alleles have been
documented at each HLA locus. This results in
HLA Typing and Nomenclature millions of possible HLA phenotypes. However,
HLA typing was originally based on complement- HLA alleles are inherited in haplotypes. This
dependent cytolysis. Here, the cells to be typed means fixed combinations of alleles on the loci
are incubated against a standardized selec- A, B, and DR often occur together. Nevertheless,
tion of test antibodies from the International it is nearly impossible to pick an HLA identi-
Histocompatibility Workshop (IHW). This library cal individual just by chance. This can only be
of IHW test sera was constantly extended as new achieved by means of a concerted sequential
alleles had been discovered. However, the first- search in a donor population. HLA matching is
generation test sera were not able to differenti- the search for a donor who exclusively possesses
ate between some related alleles. Monoclonal HLA alleles that are also present in the recipient.
antibodies later enabled to subdivide many of All foreign HLA alleles of the donor are coined
the original HLA alleles. These more specific HLA mismatches. In solid organ transplantation,
entities were termed splits of the (original) the loci HLA A, B, and DR are exclusively con-
broad HLA antigens. Nowadays, HLA typ- sidered for matching. This limits the maximum
ing is performed with highly specific multiplex count of mismatches from a single donor to
96 D. Bhringer and T. Reinhard
poorer than at the DR locus. This was a benefit clinical routine in keratoplasty. This is most
independent of the additional HLA class I match- likely due to lack of clear level I evidence at the
ing effect. time of writing.
was not relevant [10]. The prevalence of HLA A1 routine. It is nowadays possible, e.g., to replace a
male donors is only 13 % in, e.g., Germany. For failed graft endothelium with Descemet mem-
this reason, generally avoiding transplantation of brane transplantation. This almost completely
male donors to female recipients does not make avoids subsequent rejection episodes. However,
sense [22]. However, allocating male HLA-A1 tissue typing still makes sense for specialty cen-
donors to female recipients may be a discrete risk ters that deal particularly with high-risk trans-
factor for immune reactions after penetrating plantations in vascularized grafts or with limbal
keratoplasty. allografts. Here, all corneal donors should be
HLA typed at least at the loci A, B, and DR. DNA
HA-3 typing is the method of choice. An alternative
The HA-3 epitope is also HLA-A1 restricted. source of typed grafts is, e.g., Bio Implant
This epitope is derived from the lymphoid blast Services, Leiden, the Netherlands. Blood groups
crisis (Lbc) oncoprotein and H antigen that has may be additionally typed. The potential benefit
been expressed in the cornea. The HA-3 epitope from this is at a lower level of evidence, though.
comes in two alleles: VTEPGTAQY (HA-3 T) Lobbying is still required because costs from
and VMEPGTAQY (HA-3 M). However, only HLA typing of the donor are poorly reimbursed
grafting into the direction of HA-3 T is considered in most health systems. However, from the pay-
immunogenic. This does not seem to be highly ers perspective, the additional cumulative costs
relevant in penetrating keratoplasty, though [10]. from HLA typing have been recently calculated
as low as 4.62 EUR per additional day of graft
Blood Group (ABO) survival after penetrating keratoplasty [7].
Blood group antigens are sometimes also referred Patients awaiting penetrating keratoplasty
as minor antigens. The allelic nature of the syn- should be provided a histocompatible graft (HLA
thesizing enzyme gives rise to the ABO system. and AB0) whenever possible. This is especially
These are immunogenic glycoproteins attached true for high-risk keratoplasties. The expected
to erythrocyte membranes but also present on a time on the waiting list should be calculated and
wide variety of human tissues. The ABO antigens discussed with the patient in advance. The
are not physiologically expressed in the corneal HLAMatchmaker algorithm can help in discrimi-
stroma and corneal endothelium. However, they nating between harmless and dangerous mis-
have been detected in failed corneal grafts [3]. matches to increase the donor pool and shorten
The evidence on blood group matching in ker- the waiting time.
atoplasty is controversial. A beneficial effect has
been observed in high-risk penetrating kerato-
plasty, but not in normal-risk keratoplasties References
[12,23,38]. Other blood group antigens may play
a role in normal-risk keratoplasties [33]. More 1. Anshu A, Price MO, Price FWJ. Risk of corneal
transplant rejection significantly reduced with
research is warranted to work out the exact mech-
descemets membrane endothelial keratoplasty.
anisms in blood group histocompatibility. These Ophthalmology. 2012;119(3):53640. doi:10.1016/j.
retrospective nonrandomized results may well be ophtha.2011.09.019.
confounded by peptidic H antigens originating, 2. Archbold JK, Ely LK, Kjer-Nielsen L, Burrows SR,
Rossjohn J, McCluskey J, Macdonald WA. T cell
e.g., from the ABO-specific glycosyltransferases
allorecognition and MHC restriction a case of
or other factors. Jekyll and Hyde? Mol Immunol. 2008;45(3):58398.
doi:10.1016/j.molimm.2006.05.018.
Conclusions and Recommended 3. Ardjomand N, Komericki P, Klein A, Mattes
D, El-Shabrawi Y, Radner H. ABO blood
Clinical Practice group expression in corneal allograft failures.
The recent rise of lamellar grafting certainly Ophthalmologe. 2005;102(10):9816. doi:10.1007/
reduces the need for tissue typing in the clinical s00347-005-1199-1.
7 Immunology of Keratoplasty 99
Abstract
Corneal transplantation has been successfully performed for over 100
years. Despite HLA typing and systemic immunosuppression not being
routinely undertaken, 5-year survival rates exceed 90 % in corneal grafts
with no current or past history of inflammation. However, graft survival
decreases dramatically in the presence of risk factors that place it at high
rejection risk, and immunological graft rejection remains the leading
cause for graft failure. Post-operative management of corneal grafts
requires stratification according to the risk for rejection and addressing
this with appropriate prophylaxis. It is critically important to recognise
corneal graft rejection early and initiate appropriate treatment, as a delay
in diagnosis and treatment will result in failure to reverse rejection, or at
least shorter graft survival if rejection is reversed.
Keywords
Graft rejection Rejection prophylaxis Post-operative care Systemic
immunosuppression
forming the blood-eye barrier result in the rela- Clinical Factors Predisposing to High
tive sequestration of the cornea from potential Risk of Corneal Graft Rejection
systemic immune responses [3]. Secondly, the
aqueous humour contains a rich milieu of immu- A corneal allograft becomes predisposed to
nomodulatory molecules which downregulate rejection when facets of immune privilege are
immune responses which are potentially harmful overwhelmed by pre-transplant alterations in
to transplanted donor cornea. Some of these con- recipient tissue or breached by post-transplant
tribute towards the downregulation of systemic clinical events.
immune responses, in particular alloantigen-spe- The Australian Corneal Graft Registry with a
cific suppression of delayed-typed hypersensitiv- database of over 23,000 grafts reports the overall
ity (DTH) responses, which was first described survival of corneal grafts as 87 % at 1 year and
over 30 years ago as anterior chamber-associated 73 % at 5 years. For some indications such as a
immune deviation (ACAID) and shown in rodents first graft for keratoconus, graft survival is 97 and
to reduce the impact of corneal allograft rejec- 95 % at 1 and 5 years, respectively [16]. However,
tion [4, 5]. Thirdly, the cornea itself possesses this dramatically decreases in the presence of risk
several mechanisms that neutralise elements of factors that confer the graft at high risk of rejec-
the immune effector response. These include the tion. For example, 5-year graft survival for cor-
expression of cell membrane-bound molecules neal grafts with 2 or more quadrants of stromal
on the epithelial and endothelial surfaces such vascularisation ranges from 45 to 58 %, and
as (i) Fas ligand (CD95L), which induces apop- grafts with ocular inflammation at time of sur-
tosis of neutrophils and lymphocytes that ligate gery range from 50 to 56 % [16].
these molecules on the cornea during inflamma- Factors that have been consistently dem-
tion [6]; (ii) programmed death-ligand 1 (PD-L1) onstrated to affect prognosis of corneal grafts
that inhibits T lymphocyte proliferation, induces include (i) two or more quadrants of stromal vas-
T lymphocyte apoptosis and prevents T lym- cularisation in the graft recipient bed, (ii) inflam-
phocyte production of interferon- (IFN-) [7, mation at the time of surgery and (iii) history of
8]; and (iii) both membrane-bound complement a previously rejected corneal graft in that eye
regulatory proteins (CRP) on corneal epithelial [1723].
cells and soluble CRP in the aqueous humour Corneal vascularisation is an almost invariable
that buffer the capacity of complement-fixing consequence of acute or chronic inflammation.
antibodies to produce corneal injury in rejection The extent of vascularisation of the recipient cor-
[9, 10]. The corneal endothelium is also unique in nea, as categorised as quadrants of blood vessel
its paucity of major histocompatibility complex growth, at the time of transplantation correlates
(MHC) class I molecules [11]. This would usu- strongly with graft survival (Fig. 8.1) [18, 22].
ally trigger natural killer (NK) cells as members However, it is worth noting that recent research
of the innate immune system to kill any cells that has shown that it may be the presence of lymph
fail to express MHC class I molecules termed vessels rather than blood vessels that robs the
missing self hypothesis as many neoplasms corneal allograft of its immune privilege. Dietrich
downregulate their expression of MHC class et al. reported that administration of a molecule
I molecules to escape cytotoxic T lymphocyte antagonist of 51 integrin or anti-VEGFR3
(CTL)-mediated immune surveillance. However, antibody that preferentially inhibits lymphangio-
this has not been convincingly demonstrated in genesis, but not haemangiogenesis, produced a
the cornea to date and has been attributed to the significant enhancement of graft acceptance in
presence of at least two molecules that inhibit NK murine hosts who were pretreated with sutures to
cell-mediated cytolysis in the aqueous humour stimulate highly vascularised graft beds [24].
bathing the corneal endothelium, namely, mac- However, the long-held hypothesis that the pres-
rophage migration inhibitory factor (MIF) and ence of blood vessels in the corneal graft bed
transforming growth factor- (TGF-) [1215]. increases the risk of rejection is still valid as
8 Post-operative Management 103
demonstrate any advantage in addition to that of Koay and colleagues in their survey of corneal
a single dose at diagnosis [46]. surgeons in the Bowman Club in the United
However, a subsequent prospective ran- Kingdom reported that all surgeons used topical
domised trial by Hudde et al. did not demonstrate steroids post-operatively, with 50 % favouring
a statistically significant benefit in receiving a prednisolone acetate 1 % and 36 % favouring
single intravenous methylprednisolone pulse in dexamethasone 0.1 %. Average duration of topi-
addition to intensive local corticosteroid in terms cal treatment was 8.7 months, although 5.5 % of
of reversal of the rejection episodes, later recur- respondents continued treatment indefinitely in
rence of graft rejection or graft failure with a low-risk grafts [52]. This is in stark contrast to
follow-up duration of 2 years. The intensive local that reported by Price and colleagues, who sur-
corticosteroid regime used in that study consisted veyed 250 corneal surgeons attending an endo-
of one dose of subconjunctival betamethasone thelial keratoplasty course at a tertiary referral
(2 mg) and hourly dexamethasone 0.1 % for 24 h centre between 2006 and 2008; the majority
[47]. Another study reported a higher rate of (87 %) of whom were from the United States.
rejection reversal in patients receiving subcon- They reported that 46 and 22 % of respondents
junctival triamcinolone (20 mg) versus a single continued topical steroids indefinitely for pseu-
dose of intravenous methylprednisolone in addi- dophakic/aphakic and phakic patients, respec-
tion to topical prednisolone acetate 1 % [48]. tively, in low-risk grafts [55].
Successful reversal of an endothelial rejection Price and colleagues also found that the major-
episode ranges from 51 to 92 % [43, 47]. ity (76 %) of respondents used intraoperative cor-
Other studies have examined the use of topical ticosteroids, of which 72 % were delivered as
[49, 50] and systemic [51] cyclosporine in the sub-tenon or subconjunctival injections, 8 %
treatment of endothelial rejection: Poon et al. in a were intravenous, 7 % were oral and 2 % were
prospective randomised trial did not find a sig- intraocular. Again, all surgeons used topical ste-
nificant benefit in using a commercially available roids post-operatively, with 95 % using predniso-
preparation of topical cyclosporine (0.05 %) in lone acetate 1 %. Most surgeons (57 %) used the
addition to intensive topical steroids [49]. same regimen regardless of lens status. However,
14 % of respondents who initially prescribed
prednisolone acetate 1 % for phakic patients had
Prevention of Corneal Transplant switched to a lower-strength corticosteroid such
Rejection as fluorometholone or loteprednol at 6 months,
and 20 % had withdrawn their patients topical
Patients with Low Rejection Risk steroid. In contrast, 10 % of respondents had
In patients without risk factors for graft rejection switched their pseudophakic/aphakic patients to
identified prior to transplantation, typical post- a lower-strength steroid, and 10 % had withdrawn
operative immunosuppression consists of dexa- topical steroids [55].
methasone 0.1 % or prednisolone acetate 1 % Nguyen and colleagues in a recent prospective
four times daily for the first 23 months, reduc- randomised trial of 406 eyes following normal-
ing gradually to zero by 612 months following risk keratoplasty reported significantly higher
transplantation. There are no definitive ran- rejection rates in grafts where topical steroids
domised controlled trials into the optimal immu- were stopped at 6 months (9.1 %) compared to 12
nosuppression regime for low-risk grafts, months (4.9 %) [56]. The use of topical cyclospo-
although there is remarkable consensus world- rine 0.05 % four times daily for 1 year has also
wide regarding the need for prophylaxis post- been undertaken and found to be significantly
operatively with topical corticosteroid as less effective than historical controls using topi-
demonstrated by surveys of practice patterns cal corticosteroid for a median of 7 months as
[5254]. rejection prophylaxis in low-risk grafts [57].
106 S.-P. Chow and D.F.P. Larkin
Patients with High Rejection Risk Both topical and systemic immunosuppres-
There is much less consensus on the post- sive agents have been evaluated for prophy-
operative management of grafts with high rejec- laxis against graft rejection in high-risk grafts.
tion risk (Fig. 8.2). Due to the shortage of large However, systemic rather than local admin-
comparative prospective studies into immuno- istration is justified by evidence in experi-
suppression regimes, different centres use vary- mental models that alloantigen immunisation
ing protocols based on individual clinical does not occur in the eye, but that transported
experience and informed by experimental evi- corneal alloantigens lead to clonal expansion of
dence, small uncontrolled or retrospective clini- alloreactive T lymphocytes in regional lymph
cal studies and extrapolation from what has nodes and possibly spleen [5860].
proven effective in solid organ transplantation. The majority of reports on systemic immuno-
This is compounded by the lack of a consensus suppression as prophylaxis against corneal
definition of what constitutes a high-risk graft, allograft rejection utilise one of the calcineurin
which also makes direct comparison between inhibitors, cyclosporine and tacrolimus, as mono-
studies difficult. Some reports include risk fac- therapy. This is in contrast to renal transplant
tors for graft failure independent of rejection as recipients, who commence dual- or triple-agent
part of their high-risk definition, and others prophylaxis that typically includes prednisolone,
include a subset of patients who received HLA- mycophenolate mofetil and calcineurin inhibitors
matched donor corneas, a factor that may inde- or sirolimus. Hence, the poorer prophylaxis out-
pendently affect transplant outcomes with respect comes in corneal patients compared to renal trans-
to rejection. plant recipients may be due to (i) low drug doses,
Furthermore, as corneal transplantation is not (ii) short duration rather lifelong prophylaxis and
a life-saving procedure, ophthalmologists are (iii) the narrow spectrum of activity within the
hesitant to commit patients to long-term systemic alloreactive cell phenotypes of monotherapy [61].
immunosuppression due to the potential side Monotherapy with calcineurin inhibitors, which
effects and risk of developing malignancies. block T lymphocyte clonal expansion by interfer-
However, in cases where there is a high rejection ing with interleukin-2 gene transcription, may also
risk and patients are reliant on graft survival in be less effective as most graft-reactive cells in the
order to undertake activities of daily living, the anterior chamber after rejection onset in humans
risks of systemic immunosuppression may be are CD14+ cells of monocyte-derived macrophage
more justifiable. lineage rather than lymphocytes [62].
a b
Fig. 8.2 (a) Endothelial rejection. A horizontal endothe- Scattered anterior stromal infiltrates shown are restricted
lial line, scattered keratic precipitates and Descemet to donor cornea (Reproduced from Larkin [41] with per-
membrane folds are shown. (b) Stromal rejection. mission of BMJ Publishing group)
8 Post-operative Management 107
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migration inhibitory factor in inhibiting NK cell
domised controlled trials are required to identify
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forming growth factor beta on the functions of
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Outcomes: Recurrence of Disease
9
Per Fagerholm
Abstract
The inherited diseases or true corneal dystrophies tend to recur in the
grafts. The frequency and intensity of recurrence vary extensively. With
time more sophisticated genetic analyses have made the old clinical clas-
sification less reliable and the IC3D classification system welcome.
Heredity is part of the definition of a corneal dystrophy something that is
rarely found in basement layer corneal dystrophy and in what is generally
named Fuchs dystrophy. Future studies need to accommodate to strict
modern classification. Large variation in recurrence frequency can be
found in clinical similar forms of granular dystrophy but having different
genetic lesions. Keratoconus is overrepresented within many families, but
the mode of inheritance is unclear. The disease can progress within the
host cornea, the graft received may harbor keratoconus, and keratoconus
may develop within an otherwise healthy graft. The exchange of cells
between the host and the graft has been studied, but there are no strict
rules of how stromal and endothelial cells carrying the genetic defect
from the host will be distributed within the graft and cause a recurrence.
A degeneration such as Salzmanns nodular degeneration can recur in a
graft. Well known is also the recurrence of herpes simplex keratitis. Here
prophylactic treatment postoperatively using oral acyclovir over long
periods has proven beneficial. Corneal dystrophies with a distinct hered-
ity, keratoconus with a presumed heredity, degenerations with no hered-
ity, and infections like herpes simplex are examples of diseases that may
recur in the graft.
Keywords
Cornea Corneal transplantation Dystrophy Degeneration Herpes
simplex keratitis Recurrence Reoperation
0
0 100 200 300 400
Graft age (months)
identified. In a two-dimensional study of the Modern molecular genetics have enabled the
endothelium in the 36 corneal buttons, the distri- subdivision of the dystrophies based on gene
bution showed a surprising variability in the pat- location and mutation analysis. Several dystro-
tern and extent of the donor and recipient cell phies emanate from different mutations in the
population, indicating a dynamic nature of the same gene. Therefore, a more precise prognosis
endothelium to a not expected degree (Figs. 9.1 can be decided only on the basis of type of muta-
and 9.2). tion in the individual [30].
Interestingly, the mix of donor and recipient In the literature, a recurrence of the inherited
cells may be responsible for an altered phenotype disease is either classified as signs of the original
of the recurrence of corneal dystrophies [27]. disease in the graft or as an actual reoperation
caused by the recurrence.
With few exceptions, Bowman layer corneal
Recurrence Following Corneal dystrophies are the most anterior changes that are
Grafting for Corneal Dystrophies subjected to corneal grafting. Both Reis-
Bcklers (CDB1) and Thiel-Behnke (CDB ll)
In a classic review (1978), Waring 3rd et al. [28, dystrophies are mutations in the BIGH 3 gene,
29] describe the corneal dystrophies and their and there are indications that the epithelium may
tendency to recur after PKP. Due to advances in be responsible for the pathologic changes. Both
molecular genetics, the focus here has been (there may be several subtypes) can recur in the
placed on the more recent literature. graft.
The Bowman layer dystrophies, the Reis- In a study of 73 patients (110 eyes) grafted for
Bcklers and the Thiel-Behnke and the stromal corneal dystrophies originating in the BIGH 3
dystrophies, the granular types, and the lattice gene, 17 patients (27 eyes) were grafted for Reis-
types of dystrophies are subjected to PKP Bcklers (R 124 L) and 8 patients (13 eyes)
(penetrating keratoplasty) or DALK (deep ante- from Thiel-Behnke dystrophy (R555Q). Of the
rior lamellar keratoplasty). The more superficial Reis-Bcklers cases, significant recurrence was
dystrophies, the epithelial, are generally treated found in 24 of the 27 operated eyes within a
with phototherapeutic keratectomy or by other mean time of 5.9 years. In the Thiel-Behnke
means. eyes, dystrophic changes recurred in the graft in
116 P. Fagerholm
a b c
Fig. 9.3 Classic lattice dystrophy (a). Recurrence of lattice changes in the form of superficial opacifications without
lattice lines (b). The superficial changes can successfully be removed with phototherapeutic keratectomy (c)
9 Outcomes: Recurrence of Disease 117
a b
Fig. 9.4 A 56-year-old male with macular dystrophy in the right eye (a) and recurrence of the changes 6 years following
a penetrating corneal graft (b)
7.2 % were due to recurrence of corneal dystro- dystrophies [28]. There is however a consider-
phies [33]. able variation in the literature.
DALK has been evaluated as an alternative to In a cohort of patients operated on in Saudi
PKP in lattice dystrophy l, and the outcome was Arabia with PKP for macular dystrophy (229
compared to DALK in macular dystrophy [34]. eyes in 141 patients) followed for a mean of
Sixty eyes with lattice dystrophy and 24 eyes 5.9 years, clinical significant recurrence was
with macular dystrophy were operated on with a observed in 5.2 % of the grafts [37] (Fig. 9.4).
DALK technique. It was concluded that DALK In two recent reports, a comparison of PKP
was a favorable technique for lattice dystrophy, and DALK for macular corneal dystrophy was
whereas for macular dystrophy, the DALK was analyzed.
not as good [34]. Endothelial density deteriorated The highest recurrence figures were reported
faster in macular dystrophy. DALK has also been in a retrospective study where PKP was per-
evaluated for granular dystrophy. Recurrences formed in 57 eyes and DALK in 21 eyes. Mean
were common. Simple recurrence occurred in 5 follow-up time was 5.1 years. Seventeen per-
out of 7 eyes (mean time to recurrence was cent of PKP-treated eyes showed recurrences
15.6 months). Clinical significant recurrence and so did 42.9 % of the DALK eyes. The
occurred 34 month after surgery in 3 out of 7 younger the onset of the disease and the younger
eyes. Two eyes showed no recurrence [35]. at surgery, the higher the risk of recurrences
In another more recent material where DALK [38].
was performed in 9 eyes with granular dystrophy, In a randomized trial [31] (54 patients an 82
2 eyes showed a recurrence (22 %), one of which eyes), recurrence of disease (follow-up 30.5
as early as after 14 months. The mean follow-up months) was 4.8 % in the PKP group and 5.7 %
time was 43.5 months. in the DALK group. There was less endothelial
In the same material 1 out of 43 grafts with damage in the DALK group [39].
macular dystrophy (2.3 %) and 6 eyes with lattice In a British material, 16 patients who under-
dystrophy (35.3 %) recurred [36]. went 41 transplants in 31 eyes were followed
between 25 and 408 months from the initial diag-
nosis. Six eyes of four patients were regrafted
Macular Dystrophy after recurrence of the disease. Clinical recur-
rence was observed in two more eyes. It was fur-
Opacities from macular corneal dystrophy recur thermore assessed that a larger graft showed less
less commonly than in lattice and granular recurrence [40].
118 P. Fagerholm
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National Corneal Transplant
Registries 10
W. John Armitage and Margareta Claesson
Abstract
National corneal transplant registries collect and analyze observational,
longitudinal data and report outcomes on large numbers of patients across
multiple transplant centres. Registry data are valuable for monitoring
activity and outcomes, including rare events such as primary graft failure,
and for showing the uptake of new surgical techniques. While randomized
controlled trials (RCT) are considered to provide the highest level of evi-
dence for comparative studies, the strict inclusion and exclusion criteria
make generalization of the results and translation into routine practice at
times uncertain. The greater heterogeneity of patient characteristics in reg-
istries provides a perhaps more realistic picture of expected outcomes. The
same is true of carefully conducted single-centre case series, which can
often provide benchmark data, but do not necessarily reflect the outcomes
in routine practice in multiple centres. National registries provide an
important source of information that contributes, along with RCTs, single-
centre studies, expert opinion and meta-analyses, to a better understanding
of corneal transplant outcomes.
Keywords
Corneal transplant registries Corneal transplant outcomes Corneal
transplantation Transplant outcomes Registry data
1.0
Penetrating
0.8 n = 15,583
Probability of graft survival
0.6
0.4 Lamellar
n = 990
0.2
Limbal
n = 92
0.0
0.00 3.00 6.00 9.00 12.00 15.00 18.00 21.00 24.00
Trial time (years post graft)
Fig. 10.1 An example of national registry data from the toplasty, lamellar keratoplasty and limbal allografts
Australian Corneal Graft Registry (http://hdl.handle. (Reproduced with permission of the Australian Corneal
net/2328/25860). Long-term survival of penetrating kera- Graft Registry)
transplant registries: they are, however, either the comes, which, in turn, will improve patient selec-
most widely regarded (i.e. the Australian Corneal tion and postoperative management and extend
Graft Registry) or are the best known to the the quality of information provided by surgeons
authors (i.e. the UK Transplant Registry and to their patients.
Swedish Cornea Registry). At their best, single-
centre registries and case series provide valuable,
often benchmark, data that have been rigorously Setting Up a Registry
collected by pioneering clinics at the forefront of
new developments in surgical techniques and Registry design, extent and mode of operation
practice [11, 19, 22] (Fig. 10.2); however, given will be influenced by multiple factors ranging
the large numbers of factors that influence cor- from individual surgeon preferences through to
neal transplant survival and visual outcome, the the availability of funding and appropriate
value of some single-centre reports may be lim- infrastructure at local, regional and national lev-
ited owing to small numbers of transplants and, els. There is no best way to organize a corneal
as a consequence, unintended selection bias. The transplant registry, which could be achieved
ultimate aim of data collection and analysis, through professional or academic organizations
whether through registries or single-centre case as well as with government support. Keys to suc-
series, is to better inform surgeons about out- cess include: active surgeon involvement and
10 National Corneal Transplant Registries 131
30
20
10
70
0 1 2 3 4 5
Time after transplant (years)
commitment to help define the clinical questions collection of follow-up data on all patients with-
to be answered (which are likely to change with out limit [4]. Not surprisingly, loss to follow-up,
time) and to provide clinical data on their patients, especially among the older patient population,
expert statistical advice at all stages, staff to sup- becomes an increasingly important factor with
port and maintain the registry and an appropriate extended follow-up times. Kaplan-Meier survival
platform for the storage and analysis of clinical curves are used extensively for the analysis of
follow-up data. Other considerations will include graft survival [1]. Unfortunately, the right-hand
the ethical and regulatory environments existing side of Kaplan-Meier survival curves becomes
in different countries, for example, patient confi- increasingly less reliable at longer postoperative
dentiality, data protection and issues of consent times as the numbers of transplants at risk
for the storage of data for the greater good rather declines through loss to follow-up and graft fail-
than being specifically linked to the treatment of ures; moreover, the assumption that transplants
an individual patient. lost to follow-up would have behaved in the same
The three aforementioned national registries way as those available for examination becomes
reflect these varying circumstances and, as a ever more uncertain.
result, operate in different ways; for example, the In Sweden, there is substantial government
Australian Corneal Graft Registry (ACGR) support available for clinical registries across a
(http://hdl.handle.net/2328/25860), the oldest range of clinical specialties. EyeNet Sweden
and largest of the three, which is based in an aca- (www.eyenetsweden.se), which was established
demic department, has been collecting data since in 2003, hosts the Swedish Cataract Registry
May 1985 and can report very long-term survival [3] and the Swedish Cornea Registry (www.
data extending for more than 20 years [25]. The cornea.nu), which began collecting data in 1996.
Swedish and UK registries both limit the follow- (NB The EyeNet website includes advice, in
up of transplants to 2 and 5 years, respectively [2, English, on setting up quality registers.) The
6]; however, longer-term follow-up studies are Swedish registry collects data at two time points,
possible by collecting additional data on selected viz., at the time of transplant and at 2 years post-
groups of patients rather than through continual operatively. In 2007, the Swedish Cornea
132 W.J. Armitage and M. Claesson
Registry abandoned paper-based data submission Table 10.1 Five-year graft (PK) survival by indication
from the Australian Corneal Graft Registry (ACGR) and
and implemented a web-based application
UK Transplant Registry (UKTR)
through EyeNet with direct online data entry by
each individual clinic. This greatly reduced the 5-year graft survival
Indication ACGR (%) UKTR (%)
risk of transcription errors and improved the
Keratoconus 95 93
accuracy of the data held in the registry. The par-
Corneal dystrophy 82 80
ticipating clinics, which include transplant units
Bullous keratopathy 56 59
in Denmark and Norway, can access their own
data on line and compare their outcomes and
activity directly with national data. invaluable resource for clinical research, enabling
The UK Transplant Registry is also supported large-scale studies that improve our understand-
by government funding. It is maintained by NHS ing of the factors that influence corneal transplant
Blood and Transplant (NHSBT) and holds outcomes. Indeed, registry data can help identify
national outcome data both for solid organ and questions that would be best answered by con-
corneal transplants. Data are collected at the time trolled clinical trials and provide supporting infor-
of surgery and then at 1, 2 and 5 years postopera- mation for their planning and design.
tively using standardized follow-up forms; how- Graft survivals reported in the registries are
ever, a move to online input of data is, at the time very similar (e.g. see Table 10.1 comparing
of writing, under discussion. This registry has the Australian and UK data). All three registries
added benefit in that it includes donor and eye have confirmed that the indication for transplan-
bank information for each cornea transplanted. tation, preoperative risk factors, such as vascu-
As a result, it enables robust traceability between larization and glaucoma, and postoperative
donors and recipients for the purposes of investi- complications, such as rejection, are the major
gating serious adverse events and reactions in factors influencing graft survival after penetrat-
corneal transplant recipients, thus meeting the ing keratoplasty (PK) [2, 6, 23, 25]. Registries
regulatory requirements set out in the EU Tissues also provide information relevant to the postop-
and Cells Directive (2004/23/EC) and its accom- erative management of graft patients; for exam-
panying Commission Directives (2006/17/EC ple, studies using UK Transplant Registry data
and 2006/86/EC) (http://ec.europa.eu). have demonstrated that long-term topical steroid
use reduces the risk of graft failure after PK for
pseudophakic bullous keratopathy [20] and that
Uses of Data from Corneal oral antiviral treatment is more effective than
Transplant Registries topical treatment for reducing the risk of graft
failure in patients undergoing PK for herpetic
Graft Survival keratitis [10] (Fig. 10.3). The ACGR has also
highlighted the negative impact of reversed
Because of their size, national registries provide a rejection episodes on long-term graft survival: at
broader perspective than single-centre studies and 10 years, overall survival of transplants that have
can provide information not necessarily available experienced no rejection is 68 % compared with
through other means, for example, the routine just 35 % for those that have suffered one or
monitoring and analysis of rare events and com- more rejection episodes [8, 25].
plications including primary graft failure and
postoperative endophthalmitis. Registry data can
be used to monitor transplant activity and out- Visual Outcome
comes, trends and patient demographics, which
are not just of interest to surgeons but are impor- The majority of corneal transplants are performed
tant for informing the development of healthcare to improve a patients vision. It is therefore of
policies and resource planning. The data are an value to be able to use registry data to assess
10 National Corneal Transplant Registries 133
% graft survival 80
70
50
0 1 2 3 4 5
outcomes in terms of vision rather than simply while the outcome for bullous keratopathy
graft survival. The Swedish Cornea Transplant regrafts was less affected but still reduced to
Registry was started in 1996 with the principal about 10 % [5].
aim of reporting visual outcomes [6] (Fig. 10.4).
These analyses have shown the dependence on
indication of the expectations for postoperative Patient-Reported Outcome Measures
visual rehabilitation, principally visual acuity (PROM)
(VA). While >80 % of patients had a preoperative
VA 0.2 across all indications, almost 80 % of Registries and single-centre studies typically
patients with grafts for keratoconus achieved a focus on clinical outcome measures (COM), such
VA of 0.5 at 2 years after surgery compared as graft survival, complications (e.g. rejection
with just over 50 % of grafts for Fuchs and only episodes) and visual outcome. There are, how-
20 % for bullous keratopathy. These results do ever, few studies of the impact of corneal trans-
not take into account the increasing occurrence of plantation on self-assessed, patient-reported
co-morbidity, such as retinal disease, in the older outcome measures (PROM). These aim to deter-
patients; however, this information is collected mine improvement or otherwise in visual disabil-
by the Swedish registry and can be included as a ity as perceived by transplant recipients. An early
variable in analyses of visual outcome. study from the ACGR looked at this important
Interestingly, for regrafts, the respective percent- aspect of corneal transplant outcome [24], but
ages of grafts achieving 0.5 VA for keratoconus little attention has since been paid to this area.
and Fuchs were somewhat reduced at 55 and The Swedish Cataract Register has conducted
19 %, respectively, compared with first grafts, widespread studies on PROMs and compared
134 W.J. Armitage and M. Claesson
80 80
Pre-op
70 70 Post-op
60 60
50 50
40 40
30 30
20 20
10 10
Frequency (%)
0 0
<=0.2 0.30.4 >=0.5 <=0.2 0.30.4 >=0.5
90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
<=0.2 0.30.4 >=0.5 <=0.2 0.30.4 >=0.5
Visual acuity
Fig. 10.4 Visual outcome data from the Swedish Corneal endothelial dystrophy, bullous keratopathy and other
Transplant Registry showing percentages of grafts achiev- indications (Reproduced from Claesson et al. [6], with
ing VAs of 0.2, >0.2 and <0.5, and 0.5 preoperatively permission of BMJ Publishing Group)
and at 2-year postoperative for keratoconus, Fuchs
them to COMs [14]. These studies have used the single score of visual disability (high scores
Catquest 9-SF visual disability instrument, which equate to greater disability), which are amenable
consists of just 9 questions that patients complete to parametric statistical analysis. A study is cur-
before and after surgery [13] (Table 10.2). The rently underway in Sweden to complete the vali-
answers are resolved by Rasch analysis into a dation of Catquest 9-SF for corneal transplant
10 National Corneal Transplant Registries 135
Table 10.2 Catquest 9-SF visual disability questionnaire itation [11, 19]. Such studies show the potential
Difficulty items that can be achieved with these newer techniques
Answers: No, no problems; Yes, some problems; Yes, and provide a valuable benchmark for compari-
great problems; Yes, very great problems; Cannot son, as well as a forum for sharing insightful
answer
advice. However, perhaps because national reg-
1. Reading text in the newspaper
istry data report the outcomes across multiple
2. Recognizing faces of people you meet
centres and from patients with a broader case
3. Seeing prices of goods when shopping
mix, the registry outcomes for DALK and EK
4. Seeing to walk on uneven ground
do not reflect the excellent results reported from
5. Seeing to do needlework and handicraft
single-centre case series [7, 12]. This suggests
6. Reading text on TV
that while many centres may well be achieving
7. Seeing to carry out a preferred hobby
similar results to the single-centre reports, some
Global assessment items
will be falling short. This important information
Answers: Yes, very satisfied; Yes, fairly satisfied; No,
rather dissatisfied; No, very dissatisfied; Cannot is crucial for the optimum translation of newer
answer techniques into general, routine practice for the
8. Do you experience that your present vision gives benefit of all patients and is an example where
you difficulties in any way in your daily life? both single-centre reports and national registry
9. Are you satisfied or dissatisfied with your present data are needed for meaningful assessment.
vision?
Reproduced from Lundstrom and Pesudovs [13], with
permission of Elsevier
Patients are asked a series of nine questions before and The Value of Corneal Transplant
after surgery. The answers are resolved into a single Rasch Registries to Eye Banking
score for statistical analysis
Eye bank standards for donor selection, including
recipients and to apply this visual disability donor age, post-mortem times to corneal retrieval
instrument to determine the factors that most and preservation, preservation method, storage
influence PROMs as opposed to COMs. Patients time and quality assessment based on endothelial
will be asked to complete the questionnaire cell density, are defined by eye banking organiza-
before surgery and at 2 years after surgery tions, such as the Eye Bank Association of
(Claesson M, personal communication, 2014). America, the European Eye Bank Association,
the Eye Bank Association of Australia and New
Zealand and the Eye Bank Association of India,
New Surgical Techniques or left to the discretion of eye bank medical direc-
tors, usually a combination of both. When eye
Over the past few years, there has been a marked bank and donor information are included in cor-
change in the surgical treatment of corneal dis- neal transplant registries, there is an opportunity
ease with a move away from full-thickness grafts to assess the influence of donor factors on both
(penetrating keratoplasty, PK) to lamellar tech- the suitability of corneas for transplantation and
niques that seek to replace only the dysfunctional on graft survival [2, 25]. Large-scale analyses
part of the cornea, viz. deep anterior lamellar ker- involving several thousand corneas and corneal
atoplasty (DALK) for keratoconus and superficial transplants are not able necessarily to set
corneal scars, and endothelial keratoplasty (EK) standards, such as maximum acceptable death to
for endothelial dysfunction [15]. The evolution of preservation times or minimum endothelial cell
these techniques has been pioneered by surgeons density, but they can support and validate exist-
who have reported their outcomes, typically in ing standards or suggest that standards should be
single-centre case series, which show the ben- raised. A study in the UK, for example, showed
efit, especially of EK, in terms of graft survival, that the major factors affecting the suitability of
reduced risk of rejection and faster visual rehabil- corneas for PK (defined as a minimum endothelial
136 W.J. Armitage and M. Claesson
cell density of 2200 cells/mm2) included donor Registry data fall into Level II evidence, which
age and storage time in organ culture while death includes well-designed trials without randomiza-
to enucleation times up to 24 h had little influ- tion and cohort or case-controlled studies.
ence on suitability. Provided corneas had an The pre-eminence of RCTs is not universally
endothelial cell density of 2200 cells/mm2, donor accepted [18], and they do have a number of
age (up to 90+ years) and storage time in organ drawbacks and disadvantages. Randomized con-
culture (up to 4 weeks) had no influence on trolled trials can be expensive and difficult to
5-year PK survival, which was dominated by design and implement, and techniques may
recipient factors [2]. It is clear that there are dif- undergo further development during the course
ferences in eye banking standards between differ- of an RCT rendering its findings redundant [17].
ent countries. Once a standard has been accepted, Patient recruitment may be hindered through
such as maximum donor age or post-mortem refusal of surgeons to randomize patients between
retrieval time, there is an understandable reluc- the study groups because of ethical concerns or
tance to introduce what may be considered to be lack of resources. Another major problem con-
a relaxation of a standard even though there may cerns the wider application of findings from
be evidence from registry data from other coun- RCTs, which have strictly controlled inclusion
tries to support a change and where such a change and exclusion criteria, to routine practice where
may lead to an increase in availability of corneas the patient population is far more heterogeneous,
for transplantation. The most rational way for- for example, greater diversity of disease severity
ward in this instance would be a prospective ran- at time or presentation/treatment and the pres-
domized trial, such as the Cornea Donor Study in ence of risk factors and co-morbidities, especially
the USA designed to determine whether corneas in older patients, which may be excluded from an
from older donors up to 75 years would be RCT. There are, however, excellent examples of
acceptable for PK [21]. However, as will be dis- RCTs, such as the Cornea Donor Study in the
cussed later, randomized controlled trials require USA, which has provided a wealth of informa-
substantial organization and funding, and gener- tion about the influence of donor age on PK out-
alization of their results to reflect routine practice come at 5 and 10 years after transplantation [9,
may not always be appropriate. Therefore, eye 21, 27, 28]. This study was limited to PK and
bank data recorded along with corneal transplant endothelial disease in moderate risk grafts with-
outcomes in registries are an additional important out known risk factors for graft failure. It there-
source of information for the validation of eye fore leaves open the question of applicability to a
bank standards and practice. wider range of indications including both low-
and high-risk grafts. However, its conclusions are
broadly supported by retrospective analyses of
Different Sources of Information observational registry data, which show little
Used for Decision Making influence of donor age on PK survival, provided
corneas meet minimum criteria for endothelial
Evidence-based medicine is widely considered cell density [2, 25]. The support is mutual, with
essential to the rational development of health- the RCT affording credibility to the registry find-
care policies and clinical practice. In assessing ings concerning donor age. However, direct com-
the validity of the information/evidence provided parisons and benchmarking studies between
by a study, the US Preventive Services Task Force registries and RCTs and between studies in dif-
methodology (www.uspreventiveservicestask- ferent countries need to be treated with caution as
force.org) uses a hierarchy of research design, the definitions used for indications, risk factors
which ranges from the strongest level of evi- and postoperative complications can and do vary.
dence, Level I, based on randomized controlled Registries, as with other means of collecting
trials (RCT), down to Level III, which includes data, do have limitations and are potentially vul-
case reports, clinical practice and expert opinion. nerable to errors stemming from inadequate data
10 National Corneal Transplant Registries 137
accuracy and poor data return rates, causing criteria. Registries provide a critical insight into
selection bias. Data in registries are collected how well outcomes from controlled trials and
prospectively, and the usefulness of the informa- single-centre studies are reflected in routine prac-
tion gathered depends on the willingness of cen- tice [7, 18]. Moreover, data and analyses from
tres to submit complete and accurate data with a registries can help to identify questions and guide
high return rate; but this has to be done without the setting up of RCTs. When trying to answer
necessarily having the motivation of a specific questions such as, How well does this treatment
question to answer. Collection of high-quality work? or, perhaps of greater importance, Has the
data from large numbers of patients across many patient benefitted from this treatment?, questions
centres helps to correct bias from centres with that are fundamental to the evaluation of new pro-
poor return rates and/or inadequate data accu- cedures and interventions intended to improve
racy. A data collection initiative launched by the transplant outcomes, it is important for evidence
American Academy of Ophthalmology, which to be gathered from as many sources as possible,
gathers data directly from electronic health including RCTs, registry data, well-controlled
records (www.aao.iris-registry), should also help single-centre case series, case reports, expert
address these concerns. Whereas RCTs and other opinion and meta-analyses such as the those spon-
well-controlled trials are designed with a specific sored by the Cochrane Eyes and Vision Group
question in mind, which in turn defines the clini- [16, 26]. It is clear, however, that national corneal
cal dataset required for the analysis, registries transplant registries have an important role to play
often lack such specific drivers for defining their in the monitoring of outcomes in everyday prac-
datasets. They may, therefore, fail to seek specific tice across multiple transplant centres.
relevant information that may have an important
influence on the outcome measure of interest in a
future analysis. However, the amount of data
requested for each patient must take into account
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Economic Evaluation
ofKeratoplasty 11
IsabelleBrunette, CatherineBeauchemin,
andJeanLachaine
Abstract
The economic evaluation of healthcare interventions is now a prerequisite
in many jurisdictions. Adoption of new healthcare interventions cannot
only be based on their efficacy and safety. In the context of limited health-
care resources we are facing, their economic impact should also be consid-
ered. To estimate the economic impact of health interventions, methods
for economic evaluation have been developed and adopted. The main
objective of these economic evaluations is to help the healthcare decision
makers to select interventions that will support a better allocation of
resources.
Alongside the development of different surgical techniques for corneal
transplantation, economic evaluations have been performed. The new sur-
gical procedures have improved the clinical performance of corneal trans-
plantation, and in most cases these new interventions were shown to be
cost-effective.
Only a few economic evaluations of corneal transplantation techniques
have been performed in only a few different countries. Additional eco-
nomic evaluations are needed to assess the economic impact of these inter-
ventions over many more contexts of use.
Keywords
Corneal transplantation Economic evaluation Cost-effectiveness analy-
sis and cost-utility analysis
Cost-Minimization Analysis
ethods forEconomic Evaluation
M
(See Table11.1) When interventions are considered similar in all
relevant aspects, a cost-minimization analysis
An economic evaluation typically takes into can be considered. In a cost-minimization analy-
account both the resources consumed by an inter- sis, the preferred intervention would be the alter-
vention and the consequences of that interven- native with the lowest cost. For this type of
tion. The intervention of interest is also always economic evaluation, the critical issue is to con-
compared to at least one alternative intervention. firm that there are no meaningful differences
The following five methods can be considered between the alternatives for all important patient
when performing an economic evaluation: cost- outcomes, including efficacy, adverse events,
consequence analysis, cost-minimization analy- impact on quality of life, treatment adherence or
sis, cost-effectiveness analysis, cost-utility convenience, etc. Once the equivalence of the
analysis, and cost-benefit analysis [1, 2]. compared alternatives is established, then the less
approach has been developed, but this approach when performing an economic evaluation of cor-
is associated with significant difficulties, espe- neal transplantation, the time horizon of the eval-
cially because it depends on individuals ability uation should be long enough to capture all the
to earn income. costs and health consequences associated with
There are some specifics to consider when the intervention but also all those associated with
performing an economic evaluation. These com- short-term and long-term complications and
prise: the comparator, the perspective, the time recurrences.
horizon, and the generalizability.
Generalizability
Comparator
Generally in medicine, outcomes of an interven-
By definition, an economic evaluation is always tion performed in one location are expected to be
comparative, thus at least two interventions are replicable in other places. For example, the suc-
compared [3]. The appropriate comparator should cess of a medication or the rate of complications
represent the intervention to be eventually of a surgery is expected to be similar from one
replaced by the intervention of interest. For country to another, as long as the medication is
example, lamellar keratoplasty was compared to used and the surgery is performed in similar con-
penetrating keratoplasty (PK). As well, PK was ditions. Therefore, results of health intervention
compared to the absence of surgical intervention, are in general considered to be generalizable.
since at the time PK was introduced, no other This is not the case with the results of an eco-
type of surgery was available. nomic evaluation. Given the significant differ-
ences in cost structure and dispensation of care
from one country to another, an intervention
Perspective deemed cost-effective in one country may not be
cost-effective in another country.
The perspective of the analysis is also an impor-
tant consideration for an economic evaluation. It
basically defines the point of view of the analysis. Interpretation oftheResults
The most common perspectives are the societal
perspective, the healthcare system perspective, Another key consideration with economic evalu-
and the third-party payers perspective. The ation is the interpretation of the results. Results
selected perspective defines which cost would be of the cost-minimization and the cost-benefit
considered in the economic evaluation. For analyses are easy to interpret. In the first instance,
example, the cost of the surgery will be com- the least costly alternative is selected, while in
prised in all of these three perspectives, but the the latter, the alternative with the highest net ben-
cost associated with the productivity losses while efits will be selected. For the cost-consequence
the patient is hospitalized would be included in analysis, the decision maker has to determine
the societal perspective only. which of the alternative interventions would be
preferable after considering the various vectors
of efficacy and costs. The cost-effectiveness and
Time Horizon cost-utility analyses are the most frequently used
methods for economic evaluation, and these anal-
An economic evaluation should encompass all yses result in an ICER or an ICUR, respectively.
relevant costs and health consequences associ- The ICER and the ICUR basically estimate the
ated with the intervention under evaluation. For incremental cost required to obtain an additional
this, the time horizon should be long enough to unit of health benefit. For example, results can be
capture all related events and costs. For example expressed in terms of $20,000 per life-year
11 Economic Evaluation ofKeratoplasty 143
gained or $5000 per surgical success or $40,000 The surgical techniques for corneal transplan-
per QALY. To determine if an intervention is tation have been relentlessly evolving during the
cost-effective, the decision maker has to decide if past decades. The paradigm of systematic full-
the ICER or the ICUR is below its willingness to thickness corneal replacement has been funda-
pay for the health benefit. If the decision maker is mentally revised, to be replaced by that of
willing to pay $50,000 for a QALY and the ICUR lamellar transplantation designed to replace only
for the intervention is $40,000, then this interven- the diseased tissue while leaving intact the
tion would be considered cost-effective. In con- healthy corneal layers.
trast, an intervention with an ICUR of $60,000
would not be considered cost-effective.
Endothelial Keratoplasty
in eyes where the posterior layers, and more spe- few economic evaluations of corneal transplanta-
cifically the corneal endothelium, remain healthy, tion have been published. Six of these economic
as this is usually the case in keratoconus, for evaluations are cost-utility analyses, two are cost-
instance. The deep anterior lamellar keratoplasty effectiveness analyses, and one is a cost-
(DALK) is a surgical procedure consisting in the minimization analysis. The adopted perspective
removal and replacement of the anterior layers, of these economic evaluations was either a
down to Descemets membrane. healthcare system perspective or a third-party
Both observed and long-term predicted graft sur- payer perspective, and the time horizons ranged
vival and endothelial densities are higher after from 1 year to a lifetime period. Three economic
DALK than after PK, making it a preferred tech- evaluations were performed in Singapore, two in
nique for younger patients with corneal diseases not the United States, two in the Netherlands, one in
involving the endothelium [43]. The median pre- Germany, and one in Canada.
dicted graft survival is 49 years in patients who A German study first reported in 2006 the
underwent DALK and 17 years in patients who costs and utility associated to PK in patients with
underwent PK and had normal recipient endothe- poor binocular visual acuity [48]. In this study by
lium (P<0.0001) [44]. DALK is superior to PK for Hirneiss and al., costs and patients utility related
preserving endothelial cell densities, with an average to PK in one eye were evaluated using a 10-year
5-year postoperative endothelial cell loss of 22 % time frame. Clinical data, in terms of patients
after DALK and 50 % after PK (P<0.0001) [44]. visual acuity, were obtained from a retrospective
The risk of endothelial rejection is also eliminated, analysis of 60 patients with a mean age of 46
and the incidence of rejection episodes after DALK years. Costs included in this analysis comprised
was reported to be 50 % less than after PK [45]. those associated with surgery, ophthalmic medi-
On the other hand, there are no advantages to cations, ophthalmic medical evaluations, contact
DALK for refractive error and best-corrected lenses, and disinfection solutions. Utility values
visual acuity outcomes [46]. Overall visual acu- were obtained by converting patients best-
ity after DALK and PK is the same. It must be corrected binocular visual acuity into patients
said, however, that DALK with a manual dissec- utility values, using the Brown and Sharma con-
tion technique results in lower visual acuity than version chart [7, 48, 57]. The ICUR related to PK
PK (average difference of 1.01.8 line) or DALK was estimated at US$11,557 per QALY, which
using a big-bubble dissection technique (average represents a cost-effective strategy according to
difference of 2.22.5 lines) [44]. the authors.
As an extraocular procedure, DALK has An economic analysis by Roe and al. was con-
important theoretic safety advantages. However, ducted in order to evaluate the cost-utility of PK
DALK has not yet reach levels of popularity for patients with severe keratoconus, over a life-
comparable with current endothelial keratoplasty time period [55]. Visual acuity data were
techniques [6]. The standardization of the big- extracted from a retrospective multicenter study
bubble dissection technique warranted to reduce that included a total of 123 patients with kerato-
the incidence of Descemets membrane perfora- conus who underwent PK. Postoperative compli-
tion [47] would increase the corneal surgeons cation rates, including graft failure, graft
confidence in the technique. rejection, increased intraocular pressure, astig-
matism, suture abscess, and cataract, were
obtained from published clinical studies. Mean
conomic Evaluations ofCorneal
E pre- and postoperative best-corrected visual acu-
Transplantation Techniques ities were used to estimate patients utilities. The
(See Table11.2) ICUR of PK for treating one eye, when compared
to no treatment, was estimated at US$1942 per
Although clinical results of lamellar keratoplasty QALY.
have been extensively reported in the past years, Endothelial keratoplasty techniques were com-
little is known about its economic impact. Only pared to PK in a few economic evaluations. The
Table 11.2 Economic evaluations of corneal transplantation
146
Type
Author (year) Perspective
Country Time horizon Comparators Costs included Base case results
Hirneiss et al. (2006) Cost-utility PK versus no surgical Donor tissue preparation, surgery, ICUR PK versus no surgical
[48] Healthcare system intervention follow-up, medications intervention:
Germany 10-year period US$11,557/QALY
Bose et al. (2013) [49] Cost-utility using a decision tree DSEK versus PK Medical charges associated with the ICUR DSEK versus PK:
Singapore Healthcare system PK versus no surgical initial procedure and related US$5209/QALY
3-year period intervention complications
DSEK versus no surgical
intervention
Prabhu et al. (2013) Cost-utility using decision tree DSAEK versus PK Donor tissue preparation, surgery, DSAEK dominates PK
[50] Third-party payer follow-up, postoperative
USA 5-year period complications, procedures,
medications
van den Biggelaar Cost-effectiveness PK versus FS-DSEK versus Preoperative costs, surgical FS-DSEK dominated by DSAEK
et al. (2012) [51] Healthcare system DSAEK procedures, hospitalization, FS-DSEK dominated by PK
The Netherlands 15-month period follow-up visits, postoperative drugs ICER DSAEK versus PK:
(3 months pre- US$5920 per clinically improved patient
operation+12 months (defined as a patient with a combined
post-operation) effectiveness of both a clinically
improved best spectacle-corrected visual
acuity and a clinically acceptable
refractive astigmatism)
Van den Biggelaar Cost-effectiveness DALK versus PK Preoperative costs, surgical ICER DALK versus PK:
et al. (2011) [52] Healthcare system procedures, additional procedures, US$13,768 per clinically improved
The Netherlands 13.5-month period hospitalization, follow-up visits, patient on the 25-item National Eye
(1.5 months pre- postoperative drugs Institute Visual Functioning
operation+12 months Questionnaire
post-operation) US$9522 per patient with an endothelial
cell loss of maximally 20 % within the
first year
Koo et al. (2011) [53] Cost-utility using decision tree PK versus no surgical Medical costs associated with the ICUR PK versus no surgical treatment:
Singapore Healthcare system treatment primary cornea surgeries and any US$3003/QALY
20-year period DALK versus PK subsequent treatments for ICUR DALK versus PK:
complications US$2423/QALY
I. Brunette et al.
Table 11.2 (continued)
Beauchemin etal. Cost-utility using Markov PK versus PLK techniques Surgery, follow-up, postsurgical PLK dominates PK
(2010) [54] model (including DLEK, DSEK complications
Canada Healthcare system and DSAEK)
Lifetime period
Roe et al. (2008) [55] Cost-utility using decision tree PK versus no surgical Surgery, postoperative medications, ICUR PK versus no surgical
USA Third-party payer intervention follow-up visits, postsurgical intervention:
5-year period complications In 1 eye: US$1942
In the second eye: US$2228
In both eyes: US$2003
Tan et al. (2014) [56] Cost-minimization Tissue-engineered Investment cost, amortization of Tissue-engineered constructs for EK
Singapore Ophthalmic institution constructs versus donor investment cost, annual recurring could be produced at a cost of US$880
1-year period tissue procured from eye cost per transplant
11 Economic Evaluation ofKeratoplasty
first of these evaluations, by Beauchemin etal. and PK. This analysis was based on data from a
[54], was performed in Canada and compared multicenter randomized clinical trial and a non-
DLEK, DSEK, DSAEK, and PK using a cost- comparative prospective study. The health out-
utility analysis based on a Markov model over a come considered was the number of clinically
lifetime period. The health states included in the improved patients. The analysis was based on a
model comprised: waiting time for transplant, 1-year time horizon. The percentages of clinically
graft survival with or without complications, irre- improved patients were 52, 44, and 43 % with
versible graft failure, non-eligibility, and death. In DSAEK, PK, and FS-DSEK, respectively. Mean
this economic evaluation, endothelial keratoplasty total costs per patients were US$8416 with
was more effective, providing more QALY, and DSAEK, US$7942 with PK, and US$14,807 with
was less costly than PK. Therefore, endothelial FS-DSEK. Therefore, FS-DSEK is dominated by
keratoplasty was shown to be a dominant strategy both PK and DSAEK, as it is more costly and less
compared to PK. The robustness of the results effective than the two alternatives considered.
was confirmed by deterministic and probabilistic DSAEK was shown to be more costly than PK,
sensitivity analyses. but also more effective, with an ICER of US$5920
Based on a retrospective study, Bose etal. [49] per additional clinically improved patient.
performed a cost-utility analysis comparing In another study, van Den Biggelaar etal. [52]
DSEK and PK. Improvement in best spectacle- performed a cost-effectiveness analysis compar-
corrected visual acuity was used to calculate the ing DALK to PK. This analysis was performed in
change in QALY over a 3-year period following the Netherlands alongside a randomized multi-
the procedure. Cumulated costs over the 3-year center clinical trial with a time horizon of
period were slightly higher with the DSEK proce- 13.5 month (1.5 months before and 12 months
dure, but the number of QALY gained was also after surgery). The health outcome measures
higher. The ICUR for DSEK compared to PK was were the proportion of clinically improved
estimated at US$5209 per QALY, which is much patients on the 25-item National Eye Institute
lower than the threshold usually used in Singapore, Visual Functioning Questionnaire (NEIVFQ) and
where the study was performed. Therefore, it can the proportion of patients with endothelial cell
be concluded from the results of this study that loss of 20 % or less within the first year. DALK
DSEK is a cost-effective procedure. was more costly than PK, but it was also more
In the US study by Prabhu et al. [50], DSAEK effective than PK for both outcomes measures
was compared to PK in a cost-utility analysis with (NEIVFQ and cell loss) (NEIVFQ and cell loss).
a 5-year time horizon based on published litera- The ICER was estimated at US$13,768 per clini-
ture. The utility values used to estimate the num- cally improved patients on the 25-item NEIVFQ
ber of QALY were based on visual acuity and at US$9522 per patient with cell loss of 20 %
outcomes. The economic model developed to per- or less.
form this economic evaluation considered compli- DALK has also been compared to PK in a
cations, graft dislocation, early graft failure, graft cost-utility analysis performed in Singapore by
rejection, and high intraocular pressure. After the Koo et al. [53]. One-year costs and outcomes
5-year period, costs associated with DSAEK were were collected from patients seen for corneal
lower than with PK, and the number of QALY graft between January 1991 and January 2009.
gained was higher with DSAEK. Therefore, based Costs associated with DALK were higher than
on this analysis, DSAEK is a dominant strategy for PK, but the number of QALY gained were
compared to PK, being more effective and less also higher with DALK. The ICUR of DALK
costly. compared to PK was estimated at US$3025 per
van den Biggelaar etal. [51] in the Netherlands QALY, which is much lower than the threshold
performed a cost-effectiveness study comparing that would usually be used in Singapore.
femtosecond laser-assisted Descemets stripping Therefore, DALK can be considered as a cost-
endothelial keratoplasty (FS-DSEK), DSAEK, effective procedure.
11 Economic Evaluation ofKeratoplasty 149
Finally, Tan etal. [56] recently performed a year in perfect health. Although there may not
cost-minimization analysis comparing a tissue- be a consensus on the value of a QALY, the
engineering strategy to a procured tissue strategy. cost per QALY found in all the cost-utility
They compiled all the cost associated with these analyses on corneal transplantation proce-
two strategies according to the perspective of an dures was much lower than the usual thresh-
ophthalmic institution in Singapore that pos- old. Even more, in some cases the procedure
sesses the surgical expertise to perform endothe- was considered as dominant, being more
lial keratoplasty. The cost per transplant was effective and less costly than the alternative
lower with the tissue-engineering strategy ($880) interventions.
compared to a procured tissue strategy ($3710). Much progress has been made in recent
Therefore, based on this cost-minimization anal- years to improve the success of corneal trans-
ysis, the tissue-engineering strategy would be plantation interventions. Although other eco-
cost-effective. nomic evaluations deserve to be made to learn
more about the economic impact of these
Conclusions interventions over many different contexts of
In a context of healthcare economic constraint, use, the results to this day indicate that most of
economic evaluations allow for a better allo- these new interventions are cost-effective.
cation of resources. Although the number of
economic evaluation on the many procedures
for corneal transplantation is limited and not References
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H. Quality of life associated with unilateral and bilat-
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Ophthalmology. 2007;114(4):6319. doi:10.1016/j. fuchs endothelial dystrophy. Cornea. 2013;32(5):e60
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jcrs.2005.12.078. Descemets membrane endothelial keratoplasty.
11 Economic Evaluation ofKeratoplasty 151
Abstract
Astigmatism is the leading factor to limit visual rehabilitation after other-
wise successful keratoplasty. Reasons for post-keratoplasty astigmatism
are multifactorial, and they can be divided into donor-related factors,
recipient-related factors, intraoperative factors, and postoperative factors.
In most reports the post-keratoplasty astigmatism is between two and four
diopters after penetrating keratoplasty (PKP) and deep anterior lamellar
keratoplasty (DALK). However, the amount of astigmatism varies and can
be large enough to require surgical intervention to reach adequate optical
correction. Endothelial transplantation does not usually induce astigma-
tism and surgical intervention is not necessary. The safest method to cor-
rect post-keratoplasty astigmatism is by use of spectacles followed by
different types of contact lenses. Surgical correction of post-keratoplasty
astigmatism includes astigmatic keratotomy, wedge resection, intracor-
neal ring segments, or excimer laser. Even higher amounts of regular
corneal astigmatism can be corrected using toric intraocular lenses
implanted both to phakic and pseudophakic eyes. Surgical treatment of
post-keratoplasty astigmatism is always planned on individual basis and
after careful examination. None of the single surgical methods fully
correct the astigmatism, and often different surgical methods need to be
combined. Here we have reviewed the reasons and different treatment
modalities for post-keratoplasty astigmatism.
Keywords
Post-keratoplasty astigmatism Toric IOL Femtosecond laser
Astigmatic keratotomy Wedge resection Corneal transplantation
We have recently shown that FS laser-assisted 1-year follow-up [37]. Recently, a technique
intrastromal AKs are safe, and the refractive and which utilizes FS laser has been introduced
topographic results are comparable to [14], but has not gained wide popularity.
epithelium-penetrating techniques [60]. We Krachmer and Fenzl [23] compared relaxing
found significant 3038 % improvements in incisions (N = 16) and wedge resections (N = 10),
topographic and refractive cylinders. Because finding a 43 % reduction with incisions and
both anterior and posterior topographic cylin- 59 % with resections.
ders had a significant reduction in astigmatism,
this indicates that the effect of intrastromal inci- Intracorneal Ring Segments
sions extends throughout the whole cornea. The Intracorneal ring segments (ICRSs) provide
theoretical advantages of intrastromal relaxing another means to correct ametropia following
incisions for treating astigmatism are its relative keratoplasty. The idea behind this technique is
simplicity, less risk of postoperative infections, the flattening effect to the cornea caused by the
and reduced discomfort to the patient. In our implantation of one or two intracorneal seg-
patient material no infections were recorded and ments. Altogether four studies have addressed
patients did not report pain or unpleasant effects the efficacy and safety of these implants. Very
due to incisions. It is not, however, possible to recently, Lisa et al. [29] showed in their cohort
differentiate superiority between intrastromal study of 32 eyes that implantation of ICRS
incisions and epithelium-penetrating FS laser increased both uncorrected (UDVA) and cor-
incisions or manual AK based on this popula- rected distant visual acuity (CDVA) as well as
tion, as the other methods also have a very low decreased both spherical equivalent and astig-
rate of complications. Intrastromal relaxing matism. Likewise, Coscarelli and collaborators
incisions seem to be a good alternative to more [10] in their larger retrospective analysis of 59
penetrating methods of treating post-kerato- eyes showed that the corrected visual acuity
plasty astigmatism. Based on our experience the improved by 1.5 lines, and the mean spherical
effect of FS laser-assisted intrastromal AKs is equivalent decreased from 6.3 3.4 D to
good, the rate of adverse effects or complica- 2.7 2.5 D. The topographic astigmatism
tions is low, and reoperations are simple to per- decreased from 3.4 2.1 D to 1.7 1.0
form when needed [60]. D. Somewhat similar results were obtained by
Prazeres et al. in [39] and Arriola-Villalobos
Wedge Resection and collaborators in [5].
Troutman [54] was the first to introduce corneal
wedge resections to treat high (over 10 D) Excimer Laser
post-keratoplasty astigmatism. The technique Photorefractive keratectomy (PRK) and laser-
follows the idea of AKs, but instead of relaxing assisted in-situ keratomileusis (LASIK) have
the strain in the cornea, wedge resections been widely used to treat post-keratoplasty
remove corneal tissue, and the opposing wound refractive errors. Graft rejection as well as scar
edges are sutured with 10-0 or 11-0 nylon and haze formation has been reported after PRK
sutures to initially overcorrect the astigmatism. limiting the applicability of this technique.
As a rule of thumb, resection of 1 mm of corneal LASIK has certain advantages over PRK in that
tissue should decrease astigmatism by 1020 larger amounts of spherical and astigmatic
D. Obviously, the technique suffers from low refractive errors can be treated with this tech-
predictability, and when performed manually nique, and it seems to provide somewhat pre-
the technique is very demanding. De la Paz and dictable refractive outcomes and seems to be
collaborators showed in their analysis of 21 effective.
patients that wedge resections were safe and Bilgihan and colleagues showed that PRK
decreased refractive, topographic, and kerato- reduced astigmatism by approx. 40 % in low to
metric astigmatism by more than 50 % in their moderate post-keratoplasty astigmatism patients.
12 Post-keratoplasty Astigmatism 157
Yet, one-third of the patients suffered from LASIK flap is created in one session, lifted, and
significant haze which resolved in most cases, allowed to heal. In theory, this could alleviate the
and roughly 10 % of patients experienced graft strain within the corneal graft, thus reducing
rejection [7]. Forseto Ados et al. studied the astigmatism. In the second step, the flap is lifted
safety and efficacy of mitomycin C (MMC)-PRK and refractive correction is performed to the stro-
in post-keratoplasty patients and found that the mal bed. To our knowledge, however, no conclu-
procedure had an index of success of 55 % in cor- sive studies have been performed to prove that
recting astigmatism. Haze developed in roughly the 2-step LASIK is more effective than the
10 % of patients [12]. Similarly, Ward and col- 1-step LASIK. Furthermore, it is unclear if FS
laborators in their retrospective analysis of 20 laser-assisted LASIK flaps would offer any
patients found that MMC-PRK decreased astig- advantage over flaps made by microkeratomes or
matism from 4.9 D to 2.0 D [58]. if wave-front- or topography-guided excimer
Kovoor et al. compared in their small clinical procedures would offer advantage over conven-
trial the efficacy of PRK and LASIK in reducing tional treatments.
refractive errors after keratoplasty. Essentially,
they found that both procedures were effective in
treating post-keratoplasty refractive errors with- Intraocular Surgery
out significant differences between the two tech-
niques. They found that both methods reduced Regular corneal astigmatism can be corrected
astigmatism by 4050 % [22]. using toric intraocular lenses (tIOLs). For eyes
LASIK is generally considered to be more having normal crystalline lens, possible alterna-
effective than PRK in treating myopia and astig- tives are in the anterior chamber implantable iris-
matism in patients that have had a corneal trans- claw or in the sulcus implantable collamer lenses.
plant [24]. Yet, LASIK in post-keratoplasty For pseudophakic eyes, iris-claw or in the sulcus
patients is less efficient in treating the astigmatic implantable add-on supplementary lenses can be
component than the spherical component. Some used. Supplementary add-on IOLs are designed
authors, however, have reported up to 6 D reduc- to be implanted in the ciliary sulcus of a pseudo-
tion in astigmatism with LASIK [4, 59]. Post- phakic eye in addition to an IOL in the capsular
keratoplasty LASIK patients are prone to bag. Product specifications for the toric anterior
complications with increased risk of graft rejec- chamber or posterior chamber sulcus IOLs which
tion, graft dehiscence, epithelial ingrowth, and have been used for correction of post-keratoplasty
graft decompensation [24]. astigmatism are listed in Table 12.1. For implan-
Intriguingly, LASIK can be performed as a tation in the capsular bag after removal of the
2-step procedure [3, 8]. In this technique a cataractous nucleus, ten different monofocal
Table 12.1 Product specifications for anterior chamber or sulcus implantable toric intraocular lenses (IOLs) or sulcus
implantable supplementary add-on IOLs for correction of post-keratoplasty astigmatism
Manufacturer Material Power range (D)
IOL
Artisan Ophtec, the Netherlands PMMA Sph. 23.0 to (+7.5)
Cyl. 1 to (7.5)
ICL Staar Surgical, USA Collamer Sph. 3.0 to (23.0)
Cyl. +1.0 to (+6.0)
Add-on IOLs
Sulcoflex Rayner, UK Hydrophilic acrylic Sph. 7.0 to (+7.0)
Cyl. +1.0 to (+6.0)
Torica HumanOptics/Dr. Schmidt, Hydrophobic MicroSil Sph. 30.0 to (+6.0)
Germany Cyl. +1.0 to (+30.0)
158 K. Krootila et al.
tIOLs are available [56]. Use of tIOLs for correc- ultraviolet-absorbing chromophore in the poly-
tion of post-keratoplasty astigmatism offers mer chains. This lens can be implanted into the
simultaneous option to correct spherical ametro- eye through a 3.0 mm corneal incision, and its
pia at the same time. implantation is indicated in phakic eyes. The lat-
est model of the ICL has a central hole allow-
Anterior Chamber Iris-Claw Lens ing aqueous flow from posterior chamber through
The single-piece iris-enclavated Artisan IOL is the hole into the anterior chamber, which elimi-
made of hard polymethyl methacrylate (PMMA). nates the need of peripheral iridotomy or iridec-
It can be implanted through a 5.5 mm wound, tomy. Peripheral iridotomy or iridectomy was
which subsequently requires suturing. Suturing required when using previous model of ICL.
the wound makes controlling the astigmatism The efficacy and safety of toric ICL for cor-
more challenging and also often delays the final rection of post-keratoplasty astigmatism have
outcome of the surgery. Using this anterior cham- been addressed in three publications. Results of
ber IOL also necessitates peripheral iridotomy or altogether 14 eyes of 14 patients in two different
iridectomy. Iris-claw IOLs can be used in phakic publications have been presented [2, 18], and in
and pseudophakic eyes. one publication, a single patient was reported [1].
Tehrani and Dick presented a report of a ker- In these studies, the refractive cylinder decreased
atoconus patient who had 7.6 diopters of corneal by 6090 % at 1224 months. From all 15 eyes,
astigmatism after keratoplasty and CDVA of in five (33 %) the CDVA improved, in nine
20/32 [51]. Using a toric iris-claw Artisan (60 %) remained the same, and in one (7 %)
lens, the UDVA improved to 20/20 after 6 decreased one line. The refractive astigmatisms
months. In a larger material of 36 eyes of 35 were reported to be stable during the follow-up
patients, the refractive cylinder of 7.1 2.0 D periods, and no lens rotations or lens-related
decreased to 2.0 1.9 D at 3 years [50]. At the adverse effects were reported. The endothelial
last follow-up, 28 % of the eyes had a refractive cell loss was reported not to differ from the
cylinder less than 1 D, 58 % of the eyes had a expected endothelial cell loss after corneal trans-
refractive cylinder less than 2 D, and 92 % of plantation [1, 2].
the eyes had a refractive cylinder less than 4 Two different models of toric supplementary
D. In 50 % of eyes the achieved cylinder correc- add-on IOLs are available on the market
tion was within 1 D and in 72 % of eyes within (Table 12.1). The Torica (HumanOptics/Dr.
2 D of the intended correction. The UDVA Schmidt) is a three-piece IOL, in which the optic
improved significantly, while the CDVA is made of silicone elastomer and the haptics of
remained the same. Three eyes (8.3 %) lost polymethyl methacrylate. It can be implanted
CDVA more than 2 lines, three eyes lost CDVA through a 3.5 mm incision. Its toricity is available
1 to 2 lines, in 22 (61.1 %) the CDVA remained up to 30.0 D.
the same or improved 12 lines, and in three Thomas et al. described a case series of 20
eyes (8.3 %) CDVA improved more than 2 lines. patients implanted with add-on Torica IOL. The
Endothelial cell loss at 6 months postoperatively series included 15 eyes of 14 patients who had
was 13.8 18.7 % compared to preoperative val- post-keratoplasty astigmatism [53]. Refractive
ues, and a progressive endothelial cell loss was cylinder decreased significantly in this subgroup
observed at least up to 3 years. At 3 years the of keratoplasty eyes from 9.7 3.8 D to 2.4 1.7
endothelial cell loss was 30.4 32.0 % com- D at 26 months postoperatively. The UDVA
pared to preoperative values. improved significantly, while the CDVA remained
the same. Postoperative surgical IOL rotation
Posterior Chamber Sulcus Lenses was performed in five eyes (24 %). In two eyes,
The Implantable Collamer Lens (ICL) is graft failures occurred leading to re-graft. In
made of hydrophilic porcine collagen and addition, two case reports of Torica add-on IOL
hydroxyethyl methacrylate copolymer including use have been reported with successful outcome
12 Post-keratoplasty Astigmatism 159
both in reducing the refractive astigmatism and (range 08) and 5 (range 09), respectively.
improving the UDVA [28, 46]. Customized tIOLs are also available by the same
Sulcoflex is a single-piece hydrophilic acrylic manufacturer, and reports of successful use of
IOL that can be implanted through a 2.75 mm tIOLs with cylinders up to 15.0 D and 30.0 D
incision. The haptics are 10 posteriorly angu- have been reported [30, 52].
lated compared to the optic to avoid pigment dis- Using a tIOL made of hydrophilic acrylic
persion and iris capture of this sulcus-fixated optic (Rayner, UK), the post-keratoplasty refrac-
lens. Use of Sulcoflex in correction of post- tive astigmatism has been shown to decrease in 1
keratoplasty astigmatism in two eyes of two month from 6.2 2.7 D to 2.9 2.2 D (eight eyes).
patients has been reported recently [46]. In both The rotation of the IOL during the 1 month was
eyes, a reduction of refractive cylinder and an 8.1 9.4, and two patients required operative
improvement of UDVA were achieved, while the realigning of the IOL [48]. In another report of
CDVA remained constant. Excessive endothelial three cases using the same customized tIOL, the
cell loss was not observed. refractive astigmatism decreased from 8.3 2.1 D
to 0.7 0.6 D with a mean rotation of 3.3 1.2
Posterior Chamber In-The-Bag Lenses during the 12-month follow-up period [44].
Delaying the possible cataract operation at the
time of keratoplasty until sutures have been
removed and refraction stabilizes offers an option Treatment Planning
to use tIOLs in the capsular bag after cataract
removal to correct possible ametropias. Several Treatment planning for post-keratoplasty astigma-
reports of using tIOLs consisting of a single or a tism is made on an individual basis, and therefore it
few patients are available. is impossible to give definitive recommendations.
Wade and coworkers reported a larger case The patient age, corneal graft prognosis, amount
series using toric acrylic AcrySof IOL [57]. and regularity of astigmatism, endothelial cell
Results of 21 eyes of 16 patients with a mean count, lens status, and other ocular pathologies
follow-up of 14.7 months were reported. The pre- should be taken into account when planning the
operative topographic astigmatism of 4.6 2.1 D astigmatic and refractive error treatment.
was reduced to refractive astigmatism of 1.6 1.3 Furthermore, the status of the patients other eye
after cataract removal and use of in-the-bag should be taken into consideration, and if it is
tIOL. The UDVA and CDVA improved signifi- healthy the purpose and goal of treatment should be
cantly. The refractive astigmatism and the visual reflected with the expectations of the patient. In
acuities remained constant over the follow-up almost all cases the visual performance after cor-
period and up to 3 years for some patients. neal grafting is certainly impaired compared to a
Possible rotational stability was not recorded in virgin eye. Anterior segment optical coherence
the study. tomography (OCT) is a useful tool for analyzing the
Using a silicon optic tIOL (MicroSil 6116 TU, transplant contour and profile, eccentricity, and pos-
HumanOptics), the astigmatism has been reported sible bulging, which all may affect the surgical deci-
to decrease after in-the-bag implantation in two sion. Comparing different surgical methods, it is
different reports from the preoperative topo- obvious that none of the methods fully correct the
graphic astigmatism of 9.2 4.1 D to postopera- astigmatism (Table 12.2). The realistic goal of treat-
tive refractive astigmatism of 1.6 1.5 D and ment of the post-keratoplasty astigmatism is such
from 10.2 D to 2.75 D, respectively [20, 55]. The an amount that can be finally corrected by specta-
follow-up times were 3.5 months and 1 month cles or contact lenses, and not a plano refraction.
and the numbers of eyes were 11 and seven, If the corneal graft is clear and the endothelial
respectively. In all cases both the UDVA and cell count is low, we usually approach corneal
CDVA improved. The accuracy of the axis of the astigmatism by corneal interventions. In the case
IOLs during the follow-up period were 4 3 of very high corneal astigmatism, AKs followed
160 K. Krootila et al.
by wedge resection seem to be the treatment of or anterior chamber lenses provided that the lens
choice. If this is unsuccessful, re-grafting can be is clear and the anterior chamber is deep enough.
justified. If the treatment provides a reasonable Yet, possible damage to the endothelial cells lim-
effect, this may be followed by re-AKs and later its the usefulness of this approach. If the nucleus
possibly by intraocular approach with tIOL. is less transparent, tIOL in the capsular bag may
In moderate levels of astigmatism, we have be the treatment of choice.
currently a multitude of different techniques. If the endothelial cell count is high and the
These include both corneal and intraocular graft shows moderate (less than 5 D) astigma-
approaches. Excimer laser surgery, intracorneal tism, one has again a larger choice of treatment
ring segments, manual or FS laser-assisted AKs, modalities that basically include all of the above.
and FS-assisted intrastromal AKs seem all to Our own approach in these cases is to first pro-
produce relatively good results. The choice of vide optimal reduction in corneal astigmatism
treatment is based on corneal regularity, amount followed by lens-based approach.
of astigmatism and other refractive errors, the
surgeons experience, and available instrumenta-
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Optics of Transplanted Grafts: IOL
Calculation in Grafted Patients 13
Ugo De Sanctis
Abstract
Modern methods of intraocular lens (IOL) calculation have significantly
reduced the risk of employing an improper IOL power. The development
of theoretical formulas has improved the accuracy of predicting the effec-
tive lens position, while the use of laser partial coherence interferometry
has increased the accuracy of axial length measurement. IOL calculation
in grafted patients, however, is more challenging due to different and
peculiar clinical situations. These situations fall into two main scenarios.
The first comprises patients who are candidates to combined cataract
extraction, IOL implantation, and corneal graft (the triple procedure). The
second includes patients who have previously undergone corneal graft. In
this second scenario, IOL calculation may be required for cataract extrac-
tion, piggyback IOL, and phakic IOL implantation.
This chapter examines the challenges inherent in each clinical situation
and discusses the strategies that can be adopted to tackle these situations
and optimize IOL power calculation.
Keywords
Intraocular lens power calculation Triple procedure Toric intraocular
lenses
corneal power measurement. Before the interven- these cases (Fig. 13.1). However, the reliability of
tion, the examiner must compute the keratomet- these instruments also decreases when the sharp-
ric readings to be inserted into the IOL calculation ness of the optical cross section acquired during
formula without knowing what the corneal power corneal scanning is reduced by stromal edema. If
will be after the graft. reliable measurement of corneal power is
The advent of endothelial keratoplasty tech- impossible, the keratometric values of the fellow
niques, such as Descemets stripping automated eye should be employed.
endothelial keratoplasty (DSAEK) and Descemets To calculate IOL power in candidates to the
membrane endothelial keratoplasty (DMEK), has new triple procedure, the hyperopic shift induced
greatly increased the predictability of post-graft by the endothelial lamellar graft must be taken into
corneal power. These techniques induce smaller account. A number of studies have shown that
changes of corneal power and, as a consequence, microkeratome-prepared posterior lamellae
lead to more predictable refractive outcomes than change the postoperative sphero-equivalent of
is the case with penetrating keratoplasty (PKP); manifest refraction by between +0.62 and +1.26
this is a major advantage of these procedures, diopters (D) [16]. The postoperative hyperopic
which have been widely adopted in recent years. shift is caused by the endothelial lamellar grafts
decreasing the cornea power, by flattening the
anterior cornea and steepening the posterior cor-
The New Triple Procedure nea [3, 4, 610]. The more significant changes
occur on the posterior cornea. Microkeratome-
The intervention comprising phacoemulsifica- prepared lamellae have a minus lens shape, which
tion, IOL implantation, and DSAEK has become alters the corneal thickness profile and increases
the gold standard for the simultaneous surgical posterior curvature. In 23 consecutive patients
treatment of corneal endothelial diseases and who had undergone DSAEK, the microkeratome-
cataract. What has been called the new triple prepared lamella graft was found to have decreased
procedure offers numerous advantages over the the anterior corneal power by 0.24 0.61 diopters
standard technique, which comprises PKP and (D), on average, and increased the negative poste-
cataract extraction. The main advantages of the rior corneal power by 0.96 0.42 D [10].
new triple procedure are that surgery is per- A number of different methods for IOL power
formed through a small incision, corneal innerva- calculation have been proposed to compensate
tion and biomechanical strength are preserved, for this reduction in corneal power induced by
the change in corneal refractive power is moder- the posterior lamellar graft. These methods
ate, and visual recovery is faster. include:
The advantages of the new triple procedure
have increased patients expectations of visual Selection of an IOL power with predicted
recovery, and these expectations can be met if the refraction more myopic than desired
IOL power calculation is accurate. In eyes with Adjustment of the keratometric (K) readings
corneal endothelial diseases, however, the accu- used in the IOL calculation formula
racy of this calculation may be reduced due to the Optimization of the IOL A constant.
difficulty of determining the corneal power.
Anterior surface irregularities caused by epithelial The first method was used by Covert and
edema impede precise measurement of corneal Koenig [11], who selected IOL power with pre-
power when keratometry or Placido disk-based dicted refraction ranging from 0.50 to 1.15 D,
topography is employed. Corneal tomographers and by Terry et al. [12], who selected implants
that use slit-scanning or rotating Scheimpflug with predicted refraction ranging from 0.80 to
cameras might give reliable measurements in 1.25 D. This method led to accurate IOL power
13 Optics of Transplanted Grafts: IOL Calculation in Grafted Patients 165
c
166 U. De Sanctis
Table 13.1 Refractive error after cataract surgery combined with Descemets stripping automated endothelial
keratoplasty
Proportion of eyes
Follow-up Absolute prediction 1.00/ 2.00 D of target
Author Number of eyes (months) error (D) refraction
Covert and Koenig, 21 6 NA 62 %/100 %a
Ophthalmology [11]
Terry et al., Ophthalmology 135 6 NA 74 %/97 %a
[12]
de Sanctis et al., Am J 39 6 0.59 0.42 83 %/100 %
Ophthalmol [13]
Bonfadini et al., 30 18.4 9.8 0.61 0.40 83 %/NA
Ophthalmology [14]
NA not available
a
Proportion of eyes with achieved refraction within 1.00 and 2.00 diopters (D) of target refraction or emmetropia
calculations. After surgery, 6274 % of eyes proportion of eyes falling within 0.50 (43 % ver-
were within 1.00 D of emmetropia (Table 13.1). sus 20 %) and within 1.00 D (83 % versus 50 %)
However this method requires complex calcula- of the target refraction (Table 13.1).
tion. The change in corneal power induced by the The results of the above studies [1114] high-
lamellar graft modifies both the IOL power cal- light the fact that the refractive outcome of the new
culation and the predicted refraction, depending triple procedure is highly predictable, provided
on the biometric characteristics of the eye. Thus, that the IOL power is calculated taking into
to optimize the use of this method, the degree of account the postoperative refractive shift induced
myopia in the predicted refraction must be calcu- by the lamellar graft. The absolute prediction error
lated taking corneal curvature, anterior chamber is just slightly higher than that normally observed
depth, and axial length of each eye into consider- after phacoemulsification with posterior chamber
ation [15]. IOL implantation. Seven highly experienced
The adjustment of keratometric (K) readings senior surgeons found a mean absolute prediction
used for IOL calculation should take into account error of 0.25 D after simple phacoemulsification
the average expected reduction of corneal power with posterior chamber IOL implantation [16], a
induced by the endothelial lamellar graft [10]. result that is considered a benchmark of excellence
This method was used in 39 consecutive patients for cataract surgery. In other studies, the mean
operated for cataract and Fuchs endothelial dys- absolute prediction error after phacoemulsification
trophy and gave predictable postoperative refrac- with IOL implantation was comparable to that
tive results (Table 13.1). Six months after surgery, obtained after the new triple procedure, varying
the absolute prediction error (absolute difference between 0.32 and 0.71 D [1721].
between predicted and achieved refraction) was The accuracy of IOL power calculation, and
0.59 0.42 D (range +0.05 to 1.52 D). The thus the postoperative refractive outcome of the
achieved refraction fell within 0.50 D, 1.00 D, triple procedure, might further be improved by
and 2.00 D of the predicted refraction in 55.5 %, combining cataract surgery with DMEK. DMEK
83.3 %, and 100 % of cases, respectively. grafts, which contain only donor Descemets
An optimized IOL A constant was used by membrane and endothelium, should induce very
Bonfadini et al. in 30 eyes undergoing the new slight changes in corneal power. The minus lens
triple procedure using pre-sectioned lamellar effect cannot occur, because the grafts do not con-
endothelial graft [14]. This approach significantly tain donor stroma. However, a postoperative
decreased the mean absolute error (from 1.09 0.63 hyperopic shift has also been reported using this
D to 0.61 0.40 D; p = 0.004) and increased the technique [22, 23]. Ham et al. [22] analyzed
13 Optics of Transplanted Grafts: IOL Calculation in Grafted Patients 167
corneal power by Scheimpflug imaging and surgical technique that is standardized in terms of
showed that the negative power of the posterior trephination method, donor-recipient disparity,
cornea increased on average by +1.00 D after and suture technique. However, the resulting pre-
DMEK. The study authors attributed this change dictability of postoperative refractive outcome is
to the postoperative de-swelling of the posterior only moderate. Davis et al. [26] report on a series
stroma, which leads to a steepening of the poste- that included 106 eyes; they found postoperative
rior corneal curvature. Lasser et al. also reported a sphero-equivalent values in the range of 6.00 D
postoperative hyperopic shift in 61 eyes that to +4.00 D and differences from the target refrac-
underwent DMEK combined with phacoemulsifi- tion of 2.00 D in 48 % of cases. Javadi et al.
cation and IOL implantation [23]; they suggested reported similar results [27]; in a series of 76
selecting IOL power with a predicted refraction of interventions, the postoperative sphero-equivalent
0.75, to optimize postoperative results. Using values ranged from 6.55 to +3.78 D and the dif-
this approach, 54.5 % of eyes were within 1 D of ference from target refraction was 2.00 D in
emmetropia and 77.3 % were within 2 D of 54 % of cases.
emmetropia, 6 months after surgery. The refractive results would be better if phaco-
emulsification with IOL implantation were per-
formed as a secondary procedure, after the
Cataract Surgery Combined corneal graft [28]. However, the surgical trauma
with Penetrating Keratoplasty due to cataract extraction increases postoperative
endothelial cell loss, and this two-step approach
Cataract surgery combined with PKP is routinely delays postoperative visual recovery, since cata-
performed for the simultaneous surgical treat- ract surgery is not usually performed until 1224
ment of cataract and corneal stromal diseases, months after PKP, when all sutures have been
such as ectasia, postinfectious scars, traumatic removed.
leukomas, and dystrophies. In eyes scheduled for
cataract surgery combined with PKP, IOL power
calculation is truly challenging: the postoperative IOL Calculation in Patients
refractive power of the corneal graft is extremely with Prior Corneal Graft
variable, the eyes axial length may change after
the procedure, and the reliability of theoretical Cataract extraction is the most frequent clinical
formulas that calculate the effective lens position situation that requires IOL power calculation in
from the preoperative corneal curvature and axial eyes with prior corneal graft; other special cir-
length is reduced [24]. cumstances include piggyback IOL and phakic
The great variability of postoperative corneal IOL implantation. In these clinical situations,
power is caused by the full-thickness trephination IOL power calculation should be planned 23
of the recipient cornea and the suturing of the months after suture removal, when serial topo-
donor tissue. After suture removal, the corneal graphical analysis demonstrates corneal curva-
power may be below 40 D or above 48 D. Since ture to be stable.
the postoperative corneal power is highly unpre-
dictable, Katz and Foster have suggested using
the keratometric readings of the fellow eye to cal- Cataract Surgery in Eyes
culate IOL power [25]. However, this approach is with Previous Corneal Graft
only suitable for patients with unilateral diseases
and leads to unpredictable refractive results. Cataract occurs quite commonly in eyes with
Today, many surgeons use the average postopera- prior corneal graft, because of preoperative and
tive keratometric readings obtained from a previ- postoperative intraocular inflammation, surgical
ous series of corneal grafts; for this purpose, the trauma, and prolonged use of corticosteroids.
series should comprise grafts performed using a Cataract is frequently associated with clinically
168 U. De Sanctis
significant corneal astigmatism. The multicenter corneal astigmatism and cataract with a single
Corneal Transplant Follow-up Study showed that procedure. The first toric IOL for correcting post-
corneal astigmatism after keratoplasty was 4 D PKP astigmatism was implanted during cataract
in 43 % of eyes and 6 D in 20 % of eyes [29]. In surgery in 1999 [30]. It was made of PMMA and
eyes with marked corneal astigmatism, postop- required a 6 mm incision. Since then, many toric
erative visual recovery is generally only modest IOL models, made of different materials and with
after phacoemulsification with monofocal IOL different designs, have become available
implantation. After surgery, anisometropia makes (Table 13.2). The surface adhesiveness of acrylic
this refractive error difficult to correct fully by materials and the new designs that have been
means of spectacles. Contact lenses are difficult introduced have increased toric IOL stability in
to fit and frequently not tolerated and carry the the capsular bag and decreased the risk of postop-
risk of severe complications. Moreover, keratore- erative rotation [31].
fractive procedures to correct severe astigmatism A number of studies and case reports have
on corneal grafts have moderate predictability found phacoemulsification with toric IOL
and high complication rates. implantation to be effective for the simultaneous
Phacoemulsification with toric IOL implanta- correction of post-keratoplasty astigmatism and
tion provides an opportunity to correct both cataract [30, 3237]. The largest series was
reported by Wade et al. [38] and included 21 eyes posterior corneal surfaces. Working from multiple
with cataract and mean post-PKP corneal astig- measurements, it is possible to compare data and
matism of 4.57 2.05 D. After phacoemulsifica- to determine the principal meridians precisely.
tion with implantation of a single-piece acrylic The angular position of the principal meridians is
toric IOL (SN6AT, Alcon, Fort Worth, USA), the the point of reference for aligning the toric IOL
uncorrected distance visual acuity (UDVA) was during surgery; an error of 5 or 10 in positioning
20/30 in 67 % of eyes, and the refractive astig- the IOL reduces the efficacy of cylindrical correc-
matism was within 1 D of the predicted value in tion by 15 % or 30 %, respectively.
76 % of eyes. Surgically induced astigmatism must be taken
Toric IOL with customized cylindrical power into account. It varies with position (temporal/
can correct very severe corneal astigmatism. A superior), site (corneal/scleral), and length of the
hydrophilic acrylic toric IOL (T-flex 623 T, incision. A surgeon should determine his/her per-
Rayner, UK) with customized cylindrical power sonal value from a series of patients he/she has
was used in 3 eyes with cataract and post-PKP operated previously, using the same incision
astigmatism ranging from 6.75 to 8.75 D [35]. technique.
After phacoemulsification, rotation of the toric A number of companies have developed
IOL was <5. The UDVA was 20/40, and resid- online software to calculate toric IOL power. The
ual refractive astigmatism was less than 1.00 D in corneal power and astigmatism, surgically
all three cases (Fig. 13.2). induced astigmatism, incision position, anterior
Calculation of toric IOL power requires care- chamber depth, axial length, and target postop-
ful preoperative assessment of corneal astigma- erative refraction must be entered. Then the IOL
tism. Cases with irregular astigmatism are spherical/cylindrical power and the residual
contraindicated. The magnitude and principal refractive cylinder are automatically calculated.
meridians of corneal astigmatism must be mea- Online software offers simple and fast access
sured, using manual/automatic keratometers, to toric IOL power calculation. However, some of
Placido disk-based topographers, and corneal the available packages suffer from a major limita-
tomographers. Corneal tomographers analyze the tion; they calculate IOL toric power using a fixed
contributions made by both the anterior and the ratio between cylindrical power at the IOL plane
a b
Fig. 13.2 This patients left eye showed high corneal +10.50 sphere/+11.00 cylinder T-flex 603 (Rayner, UK)
astigmatism after penetrating keratoplasty 8.13 D 172; was scheduled. After surgery, the customized toric IOL
(a) and cataract extraction. The uncorrected and corrected was well aligned (b). The uncorrected and corrected dis-
distance visual acuities were 20/200 and 20/40, respec- tance visual acuities were 20/30 and 20/25, respectively,
tively, and the manifest refraction was +1.009.00 80. and the manifest refraction was 1.00 70
Phacoemulsification with implantation of a customized
170 U. De Sanctis
and at the corneal plane. This method can cause They are 3-piece silicone IOLs with rounded
significant errors in determining toric IOL power edges, 6.3 mm optic diameter, and 13.5 mm hap-
in eyes with short or long axial lengths [39]. The tic diameter. The Sulcoflex (Rayner, UK) is an
effective IOL cylindrical power at the corneal IOL specifically designed to be placed in the cili-
plane is a function of the effective lens position ary sulcus as secondary piggyback. It is a single-
and the sphero-equivalent power of the IOL. More piece hydrophilic acrylic IOL, with a round-edged
precise calculation entails converting the IOL 6.5 mm optic and 14 mm undulating round-edged
cylindrical and spherical powers into the two haptics. The optic has a concave posterior surface
principal lens powers [40]. Both lens powers are to prevent contact with the IOL in the bag. The
calculated to the corneal plane using a standard haptics have a 10 angle to prevent contact with
vertex formula. The difference between the two the iris. The aspherical model is available in half-
lens powers at the corneal plane is then used to diopter steps from 10 D to +10 D. The toric
select the IOL cylindrical power. model is available over the range of 6 D to +6 D,
with up to 6 D of cylindrical correction in
half-diopter steps.
Piggyback IOL The calculation of piggyback IOL power is
independent of eye axial length; it is calculated
The need for a primary piggyback IOL might from the sphero-equivalent of the patients refrac-
arise in eyes with extreme hyperopia that undergo tive error, using the Holladay refraction formula
cataract surgery simultaneously with, or after, [41]. The sphero-equivalent is multiplied by 1.50,
corneal graft. A secondary piggyback IOL, how- in the case of hyperopic error, and by 1.0 in the
ever, is more frequently required to treat post- case of myopic error. Several variations of this
keratoplasty refractive errors in pseudophakic formula have been proposed [42, 43].
eyes.
Secondary piggyback IOLs are placed in the
sulcus between the anterior surface of the pri- Phakic IOLS
mary IOL and posterior surface of the iris. These
IOLs should have a large optic diameter with Iris-fixated and posterior chamber phakic IOLs
rounded edge and haptic length sufficiently large are available for the correction of post-
for the size of the ciliary sulcus. For many sur- keratoplasty refractive errors in phakic eyes
geons, the Staar Surgical AQ5010 (powers from (Table 13.3). Calculation of the phakic IOL
4.00 D to +4.00 D) and AQ2010 (powers from power is independent of the eyes axial length. It
+5.00 upward) have been the favorite models. is provided by the manufacturer on receipt of the
Phakic IOL Material Haptic Diameter (mm) Power (diopters) Incision size
model Sphere Cylinder (steps) (mm)
Artisan PMMA Iris claw 7.50/8.50 23.5/+12.0 1.00/7.50 5.2/6.2
(Ophtec) 5.00/6.00 (0.50)
Verisyse
(AMO)
Artiflex Silicone with Iris claw 8.50/6.00 2.0/14.5 1.00/5.00 3.2
(Ophtec) PMMA (0.50
Veriflex haptics
(AMO)
Visian ICLa Collamer Plate 3.0/23.0 1.00/6.00 3.0
(Staar +3.0/+21.0 (0.50)
Surgical)
a
The toric model of Visian Implantable Collamer Lens is available only with negative spherical powers
13 Optics of Transplanted Grafts: IOL Calculation in Grafted Patients 171
following measurements: spherical and cylindri- 3. Jun B, Kuo AN, Afshari NA, et al. Refractive change
after descemet stripping automated endothelial kera-
cal error, keratometric readings of the principal
toplasty surgery and its correlation with graft thick-
meridian, anterior chamber depth, and postopera- ness and diameter. Cornea. 2009;28:1923.
tive refraction target. For the posterior chamber 4. Holz HA, Meyer JJ, Espandar L, et al. Corneal profile
ICLs (implantable collamer lenses), white-to- analysis after Descemet stripping endothelial kerato-
plasty and its relationship to postoperative hyperopic
white measurement is also required. This is a
shift. J Cataract Refract Surg. 2008;34:2114.
critical step for proper calculation of IOL sizing 5. Chen ES, Terry MA, Shamie N, et al. Stability of
and vaulting in the ciliary sulcus. The horizontal hyperopic refractive shift following descemet-stripping
white-to-white is measured using validated cali- automated endothelial keratoplasty. J Cataract Refract
Surg. 2009;35:11320.
pers and topographers. Ultrasound biomicros-
6. Scorcia V, Matteoni S, Scorcia GB, et al. Pentacam
copy and very-high-frequency ultrasound can be assessment of posterior lamellar grafts to explain
employed to measure the posterior chamber hyperopization after descemets stripping automated
diameter. endothelial keratoplasty. Ophthalmology. 2009;116:
16515.
7. Koenig SB, Covert DJ. Early results of small-incision
Conclusions descemets stripping and automated endothelial kera-
The biggest challenge in calculating IOL toplasty. Ophthalmology. 2007;114:2216.
power for grafted versus normal eyes is to 8. Yoo SH, Kymionis GD, Deobhakta AA, et al. One-
year results and anterior segment optical coherence
determine the corneal power accurately. In eye
tomography findings of descemet stripping automated
candidates to the triple procedure, this prob- endothelial keratoplasty combined with phacoemulsi-
lem has been significantly reduced by the fication. Arch Ophthalmol. 2008;126:10525.
advent of endothelial keratoplasty techniques. 9. Rao SK, Leung CKS, Cheung CYL, et al. Descemet
stripping endothelial keratoplasty: effect of the surgi-
These techniques induce small changes to the
cal procedure on corneal optics. Am J Ophthalmol.
corneal power; however, these must be taken 2008;145:9916.
into account when calculating IOL power. 10. de Sanctis U, Angeloni M, Zilio C, et al. Corneal
This approach leads to highly predictable power after DSAEK using microkeratome-prepared
tissues. Opt Vis Sci. 2011;88:697702.
postoperative refractive results, which are
11. Covert DJ, Koenig SB. New triple procedure: descemets
very close to those obtained after simple stripping and automated endothelial keratoplasty com-
phacoemulsification. bined with phacoemulsification and intraocular lens
In eyes with prior graft, IOL power calcu- implantation. Ophthalmology. 2007;114:12727.
12. Terry MA, Shamie N, Chen ES, et al. Endothelial
lation is required for cataract extraction and to
keratoplasty for Fuchs dystrophy with cataract: com-
correct postoperative errors. In these eyes cor- plications and clinical results with the new triple pro-
neal astigmatism is frequently high, and IOL cedure. Ophthalmology. 2009;116:6319.
selection comprises pseudophakic and phakic 13. de Sanctis U, Damiani F, Brusasco L, Grignolo
FM. Refractive error after cataract surgery combined
toric IOL models that provide the opportunity
with descemet stripping automated endothelial kera-
to correct both spherical and cylindrical errors toplasty. Am J Ophthalmol. 2013;156:2549.
simultaneously. Precise assessment of the 14. Bonfadini G, Ladas JD, Moreira H, et al. Optimization
magnitude and orientation of corneal astigma- of intraocular lens constant improves refractive out-
comes in combined endothelial keratoplasty and cata-
tism is crucial to optimize calculation of the
ract surgery. Ophthalmology. 2013;120:2349.
power of these IOLs. 15. McEwan JR, Massengill RK, Friedel SD. Effect of
keratometer and axial length measurement errors on
primary implant power calculations. J Cataract
Refract Surg. 1990;16:6170.
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Mechanical Microkeratomes
14
Elena Alb and Massimo Busin
Abstract
During the last decade several techniques of lamellar keratoplasty (LK)
have been developed with the purpose of retaining the advantages of pen-
etrating keratoplasty (PK) while avoiding the removal of healthy portions
of the cornea, thus selectively replacing the dysfunctional parts, limiting
the rate of rejection, and increasing long-term graft stability. This chapter
will review the different instruments and techniques to prepare donor tissue
for endothelial keratoplasty (EK) and deep anterior lamellar keratoplasty
(DALK). Descemets stripping automated endothelial keratoplasty
(DSAEK) foresees the transplantation of a donor graft consisting of endo-
thelium, Descemets membrane, and a variable amount of posterior stroma
in case of eyes with decompensated endothelium. In order to optimize
visual rehabilitation, the present trend is toward minimizing the amount of
stroma transplanted, and this can be done with both single- and double-cut
procedures. DALK has been gaining popularity as the optimal approach for
treating non-endothelial disorders affecting Bowmans layer and stroma.
Hand dissection of the stroma is technically difficult, and the quality of the
surfaces obtained is rarely compatible with optimal vision, while pneu-
matic dissection technique as the big bubble is difficult to learn and can
be complicated by micro-macro perforations making a conversion to PK
necessary. As an alternative, microkeratome-assisted LK has the advantage
of being a standardized, technically easy procedure, yielding extremely
smooth dissected surfaces, therefore compatible with 20/20 vision.
Keywords
Microkeratome Artificial anterior chamber Descemets stripping auto-
mated endothelial keratoplasty Deep anterior lamellar keratoplasty
Microkeratome-assisted lamellar keratoplasty
E. Alb, MD (*)
Department of Ophthalmology, M. Busin, MD
Istituto Clinico Humnaitas, Rozzano, Italy Department of Ophthalmology, Villa Igea Hospital,
e-mail: elena.albe@gmail.com Forl, Italy
all Moria microkeratomes (LSK, M2, CB units). Chiron automated corneal shaper (ACS),
It has two pumps that provide a quick and stable equipped with a system of gears to ensure a con-
vacuum for the procedure. The Moria ALTK sys- stant rate of movement on the suction ring, was
tem can be used for automated therapeutic lamel- developed to create a more reproducible corneal
lar keratoplasty or for DSAEK. In this system the flap with a nasal hinge. The height of the suction
high-speed, high-power turbine (30,000 cuts/min) ring could be adjusted to vary the diameter of the
creates a smooth keratectomy for a seamless-edge second cut, avoiding the need of changing rings.
margin. The single-piece construction of the However, this automated lamellar keratoplasty
microkeratome heads are pre-calibrated for vari- (ALK) technique was imperfect and poorly
ous depths of cuts (90400 m). Both Bausch & reproducible; it was abandoned in 1995 in favor
Lomb and Katena ACCs can be used for manual of LASIK, in which photoablation with a 193 nm
dissection of donor lamellar tissue. They are not excimer laser replaced the second refractive
designed to be used with a microkeratome. The mechanical cut [8]. In 1996 the Carriazo-
pressure inside the chamber is optimized by Barraquer pivoted rotating microkeratome (CB)
injecting fluid from the attached syringe and clos- was presented to the ophthalmic community with
ing the valve to maintain the system pressure. The the theoretical advantage of allowing the hinge to
Barron AAC (Katena, Inc., Denville, NJ, USA) is be placed wherever required. The use of an upper
a sterile, disposable device consisting of three hinge limited the risk of flap displacement during
pieces. blinking. Moria, the company that manufactured
the device, also markets disposable adaptable
microkeratome heads. In 1997, Chiron released
Microkeratome the Hansatome automated microkeratome, that
also produces a corneal flap with an upper hinge.
Initially, microkeratomes were developed to treat In 2001 Carriazo unveiled the first generation of
refractive errors in a safe and reproducible way. pendular microkeratomes (Carriazo-Pendular,
The first manual microkeratome was developed Schwind). The cutting head of this device moves
in 1958 by Jos Ignacio Barraquer, the initiator of vertically, rather than horizontally, and the pen-
modern corneal refractive surgery. The device dular motion requires a slightly lower cutting
had a cutting angle of 0 for keratophakia and pressure than do conventional microkeratomes,
keratomileusis [3]. Until 1984 the microkeratome leading to less mechanical friction and smaller
was used to cut a free corneal flap, which was size.
frozen, cryolathed on its posterior surface, Over the last decade, femtosecond laser-
thawed, and then sutured back in place [4]. In assisted dissection has replaced microkeratome-
1985 Krumeich and Swinger introduced the non- assisted dissection in the hands of most refractive
freeze keratomileusis technique. The lenticule surgeons. Instead, therapeutic keratoplasty, espe-
was processed unfrozen on its stromal side with a cially DSAEK, has become the main field of use
BKS 1000TM refractive set [5]. In 1986, Ruiz for these instruments, with new devices being
developed the in situ keratomileusis technique, in marketed recently (Gebauer, Horizon).
which a microkeratome was used to make two
consecutive cuts with a diameter and depth that
varied according to the degree of ametropia, Description of Mechanical
using a set of suction rings of different sizes, cali- Microkeratome
brated applanation lenses, and various plates [6].
In 1991 Dr. Ioannis Pallikaris introduced the con- The last several years have seen many microkera-
cept of corneal hinge [7]. Motorized microkera- tome models. Manufacturers continue to offer new
tomes, of which the Castroviejo electrokeratome and improved versions of equipment in an attempt
(unveiled in 1963) was the precursor, became to improve results. However, a microkeratome still
available in the same year. Ruiz and Lenchigs consists of few basic components: a peripheral
176 E. Alb and M. Busin
part, a central unit, and connections/accessories. thickness. Each head is designated by a number
The microkeratome itself is the actual peripheral in microns corresponding to the height of its
component with three main parts: the suction ring, guard (space between the blade and the applana-
the microkeratome cutting head, and the drive tion plate). This height does not always corre-
unit. The suction ring fixates and stiffens the globe spond exactly to the predicted flap thickness.
during the keratectomy. The choice of suction ring Variations within few microns from the predicted
depends on the corneal curvature and on the flap values are considered tolerable. There are usually
diameter required. The upper part of the suction two cavities to accommodate the oscillating
ring, called plate, can have variable diameters blade/blade holder unit and the flap itself. Some
and allocates the protruding cornea during the cut. microkeratomes use disposable sterile heads with
The microkeratome head tracking system is part of preassembled blades. The blade is usually made
the plate: it consists of two parallel dovetail of stainless steel or sometimes of chrome-
grooves for rectilinear translation or a single arci- platinum. The angle of tissue engagement varies
form rail (smooth or geared). In the latter case the from 24 to 30, and the standard oscillation
rotational axis is an eccentric plot located diamet- speed of the blade is approximately 15,000 rpm.
rically opposite the rail. A stopper is used to create The head translation could be linear when the
hinges with variable diameters. The central part of cutting head is guided by two parallel rails in the
the suction system is connected to the suction horizontal plane and can create only a nasal
chamber of the ring by a supple silicone tube either hinge, arciform when the cutting head is guided
fixed to a hollow hand grip or connected directly to in the horizontal plane around an eccentric axis
the ring. The skirt is the vertical outer part of the by a single smooth or geared arciform rail offer-
suction ring. Its lower edge must ensure hermetic ing a wide choice of hinge positions, or pendular
sealing to allow proper suction. Some manufactur- as with the Carriazo-Pendular microkeratome,
ers offer a choice of suction rings with different which has a pendulum-like cutting action via a
angulations of the lower edge of the skirt. The cor- horizontal axis located above the corneal apex.
rect choice of ring minimizes the risk of complica- Many other factors can influence the flap thick-
tions during flap creation in eyes with extremely ness. It varies proportionally to the intraocular
low or extremely high keratometric values. The pressure (IOP) reached while cutting and to the
ring also determines the diameter of the flap. In preoperative pachymetry and inversely to the
some models the diameter of the aperture of the oscillation blade and head translation rates.
ring may vary; in others the diameter of the flap to The excised lamella may be often 3040 microns
be obtained is determined by the ring thickness. thicker than planned due to tissue compression
Some manufacturers provide a nomogram to help while passing through the microkeratome slit.
choose the ring according to the required flap The motorized drive unit is connected on one
diameter and to adjust the hinge support. side to the unit; the other side is clipped or
The microkeratome cutting head consists of a screwed to the microkeratome head in order to
non-vibrating block and an oscillating blade/ ensure that the drive axis fits the blade properly
blade holder unit. The latter unit is either assem- and oscillates correctly. The drive unit consists of
bled on the operating table or delivered pre- a single or dual electric motor or a gas turbine for
mounted and sterile (for single use). The block is blade oscillation in models with manual head
composed of a tracking system, an applanation translation.
plate, and cavities. The first one matches the suc- The central unit delivers the calibrated energy
tion ring and can be dual (linear microkeratomes) necessary to power the motors and creates the
or single (pivoted rotating microkeratomes). The vacuum between the eyeball and the suction ring.
applanation plate is the part of the head that pre- One pedal is used to start/stop the vacuum pump.
cedes the oscillating blade and flattens the cor- A second pedal controls blade oscillation and in
nea, allowing a constant angle of engagement for some automated microkeratomes the forward
the blade, which in turn yields constant flap translation of the head.
14 Mechanical Microkeratomes 177
Head propulsion can be automated or manual. from the Innovatome (Innovative Optics) at 6
The first has the advantage of offering a regular and the Hansatome (Bausch & Lomb) at 14,
speed of cut and therefore, in theory, a constant all other instruments fall between a 25 and
flap thickness. In contrast, if premature blade 30 angle of engagement.
stop occurs, withdrawal can be difficult with a Theoretically, a quicker pass could result in a
high risk of flap damage. Manual drive is strictly thinner flap. The exact difference in the pass
surgeon dependent: the surgeon determines the speed resulting in a substantial difference in
speed of head translation, which can be inconsis- flap thickness has yet to be determined.
tent and create an irregular flap thickness and bed Automated drive models would intuitively
surface. seem to provide a more consistent excursion
To reduce the incidence of infections, single- rate, but no data have shown a clinically rele-
use, sterile components have become increas- vant advantage. Independent motor drives for
ingly popular and include the head alone blade movement rate and oscillation are ideal
(equipped with a preassembled blade), both head and are the standard in todays market. Manual
and the suction ring, and all peripheral compo- drive models have rather smooth sliding
nents (suction ring, preassembled head and blade, mechanisms but are obviously dependent on
and handpiece). the surgeon to provide smooth and consistent
blade movement. Blade oscillation is essen-
tially independent of travel, but a quicker pass
Technical Considerations by the surgeon could result in a thinner flap as
the blade skims through the cornea. A more
Several variables are important in determining rapid pass could also lead to increased resis-
the overall bed smoothness and depth consis- tance, thereby relatively slowing the cut rate.
tency. These variables include blade quality, Most systems require elevated intraocular
engagement angle of the blade into the cornea, pressure created by a vacuum ring or device to
blade translation rate and consistency across the stabilize the cornea. Variations from eye to eye
cornea, suction pressure and overall globe fixa- do exist in the vacuum obtained. It is generally
tion, blade oscillation rate, and cut mechanism. considered that an intraocular pressure (IOP)
higher than 65 mmHg is necessary to assure a
Overall blade quality and sharpness play a high-quality dissection, but some reports have
role in the quality of flap cut. Electron micros- shown that IOP may rise much higher in some
copy has been performed on blades from sev- instances. In addition, relative barometric
eral different manufacturers, showing pressure does vary based on altitude and could
substantial difference [9]. Several reports also have an impact on final flap characteristics.
demonstrate that blades used on the second The correlation between the amount of vac-
eye yield up to 10 % thinner flaps. uum generated by the suction ring and the true
Theoretically, this would be due to some dull- intraocular pressure at the time of dissection
ing of the blade during the first pass. on one side and flap thickness on the other
Variations in blade engagement angle exist side is as yet unclear.
from 0 to 30. A steeper angle of blade The blade cutting rates range from 2500 to
engagement allows the predetermined flap 20,000 oscillations per minute. While a mini-
depth to be reached more rapidly; therefore, a mum speed probably does exist below which
gutter is created at the initial incision site. flap quality is negatively affected, rates above
As a result, the flap has a more uniform thick- 10,000 rotations per minute are used routinely
ness and is easier to align at the conclusion of and do seem to dissect the tissue adequately.
the procedure. A more shallow blade engage- All traditional microkeratomes in use today
ment angle results in thinner flap edges and employ surgical stainless steel blades.
may subsequently limit flap stability. Aside Chrome-platinum alloy and crystalline blades
178 E. Alb and M. Busin
Abstract
Femtosecond lasers offer a controlled, precise means of disrupting clear ocu-
lar tissue, facilitating full thickness and lamellar corneal transplantation. This
provides an opportunity to create reproducible and accurate incisional depths,
lamellar stromal beds, and potentially the ability to follow the curvature of
the cornea. The femtosecond laser has been employed in penetrating, anterior
lamellar and endothelial keratoplasty. To date, the greatest promise has been
demonstrated in the ability to create improved wound configurations with
faster recovery and reduced astigmatism. Final visual outcomes are currently
comparable to conventional surgery for femto-assisted penetrating kerato-
plasty (PK). For both Femto-PK and deep anterior lamellar keratoplasty
(DALK), there is evidence of a faster rate of astigmatic correction and visual
recovery, in part because of novel interfaces and the ability to remove sutures
earlier. The technology appears to be safe with regard to corneal endothelial
cell preservation in PK and DALK, but the exact limits of trephination remain
to be determined. The promise with endothelial keratoplasty (EK) however is
currently limited by concerns regarding the effects on the endothelium and
stromal bed smoothness and there is little long-term data on corneal graft
rejection. At present, a major barrier to its wider application is cost, the nature
of the applanation device and optimization of the imaging systems that will
facilitate real-time enhancement of lamellar trephination. Although this tech-
nology is relatively new, its full potential has yet to be realized.
Keywords
Femtosecond Femto- Laser Keratoplasty Transplantation
Table 15.1 Summary of femtosecond lasers employed for corneal applications including keratoplasty and LASIK
Approximate
Platform Company Docking system Repetition rate energy pulse
IntraLase iFS Abbott Medical Optics, Flat applanation 60150 kHz 1000 nj
USA
LDV Z6 Ziemer, Switzerland Flat applanation 5 MHz < 50 nj
VisuMax Zeiss, Germany Curved applanation 200500 kHz 170 nj
520 F (replacement Technolas Perfect Vision Curved applanation 4080 kHz 4800 nj
for Femtec) (Bausch & Lomb),
Germany
Wavelight FS200 Alcon Laboratories, USA Flat applanation 200 kHz 800 nj
followed by several others that have differences complications seen in LASIK such as light sensi-
in their energy, interface, and mechanism of tivity and gas breakthrough.
action (Table 15.1).
A common misconception in understanding
the use and application of this technology is that Applications
there is uniformity in the underlying commer-
cially available systems. Lamellar cutting may be Penetrating Keratoplasty
achieved through raster patters, progressive side
to side dissections such as the Ziemer Z6; cen- Penetrating keratoplasty (PK) forms the corner-
trifugal, circular in to out or centripetal, circu- stone of corneal transplantation and in some cir-
lar out to in such as the Technolas 520 F; or cumstances remains the only option for ocular
both, for example, Zeiss VisuMax during preservation or restoration of sight. Potential
LASIK. The latter offers the advantage of allow- problems with mechanical trephination tech-
ing patients to track a target more efficiently and niques involved in PKs include divergent recipi-
reduces the chance of suction loss or eccentric ent cut angles and convergent donor cut angles
cuts by eye movement. A caveat to this is the abil- resulting in tissue deficit at the posterior corneal
ity to see a target under supraphysiological pres- plane resulting in potential misalignment. These
sures created by the docking platforms. problems may be compounded in eyes with nar-
The energy required to undertake anterior or row palpebral apertures. Femtosecond wound
side cuts is higher than for lamellar cuts. construction allows improved centration without
Experimental data suggests that the energy deliv- undercutting. This may also help reduce damage
ery between platforms influences the collagen to the endothelium, with evidence from animal
disruption and this can be visualized at a and human studies demonstrating preservation of
nanoscale level by helium ion microscopy [53]. cell counts [3, 40].
The IntraLase (high-energy, low-frequency Even in conventional PK, suction-based treph-
pulse) system induces greater cavitation than the ination systems allow better stability during
VisuMax (low energy, high frequency) system trephination, are faster, and facilitate rounder
resulting in excessive tissue bridges and diffi- trephination with less slippage. There are prob-
culty in flap elevation during LASIK [53]. lems however with intraocular pressure eleva-
Furthermore, wound healing and scar tissue for- tion, centration, and in eyes with reduced scleral
mation may be reduced by platforms that deliver support such as in aphakia. The application of
low-energy, high-frequency systems such as suction, common to most femtosecond platforms,
VisuMax and the Ziemer LDV Z6 for LASIK flap may also be associated with elevated IOP. A
formation [52]. Further investigation in lamellar demonstrable reduction in intraocular pressure
keratoplastic procedures may determine whether variation in femtosecond laser-assisted PK has
an improved interface recovery with reduced been shown in the VisuMax system compared
energy has a commensurate reduction in with manual trephination [3]. There is
184 G.P. Williams and J.S. Mehta
considerable variability in IOP elevation between period (between 8.4 and 5.8 D at 46 months),
platforms however, and this is discussed later in this difference was not seen after 6 months
this chapter. [13, 25]. Other studies have failed to demonstrate
The data from clinical trials to date is rela- an improvement compared to conventional sur-
tively limited but increasing, summarized in gery in astigmatism, albeit paradoxically with
Table 15.2. The variable results seen by Femto- improvement in vision [27]. It is worth consider-
assisted PK reflect the myriad outcome measures ing that the same early effect was seen with
determined in individual trials or large case series straight cuts as outlined above [33].
including indication and graft size. Furthermore, Third, there appears to be variable results in
many of the studies to date have evaluated the the reduction in endothelial cell loss compared to
first commercially available platform, IntraLase, conventional PK. Kamiya and colleagues series
and data on many of the newer platforms is there- with the VisuMax platform did not demonstrate a
fore restricted. Nonetheless, the principle consid- difference between Femto-PK vs. conventional
erations with regard to this technology relate to PK [33]. Other clinical trials have shown
wound integrity and recovery, astigmatism and postoperative endothelial cell counts in the range
visual outcome, and endothelial cell preservation of 12002000 cells/mm2 at 612 months [19, 30,
and rejection. These issues may well be addressed 46]. Graft rejection rates in most series have been
further by well-constructed randomized control variable, but it is worth noting that few studies
trials. have follow-up data for greater than 12 months,
The first major decision in choosing Femto- compounded by the variable timing of suture
assisted penetrating keratoplasty over conven- removal. Larger series have suggested that com-
tional grafting is better wound strength and plete suture removal can be achieved earlier than
alignment. The strength of the wounds con- in conventional PK [7].
structed with femtosecond laser has been shown Finally, all three parameters must also be pre-
to be resistant to leakage even with less sutures ceded with a fundamental question regarding the
[42]. The second outcome to contemplate (and choice as to whether one should undertake PK
related to the first) is astigmatism and visual over a lamellar procedure. This has not been fully
recovery. A retrospective series directly compar- addressed and will be considered in the following
ing a straight-cut conventional PK and Femto- sections of this chapter.
assisted PK (n = 20 in each group) suggested that
there was less induced astigmatism (6.06 vs. 4.06
D; p 0.04) and faster visual recovery with Femto Anterior Lamellar Keratoplasty
assistance, but the overall visual outcomes were
similar (0.39 vs. 0.22; p = 0.8 LogMar) [33]. Targeted replacement of the anterior stromal lay-
Femto-trephination can also facilitate novel ers of the cornea by anterior lamellar keratoplasty
and potentially more stable wounds with a theo- may involve the superficial layers (by manual dis-
retical reduction in astigmatism. Improved wound section or microkeratome) or deeper layers
construction and alignment with a femtosecond (through manual dissection or the use of a big
laser assistance has been proposed with a number bubble). Deep anterior lamellar keratoplasty
of methods including zigzag shapes, mushrooms, (DALK) has the advantage of facilitating an extra-
top hat (see above), dove and tail, decagonal and ocular procedure and theoretically reduces the
lock, and key designs among others [23, 26, 39, risk of both rejection and endothelial cell damage
46, 49, 58]. The advantages with shelved or where the endothelium is unaffected. To date, out-
stepped interfaces are a potential reduction in the comes from large national datasets in the United
number of sutures and faster postoperative recov- Kingdom and Australia have indicated worse
ery. Although a reduction in astigmatism by visual outcomes and survival than for penetrating
improved tissue apposition has been shown with keratoplasty [21, 31]. Advocates of DALK argue
zigzag configurations in the initial postoperative that the published data relates to (relatively)
15
historical series when more surgeons were under- femtosecond laser offers theoretical improvement
going the learning curve, and this may be borne in control in creating an interface during tissue
out by higher rates of primary graft failure in the separation. Laboratory data shows that the inter-
early weeks posttransplantation for this group. face created by femtosecond lasers is smoother,
This issue is one of contention however and an and as previously discussed, low-energy high-
ophthalmic technology assessment undertaken by frequency platforms may offer an enhanced role
the American Academy of Ophthalmology pub- for Femto-assisted DALK [5153]. Femto-
lished in 2011 (albeit predating the work by assisted lamellar trephination also lends itself to
Coster and colleagues) found that there was no treating superficial pathology and no difference
difference between DALK and PK with regard to was seen at 12 months follow-up when comparing
visual acuity, but endothelial cell counts were bet- the visual acuity of Femto-anterior lamellar kera-
ter preserved with DALK [50]. toplasty cut at <250 m and >250 m [1].
An apparent advantage with DALK is cost- There is a paucity of clinical trials evaluating
effectiveness. Two cost-utility analyses to date Femto-DALK, but a number of series have been
have demonstrated that despite the higher costs published regarding the technique. Both Farid
of undertaking DALK (in part due to increased and Price separately presented a zigzag adapta-
operative time), there are financial longer-term tion of a debulking big-bubble technique where
benefits [35, 63]. The rates of lamellar (including a zigzag side cut is combined with a 300 or 250 m
anterior lamellar surgery) continue to rise inter- lamellar dissection, respectively. This facilitates
nationally and we will therefore consider how the a big-bubble separation of the residual stroma
femtosecond laser may enhance the application [24, 47]. Buzzonetti and colleagues also describe
of this procedure. an adaptation of Anwars original big-bubble pro-
In addition to the problems seen in Femto-PK cedure [4] whereby the IntraLase femtosecond
relating to wound configuration and astigmatism, laser is employed to facilitate a side cut of 50 m
the major consideration relating to femtosecond- and a lamellar cut of 100 m anterior to the thin-
DALK, like conventional DALK, is the technical nest point [11, 12]. This in turn is supplemented
challenge presented with creating a clear graft- by the injection of air to separate Descemets in a
host interface and leaving the minimal amount of technique termed Intra-Bubble. Outcomes from a
residual tissue bed. This difficulty in theory should 1-year case series (n = 11) by the same group
be circumvented by the automated lamellar dissec- determined that the best-corrected distance visual
tion offered with femtosecond laser, which may acuity was 0.52 1 with a refractive outcome of
offer a smoother interface. A caveat however is 1.50 1.7 diopters (D) sphere and 2.00 2.6 D
that with deeper dissection, there is enhanced light cylinder (two attempts were converted to PK at
scatter and potentially a less smooth surface. outset) [12]. Longer follow-up also shows mean
Differences in collagen disruption have also been BCVA of 0.3 0.1 at 24 months (n = 12) and a
determined with the construction of differential mean cylinder of 1.7 1.4 D [56].
laser firing during refractive lenticule construction The bespoke interfaces used in femtosecond-
[51]. Whether this will have an influence on lamel- penetrating keratoplasty such as a top-hat con-
lar construction in the context of keratoplasty is figuration may improve the speed of recovery in
yet to be determined. Visual outcomes in DALK femtosecond-DALK [14]. The integrity of zig-
may in part be explained by the thickness of the zags, top-hat, and mushroom configurations has
host tissue bed [5]. Notwithstanding the effects of been evaluated in an experimental model to
scatter, Femto-dissection could create potentially determine burst pressure with these cuts [36].
thinner dissections without the inherent risk posed Although the pressure required to induce wound
by manual dissection alone. burst was variable, direct comparisons were not
Although microkeratomes facilitate anterior undertaken, and it is therefore difficult to draw
cuts, pneumatic dissections for deep lamellar definitive conclusions regarding the optimal
procedures carry a risk of perforation. The technique.
15 Technology: Femtosecond Laser in Keratoplasty 187
Sutureless techniques have also been described stripping automated endothelial keratoplasty
with variable mean uncorrected and best- (DSAEK). The accuracy of depth of microkera-
corrected visual improvement [8, 67]. Evidence tome cuts may be less consistent than with
from retrospective series has indicated a faster Femto-assisted dissection. Femtosecond laser-
visual recovery when comparing mushroom con- assisted ablations have been shown to have a
figurations with conventional straight cuts under- mean deviation in attempted depth of 15 m [44].
taken with the IntraLase system but with no Further adaptations such as double-pass tech-
difference in overall visual recovery or astigmatic niques may consistently achieve sub-150 m
outcome, similar to the findings in Femto-assisted grafts with improved visual acuity however [9].
PK [55]. Although conventional DALK is under- Femtosecond beds have been shown to be
taken to prevent endothelial cell loss, it is worth smooth under histological evaluation [17, 43].
considering the potential effects of the femtosec- Another study evaluating the effects of the
ond laser due to the application of energy in the IntraLase 30 kHz femtosecond laser has demon-
host bed. strated the mechanical microkeratome may
The uptake for Femto-DALK has been limited improve the depth and smoothness of the cut
in part due to the technical difficulty of achieving [32]. The rougher interface created by the fem-
a safe dissection in the context of severe ectatic tosecond laser was postulated as having a poten-
disease and reflected by the absence of controlled tially improved interface for maintaining
trials to date. This is further highlighted when the adherence however, the rate of graft dislocation
surgeon is faced with existing posterior stromal has previously been shown to be as high as 20 %
scarring, a situation that complicates previous when undertaking Femto DSAEK [16]. Whether
hydrops. Limitations in visualizing the cornea in this relates to surgical technique or the smooth
real time by OCT and Scheimpflug imaging raise tissue bed created remains to be elucidated.
legitimate concerns about proceeding with fem- Furthermore, the type of laser may influence the
tosecond laser-assisted surgery following dock- interface created and another comparisons using
ing, as small movement may have catastrophic the IntraLase platform found rougher surfaces
consequences on the already-friable host bed. were created with the femtosecond laser com-
High-resolution intraoperative OCT has been pared to microkeratomes [45].
shown to enhance the ability to undertake DALK Endothelial cell loss is an important consid-
safely by conventional methods [22]. It is hoped eration in judging the safety of Femto-assisted
that recent improvements in imaging platforms endothelial keratoplasty. Both the aforemen-
attached to femtosecond platforms may offer an tioned studies comparing smoothness of the
improvement in this regard and a safer option to interface created by microkeratome found no
undertake femtosecond-DALK. difference in the reduction of endothelial cell
count [32, 45]. Inverse cutting techniques have
also been proposed as a means of safely main-
Endothelial Keratoplasty taining endothelial cell counts when creating
lamellar cuts [29]. A study comparing 50 vs.
In contrast to anterior lamellar keratoplasty, the 150 m dissection in rabbits using the Wavelight
uptake of Femto-assisted dissection of graft mate- FS200 however showed significantly higher
rial for endothelial keratoplasty has been more rates of endothelial cell damage and apoptosis
widely adopted. Endothelial keratoplasty, like its with thinner cuts [41]. A large randomized con-
anterior counterpart, potentially facilitates trol trial also found that rates of endothelial cell
smoother and more accurate cutting of the desired loss were higher with Femto-assisted endothelial
tissue bed. This is particularly important when keratoplasty compared to conventional penetrat-
minimizing the residual stromal bed transplanted. ing keratoplasty (1200 vs. 2150 cells/mm2 at 3
Manual or microkeratome dissection has tra- months) [18]. The difficulty in comparing two
ditionally been employed for Descemets separate techniques and by laser and conven-
188 G.P. Williams and J.S. Mehta
Table 15.3 Summary table of clinical trials involving femtosecond endothelial keratoplasty
Study design and
Title Authors Journal Platform objective Outcome
Economic van den Am J Ophthalmol. Intralase Randomized CT: DSAEK most
evaluation of Biggelaar FJ 2012;154(2):272281. Cost evaluation cost-effective,
endothelial et al. [62] e2 in 118 eyes Femto DSAEK
keratoplasty least
techniques and cost-effective
penetrating
keratoplasty in
the Netherlands
Quality of vision Cheng YY Am J Ophthalmol. IntraLase Randomized CT Straylight and
after femtosecond et al. [20] 2011;152(4):556566. in 80 eyes contrast
laser-assisted e1 sensitivity
Descemets improved with
stripping FLEK
endothelial VA improved
keratoplasty with PK
(FLEK) and
penetrating
keratoplasty
(PK): a
randomized,
multicenter
clinical trial
Efficacy and Cheng YY Transplantation. 2009 IntraLase Randomized CT Astigmatism
safety of et al. [18] 15;88(11):1294302 of 80 eyes better with FLEK
femtosecond VA better with
laser-assisted PK
corneal ECC better with
endothelial PK
keratoplasty
(FLEK): a
randomized
multicenter
clinical trial
CT control trial, ECC endothelial cell count, VA visual acuity
tional means makes this more difficult to inter- conventional PK and may also reflect the quality
pret. Furthermore, the authors concede that the of the interface [20].
method by which the graft was inserted (by for- These findings were supported in another
ceps with a folded graft) will have contributed to large case series comparing microkeratome and
the endothelial cell attrition. The limits by which femtosecond laser DSAEK where the visual out-
safe dissection can be achieved need to be evalu- come was worse in the femtosecond laser group
ated further. This of course represents a challenge although this was smaller (n = 6) than the micro-
for undertaking the very thin cuts needed to facil- keratome group (n = 41) and four of the six had
itate ultrathin Descemets stripping endothelial significant preexisting visual comorbidities [28].
keratoplasty (UT-DSEK). Other studies have shown more favorable results
Outcomes of randomized clinical trials involv- with femtosecond dissection in a technique
ing femtosecond laser-assisted endothelial kera- involving femtosecond followed by microkera-
toplasty are also sparse but summarized in tome cutting [54]. This may add more weight to
Table 15.3. It is interesting to note that the visual those advocating the use of microkeratomes over
acuity was reduced in the large trial comparing the femtosecond laser in the context of endothelial
15 Technology: Femtosecond Laser in Keratoplasty 189
keratoplasty. Again there is a need for directly base trephine and the VisuMax revealed similar
comparable randomized trials between the two IOP but greater variation during the procedure
techniques as well as between conventional and with manual suction trephination [3]. Clearly
femtosecond EK. patients with glaucoma or those at higher risk
from IOP fluctuation will represent a relative or
absolute contraindication when considering
Limitations and Costs patients for Femto-keratoplasty. The consider-
able variation between platforms and the length
The immediate and future application of femto- of the docking procedure in addition to maximal
second lasers offers exciting opportunities to IOP must be considered.
enhance corneal transplantation. There are how- The effects of femtosecond laser systems on
ever several limitation both in the flexibility of the corneal endothelium have been discussed ear-
the technology and their cost implications. An lier in this chapter. Safety concerns regarding the
example is the effect of corneal edema and scar- application of femtosecond laser in relation to
ring have not been fully evaluated, and the limits undertaking future transplantation were consid-
by which femtosecond laser platforms can ered by Klingler and colleagues [34]. Patients
achieve reliable cuts warrant further investiga- who have undergone either femtosecond-assisted
tion. The problem of judging the efficacy of dif- or microkeratome-assisted LASIK revealed no
ferent platforms is also compounded by the attrition in the endothelial cell count at 5 years
mixture of underlying pathologies compared in postsurgery, suggesting that those who have
many of the current studies, and clear disease- undergone this refractive procedure may be suit-
orientated criteria cannot be established as yet. able candidates for future donation of tissue [34].
The reliance on creating suction and the asso- Another important laser-related complication is
ciated elevation in intraocular pressure mean an incomplete incision pattern. Failure to com-
there is a limited role in tectonic or emergency plete a wound once the laser sequence has been
transplantation, in particular in the context of initiated, for instance, if suction breaks or there is
infections with associated severe thinning or excessive movement, can result in this problem.
impending perforation. Intraocular pressure Price and colleagues determined that when creat-
(IOP) rises are higher during microkeratome suc- ing a Femto-PK wound configuration an incom-
tion compared to femtosecond docking with the plete cut did not affect the tensile strength to
VisuMax system in a rabbit model (mean 141 complete surgery [48]. The consequences in
20 vs. 62 3 mmHg, p < 0.001) [15]. By contrast, lamellar cuts, especially those close to the endo-
a study undertaken with porcine eyes with the thelium, are potentially more serious, and further
IntraLase platform showed no difference in IOP investigation is warranted.
elevation compared to the microkeratome Many units will likely consider whether they
(135 16 mmHg vs. 152 24 mmHg) [66]. Other wish to invest in a platform for refractive work,
studies have shown higher pressures with the corneal transplantation, and/or cataract surgery.
IntraLase platform (when directly compared with At present, the choices are limited in achieving
VisuMax) have also been demonstrated with the this with the same docking procedure and
Femtec and Ziemer LDV models [64, 65]. In with the same machine. This is likely to have
part, this may reflect the effect of a flat applana- changed by the time of publication and may
tion system with the IntraLase and LDV Z6 sys- encourage greater uptake and drive down costs
tems. The effects of liquid interface systems for further. Publicly funded healthcare systems may
keratoplastic procedures remain to be therefore lag behind in the introduction of these
determined. systems, in particular when refractive applica-
The closest approximation to human kerato- tions are not widely available in these settings
plasty has been demonstrated in a rabbit model of and can be incorporated more easily for
IOP in PK. Direct comparisons between suction keratoplasty.
190 G.P. Williams and J.S. Mehta
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Limbal Stem-Cell Expansion
and Transplantation 16
Paolo Rama, Stanislav Matuska,
and Graziella Pellegrini
Abstract
Limbal stem-cell transplantation is indicated for treating a corneal epithe-
lial stem-cell disorder known as limbal stem-cell deficiency (LSCD).
Lamellar and/or penetrating keratoplasty cannot be used successfully in
these cases as donor corneal epithelium is replaced by that of the recipient
within months. In the presence of corneal epithelial stem-cell compart-
ment deficiency, donor graft reepithelialization will not take place, with
subsequent epithelial defects and the ultimate recurrence of conjunctival-
ization and the risk of rejection and failure. Unilateral limbal stem-cell
deficiency has been successfully treated for years by directly grafting a
portion of the healthy limbal tissue taken from the contralateral eye, but
some concerns exist regarding potential donor eye risks. To overcome
risks for the donor eye, a technique to reduce biopsy dimension using cell
expansion in culture has been developed. Autologous cultivated limbal
stem-cell transplantation is an effective and safe procedure to treat limbal
stem-cell deficiency when there is an undamaged, even small, portion of
the limbus that will provide donor cells to be expanded in vitro. Ex vivo
limbal grafts have several advantages compared with the previously used
technique of directly grafting limbal tissue, including fewer risks for the
donor eye, possibility to treat bilateral LSCD, and possibility of regraft
after failure. Unilateral and partial bilateral limbal deficiency can thus be
successfully treated with long-term survival and without the need for sys-
temic immunosuppression.
Keywords
Cornea Limbus Limbal stem cells Corneal epithelial stem cells
Limbal stem-cell deficiency Limbal stem-cell transplantation Cultivated
limbal stem-cell transplantation Ex vivo expansion
Limbal stem-cell transplantation is indicated for Unilateral limbal stem-cell deficiency has been
treating a corneal epithelial stem-cell disorder known successfully treated for years by directly grafting
as limbal stem-cell deficiency (LSCD) [8, 36]. a portion of the healthy limbal tissue taken from
LSCD includes a group of heterogeneous dis- the contralateral eye [12, 15, 19]. Some concerns
eases involving failure of the corneal epithelial exist regarding potential donor eye risks [1]
stem cells caused by congenital abnormalities, although few reports have shown consequences
acquired diseases such as chemical and thermal related to harvesting [17], patients are often unen-
injuries, immunological diseases, toxicity, and thusiastic about having the good eye touched,
infections [8, 36]. Such diseases may not only together with the great responsibility felt by sur-
damage the limbus but also the eyelids, conjunc- geons. Moreover, further harvesting of the limbus
tiva, corneal nerves, stroma, and lacrimal system. following possible failure is not advisable.
Ocular surface disease is the most appropriate To overcome risks for the donor eye, much
term for such a complex disorder. effort has been made to develop a technique to
Impairment of the limbal stem-cell compart- reduce biopsy dimension using cell expansion in
ment causes corneal epithelial turnover break- culture. The pioneering work of Rheinwald and
down, resulting in damage to the corneal Green showed that it was possible to obtain a
epithelium, which will ultimately repair due to layer of stratified squamous epithelium from a
conjunctiva migration on to the cornea [8, 36]. single cell after serial cultivation of human epi-
Conjunctival migration, or conjunctivalization, dermal epithelial cells (keratinocytes) on a layer
is a compensatory repair mechanism that protects of lethally irradiated murine fibroblasts (3 T3
the cornea from infection, stromal ulceration, cells) [34]. Some years later, cultivated skin
melting, and perforation. While it provides a stable grafts were successfully used to treat severe-burn
and protective superficial layer to the cornea, it is patients [13]. In 1997, Pellegrini et al., using the
often accompanied by persistent inflammation, Rheinwald and Green protocol, showed that
severe visual impairment, and other symptoms. autologous grafts of cultivated cells obtained
Lamellar and/or penetrating keratoplasty can- from a 1 mm2 limbal biopsy restored the corneal
not be used successfully in these cases as donor surface in two patients with complete loss of the
corneal epithelium is replaced by that of the corneal-limbus epithelium [27]. The culture pro-
recipient within months. In the presence of cor- cedure was then standardized [26], and to date
neal epithelial stem-cell compartment deficiency, more than 270 grafts have been transplanted in
donor graft reepithelialization will not take place, various centers throughout Italy, with long-term
with subsequent epithelial defects and the ulti- stability reported in more than 150 patients and
mate recurrence of conjunctivalization and the with a success rate in 7080 % of cases [29, 32].
risk of rejection and failure. Ex vivo limbal grafts might have several
Limbal stem-cell transplantation (LSCT) is a advantages compared with the previously used
step in the reconstruction of the ocular surface, technique of directly grafting limbal tissue: (i)
while lamellar or penetrating corneal graft will fewer risks for the donor eye; (ii) possibility to
finally restore corneal transparency, leading to treat bilateral LSCD should there be a spared part
the recovery of visual capacity. of the limbus, albeit small; (iii) possibility of
16 Limbal Stem-Cell Expansion and Transplantation 195
a b
c d
Fig. 16.1 Failure of autologous limbal transplantation failure of the first graft (red arrow) (b). One year after
with recurrence of corneal conjunctivalization (a). successful cultivated limbal stem-cell transplantation with
Contralateral donor eye with signs of a large previous lim- transparent, avascular, and stable epithelium (c). The same
bal harvesting for limbal transplantation (white arrows) patient after penetrating keratoplasty combined with cata-
and the small biopsy for ex vivo expansion done after ract extraction, lens implantation, and pupilloplasty (d)
regraft after failure (Fig. 16.1); (iv) cells can be have been reported on the use of allogeneic kera-
frozen and stored, allowing additional transplan- tolimbal grafts, with an overall success rate of
tation or banking if required; (v) association with 73 % [1]. Both clinical successes and failures
gene therapy; and (vi) proof of concepts to use have been observed in the presence of systemic
another cell source to treat total bilateral disease. immunosuppressive therapy [6, 16, 23], while
positive clinical results have been reported in the
absence of immunosuppression [20, 33] and/or in
Autologous Versus Allogeneic the absence of allogeneic cell survival [2, 14]. In
Limbal Grafts most cases, however, the interpretation of results
has been hampered, either by the lack of a proper
In unilateral LSCD, or in bilateral LSCD, where genetic evaluation of the presumptive long-term
a small portion of healthy limbus can be used as engraftment of allogeneic limbal grafts or by the
donor tissue for ex vivo expansion, autologous inadequate length of follow-up. In the absence of
limbal grafts are advised [30, 32]. On the con- demonstrated surviving donor cells, a possible
trary, in total LSCD when the limbus is com- explanation for clinical success is that patients
pletely destroyed in both eyes, limbal tissue taken with non-total limbal stem-cell deficiency have
from a deceased donor or from a living relative been included, and the grafted allogeneic limbal
can be used. In the literature, contrasting results cells might have induced modification of the
196 P. Rama et al.
microenvironment and promoted proliferation of valid method for its assessment. We do not
the patients own dormant stem cells, whose include in our clinical protocol for limbal trans-
progeny gradually replaces donor cells. While plantation patients showing severe active inflam-
remaining in situ in the injured eye, these limbal mation. As for tear film, we are still far from
cells are evidently unable to generate corneal epi- having reproducible clinical assessment and
thelium, either because of the lack of a suitable inflammation grading, with the exception of red-
microenvironment for multiplication or because ness scoring.
of fibrotic obstruction to their migration over the
cornea. This would explain the mixed population
of donor and recipient corneal cells observed at Diagnosis of LSCD
short-term follow-up. These findings are consis-
tent with reports showing that clinical improve- LSCD diagnosis is based on the evidence of a
ment observed following allogeneic keratolimbal previous insult (cause) and peculiar clinical fea-
grafts does not necessarily correlate with the tures (signs) and is eventually confirmed by
long-term survival of donor cells [2, 14]. instrumental tests [8, 36]. The causes of LSCD
Similarly, cultured allogeneic epidermal kerati- are shown in Table 16.1.
nocytes do not engraft permanently, but provoke
epidermal regeneration in partial-thickness skin
burns, presumably by stimulating residual hair Clinical Features
follicle stem cells [3].
Symptoms
depends on the extension of the damage. problem. Therefore, impression cytology should
However, when the visual axis is not involved, only be implemented in those cases where there
there is no reason to propose surgical treatment. is a specific question needing to be answered.
Conservative treatment for symptom relief, such
as preservative-free artificial tears, autologous
serum eyedrops, therapeutic soft or scleral con- Confocal Microscopy
tact lenses, and short courses of low-dose topical
steroids, is therefore indicated. Confocal microscopy is a noninvasive procedure
that can distinguish between corneal and con-
junctival epithelial cells and is therefore useful in
Signs the diagnosis of limbal stem-cell deficiency
(Fig. 16.2) [9, 21, 37]. In a recent study by Nubile
Corneal signs can be, depending on the severity et al., confocal microscopy was compared with
of the damage, the loss of normal limbal anatomy impression cytology in patients with limbal dis-
with disappearance of the palisades of Vogt, orders with concordance in 90 % of cases [25].
irregular epithelium with fluorescein uptake, Confocal microscopy is therefore a useful nonin-
recurrent or persistent epithelial defects, superfi- vasive method to confirm limbal stem-cell defi-
cial neovascularization (conjunctivalization) ciency. We should remember, however, that
and/or fibrovascular pannus formation, deep stro- confocal microscopy evaluates cell morphology
mal neovascularization, and chronic inflamma- but cannot recognize their true phenotype: with-
tion (Figs. 16.1a and 16.3a) [8, 36]. out specific markers we might mistake transient
morphological changes of corneal epithelial cells
for conjunctival cells.
Supplementary Tests
Cytokeratins (CKs) are intermediate filaments Various protocols for the cultivation of limbal
present in almost all epithelial cells [11]. Epithelia stem cells for transplantation have been proposed
from different parts of the body express keratins, and recently reviewed by Shortt et al. and Joe and
which are unique for each location: this specific- Yeung, including methods to extract cells from
ity can be thus used to differentiate genotypically the biopsy (mechanical disruption or enzymatic
different cell types [24]. The cornea expresses the dissociation), substrates and carriers (fibrin sheet,
cytokeratins K3 and K12, but not K19, while the amniotic membrane, polymers, contact lenses,
conjunctiva specifically expresses K19, but not collagen), or mediums with animal-derived com-
K3 and K12 [10, 35]. ponents or xeno-free [18, 36]. Although good
We previously showed that immunocytochem- clinical outcomes have been reported with all of
istry carried out on corneal impression cytology these different culture procedures, few studies
specimens allows us to distinguish between cor- have evaluated the clonal characteristics of the
neal and conjunctival epithelial cells with posi- cultivated cells and their proliferative potential.
tive/negative staining of K3/K12 (cornea) and When dealing with stem-cell-based therapies for
K19 (conjunctiva) [7]. We also showed that diseases involving cell-renewing tissue, it should
impression cytology can be used to grade limbal be mandatory to demonstrate the presence, sur-
stem-cell deficiency and assess the final results vival, and concentration of stem cells in culture
after limbal stem-cell grafting [31] However, it is and in the graft and validate the procedure under
an invasive procedure that, despite its simplicity, GMP conditions [4, 28].
may cause painful epithelial defects that might be We previously showed, analyzing the prolif-
difficult to treat due to the underlying limbal erative potential and cloning characteristics,
198 P. Rama et al.
a b
Fig. 16.2 Cornea with partial limbal stem-cell deficiency be proposed, but not so obvious (c). In these cases, further
(a). Although in some cases the detection of conjunctival confirmation with clinical findings and/or standard
pannus is obvious with confocal microscopy (b), in some impression cytology techniques with staining for specific
other cases the presence of conjunctival epithelium may markers may clarify the diagnosis
that corneal stem cells are segregated in the [5, 29, 32]. Clinical success was statistically
limbus, while conjunctival stem cells are uni- associated with the percentage of p63-positive
formly distributed in the bulbar and forniceal cells in culture. Cultures in which p63-bright
conjunctiva. Moreover, conjunctival epithelial cells made up more than 3 % were associated
cells and goblet cells derive from a common with successful transplantation rate close to
bipotent progenitor [26]. We also showed that 80 %. In contrast, cultures with less than 3 %
autologous limbal stem cells, cultivated on were associated with poor results, with success-
fibrin and 3 T3 feeder layer, maintain their ful transplantation in only 10 % of patients. On
properties and are able to restore corneal the basis of these data, only cultures that con-
integrity in severe limbal stem-cell deficiency tain more than 3 % Np63 cells are now
[31]. We later confirmed the long-term stability grafted on patients.
of the results, up to 10 years, and validated the We hereafter report our protocol: (i) biopsy,
procedure, comparing clinical results with the (ii) stem-cell expansion in culture, (iii) grafting,
level of expression of Np63 in culture and (iv) postoperative management.
16 Limbal Stem-Cell Expansion and Transplantation 199
a b
Fig. 16.3 Total limbal stem-cell deficiency after alkali burn (a). Ten years after successful cultivated limbal stem-cell
transplantation and penetrating keratoplasty with transparent, avascular, and stable epithelium (b)
It is absolutely crucial to place the fibrin sheet preservative might damage the newly regenerated
with the cultivated cells outside and not upside corneal epithelium.
down. The fibrin sheet is allowed to slide onto
the recipients prepared graft area, using BSS
and slight traction with tweezers at the edge of Treatment of Residual Corneal
the graft as required. Opacity
5. The excess of the fibrin sheet is trimmed, and
the edge is covered with the conjunctiva Injuries that cause limbal stem-cell deficiency
applying 2 or 3 stitches of Vicryl or silk 8/0. often affect the deep layers of the cornea, causing
6. Close the eyelids with Steri-Strips. stromal opacity that, in most cases, requires
lamellar or penetrating keratoplasty (Fig. 16.3).
Although it is possible to combine limbal trans-
Postoperative Management plantation with keratoplasties, we suggest plan-
ning it for a different time. The halftime of
We prefer systemic treatment for the first 2 weeks corneal reepithelialization is 9 weeks, and com-
to avoid inadvertent trauma and local toxicity: plete corneal epithelium replacement requires
oral doxycycline 100 mg (or, if allergic, amoxicil- 912 months [38] 6 months might be a sufficient
lin 500 mg) twice a day for 2 weeks and oral pred- period of time to assess the survival and function
nisone 0.5 mg/kg/day for 2 weeks, tapering the of the grafted stem cells. If the epithelium is sta-
dose after that to 0.25 mg/kg/day for 1 week and ble after 6 months, it probably means that the
0.125 mg/kg/day for 1 week and then stopped. regenerated limbus can support the physiological
After 2 weeks, topical treatment is started: turnover and will thus be able to replace the
topical preservative-free dexamethasone 0.1 % donor epithelium of the corneal graft. Even
three times per day for 2 weeks, then reduced to though in our previous studies we waited 12
1 drop twice daily for 1 week and 1 drop once months before planning keratoplasty [31, 32], we
daily for a further week and then stopped. The now believe that it can be carried out from month
topical corticosteroid can be continued in the six, if necessary.
presence of persistent ocular inflammation.
Topical preservative-free antibiotics are used Conclusions
only in the presence of epithelial defects. Autologous cultivated limbal stem-cell trans-
Eyedrops containing benzalkonium chloride plantation is an effective and safe procedure to
should be avoided. Benzalkonium chloride (as treat limbal stem-cell deficiency when there is
well as other quaternary ammonium compounds) an undamaged, even small, portion (12 mm2
is cytotoxic, and eyedrops containing this is sufficient) of the limbus that will provide
16 Limbal Stem-Cell Expansion and Transplantation 201
donor cells to be expanded in vitro. Unilateral 2. Daya SM, Watson A, Sharpe JR, Giledi O, Rowe A,
and partial bilateral limbal deficiency can thus Martin R, James SE. Outcomes and DNA analysis of
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Curcio C, Mastropasqua R, Dua HS, Mastropasqua L. In related expression of a major 64 K corneal keratin
vivo confocal microscopy in diagnosis of limbal stem in vivo and in culture suggests limbal localization of
cell deficiency. Am J Ophthalmol. 2012;155:22032. corneal epithelial stem cells. J Cell Biol.
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Bonini S, Rama P, De Luca M. Location and clonal 36. Shortt AJ, Secker GA, Notara MD, Limb GA, Khaw
analysis of stem cells and their differentiated progeny in PT, Tuft SJ, Daniels JT. Transplantation of ex vivo
the human ocular surface. J Cell Biol. cultured limbal epithelial stem cells: a review of tech-
1999;145:76982. niques and clinical results. Surv Ophthalmol.
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damaged corneal surfaces with autologous cultivated JK, Tuft SJ, Daniels JT. Ex vivo expansion and trans-
corneal epithelium. Lancet. 1997;349:9903. plantation of limbal epithelial stem cells. Ophthalmology.
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S, Pocobelli A, Colabelli RG, Spadea L, Fasciani R, Ophthalmol. 1997;41:275313.
Decision-Making in Keratoplasty
17
Anders Ivarsen and Jesper Hjortdal
Abstract
Within the last 1015 years, dramatic improvements have occurred within
the field of corneal transplantation. The advent of sutureless posterior
lamellar keratoplasty has revolutionized the treatment of endothelial dis-
ease. Similarly, developments in surgical technique and technology have
improved the outcome of anterior lamellar procedures. Despite the many
improvements, however, keratoplasty is not without complications, and
patients with one or more risk factors for graft failure still pose significant
challenges. Thus, although modern-day surgeons have several treatment
modalities available, any given corneal condition needs careful consider-
ation to decide whether or not to graft and to choose which procedure is
most beneficial for the patient as seen in context of the supply of donor
tissue and local organization.
In the present chapter, the various treatment modalities are outlined
including their indications and which treatment to consider under given
circumstances.
Keywords
Decision-making Keratoplasty Corneal transplantation DSAEK
DMEK DALK Patient information
Introduction
point in history, a lamellar approach to corneal surgeon to decide which procedure to choose,
transplantation was attempted, but results were both with respect to the individual patient and
generally unsatisfactory [8, 103]. Thus, for with respect to the supply of donor corneas and
decades, penetrating keratoplasty (PK) remained the organization at the specific place of practice.
the general surgical approach, irrespective of the This chapter aims to discuss some of the consid-
underlying corneal pathology. Within the last erations that may affect the choice of surgical
1015 years, however, surgical developments approach in various cases.
have allowed a more differentiated view, enabling
the surgeon to choose from a variety of treatment
modalities. Of these developments, the recogni- Basic Considerations
tion that a posterior lamellar graft can stick to the
recipient cornea has proven one of the most The decision to perform a keratoplasty is multi-
important advances in corneal surgery for years faceted and requires an extensive evaluation of
[6870]. The technique was refined through the the eye including eye history, intraocular pres-
contribution from several groups all over the sure and evaluation of the retinal function. An
world [36, 81, 82, 100], and today Descemets intact corneal surface is mandatory to obtain a
stripping automated endothelial keratoplasty functioning, clear graft, and any abnormalities of
(DSAEK) is the most frequently performed sur- the eyelids, changes of the ocular surface or dry
gical procedure for endothelial dysfunction [27, eye disease should be actively treated before ker-
52]. Descemets membrane endothelial kerato- atoplasty is considered in order to ensure optimal
plasty (DMEK) represents an newer and more protection of the eye and graft.
refined posterior lamellar approach that has been Although the cornea is generally considered
reported to offer an even better postoperative out- to be immune privileged, the introduction of allo-
come than DSAEK [37, 38, 104]. Irrespective of geneic tissue may elicit an immunological
the surgical technique, however, the posterior response. The most frequent immunological
lamellar approach allows the surgeon to avoid rejection occurs against donor endothelium [2,
several of the major challenges after PK includ- 66, 83], although rejection of epithelial or stro-
ing slow visual recovery, high postoperative mal cells may occur as well [73, 83, 89]. Several
astigmatism and reduced mechanical strength of host factors increase the risk of rejection and sub-
the globe. sequent graft failure (Table. 17.1).
Another major challenge after PK is endothe- Vascularization of the recipient stroma is rec-
lial rejection, why anterior lamellar keratoplasty ognized as one of the most significant risk factors
(ALK) has long been suggested as the obvious for graft rejection [2, 66]. In many cases, the
approach in patients with a functioning endothe- vascularization includes both blood and lymph
lium [8, 41]. In early attempts on ALK, visual vessels [24, 62], causing the immune privilege to
outcome was disappointing [86], but over the last be compromised.
one to two decades, more sophisticated surgical Patients with inflammatory conditions of the
approaches, microkeratomes and femtosecond eye or ocular surface are also at increased risk of
lasers (FS lasers) have renewed the interest in
ALK. Despite these technological developments,
Table 17.1 Risk factors in keratoplasty
superficial anterior lamellar procedures still have
inferior visual outcome in comparison with PK Vascularization of the recipient stroma
[4]. In contrast, the surgically more challenging Anterior synechiae
deep anterior lamellar keratoplasty (DALK) Previous graft failure due to immunological rejection
nearly rivals PK in terms of postoperative visual Previous or ongoing anterior segment inflammation
acuity [55, 74, 90, 93, 116]. Uncontrolled glaucoma or glaucoma surgery
The variety of new surgical modalities in kera- Herpes simplex keratitis
toplasty has placed an increasing demand on the Ocular surface disease
17 Decision-Making in Keratoplasty 205
graft failure due to rejection. Ocular surface mor- or selective removal of single sutures in the post-
bidity represents a significant challenge and often operative period. However, in most reports, the
have poor prognosis after keratoplasty, even if the effect of these approaches is limited and with
underlying inflammatory condition appears to be considerable variation [29, 31, 42, 110]. In addi-
under control. Similarly, long-term graft survival tion, suture regularity has been found to have
may be reduced in patients with insufficiently only little influence on the postoperative astigma-
treated intraocular inflammation [14, 61] and in tism [45].
patients with herpes simplex virus, where recur- New technological developments such as fem-
rence of the infection may lead to scarring or rejec- tosecond laser (FS) penetrating keratoplasty
tion of the graft [26, 35, 92]. Uncontrolled allow precise and identical cuts to be made in
glaucoma or need of subsequent glaucoma surgery donor and recipient. FS laser penetrating kerato-
also may lead to graft failure [115]. Also, previous plasty allows sutures to be removed earlier than
rejection and graft failure are significant indicators after PK. However, FS laser-based approaches
for renewed failure after regrafting [118]. were hoped to improve the postoperative refrac-
Thus, the indication for performing elective tive outcome, but has so far disappointed. Thus,
keratoplasty in patients with one or more risk fac- in several studies, the average astigmatism after
tors should be carefully considered. FS laser PK is reported to be of the same magni-
tude or only marginally better than that of con-
ventional surgery [13, 34].
Surgical Approaches In most cases, the unpredictable refractive
outcome after PK can be relieved with glasses or
Penetrating Keratoplasty rigid contact lenses; however, additional surgical
interventions may be needed including arcuate
In PK a full-thickness cornea with clear stroma keratotomy or laser keratorefractive surgery
and viable endothelium is transplanted. There are [58, 117]. In some patients, development of cata-
several variations upon the surgical technique, but ract may allow postoperative ametropia to be cor-
clinical outcomes are generally comparable [32]. rected during subsequent cataract surgery.
Although successful in many cases, PK has Immunological rejection is a major complica-
several disadvantages. The surgery causes sig- tion after penetrating keratoplasty. In most cases
nificant structural changes in the cornea and the immunological response is raised towards the
causes the cornea to be permanently weakened. endothelial cells leading to acute cell loss and
Thus, even years after surgery, minor blunt imminent graft failure. The patient typically
trauma may lead to devastating wound dehis- complains of slight ocular irritation or inflamma-
cence and globe rupture. tion and reduced visual acuity and clinically
Due to the slow corneal wound healing, presents with endothelial precipitates, sometimes
sutures have to remain in place for at least 1 year in a Khodadoust line, and overlying stromal
after PK. Although, optical properties tend to sta- oedema [51]. If the condition is treated promptly,
bilize during this period, large refractive changes the inflammation may be controlled leading to
may occur after suture removal [49, 59, 103]. gradual resolution. However, untreated or late-
Thus, visual recovery after PK is slow and typi- treated endothelial rejection will eventually lead
cally extends for 1.52 years after surgery, since to failure of the graft. An immunological response
unexpected postoperative ametropia or high towards stromal cells is much more rare but
astigmatism may require further surgical inter- should also be aggressively treated, since an
ventions. In a large registry study of more than untreated stromal rejection may lead to clouding
1100 eyes, an average astigmatism of 4.56 diop- of the graft [75]. The risk of endothelial rejection
tres was reported [21]. Various attempts have after PK varies with the pathology that led to cor-
been made to try to control the postoperative neal transplantation [25]. In keratoconus patients,
refractive outcome, including suture adjustments the risk of endothelial rejection is reported from
206 A. Ivarsen and J. Hjortdal
5.8 to 6.8 % within the first 5 years [3, 20], the disease. Thus, after the advent of EK, indica-
whereas in high-risk corneas (Table. 17.1), the tions have been shifting, and PK is no longer the
risk of rejection may be more than 50 % [2]. In a first choice in patients with endothelial failure.
recent graft registry study, the 10-year graft sur- Today the main indications for PK are combined
vival was reported to be 89 % in keratoconus endothelial and stromal disease or deep scars
patients, 73 % in patients with endothelial dystro- extending to the most posterior layers of the
phy, 66 % in corneal scars, 59 % in herpetic scars, stroma, which significantly reduces the possibil-
42 % in secondary endothelial failure and 37 % ity for successful deep anterior lamellar kerato-
in regrafts [118]. Thus, in patients with one or plasty (DALK). Other indications for PK include
more risk factors, the indication for PK should be regrafting in patients with failed previous PK,
carefully considered, and the expected outcome uncontrolled infectious or immunological kerati-
thoroughly discussed with the patient. tis or patients with failure during attempted
Over the last years, it has been recognized that DALK.
penetrating keratoplasty is followed by an accel-
erated loss of endothelial cells that fits a bi-
exponential decay [9]. Thus, an initial rapid loss Anterior Lamellar Keratoplasty
during the first approximately 4 years is followed
by a slower but abnormal cell loss. Since endo- As detailed above, two of the major reasons for
thelial cells are required to maintain corneal graft failure after PK are loss of endothelial cells
hydration and clarity, the accelerated loss of cells and risk of endothelial rejection [2, 9, 12]. Thus,
eventually leads to graft failure. The underlying it makes sense to conserve the endothelial cell
pathology that led to keratoplasty, however, influ- layer in patients with isolated stromal conditions
ences the rate of late endothelial changes. Thus, such as scars, stromal dystrophies or ectatic dis-
one study found that patients with bullous kera- ease. Depending on the extent of the stromal
topathy or herpetic uveitis had a higher cell loss changes and the employed equipment, different
than patients with keratoconus [61]. In another types of ALK can be performed.
study, the incidence of endothelial failure 15
years after PK was 8 % in keratoconus patients Supercial Anterior Lamellar
and 33 % in patients with bullous keratopathy Keratoplasty
[12], and it was hypothesized that a reservoir of In patients with superficial stromal changes, ALK
viable endothelial cells in the recipient cornea may be performed as an automated lamellar ther-
reduce the overall cell loss, thus explaining the apeutic keratoplasty (ALTK). In ALTK, a micro-
better outcome in patients without underlying keratome is used to create a lamellar graft and to
endothelial pathology. similarly remove the anterior part of the recipient
cornea. Depending on the thickness of the micro-
Indications for Penetrating keratome cut, a bandage contact lens may be suf-
Keratoplasty ficient to protect the graft for the first period after
Since most corneal pathologies tend to affect surgery [96]. Thus, with thin grafts, sutures may
either the endothelium or the stroma, it is desir- not be necessary giving ALTK a considerable
able to try to selectively treat the diseased part of advantage over deeper grafts or PK, where
the cornea, reducing the risk of some of the com- sutures may contribute to the unpredictable post-
plications after PK. In patients with isolated stro- operative astigmatism [21].
mal disease, an anterior lamellar approach may In contrast to manual dissection, the micro-
be preferred to PK in order to avoid the risk of keratome creates a very smooth interface, and
failure due to endothelial cell loss or rejection. In visual outcome has improved with the automated
contrast, patients with endothelial dystrophy or approach. Still, many patients do not achieve as
secondary bullous keratopathy usually have lim- good a visual acuity with ALTK as with PK [77,
ited stromal changes until in very late stages of 95]. Development of haze at the interface and
17 Decision-Making in Keratoplasty 207
variations in graft thickness may be some of the endothelial rejection and the accelerated postop-
factors that contribute to the suboptimal postop- erative endothelial cell loss that occurs after
erative visual performance. A specific challenge PK. Although rare, stromal rejection may still
with ALTK is risk of epithelial ingrowth into the occur, which requires prompt reaction and treat-
interface that may be detrimental to the final ment [73, 89]. The most frequent postoperative
postoperative outcome [97]. complication after DALK is unpredictable post-
The recent development of femtosecond lasers operative astigmatism of the same magnitude as
(FS lasers) has led to new possibilities in ALK after PK [5, 90].
surgery (FS-ALK). FS lasers allow the formation
of a planar graft with precisely defined diameter Tectonic Keratoplasty
and edge. By performing a similar cut in the A tectonic lamellar keratoplasty is a therapeutic
recipient cornea, a near-perfect match between intervention performed to reinforce the cornea or
the graft and the recipient can be obtained. replace tissue lost due to inflammatory ulceration
Studies are few, but the visual outcome has been or non-inflammatory thinning disorders. Thus,
disappointing with only half of the patients tectonic procedures are used in patients where
obtaining a best-corrected visual acuity of 20/30 ALK or PK is not possible or preferable. The
or better [15, 91]. At present, clinically controlled techniques for performing tectonic grafts are
studies are needed to determine whether FS-ALK multiple and depend on the specific condition
offers any significant advantage over traditional being treated. The donor tissue is fashioned to
ALTK when it comes to postoperative outcome. match the defect in the recipient cornea and may
include annular, horseshoe shaped, crescent
Deep Anterior Lamellar Keratoplasty shaped or oval grafts [18, 39, 40, 108]. Depending
In patients with deep stromal changes or ectatic on the location of the graft and the underlying
disease, superficial ALK is insufficient and ocular pathology, the visual outcome after tec-
deeper stromal dissection required. Traditionally, tonic grafting may be very poor, and a penetrat-
pre-Descemetic ALK has been performed by ing keratoplasty may be needed to restore the
manual dissection, in which up to 10 % of the patients visual performance after the eye has
most posterior recipient stroma is left [8]. quieted down.
However, even with a meticulous surgical tech-
nique, it is difficult to obtain a smooth interface, Indications for Anterior Lamellar
and the visual outcome is often mediocre. A Keratoplasty
newer approach, deep anterior lamellar kerato- An anterior lamellar approach is indicated in cor-
plasty (DALK), allows the surgeon to obtain stro- neas with isolated stromal changes. The decision
mal separation at, or very close to, Descemets between ALTK and DALK depends primarily on
membrane producing a smooth interface while the depth of the stromal changes, but in very
leaving the endothelium intact. The various tech- superficial cases, other treatment modalities such
niques to obtain the deep stromal separation are as excimer laser ablation may be considered if
discussed in detail elsewhere in the book. available. Superficial ALK may have the advan-
With DALK, it is possible to obtain a visual tage of being sutureless with thin grafts, reducing
outcome rivalling that of PK [5, 22, 74, 90]. the postoperative astigmatism; however, the
Unfortunately the technique is difficult to master, visual outcome is often inferior in comparison
and rupture of the thin Descemets membrane with DALK or PK. Since most patients expect a
during surgery or insufficient separation of cor- good visual outcome after surgery, it is important
neal layers is frequent complications that may that the patient is thoroughly informed about the
require conversion to conventional PK in a high benefits and disadvantages of a superficial ante-
percentage of cases. When successful, however, rior lamellar procedure.
DALK allows the recipient endothelium to In patients with deep stromal changes or
remain untouched, eliminating both the risk of ectatic disease, DALK will often be the most
208 A. Ivarsen and J. Hjortdal
obvious choice since it spares the recipient endo- changes in the recipient extracellular matrix [16,
thelium. However, the surgical procedure is dif- 17, 43, 50, 101]. Most probably several factors
ficult and more time consuming than are at play, but the importance of each of these
PK. Inadvertent perforation of the thin Descemets factors remains to be elucidated.
membrane or inability to obtain separation of the A unique complication related to endothelial
corneal layers occurs in a high percentage of keratoplasty is the risk of graft detachment within
cases. In patients with very deep stromal scars the first few days after surgery. The reported risk
after hydrops or keratitis, the risk of perforating of detachment after DSAEK varies considerably,
Descemets membrane is high, and DALK with but in eyes with a normal anterior segment, it is
hydrodissection or big-bubble technique is generally in the range of 515 % [7, 60]. The
unlikely to succeed. In these patients, PK may be underlying reason remains obscure, but detach-
considered the first choice, although pre- ment occurs more frequently in eyes where the
Descemetic ALK with manual dissection might amount of air in the anterior chamber after sur-
be attempted to reduce the risk of endothelial gery may have been insufficient. This tends to be
rejection and graft failure [72]. eyes with other ocular pathology including previ-
ous vitrectomy, iris defects, aphakia and previous
glaucoma surgery. Graft detachments can usually
Endothelial Keratoplasty be managed by re-centration of the graft and
repeated air injection (termed rebubbling).
Descemets Stripping Automated In DSAEK, the manipulation of the graft leads
Endothelial Keratoplasty to a significant loss of endothelial cells during
In DSAEK a microkeratome is used to prepare a surgery; however, in recent studies, the endothe-
stromal-endothelial graft that is introduced into lial cell density after 2 and 3 years has been found
the recipient eye, positioned and kept in place to be comparable to that of PK [80, 99].
with an air bubble. Several surgical approaches In contrast, the rejection rate appears to be
have been described, but the specific approach lower after DSAEK than after PK and has been
seems to have little influence on the clinical out- reported to be 59 % after DSAEK versus
come, and overall DSAEK is quick to perform 1520 % after PK [44, 78, 80] with no major dif-
and can be mastered with relative ease. The vari- ference between surgery for primary or second-
ous techniques are described in detail elsewhere ary endothelial failure.
in this book.
Since only the two most posterior corneal lay- Descemets Membrane Endothelial
ers are affected by DSAEK, it offers several Keratoplasty
advantages over PK, including a more stable eye, The slightly disappointing outcome in terms of
less induced astigmatism and faster visual recov- visual acuity after DSAEK has led to develop-
ery. Thus, there is no major risk of globe rupture ment of another surgical approach termed
or wound dehiscence with minor blunt trauma Descemets membrane endothelial keratoplasty
after DSAEK. Furthermore, the surgery induces (DMEK) [6971]. In DMEK, Descemets mem-
only little astigmatism, and the initial visual brane with endothelium is carefully harvested
recovery is fast, allowing most patients to func- from the donor cornea and subsequently
tion normally within a few weeks after surgery. introduced into the recipient. Several techniques
Nevertheless, even though visual acuity improves have been described and are detailed elsewhere.
for more than one year after DSAEK, it still tends In contrast to DSAEK, DMEK is surgically much
to be poorer than after PK [6, 19, 76]. There has more challenging since the thin Descemets
been much debate on the underlying cause for the membrane scrolls up with the endothelium facing
reduced visual acuity after DSAEK including outwards. Thus, the surgeon has to unscroll the
graft thickness, irregularities or haze at the donor- tissue while at the same time ensuring proper
recipient interface, lamellar orientation or centration and introducing and air bubble to keep
17 Decision-Making in Keratoplasty 209
the graft in place. In addition to being a more dif- loss of tissue, which needs be considered in
ficult procedure, the risk of graft detachment countries with shortage of donors. Second, the
after DMEK is higher than after DSAEK. Thus, time required for successful DMEK surgery is
graft detachments have recently been reported to more variable than for DSAEK, and even when
occur in as much as 3378 % of eyes within the the tissue has been prepared, DMEK may take
first 4 days after DMEK requiring rebubbling in considerably longer than DSAEK. Besides, many
730 % [105]. Furthermore, eyes with total graft cornea banks are able to deliver pre-cut tissue for
detachment after DMEK represent a considerable DSAEK, whereas only few banks as of yet are
surgical challenge since the thin graft will curl up able to deliver pre-dissected DMEK grafts.
again. Finally, patients with anterior chamber abnor-
In comparison with PK, DMEK has the same malities including anterior chamber IOLs, apha-
favourable advantages as DSAEK when it comes kia, large iridectomies, partial aniridia, previous
to globe stability, induced astigmatism and visual filtering surgery, glaucoma tubes or previous vit-
recovery; however, in terms of postoperative rectomy are generally not good candidates for
visual outcome, DMEK seems to fare better than DMEK, whereas DSAEK may be attempted.
DSAEK [37, 38, 104]. Although the initial loss Taken together, there are several factors to
of endothelial cells may be higher after DMEK, consider when choosing the optimal surgical
the long-term cell loss has been reported to be approach for endothelial failure, where local cir-
similar to that of DSAEK and PK [30]. cumstances may play a significant role, including
Furthermore, the risk of endothelial rejection has availability of donor tissue and local logistics.
been reported to be much lower after DMEK as Thus, although DMEK represents the state-of-
compared to DSAEK and PK [6]. the-art approach, DSAEK may still be the more
obvious choice at many institutions.
Indications for Endothelial
Keratoplasty
Due to the favourable outcome of EK in compari- To Graft or Not to Graft
son with PK, all endothelial pathologies should,
in principle, be treated with endothelial kerato- Keratoplasty surgery has been rapidly evolving
plasty. Most secondary stromal changes due to during the last 15 years, and indications have
endothelial pathology are reversible or may be been changing. Where corneal transplantation
addressed during surgery. Thus, patients with used to be considered primarily in patients with
long-standing endothelial failure may have depo- severe visual reduction and bilateral affection,
sition of sub-epithelial fibrotic tissue that can be there has been an increasing tendency towards
scraped or peeled off during surgery without earlier intervention as well as treatment in cases
compromising Bowmans layer. Full-thickness with unilateral disease and a normal contralateral
transplantation should only be considered in eye. However, the basic premise for doing sur-
cases where other significant stromal changes gery remains an estimation of the expected out-
such as keratoconus or stromal scars are consid- come in any given case. In other words, what are
ered to influence upon the postoperative visual the odds that the patient will benefit from the sur-
outcome. gical intervention? In most corneal
When it comes to choosing between DMEK transplantations, the main concerns will be the
and DSAEK, the decision may be more difficult. patients postoperative visual acuity, the refrac-
Overall, DMEK appears to be more favourable tion and the expected risk of graft failure. To
than DSAEK due to a better visual outcome and address these concerns, the surgeon needs to have
lower rejection risk. However, DMEK is surgi- specific knowledge of the possible surgical
cally more challenging, which should be taken approaches as well as the postoperative treat-
into account. First, harvesting the thin graft for ments. In addition, the patient needs to be thor-
DMEK requires considerable skill and may cause oughly informed about the procedure and the
210 A. Ivarsen and J. Hjortdal
expected outcome, as well as the potential risk DALK is gradually becoming more widespread.
for failure after surgery. Below, some of the most The main complication of both procedures is an
common pathologies leading to corneal trans- unpredictable refractive outcome; yet, the best-
plantation are considered. corrected visual acuity is usually good. DALK
offers the advantage of eliminating the risk of
endothelial rejection; however, graft survival
Endothelial Failure after PK in keratoconus is usually excellent, and
a 10-year survival of 89 % has been reported
In patients with endothelial failure due to Fuchs [118]. Two recent studies found similar long-
dystrophy or secondary bullous keratopathy, term graft survival after DALK or PK in kerato-
endothelial keratoplasty as either DSAEK or conus patients, with marginally better visual
DMEK is the obvious surgical approach. The outcome after PK, but fewer postoperative com-
refractive outcome is generally excellent in both plications after DALK [65, 122]. In this context,
procedures, although a minor hypermetropic both procedures may still be considered as
shift may occur [48]. However, DMEK usually acceptable approaches when keratoplasty is
offers better visual acuity than DSAEK, as well needed in keratoconus patients.
as a lower rejection rate, but the surgery is more
complicated and with higher risk of perioperative
tissue loss and postoperative graft detachment. Stromal Dystrophies
Thus, local organization and tissue availability
may make DSAEK the preferred approach. Keratoplasty for stromal dystrophies other than
Furthermore, DMEK is usually not recom- keratoconus constitute only a fraction of the total
mended in patients with anterior segment abnor- number of corneal transplantations. The surgical
malities, whereas DSAEK may be attempted in approach to stromal dystrophies varies according
these cases. to the location of the stromal changes. In patients
Both DMEK and DSAEK can be performed with predominantly superficial changes such as
as triple procedures with concurrent cataract sur- early granular dystrophy, treatment with excimer
gery. However, in patients with limited changes laser photoablation or superficial ALK may be
due to endothelial dystrophy, it may be appropri- performed. With deeper stromal changes, DALK
ate to do cataract surgery alone and postpone or PK may be considered. Overall, the outcome of
keratoplasty [109]. transplantation in stromal dystrophies is good
with respect to the risk of rejection episodes.
Unfortunately, several dystrophies show a high
Keratoconus tendency towards recurrence, which severely may
limit the outcome after transplantation, as detailed
Before keratoplasty is considered in patients with elsewhere in this book. Thus, knowledge of the
keratoconus, an attempt to correct the refraction tendency towards recurrence of the various dys-
with rigid, gas-permeable contact lenses should trophies is of high importance in order to decide
have been performed. whether keratoplasty should be performed.
Other surgical interventions including implan-
tation of intrastromal corneal ring segments
should also have been considered [23]. However, Stromal Non-herpetic Scars
if these approaches are found insufficient to help
the patient, keratoplasty may be attempted. Scars after infectious keratitis or corneal trauma
During recent years, there has been a gradual may vary considerably in their extent.
shift in the preferred treatment of keratoconus at Furthermore, stromal scars tend to diminish over
some institutions. Where PK used to be the pre- time due to slow corneal remodelling, why
ferred procedure of many surgeons, the use of keratoplasty eventually may not be needed [67].
17 Decision-Making in Keratoplasty 211
Thus, in most cases the surgeon should wait for 56 % in patients with no prophylactic treatment
several months, before surgery is considered. The [10]. Since the endothelium may be assumed to
specific surgical approach may be varied accord- be unaffected in most patients, DALK may
ing to the depth of the stromal changes. In very reduce the risk of a rejection episode and was
superficial scars, excimer laser photoablation recently reported to have better postoperative
may be attempted or superficial ALK considered. outcome than PK [119], whereas another study
With deeper scarring, DALK or PK may be pre- reported of a high percentage of postoperative
ferred, but in patients with previous corneal per- complications including rejection and graft fail-
foration, DALK is unlikely to succeed. ure [64]. Thus, both PK and DALK may be
A 10-year graft survival of 66 % has been attempted, but the indication for performing ker-
reported after PK in patients with stromal scars, atoplasty in patients with herpetic eye disease
whereas only 47 % of grafts after traumatic injury should be carefully considered, and the patient
were clear after 10 years [118]. In one report of thoroughly informed about the potential outcome
DALK for infectious scars or trauma, a six-month of the surgery.
graft survival of 94 % was reported [112]; unfor- In active herpetic eye disease, stromal melting
tunately long-term studies are lacking. and corneal perforation may occur. In these cases,
It should be noted that stromal scars due to high-dose antiviral medication should be insti-
infection or trauma represent a very diverse group tuted and emergency repair performed in order to
due to varying degree of accompanying risk fac- preserve the eye. Emergency repairs may include
tors. In many patients with stromal scarring, vas- amniotic membrane transplantation, tectonic ker-
cularization or glaucoma may be present, which atoplasty or penetrating keratoplasty; however,
will negatively affect the outcome of subsequent due to considerable inflammation and ongoing
keratoplasty. Thus, in each case, the presence of viral replication, the long-term prognosis is usu-
risk factors should be noted and incorporated into ally poor.
the preoperative assessment.
Following a successful limbal graft, subsequent intensive treatment, severe dry eye disease has a
DALK or PK will often be needed to obtain a clear poor prognosis with a very high risk of graft fail-
stroma. Unfortunately, the amount of tissue that ure after keratoplasty.
can be harvested for limbal autografting is limited
and incurs a risk for the unaffected eye, which may
reduce the expectations in patients with severe Corneal Emergencies
limbal stem-cell disease. Ex vivo expansion of
autologous cells may increase the amount of avail- In corneal emergencies, keratoplasty may be per-
able tissue [57, 79]. Unfortunately, culturing of formed in order to preserve the eye. Thus, corneal
limbal stem cells is at present only performed in perforation or near perforation due to uncon-
few laboratories over the world. trolled infectious keratitis or severe immunologi-
When tissue for autografting is not available, cal disease may call for an emergency keratoplasty.
transplantation of tissue from living-related Underlying causes may include melting due to
donors or cadaveric eyes may be attempted. herpes infection, peripheral ulcerative keratitis or
However, allogeneic conjunctival-limbal grafts Moorens ulcer. In most instances, emergency
are at considerable risk of rejection, although a keratoplasty may be performed as amniotic mem-
77 % success rate has been reported with exten- brane transplantation, a lamellar tectonic (repair)
sive systemic immunosuppression for 12 years procedure or a penetrating keratoplasty. The pur-
[47]. In addition to the guarded prognosis, the use pose of the acute surgical intervention is preserva-
of systemic immunosuppressants incurs a short- tion of the eye, giving time for control of the
and long-term risk for development of malignant underlying infectious or inflammatory condition.
tumours. Thus, the indication for limbal grafting In tectonic procedures, later penetrating kerato-
with allograft tissue should be extensively dis- plasty may be needed to restore the patients
cussed with the patient. visual performance. Similarly, in emergency pen-
In patients where systemic immunosuppres- etrating keratoplasty, the heightened immunologi-
sion is contraindicated or unwanted, pre- cal response will often reduce the long-term graft
Descemetic ALK or DALK as an isolated survival, and a 32 % 10-year graft survival has
procedure (without prior limbal grafting) may be been reported [118]. Thus, regrafting may be
attempted to obtain a short- or medium-term needed to improve the patients visual acuity at a
improvement in the patients visual performance. later time point, preferably after the eye has been
However, the patient should be carefully informed quiet for a long time.
that the prognosis usually is poor with expected
recurrence of symptoms.
High-Risk Grafts
Dry Eye Disease In patients with one or more risk factors for graft
failure (Table. 17.1), the indication for kerato-
Patients with severe dry eye due to primary or plasty needs careful consideration. If regrafting is
secondary Sjgrens syndrome or graft-versus- performed, one or more approaches may be
host disease have problems maintaining an intact attempted to reduce the postoperative failure rate.
epithelium, and persistent epithelial defects rep- In corneas with stromal vascularization,
resent a risk for secondary stromal melting [94]. attempts to reduce the amount of vessels, either
Thus, emergency corneal repair with amniotic before or during grafting, may include fine-needle
membrane transplantation, tectonic grafting or diathermy and anti-VEGF injections [28, 56,
PK may be needed. A temporary or permanent 107], but clinically controlled studies are lacking.
partial tarsorrhaphy may promote postoperative In some studies, HLA matching has been found
epithelial repair, in combination with frequent to reduce the risk of rejection. Thus, a survival rate
lubrication or serum eye drops. Still, despite of 92 % in HLA class I and II matched donors as
17 Decision-Making in Keratoplasty 213
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Index
I L
Immunology, of keratoplasty Lamellar keratoplasty. See DALK, DMEK, DSEK
anti-HLA antibodies, 97 Laser-assisted in-situ keratomileusis (LASIK),
direct vs. indirect allorecognition, 94 58, 118, 156157, 160
graft rejection, 9394 Layer-by-layer dissection method, 61
histocompatibility antigens Limbal stem-cell deficiency (LSCD)
blood group antigens, 98 autologous vs. allogeneic limbal grafts, 195196
class I and II molecules, 95 biopsy, 199
HA-3 epitope, 98 clinical features
H-Y antigens, 9798 signs, 197
matching, 9597 symptoms, 196197
minor histocompatibility antigens, 97 confocal microscopy, 197198
typing and nomenclature, 95 conjunctival epithelial cells and goblet cells, 198
recommended clinical practice, 98 conjunctival migration/conjunctivalization, 194
Impression cytology, 197 in culture, 199
Intracorneal ring segments (ICRSs), 156 future perspectives, 201
Intraocular lens (IOL) calculation grafting, 199200
cataract surgery with penetrating impression cytology, 197
keratoplasty, 167 indications and contraindications, 196
new triple procedure need, 194195
absolute prediction error, 166 postoperative management, 200
accuracy, 166 proliferative potential and cloning characteristics, 197
advantages, 164 residual corneal opacity, 200
methods, 164, 166 Limbal stem-cell transplantation (LSCT), 194
postoperative hyperopic shift, 164 LSCD. See Limbal stem-cell deficiency (LSCD)
refractive error, 166
Scheimpflug imaging, 167
phakic, 170171 M
piggyback, 170 Macular dystrophy, 117
power calculation, 163164 Major histocompatibility antigens, 95
previous corneal graft, 167170 McCarey-Kaufman medium, 27
prior corneal graft, 167 Mechanical microkeratomes
Intraocular surgery, 157158 artificial anterior chamber, 174175
Intrastromal air injection, 61 automated corneal shaper, 175
IOL calculation. See Intraocular lens (IOL) calculation big bubble technique, 174
Iridocorneal endothelial (ICE) syndrome, 45 description
Index 223
S T
SALK. See Superficial anterior lamellar keratoplasty (SALK) Tectonic keratoplasty, 5458, 71, 108, 189, 207
Salzmanns nodular degeneration, 120121 Top-hat keratoplasty, 3, 81, 185186
Schnyder dystrophy, 117118 Toric intraocular lenses (tIOLs), 157
Schwalbes line, 16 Traditional penetrating keratoplasty, 3
Selective lamellar keratoplasty, 58 Trephination technique, 71
Sickle DMEK, 37 Trypan blue exclusion assay, 27
Small-bubble technique, 60 Type 1 bubble, 60
Spectacle and contact lenses, 155 Type 2 bubble, 60
Stromal dystrophies, 115118, 210
Stromal non-herpetic scars, 210211
Submerged cornea using backgrounds away (SCUBA), 41 U
Submerged hydro-separation method, 31, 32 UK Transplant Registry, 132
Sulcoflex, 159, 170 Ulcerative keratitis, amniotic membrane
Superficial anterior lamellar keratoplasty (SALK), 206207 transplantation, 84
automated lamellar therapeutic keratoplasty Ultrathin Descemets stripping endothelial keratoplasty
complications, 55 (UT-DSEK), 188
decision making Ultrathin DSAEK, 37, 43, 179180
postoperative management, 55 Urrets-Zavalia syndrome, 86
preoperative examination, 55
purpose and indication, 54
central, 5556 W
ectopic, 57 Wedge resection, 156
peripheral, 5657
Surgical glides, device prototyping for, 3031
Swedish Cataract Registry, 131 Z
Swedish Cornea Registry, 131 Zeiss VisuMax, 183