EUPO2013 Coursebook Online

June 7-8
COPENHAGEN, Denmark
Cornea, Conjunctiva
and Refractive Surgery
EUPO Ofce Kapucijnenvoer 33 3000 Leuven Belgium www.eupo.eu
EUPO 2013
EUPO 2013
Cornea, Conjunctiva and Refractive Surgery
June 7-8
COPENHAGEN, Denmark
Cornea, Conjunctiva
and Refractive Surgery
EUPO Ofce Kapucijnenvoer 33 3000 Leuven Belgium www.eupo.eu
EUPO 2013
EUPO Course 2013 - Page 2
The sequence of the EUPO courses
2013 Copenhagen (SOE) Cornea, Conjunctiva and Refractive Surgery
2012 Leuven Neuro-ophthalmology and strabismus
2011 Geneva (SOE) Uveitis & Glaucoma
2010 Athens Retina
2009 Amsterdam (SOE) Cornea, Conjunctiva and Refractive surgery
2008 Geneva Neuro-ophthalmology and strabismus
2007 Vienna (SOE) Glaucoma and uveitis
2006 Ghent Retina
2005 Berlin (SOE) Cornea
2004 Nijmegen Neuro-ophthalmology and strabismus
2003 Madrid (SOE) Glaucoma and uveitis
2002 Erlangen Retina
2001 Istanbul (SOE) Cornea
2000 Leuven Neuro-ophthalmology and strabismus
1999 Stockholm (SOE) Glaucoma and uveitis
1998 Amsterdam (ICO) Chorioretina
1997 Budapest (SOE) Cornea, conjunctiva, lids, orbit
1996 Athens Neuro-ophthalmology and strabismus
1995 Milano (SOE) Uveitis, lens, glaucoma
1994 Montpellier Retina
1993 Santiago de Compostella The external eye
1992 Brussels (SOE) Neuro-ophthalmology and strabismus
1991 Torino Uveitis, lens, glaucoma
1990 Bonn Chorioretina
1989 Leuven The external eye and orbit
1988 Nijmegen First EUPO course
It is my pleasure to welcome you to the 26th annual Course of the European
Professors of Ophthalmology (EUPO) on Cornea, Conjunctiva and Refractive Surgery in
Copenhagen, Denmark 7-8 June 2013.
We are delighted that a superior international faculty, who are all leaders in their eld,
accepted our invitation.
These invited lecturers come from Europe and from around the world. They will present
an unsurpassed scientic programme.
The course follows a tradition established in 1988 by Professor Deutman.
After this course it was decided to organize a course once a year in different places in
Europe. Later it was decided that in the year of a congress of the European Society of
Ophthalmology (SOE), the course would be organized in connection with the European
Congress of Ophthalmology.
Most of the ophthalmology curriculum should be covered in the EUPO Courses within a
four-year period in order to permit residents and ophthalmologists to have an overview
of basic and clinical knowledge of the eye during this four-year period.
No EUPO Course would be complete without a great EUPO Party for participants and
speakers, which traditionally reects the avour of the host city. This evening gives an
informal and pleasant opportunity to meet with European residents, ophthalmologists
and the course faculty of invited speakers in an atmosphere of good gastronomy.
I welcome you to Copenhagen and thank you for making the EUPO Course 2013 a
memorable event.
Gabriel van Rij, MD, PhD
President of EUPO
Gabriel Van Rij, President of EUPO
available on www.eupo.eu
EUPO 2006
Retina
EUPO 2007
Uveitis
EUPO 2008
Neuro-Ophthalmology
and Strabismus
EUPO 2009
Cornea, Conjunctiva
and Refractive
surgery
EUPO 2010
Retina
EUPO 2011
Uveitis and Glaucoma
EUPO 2012
Neuro-ophthalmology
and Strabismus
EUPO 2013
Cornea, Conjunctiva
and Refractive
Surgery
EUPO Board
EUPO Ofce: www.eupo.eu
European University Professors of Ophthalmology
Gabriel Van Rij, President
Werner Spileers, Secretary general - Treasurer
PROGRAMME EUPO 2013 - Friday, June 7
Course directors:
Gabriel van Rij, The Netherlands
Friedrich Kruse, Germany
Jesper Hjortdal, Denmark
Course Page
08.30 - 10.00 Morphology, anomalies and dystrophies
Moderators: Andrs Berta, Hungary & Gabriel van Rij, The Netherlands
08:30 Morphology of the normal human cornea 1 11
Andrs Berta, Hungary
09:00 Corneal disorders in children and congenital anomalies of the cornea 2 21
Joaquim Murta, Portugal
09:30 Corneal dystrophies 3 25
Hans Ulrik Mller, Denmark
10.15 - 11.45 Tumours, examination and inammation
Moderators: Michael Belin, United States & Jesper Hjortdal, Denmark
10:15 Tumours of the cornea and conjunctiva 4 29
Stefan Seregard, Sweden
10:45 Corneal examination techniques: pachymetry, topography,
tomography, optical coherence tomography, confocal and wavefront 5 33
Michael Belin, United States
11:15 Role of inammation in ocular surface disease 6 37
Uwe Pleyer, Germany
13.00 - 14.30 Non-inammatory pathology and keratoplasty
Moderators: Per Fagerholm, Sweden& Jesper Hjortdal, Denmark
13:00 Non-inammatory corneal pathology, Salzmann, Terrien 7 43
Murat Irke, Turkey
13:30 Ocular surface reconstruction and articial cornea 8 63
Per Fagerholm, Sweden
14:00 Corneal transplantation: penetrating and deep anterior lamellar
keratoplasty 9 65
Course Page
14.45 - 16.15 Keratoplasty and keratoprosthesis
Moderators: Christopher Liu, United Kingdom & Friedrich Kruse, Germany
14:45 Corneal transplantation: post lamellar 10 69
15:15 Corneal transplantation: immunology and angiogenesis 11 71
Bjrn Bachmann, Germany
15:45 Bypassing the ocular surface. Restoring sight with Keratoprosthesis 12 75
Christopher Liu, United Kingdom
16.30 - 18.00 Allergy, keratoconus and herpetic disease
Moderators: Frank Larkin, United Kingdom & Berthold Seitz, Germany
16:30 Assessment and step-by-step management of allergic eye disease 13 107
Frank Larkin, United Kingdom
17:00 Keratoconus and pellucid marginal degeneration: diagnosis
and treatment 14 125
Franois Malecaze, France
17:30 Herpetic Keratitis 15 129
Berthold Seitz, Germany
18.30 EUPO Course Evening for participants and teachers 8
EUPO Course Evening for participants and teachers
The EUPO Course Evening will be held at the Aquarium at the Tivoli Gardens, in the
centre of Copenhagen. The Tivoli Gardens is among the worlds ten most popular
amusement parks. The evening should be a true Danish highlight, held in a fairy-tale
setting.
The EUPO Course Evening is open for registered EUPO participants and teachers and
is included in the EUPO registration fee. Pre-booking is mandatory and tickets are
reserved on a rst-come rst-served basis. A valid ticket must be presented in order to
obtain admittance to the evening.
Transportation will not be provided.
Dresscode: Smart casual
Welcome!
Tivoli Gardens
EUPO Course 2013 - Certicate of Attendance
A Certicate of Attendance will be prepared for your convenience.
The Certicate will be distributed on Saturday, 8 June, during the EUPO Course hours
from a desk outside of the meeting room.
PROGRAMME EUPO 2013 - Saturday, June 8
Course directors:
Gabriel van Rij, The Netherlands
Course Page
08.15 - 09.45 Bacterial, fungal and acanthamoeba keratitis
Moderators: John Dart, United Kingdom & Gabriel van Rij, The Netherlands
08:15 Bacterial keratitis 16 151
Joseph Frucht-Pery, Israel
08:45 Fungal and chlamydial infections 17 155
Philippe Kestelyn, Belgium
09:15 Acanthamoeba keratitis 18 167
John Dart, United Kingdom
10.15 - 11.45 Opening Ceremony SOE 2013

13.30 - 14.15 Key Note lecture Reza Dana, United States
Translational discoveries in cornea and ocular surface diseases

14.30 - 16.00 Dry eye, eyelids and refractive surgery
Moderators: Thanh Hoang-Xuan, France & Friedrich Kruse, Germany
14:30 Meibomian gland dysfunction, ocular rosacea 19 175
Thanh Hoang-Xuan, France
15:00 Dry eye and clinical disease of tear lm, diagnosis and management 20 177
Jesus Merayo, Spain
15:30 Surface photoablation 21 179
Timo Tervo, Finland
16.30 - 18.00 Refractive surgery
Moderators: Thomas Kohnen, Germany & Gabriel van Rij, The Netherlands
16:30 Laser in situ keratomileusis: Microkeratome or femtosecond laser 22 187
Thomas Kohnen, Germany
17:00 Femtosecond laser corneal surgery 23 189
17:30 Quality of vision after refractive surgery 24 193
Dimitri Azar, United States
01
Introduction
Both the oral and the written part of the course on corneal diseases and corneal surgery
start with the description of the morphological and histolological characteristics of the
normal human cornea. Residents should start their studies with this subject because a
well-based and detailed knowledge of the normal corneal stuctures is essential for the
study of pathological changes to be found and recognized in the cornea, either on the
macroscopic or on the microscopic level. In certain countries the study of corneal
pathology is a part of the resident training in Ophthalmology. Such informations help
the residents to recognize corneal diseases both in vivo using the slitlamp, and on
stained sections using the microscope. Proper knowledge of corneal morphology is
essential to evaluate and interpret the ndings gained using modern diagnostic methods
(corneal topography, specular microscopy, in vivo confocal microscopy, pachymetry, anterior
segment optical coherence tomography, ultrasound biomicroscopy, Scheimpug-
cameras, such as Pentacam and CorVis ST), as well as to be able to perform surgery
on the cornea (different types of corneal transplantation, and refractive surgical
interventions). Not only a thorough knowledge of corneal morphology can help the
use of diagnostic instruments, and the performance of corneal surgeries but also
experiences, research and developmental work in the eld of corneal diagnostics and
corneal surgery, constantly increase our knowledge on the structure and function of
the cornea as a whole and that of different layers and parts of the cornea in health
and in disease.
Anatomy
The average diameters of the cornea are: 12 mm and 11.5 mm in the horizontal and in
the vertical axis, respectively. This results in a 0.5 diopter, on an average, with the rule
astigmatism, that is called physiological astigmatism.
Histology
1. Epithelium
The corneal epithelium has three layers (surface cell layer, wing cell layer and basal
cell layer) that consist of different types of cells. The surface cells are at and present
Morphology of the normal human cornea
Andrs Berta, Hungary
in 2-3 layers, have at nuclei and are joined together by bridges (zonula occludens).
The surface of the outermost cells is increased by microvilli in order to facilitate the
adsorption of mucin, that makes the corneal surface more hydrophyllic. The wing cells
have wing like extensions and are arranged in 1-2 layers. The basal cells form a single
layer, are of columnar shape with nuclei located near to the apex of each cell, are able
to devide and are the source of the wing cells which in turn when shifted towards the
surface become supercial cells (Figure 1, 2A).

Figure 1. Histology of the normal cornea: Five layers of the cornea (bottom) and the
different cellular layers of the corneal epithelium (top).
01
1. Bowmans layer
Bowmans layer is only a supercial layer of the stroma, with special compact structure,
acellular and does not regenerate when injured or damaged.
2. Stroma
Corneal stroma is composed of collagen brils of uniform size, extending across the
the entire cornea, forming bundles and layers (lamellae) in a parallel and criss-crossed
manner, as well as corneal cells (keratocytes) (Figure 2C) and extracellular matrix, that is
composed of glycoproteins and glycose-aminoglycans. Rather special characteristic of
the corneal stroma is transparency (optical clarity) which is related to its highly oriented
structure and its dehidrated state.
Figure 2. Cellular structures of the normal cornea imaged with in vivo confocal
microscopy.
3. Descemets membrane
Descemets membrane is composed of thin collagen brils arranged in a lattice forming
way. Its anterior layer, that shows bands on electron microscopic picture, develops
during the intrauterine life, while the posterior layer is slowly growing, synthetized
by the endothelial cells throughout life. Descemets membrane acts as a basement
membrane of the corneal endothelium.
4. Endothelium
Endothelium is a single layer of hexagonal cells covering the inner surface of the cornea
(Figure 1, 2D). It plays a basic role in maintaining the deturgenscence of the cornea by
a continuous pumping of water and ions from the stroma to the aqueous humor in
the anterior chamber. The number (density) of corneal endothelial cells decreases with
age. As the endothelial cells are not able to regenerate. The integrity of the endothelial
cell layer is mantained by streaching out of the neighbouring cells covering the place
of a dying cell.
The human cornea contains sensory nerve bers originated from the trigeminal nerve and
sympathetic axons from the superior cervical ganglion. Stromal nerve bundles enter the
cornea at its periphery and before penetrating the Bowmans membrane, they compose
the subepithelial plexus. After dividing into several smaller branches, subbasal plexus
nerves innervate the corneal epithelium and form nerve terminals with a considerably
higher density in the central cornea than in the periphery (Figure 2B). Corneal nerves
and sensation have pivotal role in maintaining functional and morphological integrity
of the ocular surface. Several corneal disorders, refractive surgeries and penetrating
keratoplasty can completely abort the integrity of sensory innervation of the cornea
and may lead to decrease in corneal sensation and secondary dry eye disease. Deep and
detailed knowledge of corneal anatomy, especially the corneal innervation is crucial for
understanding disease mechanisms and planning surgical procedures.
The healthy human cornea is avascular, it is supplied by the anterior ciliary artery and the
facial artery. At the limbus, peripheral cornea connects to the opaque sclera (Figure 3).
01
Structure related characteristics
The special microstructure, regulation and physiology of the normal human cornea are
responsible for its complex functions. Cornea is the principal refracting component of
the eye contributing two-thirds of the total refractive power. Corneal avascularity, the
special arrangement of collagen bers and interbrillar spacing in the stromal layer as
well as intact endothelial function are essential in maintaining corneal transparency.
Endothelial cell density and morphology are important markers of the corneal health
since these hexagonal cells act like active uid pumps and have barrier function and are
responsible for preserving corneal deturgescence (Figure 4). Impairment of endothelial
function leads to corneal swelling and loss of transparency. The fundamental functions of
the normal cornea are light transmission, refraction (with the pre-corneal tear lm) and
protection. Healthy corneas show larger thickness values towards the limbus (Figure 5).
This phenomenon could be explained by the growing amount of collagen bers and the
transversely oriented anchoring lamellae in the periphery. Due to its unique microstructural
Figure 3. 35 MHz ultrasound biomicroscopy image of the normal eye.
composition and organization, cornea exhibits viscoelastic behaviour which is important
to understand the biomechanical changes in different corneal diseases and after refractive
surgery (Figure 6). The human cornea is aspheric in shape, steeper in the center and atter
in the periphery. Apart from the curvature of the anterior and posterior cornea, surface
elevation (ie. the height of a surface point relative to a best-t reference shape) represents
a clinically useful parameter in identifying corneal disorders. Therefore, a comprehensive,
clinically relevant knowledge of the corneal morphology is essential for understanding
corneal pathologies in terms of altered structure and function of the cornea.
Figure 4. Endothelial photograph (A) and image analysis (B) made by a contact
specular microscope. Endothelial cell density: 2900 cells/mm2, mean cell size:
343 m2, coefcient of variation: 0.38, corneal thickness: 530 m
Figure 5. Fourier domain anterior segment optical coherence tomography imaging of
the cornea, anterior chamber, iris, anterior lens and irido-corneal angle. Please note
the normal central pachymetry (CCT, central corneal thickness) and anterior chamber
depth (ACD).
01
Figure 6. Corneal biomechanical measurement: Scheimpug-image of corneal
deformation response to an air impulse recorded with CorVis ST
Suggested reading
Anatomy of the Human Eye http://www.missionforvision.org/2005/10/
cornea-histology.html
Morphology of the Human Eye http://www.missionforvision.org/2005/10/
cornea-histology.html
Fine BS, Yanoff M. Ocular Histology: A Text and Atlas, 2nd edn. Harper & Row, 1979.
Yanoff M, Fine BS. Ocular Pathology. A Text and Atlas, 2nd edn. Harper & Row, 1982.
Qazi Y, Wong G, Monson B, Stringham J, Ambati BK. Corneal transparency:
genesis, maintenance and dysfunction. Brain Res Bull 2010; 81:198-210.
Hassell JR, Birk DE. The molecular basis of corneal transparency. Exp Eye Res
2010; 91:326-35.
DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract
Surg 2011; 37:588-98.
Adlers Physiology of the Eye, 11th ed. edited by Levin LA, Nilsson SFE, Ver Hoeve J,
Wu S, Kaufman PL & Alm A. Elsevier Inc. 2011.
Cornea: Fundamental, Diagnosis and Management, 3rd ed. edited by Krachmer
JH, Mannis MJ, Holland EJ. Elsevier Inc. 2011.
Mller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and
function. Exp Eye Res 2003; 76:521-42.
Bonanno JA. Identity and regulation of ion transport mechanisms in the corneal
endothelium. Prog Retin Eye Res 2003; 22:69-94.
He J, Bazan NG, Bazan HE. Mapping the entire human corneal nerve architecture.
Exp Eye Res 2010; 91:513-23.
Aghamohammadzadeh H, Newton RH, Meek KM. X-ray scattering used to map
the preferred collagen orientation in the human cornea and limbus. Structure
2004; 12:249-56.
Meek KM, Tuft SJ, Huang Y, Gill PS, Hayes S, Newton RH, Bron AJ. Changes in
collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol
Vis Sci 2005; 46:1948-56.
Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation.
Exp Eye Res 2010; 90:478-92.
Guthoff RF, Zhivov A, Stachs O. In vivo confocal microscopy, an inner vision of
the cornea. A major review. Clin Experiment Ophthalmol 2009; 37:100-17.
01
Niederer RL, McGhee CN. Clinical in vivo confocal microscopy of the human
cornea in health and disease. Prog Retin Eye Res 2010; 29:30-58.
McCarey BE, Edelhauser HF, Lynn MJ. Review of corneal endothelial specular
microscopy for FDA clinical trials of refractive procedures, surgical devices, and
new intraocular drugs and solutions. Cornea 2008; 27:1-16.
Belin MW, Khachikian SS. An introduction to understanding elevation-based
topography: how elevation data are displayed - a review. Clin Experiment
Ophthalmol 2009; 37:14-29.
Roberts C. The cornea is not a piece of plastic. J Refract Surg 2000; 16:407-13.
Donnenfeld ED, Solomon K, Perry HD, Doshi SJ, Ehrenhaus M, Solomon R, Biser S.
The effect of hinge position on corneal sensation and dry eye after LASIK.
Ophthalmology 2003; 110:1023-9.
Andrs Berta, M.D., Ph.D., D.Sc., Eszter Szalai, M.D., Ph.D.
Department of Ophthalmology, Medical and Health Science Center,
University of Debrecen, DEBRECEN, HUNGARY
E-mail: aberta@med.unideb.hu
Corneal disease is still today the most common cause of blindness in the world. Diseases
affecting the cornea and anterior segment in children differ little from diseases in adult
with the exception of congenital and development abnormalities.
The initial 6 weeks, until the closure of the embryonic ssure, are the most critical
period for ocular development. Arrest of development during this period leads to
severe ocular anomalies and greatly impaired visual acuity (anophthalmia, congenital
cystic eye, congenital aphakia, typical colobomas, ...).
The congenital anomalies of the anterior segment are present at birth, usually
bilateral, but often asymmetrical, in approximately 3/100,000 newborns. The etiology
can be genetic, infectious, inammatory, traumatic, toxic or a combination of these
factors, which most often affect the normal ocular development between the sixth
and sixteenth weeks of gestation, when differentiation of the anterior segment occurs.
Different structures in the anterior segment are subject to common inuences, so that
development abnormalities of one component are often accompanied by abnormalities
of others. The development anomalies of the anterior segment are often difcult to
classify and new classications were proposed.
However precise diagnosis is necessary in order to predict the natural history of the
disease, to look for associated ocular and systemic abnormalities, to give genetic
counselling and to initiate appropriate treatment. Abnormalities in corneal size and
shape: Microcornea, Megalocornea, Keratoglobus, Cornea Plana; Abnormalities
in corneal development leading to a visually opaque cornea: Sclerocornea,
Peripheral Anterior Chamber Cleavage Abnormalities (Axenfelds Anomaly, Axenfelds
Syndrome, Riegers Anomaly, Riegers Syndrome), Central Anterior Chamber Cleavage
Abnormalities (Central posterior Keratoconus, Peters Anomaly), Inborn Errors of
Metabolism, Corneal Dystrophies present at or shortly after birth (Congenital
Hereditary Endothelial Dystrophy, Posterior Polymorphous Dystrophy, Congenital
Hereditary Stromal Dystrophy, Posterior Amorphous Corneal Dystrophy), Congenital
Glaucoma and Epibulbar Tumors (Dermoid, Osseous Choristomas) will be briey
described. Classication system of congenital corneal opacication from a perspective
of pathogenesis, surgery and prognosis will be discussed.
Corneal manifestations of systemic diseases (diseases of abnormal carbohydrate
Corneal disorders in children and
congenital anomalies of the cornea
Joaquim Murta, Portugal
02
Corneal disorders in children and congenital anomalies of the cornea
metabolism, diseases of abnormal protein metabolism, diseases of abnormal lipid
metabolism, avitaminosis, interstitial keratis secondary to syphilis, tuberculosis and
virus, Wilsons disease, Refsums syndrome) and different forms of atopic and vernal
keratoconjunctivitis, will be also showed.
Keratoconus, the most common ectatic corneal disease, appears in the early
adolescent years and can progress in the late teens into the twenties. It may seen
with other conditions as allergic disease, retinitis pigmentosa, Down, Alport or Marfan
syndromes.
Pediatric microbial keratitis is a rare but potentially devastating disease. The condition
is similar to adult but is often characterized by a more severe inammatory response;
herpes simplex and bacteria (pseudomonas aeruginosa, staphylococcus aureus and
-hemolytic streptococci) are more common and fungi being less frequent.
Ocular trauma, second only to cataracts as the most common cause of visual
impairment and the most frequent cause of unilateral blindness among children, and
child abuse will be discussed.
The management of infants corneal opacities (team approach, preoperative
examination, the use of new instrumentation as high-frequency ultrasound or anterior
segment optical coherence tomography, indications for surgery as keratoplasty, lamellar
keratoplasty, iridectomy) will be also discussed. Penetrating keratoplasty is indicated in
children who have signicant unilateral or bilateral corneal opacities that prevent visual
development. Otherwise they would develop dense amblyopia. In cases of signicant
congenital corneal opacities, surgery should be performed within the rst 3 months of
life to reduce the degree of amblyopia. Poor prognostic factors include bilateral disease,
concomitant infantile glaucoma, lensectomy and vitrectomy at the time of the surgery,
previous graft failure, extensive goniosynechiae and corneal vascularisation.
Joaquim Neto Murta, MD, PhD
Centro Hospitalar e Universitrio Coimbra, Faculty Medicine, University Coimbra,
Coimbra, Portugal
jmurta@netcabo.pt
Corneal disorders in children and congenital anomalies of the cornea
02
References:
Peter RL, Rapuano CJ. Diseases of the cornea. In: Nelson LB (ed): Harleys Pediatric
Ophthalmology, 4
th
Ed. WB Saunders Co, 1998; 215-257.
Reidy J. Penetrating keratoplasty in infancy and early childhood. Cur Opinion
Ophthalmol 2001, 12:258-261
Stretton S, Gopinathan U and Willcox MD. Corneal ulceration in pediatric patients.
A brief overview of progress in topical treatment. Pediatr Drugs 2002, 4(2):95-110.
Velasquez A, Kim T. Development corneal anomalies of size and shape. In:
Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2
nd
ed. Vol 1. Philadelphia:
Elsevier Mosby; 2005:727-737.
Brophy M, Sinclair S, Hostetler SG and Xiang H. Pediatric eye injury-related
hospitalizations in the United States. Pediatrics 2006, 117:e1263-e1271
Block RW, Palusci VJ. Child abuse pediatrics: a new pediatric subspeciality. J Pediatr
2006, 148:711-712.
Ciralsky J, Colby K. Congenital corneal opacities: a review with a focus on genetics.
Semin Ophthalmol 2007, 22(4):241-246
Nischal KK. Congenital corneal opacities a surgical approach to nomenclature
and classication. Eye 2007, 21:1326-1337.
Bonini S, Sacchetti M, Mantelli F and Lambiase A. Clinical grading of vernal
keratoconjuntivitis )review). Curr Opin Allergy Clin Immunol 2007, 7:436-441
Clinical aspects of congenital anomalies of the cornea and sclera. In. External
Disease and Cornea. Ed American Academy Ophthalmology 2007-2008: 285-302
Colby K. Changing times for pediatric keratoplasty. J AAPOS 2008, 12(3):223-224.
Chan AS, Colby K. Update on pediatric keratoplasty. Int Ophthalmolol Clin 2008,
48 (2):25-33.
Shigeyasu C, Yamada M et al. Clinical features of anterior segment dysgenesis
associated with congenital corneal opacities. Cornea 2012, 31(3):293-298
Majander AS, Lindahl PM, Vasara LK and Krootila K. Anterior segment optical
coherence tomography in congenital corneal opacities. Ophthalmology 2012,
119(12):2450-2457
Corneal dystrophies are rare, Mendelian inherited conditions which exhibit bilateral
and usually symmetrical corneal changes.
Most ophthalmologists nd corneal dystrophies intriguing: Nomenclature has been
difcult because of controversies about the phenotype. The literature from the rst half
of the last century was in German and was misinterpreted in the English and American
literature. Greyscale clinical pictures were often of poor quality. Valid information on
many got lost among unsubstantial papers, and bewildered authors published different
sorts of patients under the same headings and the same sorts of patients under different
headings. It is sometimes impossible to either conrm or exclude every corneal dystrophy
that has made its way into textbooks as an independent entity: For example, what did
Reis and Bcklers actually see when they described what is now called ReisBcklers
corneal dystrophy? The original pedigree is lost to follow up, and their clinical description
is sketchy concerning the specic signs and symptoms. Nevertheless, we still presume that
the entity they described is probably what is now established as ReisBcklers dystrophy.
Few ophthalmologists - excluding the present author - have seen a lot of cases with
all dystrophies. The present abstract is based on papers written in collaboration with
other cornea nerds[1,2] as well based my own experience[3,4]. But only through
collaboration is it possible to (almost) cover the whole clinical spectrum - this is how
difcult the subject is!
Denition
The term dystrophy is derived from the Greek words dys (meaning wrong or difcult)
and trophe (nourishment). There is no universally accepted denition of the term
dystrophy. The word dystrophy was rst used close to 150 years ago on a group of
entities clearly not of traumatic nor infectious origin and they were believed to be due
to poor nerve supply or nourishment. Most of these diseases later proved to be genetic
and thus the word stuck to this group of inherited diseases.
Inherited opaciation of the cornea in conditions affecting the whole body, like
cystinosis, is according to traditions not included among the corneal dystrophies.
Dystrophies should be distinguished from corneal degenerations, which are secondary,
non-genetic processes resulting from ageing or previous corneal inammation.
03
Corneal dystrophies
Hans Ulrik Mller, Denmark
Corneal dystrophies
Classication
Recently an international group of cornea specialist proposed a new classication of
25 entities found worthy of earning the name of dystrophy. To indicate the level of
evidence supporting the existence of a given dystrophy, the committee developed a
series of descriptive, evidential categories, see table 1.
The category assigned to a specic corneal dystrophy can be expected to change over
time as knowledge progressively advances. Eventually, all valid corneal dystrophies
should attain the classication of category 1.
The classication paper comprising an extensive description of each condition,
an attempt to set the record straight concerning old misconceptions, clinical
pictures, key references, and a few words on onset in childhood can be retrieved at
www.corneasociety.org/ic3d.[1]
Mutation rate
The founder effect (i.e., an increase in the number of cases of a certain genetic trait due
to the introduction of a new mutation in an isolated population) has, in some countries,
given rise to publication of large pedigrees of conditions that may be almost non-
existent elsewhere. Therefore the expectations of young European ophthalmologist
vary for a course like this - you have probably seen different kinds of patients depending
of the founder effect in your area.
Furthermore as the mutation rates for many of the corneal dystrophies are probably
very low, it is important to be cautious when diagnosing apparently sporadic cases and
a family history and examination of family members are mandatory.
So in conclusion when you meet an unknown corneal opacity which you consider could
be inherited and thus a dystrophy, you should download the IC3D paper and compare
the clinical picture and the description with your own ndings - having examined the
whole family!
Being a paediatric ophthalmologist - as a special treat - my lecture will also describe a
problem with corneal dystrophies in children[2,3] on which an international research
group is working - and maybe someone in the audience could be a candidate for
joining that group?
Most corneal dystrophies are progressive. But pictures of corneal dystrophies in children
- as they look when presenting in childhood - are almost non existent in the literature.
One of the next goals for the IC3D group is to publish pictures of corneal dystrophies
Corneal dystrophies
03
in kids: does anybody in the audience have large pedigrees of corneal dystrophies
in their department, where you could provide the perfect picture of a young corneal
dystrophy patient?[2]
[1] Weiss JS, Moller HU, Lisch W et al. IC3D classication of the corneal dystrophies.
Cornea 2008, Suppl 2,1-42.
http://corneasociety.org/pdf/IC3D_Class_CornealDystrophies.pdf
[2] Mller HU, Kestelyn P, Weiss JS. Pediatric corneal dystrophies. A plea for pictures.
Letter. Cornea 2010;29:1469.
[3] Mller HU in: C Hoyt & D Taylor (eds.) Paediatric Ophthalmology and Strabismus
Corneal dystrophies Elsevier Science. 2012. 4th ed
[4] Mller HU. Granular corneal dystrophy Groenouw type I. Clinical and genetic
aspects. (PhD Thesis, Aarhus). Acta Ophthalmol(Copenh) Suppl. 198. 1991; 1-40.
Table 1
Category 1 A well-dened corneal dystrophy in which the gene has been
mapped and identied and specic mutations are known;
Category 2 A well-dened corneal dystrophy that has been mapped to one or
more specic chromosomal loci, but the gene(s) remains to be identied;
Category 3 A well-dened clinical corneal dystrophy in which the disorder has not
yet been mapped to a chromosomal locus;
Category 4 This category is reserved for a suspected new, or previously
documented, corneal dystrophy, although the evidence for it being a
distinct entity is not yet convincing.
Legend. The international committee for classication of corneal dystrophies (IC3D):
The four levels of corneal dystrophies.
Hans Ulrik Mller.
Paediatric Ophthalmology Viborg/Aarhus Hospitals, Denmark.
HUM@dadlnet.dk
Tumours largely include neoplasia and reactive mass-like lesions. Neoplastic lesions may
be benign or malignant. Malignant lesions are characterized by the capacity to invade
basement membranes and the potential to generate metastases. Metastatic disease
is caused by cells which invade lymphatics or blood vessels, survive in the circulation
and then attach to the vessel wall and extravasate at a distant site. For this reason,
malignant lesions which are conned to the epithelium (i.e. without signs of break of
basement membrane invasion) do not have the capacity to generate metastatic spread.
Such lesions are typically referred to as carcinoma-in-situ or melanoma-in-situ. Nearly all
tumour-like lesions of the cornea and conjunctiva actually derive from the conjunctiva,
and any corneal lesion is usually caused by secondary tumour invasion of the cornea.
The tumours of the cornea and conjunctiva may for practical reasons be divided into
melanocytic and non-melanocytic lesions. Most melanocytic lesions are pigmented,
but a substantial proportion (e.g. approximately 30% of conjunctival naevi are non-
pigmented). Similarly, non-melanocytic lesions may show pigmentation (e.g. squamous
cell carcinoma of the conjunctiva presenting in individuals with heavy skin pigmentation).
Melanocytic lesions of the conjunctiva arise from melanocytes typically lodged in the
basal part of the conjunctival epithelium or sometimes in the conjunctival stroma. The
most common lesion is the acquired conjunctival naevus, which typically presents as
a thin, pigmented or non-pigmented lesion in the limbal or juxtalimbal region. This
lesion rarely undergoes transformation to malignant melanoma, but may be excised
for cosmetic reasons.
Individuals with abundant skin pigmentation often feature bilateral and symmetrical
conjunctival pigmentation of the limbal region. This is a normal variant referred to as
ethnic or racial melanosis and should not be confused with primary acquired melanosis
(PAM). The PAM typically features a unilateral at pigmentation without cysts. The
borders are not sharply dened and lesions may have satellites or be multifocal. Up
to 50% of PAM featuring cytological atypia may progress into (invasive) malignant
melanoma. In contrast, PAM without atypia has a very small risk (if any) for malignant
transformation and these two entities are distinctly different. Some authors argue that
PAM with severe atypia equals melanoma-in-situ and recently melanocytic intraepithelial
neoplasia (MIN) has been suggested to replace the concept of PAM with atypia. To
assess the presence of atypia, biopsy of the conjunctival lesion is usually required even
though cytological sampling by an exfoliative smear is advocated by some authors.
04
Tumours of the cornea and conjunctiva
Stefan Seregard, Sweden
Malignant melanoma is a very rare tumour typically occurring in the limbal or
juxtalimbal region of middle-aged or elderly individuals. Sometimes, a melanoma may
arise from the tarsal, forniceal or caruncular conjunctiva. Thus, a complete examination
of the entire conjunctival sac including the tarsal conjunctiva is warranted in patients
evaluated for conjunctival malignant disease. Treatment of malignant melanoma of
the conjunctiva is usually surgical taking care to provide adequate surgical margins
and to avoid seeding of tumour cells during surgery. Large conjunctival defects may be
covered by amniotic membrane grafts. Adjunctive treatment may include cryotherapy,
topical chemotherapy (typically using mitomycin) or brachytherapy. Primary orbital
exenteration has not been shown to improve survival, but exenteration may sometimes
be required to control local disease. Metastatic disease appears in some 30% of patients
usually conned to the ipsilateral regional lymph nodes or salivary glands (in particular
the ipsilateral parotid gland). Lymph nodes may be monitored by simple palpation or
imaging by ultrasound. Any lymph node suspected of harbouring metastatic disease
may be surgically excised or studied by cytology after sampling using a ne-needle
aspiration biopsy. Conrmed spread to the lymph nodes may be managed by radical
neck dissection. Later in the course of disease, systemic spread to distant sites occurs.
Patients with malignant melanoma of the conjunctiva or PAM with atypia should have
period ophthalmic follow-up for life.
Non-melanocytic lesions of the conjunctiva include a wide variety of neoplastic and
reactive mass-like lesions. Conjunctival intraepithelial neoplasia (CIN) typically occurs
in the limbal region of elderly patients and tends to encroach onto the cornea. Once
referred to as Bowens disease this in-situ carcinoma has traditionally been managed
surgically. Local recurrence is common but recently excellent results have been reported
using topical chemotherapy (5-uorouracil, mitomycin or more recently using topical
interferon). The CIN rarely progress to invasive squamous cell carcinoma, but once this
takes place the lesion carry a potential to seed metastases, usually to the ipsilateral
regional lymph nodes. The carcinomas of the conjunctiva also include the rare, but
highly aggressive mucoepidermoid carcinoma and the poorly differentiated spindle cell
carcinoma. Rarely, neoplastic disease may secondarily invade the conjunctiva from the
neighbouring skin or adnexal structures.
Reactive, and usually non-pigmented, mass-like lesions include the eshy, heavily
vascularized so-called pyogenic granuloma (often occurring at the site of previous
surgery or chalazion), the limbal dermoid (actually a choristomatous type of lesion; i.e.
a congenital lesion composed of normal cells not usually occurring at the location),
conjunctival papilloma, and lymphangieectasia.
04
In summary, the conjunctiva and cornea is the site of origin for a wide variety of
neoplastic and reactive mass-like lesions. Some of these lesions may masquerade as
others, but it is important to make a correct diagnosis as some lesions are associated
with systemic spread and may even cause death by disseminated disease. The majority
of lesions are, however, benign. Management depends on the specic type of lesion
encountered and is typically surgical, even though a number of adjunctive therapies
like cryotherapy, topical chemotherapy and brachytherapy are available. More recently
introduced techniques like sentinel lymph node biopsy may be helpful to diagnose
malignant lesions with early metastatic spread.
Classication of some epidermal and stromal tumours of the conjunctiva
Non-melanocytic Benign lesions Squamous papilloma
Keratoacanthoma
Pyogenic granuloma
Oncocytoma
Lymphocytic hyperplasia
Lymphangiectasia
Lymphangioma
Premalignant Actinic keratosis
Conjunctival intraepitelial neoplasia
Malignant Squamous cell carcinoma
Mucoepidermoid carcinoma
Lymphoma
Kaposi sarcoma
Melanocytic Benign Junctional naevus
Compound naevus
Intrastromal naevus
PAM without atypia
Premalignant PAM with atypia
(melanocytic intraepithelial neoplasia)
Malignant Melanoma
Stefan Seregard,
St Eriks Eye Hospital and Karolinska Institutet,
Stockholm, Sweden
TECHNOLOGY PRIMARY
UTILIZATION
STRENGHTS LIMITATIONS
PACHMETRY
(Ultrasound)
Refractive
screening,
Glaucoma, Grafts
Inexpensive,
portable, ease of
use,
Single point
reading, operator
dependent
TOMOGRAPHY Refractive
screening, Post
Refractive IOL,
Measuring, area of
coverage, ease of
operation
Inuenced by scars,
cannot fully image
the angle
OCT Angle, Iris tumors,
IOL evaluation
Imaging, coverage
> confocal <
Scheimpug
Not as good at
measuring as
Scheimpug
CONFOCAL Specular
microscope, Fungal
& Acanthomoeba
Real time imaging,
observation at the
cellular level
Very limited
coverage area
WAVEFRONT Refractive Pre-op ?? Visual function Not a direct corneal
measurement
Pachymetry
One of the rst devices for measuring corneal thickness was the Haag-Streit Optical
Pachymeter (FIGURE) which attached to the slit lamp and used a prism doubling device.
It was very operator dependent and capable of only a single point measurement at a time.

05
Corneal examination techniques:
pachymetry, topography, tomography,
OCT, confocal & wavefront
Michael Belin, United States
pachymetry, topography, tomography, OCT, confocal, & wavefront
This was supplanted by Ultrasonic Pachymetry which easy, fast and reasonably
reproducible, but also only capable of single point measurements and still probably the
most popular method used today.
Complete corneal thickness maps were rst introduced on the Obrtek (now called
Orbscan) which utilized slit optical cross-sectioning. This was supplanted by both
rotating Scheimpug imaging and OCT which offered greater accuracy than the
scanning slit technique.
Complete pachymetric maps offers numerous advantages over single point
measurements:
Identication of the actual thinnest point
Location of the thinnest point
Computation of the rate of change of corneal thickness
Increased ability to identify early ectatic change

Topography/Tomograpy
Early devices to convey qualitative and quantitative
information about the cornea were limited to the anterior
surface and assumed a constant relationship between the
anterior and posterior cornea. The posterior cornea surface,
due to the cornea/aqueous interface, contributed minimally
to the overall corneal power and standard assumptions
worked remarkably well in normal eyes, as evidenced by
the accuracy of IOL calculations using standard K readings.
These assumptions, however, did not hold once we
modied the cornea (e.g. refractive surgery) and the need
to measure both anterior and posterior cornea emerged.
Additionally, the posterior corneal surface serves as a more
sensitive indicator of early ectatic disease than does the
anterior cornea.
Compared to Placido derived anterior curvature, Scheimpug imaging and OCT
offer posterior corneal measurement, greater corneal coverage, and full pachymetric
mapping. They measure elevation (true shape) as opposed to Placido derived curvature.
Additionally, Scheimpug imaging, owing to its greater depth of eld allow evaluation
of the lens (FIGURE).
05

Optical Coherence Tomography (OCT)
While similar to Scheimpug imaging OCT has better imaging capability, while not
matching Scheimpug measuring accuracy. OCT is particularly good at looking at angle
anatomy (FIGURE).

Confocal microscopy
Confocal allows for a high resolution optical sections of the cornea. While having
high magnication, it has very limited depth of eld and coverage, so each corneal
layer needs to be viewed individually. Current clinical applications include evaluation
of fungal and acanthamoeba keratitis and endothelial morphology (FIGURE). It is not
useful for most bacterial and/or viral infections as these are beyond the resolution of
the instrument.
Wavefront
True wavefront is a measure of the total optical properties of the eye with each layer
(tear lm, cornea, aqueous, lens, vitreous and retina) contributing. True wavefront
is limited to measuring over the entrance pupil and wavefront will often change
dramatically with changes in pupil size.
Tomography derived wavefront is not a true wavefront measurement. It is a
mathematical way to estimate corneal wavefront from corneal shape and helps us
understand corneal irregularity and allows us to separate lens and corneal induced
aberrations. This has been suggested to be useful in selection of IOL and in determining
candidacy for multi-focal IOLs.
Suggested reading
Elevation Based Corneal Tomography (2 ed). Belin MW, Khachikian SS, Ambrosio Jr R.
Highlights of Ophthalmology, Panama City, Panama, 2012
Anterior Segment Optical Coherence Tomography. Steinert RF, Huang D. Slack Inc,
Thorofare, New Jersey, 2008
Ambrosio R, Belin MW. Imaging of the Cornea: Topography vs Tomography.
J Refract Surg 2010: 26(11): 847 - 849
Belin MW, Asota IM, Ambrosio R Jr, Khachikian SS. Whats in a name: Keratoconus,
Pellucid Marginal Degeneration and Related Thinning Disorders. Am J Ophthalmol
2011; 152(2): 157-162
Tu EY, Joslin CE, Sugar J, Booton GC, Shoff ME, Fuerst PA. The relative value of confocal
microscopy and supercial corneal scrapings in the diagnosis of Acanthamoeba
keratitis. Cornea 2008; 27: 764-72.

Michael W Belin, MD
Professor of Ophthalmology & Vision Science
Southern Arizona VA Healthcare System
University of Arizona
Tucson, Arizona (USA)
The ocular surface environment serves as a critical function as the defensive front
line. It is essential to preserve visual function and has evolved a complex network of
mechanisms to maintain homeostasis. Essential to the health of the ocular surface
is the immune system, designed to respond swiftly to environmental and infectious
agents. At the same time the ocular surface has to maintain tolerance to self-antigens
and commensal microbes.
Activation of the main components, the innate and adaptive immune system is tightly
regulated to avoid or limit any potential bystander tissue damage. However, aberrant
activation of the immune system can result in collateral damage with morphological
and pathophysiological changes. Many factors such as genetic and environmental
factors, infections, antigen modications may provide triggers to shape the outcome
of the diverse spectrum of ocular surface disorders.
Uwe Pleyer
Department of Ophthalmology
Charit, Humboldt University, Berlin, Germany
06
Role of inammation in ocular
surface disease
Uwe Pleyer, Germany
Role of inammation in ocular surface disease
References

Stern ME, Schaumburg CS, Dana R, Calonge M, Niederkorn JY, Pugfelder SC
Autoimmunity at the ocular surface: pathogenesis and regulaDon.
Mucosal Immunol. 2010;3:425-42.

Barabino S, Chen Y, Chauhan S, Dana R.
Ocular surface immunity: homeostaDc mechanisms and their disrupDon in dry eye disease.
Prog ReDn Eye Res. 2012;31:271-85.

Mantelli F, Tranchina L, Lambiase A, Bonini S.
Ocular surface damage by ophthalmic compounds.
Curr Opin Allergy Clin Immunol. 2011;11:464-70.

Ueta M, Kinoshita S.
Innate immunity of the ocular surface.
Brain Res Bull. 2010 15;81:219-28.

Prada J, Schruender S, Ngo-Tu T, Baatz H, Hartmann C, Pleyer U.
Expression of tumor necrosis factor- and interleukin-6 in
corneal cells a^er excimer laser ablaDon in Wistar rats.
Eye (Lond). 2011;25:534-6.
1
06
ImmunoregulaDon on the ocular surface: (a) the ocular surface Dssues contain a variety of soluble and
cellular factors to reduce inammaDon-induced pathology in the lacrimal funcDonal unit. Those
implicated in immunoregulaDon within the ocular surface Dssues include: (1) nTregs (e.g., CD4+, CD8+,
, and NKT cells), which include many of the conjuncDval intraepithelial lymphocytes, are thought to
dampen or inhibit the inammatory/autoimmune response on the ocular surface. (2) The anD-
inammatory cytokine transforming growth factor (TGF)- is present on the ocular surface, and has
profound suppressive aects on resident dendriDc cell (DC) maturaDon in the cornea, autoreacDve T-
cell proliferaDon, dierenDaDon, and survival, and Treg dierenDaDon and maintenance. The acDvity
of the potent acute response proinammatory cytokine interleukin (IL)-1 is modulated by the IL-1
receptor antagonist (IL-1RA), expressed and secreted by corneal and conjuncDval epithelial cells.
VasoacDve intesDnal pepDde (VIP) also seems to be protecDve; VIP secreted by sensory nerve endings
in the cornea increases producDon of TGF- and IL-10 and inhibits expression of the proinammatory
cytokines/chemokines, IL-1 , tumor necrosis factor (TNF)-, interferon (IFN)-, and CXCL2. Hormones
are also implicated in curbing inammaDon and maintaining homeostasis. In addiDon, the corneal
epithelium also expresses vascular endothelium growth factor (VEGF) receptor-1 to sequester VEGF
and reduce neovascularizaDon. (3) APCs bearing self-anDgen derived at the ocular surface may migrate
to the regional lymph nodes to induce anDgen-specic Tregs (iTregs). (b) ImmunoregulaDon in the
lymphoid organs: nTregs may exert their immunosuppressive funcDon by (1) releasing soluble factors
(e.g., TGF-, IL-10), (2) cellcell contact, which disables pathogenic eector T cells (Te) and/or APCs,
and/or (3) compeDng for soluble factors (e.g., IL-2). (4) Inducible Tregs (iTregs) may use similar
mechanisms to inhibit cells bearing or responding to autoanDgens. It is possible that these Treg-
dependent mechanisms may also funcDon within the ocular surface Dssues. (c) Other peripheral
immunoregulatory mechanisms: addiDonal mechanisms also limit access and eector funcDon of
autoreacDve T cells within the ocular surface Dssues: (1) TGF- and (2) nTregs and iTregs are suggested
to suppress inltraDng autoreacDve lymphocytes and (3) low-level expression of integrins in the
healthy ocular surface endothelial cells, coupled with expression of the programmed death ligand-1
(PD-L1), negaDvely regulates acDvated T cells within the ocular surface Dssues.

2
The immunopathogenesis of Dry Eye disease. (a) Aerent autoimmune response: stress to the ocular
surface triggers the iniDal events suggested to iniDate autoimmunity. (1) InducDon of proinammatory
factors (cytokines, chemokines, and matrix metalloproteinases (MMPs)) is a hallmark of ocular surface
autoimmunity and may be iniDated by stress signal transducDon pathways or possibly by Toll-like
receptor (TLR) signaling (a^er microbial infecDon or aberrant endogenous acDvaDon). Acute response
cytokines, such as interleukin (IL)-1 , IL-1 , tumor necrosis factor (TNF)-, and IL-6 are elevated in
paDents with Dry Eye. IL-1 and TNF- amplify inammaDon on the ocular surface through processes,
such as acDvaDon of APCs. (2) Evidence suggests that APCs internalize autoanDgen, for example, type
III muscarinic receptor (M
3
R), Kallikrein (Klk)13, process and present immunogenic epitopes on MHCII,
upregulate expression of cosDmulatory molecules, for example, CD80, and CD86 and (3) the
chemokine receptor, CCR7, which directs the acDvated APCs to the draining cervical lymph node. (b)
Eerent acDvaDon of autoreacDve lymphocytes: the local cytokine milieu inuences T-cell
dierenDaDon. (1) IL-12 present within the ocular surface Dssues and produced by mature APCs,
combined with interferon (IFN)- likely inuences the acDvaDon and dierenDaDon of autoreacDve
Th1 cells. (2) By contrast, elevated IL-6 in the presence of transforming growth factor (TGF)- and IL-23
may skew dierenDaDon toward Th17 cells. (3) B cells are also predicted to have a role in Dry Eye as
shown in Sjgren's syndrome. In this scenario, Th2 cells provide help to autoreacDve B cells and
promote clonal expansion, somaDc hypermutaDon, isotype switching, anity maturaDon and plasma
cell dierenDaDon into autoanDbody-secreDng cells. AlternaDvely, B cells may be acDvated
independently of T cells, for example, TLR and BAFF signaling. Eerent tracking of autoreacDve T
cells to the ocular surface Dssues is widely thought to be directed by adhesion molecules (e.g., LFA-1,
VLA-4) and chemokine receptors (e.g., CCR5 and CXCR3) that respond to cognate ligands expressed on
the ocular surface (e.g., ICAM-1, CCL5, and CXCL10). (c) Eerent eector funcDon of autoreacDve
lymphocytes: AutoreacDve Th1 and Th17 cells present during the immunopathogenesis of Dry Eye
potenDate the chronic autoimmune response and have pathological consequences. For example, Th1
cells sDmulate APCs to secrete proinammatory cytokines and are a prominent source of interferon
(IFN)-, which induces expression of a mulDtude of proinammatory factors, pro-apoptoDc proteins
and causes direct Dssue destrucDon. IFN- alters mucins on corneal epithelial cells that have
devastaDng eects on ocular surface integrity. IFN- is linked to (1) epithelial cell apoptosis, (2)
reduced goblet cell density, and (3) squamous metaplasia. IL-17 produced by inltraDng Th17 cells
increases MMP3/9 expression and induces corneal epithelial barrier dysfuncDon. Furthermore,
autoanDbodies may bind to target anDgens causing direct Dssue destrucDon.
3
06
The immunopathogenesis of ocular cicatricial pemphigoid (OCP). (a) Aerent
autoimmune response. (1) An environmental trigger, that is, stress to the ocular
surface Dssues in the context of geneDc predisposiDon may iniDate the events leading
to autoimmunity. InducDon of proinammatory factors (cytokines, chemokines, and
matrix metalloproteinases (MMPs)) sets the stage for (2) autoanDgen (epitopes from
example, 4 integrin, putaDve 45, and 168 kDa anDgens) presentaDon on major
histocompaDbility complex (MHC)II by APCs, upregulaDon of cosDmulatory molecules
and (3) migraDon to the draining cervical lymph node. (b) Eerent acDvaDon of
autoreacDve B and T cells. (1) T cells may provide help to B cells to undergo clonal
expansion, somaDc hypermutaDon, isotype switching, anity maturaDon, and
dierenDaDon into autoanDbody-secreDng plasma cells. (2) AlternaDvely, autologous
B-cell acDvaDon (e.g., TLR, BAFF signaling) may acDvate B cells (independently of T
cells) to become autoanDbody-secreDng plasma cells. (c) Eerent eector funcDon of
autoanDbodies, T cells, and cytokines. (1) Plasma cells secrete autoanDbodies that (2)
bind to their target self-anDgens (e.g., 4 integrin, and/or putaDve 45 and168 kDa
anDgens) to promote complement component 3 (C3) deposiDon and Dssue
destrucDon. (3) Overabundance of anD-inammatory factors, namely transforming
growth factor (TGF)-, produced by ocular surface epithelial cells and innate eectors
also contributes directly to pathology. Excessive TGF- favors producDon and
accumulaDon of extracellular matrix proteins and overt Dssue brosis. Interleukin
(IL)-13 has recently been shown to be an important contributor to conjuncDval
brosis and inammaDon in ocular cicatricial pemphigoid (OCP). Together these
factors cause Dssue scarring, which ulDmately leads to blindness.

4
NON-INFLAMMATORY
CORNEAL PATHOLOGY
Prof.Dr.Murat Irkec, MD
Director of Corneal Unit
Hacettepe University Faculty of Medicine
Ankara - Turkey
mirkec@hace*epe.edu.tr
Degeneration : deterioration and decrease in function

Degenerations may be :
Unilateral or bilateral
Often asymmetric
An inheritance pattern usually not found
Many occur later in life (normal aging)
Secondary to systemic or pathological process
Often eccentric or peripheral
Relation to vascularity
Non-inammatory corneal pathology
Murat Irke, Turkey 07
Classification of corneal degenerations
Pinguecula
Pterygium
Spheroid degeneration
Salzmanns nodular degeneration
Terriens marginal degeneration
Corneal amyloid
Lipid degeneration
Coats white ring
Band keratopathy
Neurotrophic keratopathy
Exposure keratopathy
Recurrent erosion syndrome
B.Secondary
Classification of corneal degenerations
A. Primary
Iron lines
White limbal girdle of Vogt
Cornea farinata
Ant. and post. crocodile shagreen
Corneal arcus (arcus senilis)
Hassal-Henle bodies
07
VOGTs LIMBAL GIRDLE TYPE 1
Early calcific band keratopathy
Narrow lucent area from the limbus
White band contains holes (Swiss cheese)
Destruction and calcification of Bowmans layer
WHITE LIMBAL GIRDLE OF VOGT
White, cresentic, peripheral corneal opacities
in the interpalpebral area
Two clinical forms
Type 1: rare, early band keratopathy,
clear zone from limbus
Type 2: common, 100% after 80 years of age,
more common at the nasal limbus,
no peripheral clear zone from limbus
Histology: subepithelial hyaline and elastotic changes
Bowmans membrane and superficial stroma
replaced by basophilic granular deposits
CORNEAL ARCUS
Gerontoxon in the aged (Arcus senilis)
Ant. embryotoxon in the young (A. juvenilis)
Lipid deposition in the peripheral cornea
Cholesterol, cholesterol esters,
phospholipids,neutral glycerides
Lipid is extracellular
Lipids are of vascular origin
Men affected more than women
Increased risk of CAD (<40 years)
Hyperlipoproteinemia type 2 and3
VOGTs LIMBAL GIRDLE TYPE 2
Asymptomatic and incidental
Lesion is subepithelial
Elastotic degeneration and calcium
at the level of Bowmans layer
07
IRON LINES
Iron deposition in the epithelium
Several types due to different causes
Hudson-Stahli lines (Fleischer, Ferry & Stocker)
Prevalence and intensity increase with age
Source of iron unknown
May be physiological (young people)
No sex predilection
Asymptomatic and require no treatment
SPHEROID DEGENERATION
Climatic droplet keratopathy
More than one form
Primary age-related
Secondary form
Traumatic corneal scars
Herpetic keratitis
Chronic corneal edema
Lattice dystrophy
Chronic open-angle glaucoma
Conjunctival degeneration
Pinguecula
BAND KERATOPATHY
Common secondary degeneration
Calcium phosphate deposition in the anterior cornea
Caused by local or systemic factors
Calcium deposition :
Intracellular in systemic Ca metabolism abnormalities
Extracellular in local ocular disease
SPHEROID DEGENERATION
Prevalence related to geography
Males affected more than females
Usually bilateral, may be unilateral
Clinically yellow-gold subepithelial droplets
Advance from periphery to the center
Foreign body sensation,irritation,
VA decrease possible
EC proteinaceous material at Bowmans
membrane level and anterior stroma
Treatment:
PTK, lamellar KP, lamellar keratectomy
07
BAND KERATOPATHY
Classification
Systemic abnormalities
Hypercalcemia
Hyperphosphatemia
Heredity
Norries disease
Autosomal recessive band keratopathy
BAND KERATOPATHY
Classification
Chronic ocular diseases
Uveitis (juvenile chronic arthritis)
Glaucoma
Corneal edema
Interstitial keratitis
Phthisis
Ocular trauma
Climatic exposure
Mercurial containing preservatives
BAND KERATOPATHY
Ulceration of the corneal epithelium discomfort
Reduced vision (visual axial involvement)
Treatment:
Epithelial removal chelation with Na
2
EDTA
mechanical debridement with a blade or burr
BAND KERATOPATHY
Confined to the interpalpebral fissure
Peripheral clear zone at the limbus
Begins nasally and temporally
Swiss cheese appearance (corneal nerves)
Histology:
Epithelial BM- basophilic staining
Bowmans layer /ant. stromal lamellae
- Ca
++
deposition and fragmentation
Subepithelial fibrous pannus
Scarring
07
LIPID DEGENERATION
Deposits around an area of vessels:
Crystalline or diffuse
Yellow or cream
Discrete or fan-like
Sudden appearance from NV + VA
Causes of corneal NV in lipid degeneration:
Corneal trauma
Infectious keratitis (HSV or HZV)
Spontaneous regression (occasionally)
Treatment:
Argon laser to the feeding vessel
Penetrating keratoplasty
LIPID DEGENERATION
Accumulation of cholesterol and fatty acid deposits
Primary form - rare, usually bilateral
no stromal vascularization
Secondary form - more common, leakage from
stromal vessels
SALZMANNS NODULAR DEGENERATION
Late sequelae of previous corneal inflammation
Phylectenular keratitis (common)
Trachoma (common)
Vernal disease (common)
Exposure keratopathy
Chronic keratitis
Idiopathic (rare)
Following contact lens wear
Postcorneal surgery
Epithelial basement membrane dystrophy
Etiology
First reported in 1925
Rare, noninflammatory, slowly progressive
Degeneration characterized by bluish white
nodules elevated above corneal surface
(forming circular array)
Irregular astigmatism
Hyperopic refractive shift
Foreign- body sensation
Corneal scarring and decreased VA
Glare
07
Clear area between the nodules
Thinning of the overlying epithelium
Basal epithelial cell degeneration
Replacement of Bowmans layer
by (eosinophilic) material
A fibrillar, hyaline degeneration of collagen
cellular debris.
The number of fibrocytes in the affected areas
can vary (numerous cells that are active to scarce
degenerating cells)
Schematic drawing of the surgical procedure
Tissue removal with a surgical knife
Laser ablation to smooth the surface
Masking fluid employed several times
Salzmann nodule
Laser ablation
Manual removal
From: Sujata D et al. J Cataract Refract Surg 2005
Treatment Modalities
Manual removal
PTK with or without MMC
Lamellar/penetrating keratoplasty
Bowers Jr PJ et al. J Cataract Refract Surg 2003
Marcon AS, Rapuano CJ Cornea 2002
All Salzmann cases are individual in
their appearance and experience is
needed to reach optimal surgical
technique
07
Certain lesions cannot be removed by a blade only
Lamellar or penetrating keratoplasty require donor
material and are more invasive
PK rarely recommended due to good endothelium
Lamellar grafting is useful when PTK is not successful
Interface haze is a problem in lamellar keratoplasty
Mitomycine-C may prevent recurrence, but is toxic
Please keep in mind
Before Treatment After Treatment
From: Sujata D et al. J Cataract Refract Surg 2005
PTK appears to be an effective and
safe procedure for treatment of
Salzmann's nodular degeneration
TERRIENS MARGINAL DEGENERATION
Deposition of refractile yellowish-white opacities
(superiorly peripheral anterior stroma)
Development of gutter
(parallel to the limbus)
Superior or more extensive
corneal thinning
Slowly progressive thinning of peripheral cornea
Most common in men (3:1)
Patient age: 10-70 years
Most cases are bilateral (+ asymmetry)
Early stages generally asymtomatic
Sometimes mild irritation in early stages
Induced against- the -rule astigmatism (late stages)
Spontaneous or traumatic corneal rupture (rare)
07
Most cases are non-inflammatory
Rare cases with corneal and conjunctival
vascular congestion (with moderate to severe pain)
Mixed lymphocytic and neutrophil reaction (stroma)
Relatively young patients
Gutter is steep centrally, shallow peripherally
(1)
Gutter is 1-2 mm in width
The epithelium remains intact
Superficial vessels fill the gutter to the central edge
Deposition of lipid at the central edge
Pseudopterygium development
(2)
1
2
Differential Diagnosis
Arcus senilis (early)
Moorens ulcer
Furrow degeneration
Marginal pellucid degeneration
Inflammatory peripheral keratitis
Peripheral corneal melting (autoimmune)
Pathology
A. Limbal side B.Central
Stromal thinning
Thickened epithelium
Loss of Bowmans layer
<25% of the resident cells express MHC Class II antigens
CD
4
/CD
8
cell ratio1:1
<5% of the infiltrating cells CD
22
(+) (B cells)

07
MOORENS ULCER
Inappropriate immunologic responses
Cornea infiltrated by lymphocytes and plasma cells
75% to 100% of the resident cells express
MHC class II antigens
CD
4
/CD
8
cell ratio 2.4:1
25% to 50% of the infiltrating cells CD
22
(+) B cells
MOORENS ULCER
Chronic, painful corneal ulceration
Two different clinical types:
Benign- usually unilateral, older patients
Progressive type- 25% of all cases,young patients
Starts in the peripheral cornea circumferential spread
sclera centrally
RIGHT EYE BCVA: 6/10 (-5.00 @ 35
o
)
Cheng CL et al. Ophthalmology 2005
Treatment
Observation
Astigmatic control with spectacles or contact lenses
Surgical treatment:
Excision of ectatic tissue and direct closure
Eccentric penetrating keratoplasty
Crescentic onlay lamellar keratoplasty
Compressive
C-shaped lamellar
keratoplasty
07
LEFT EYE BCVA: 8/10 (-5.00 @ 90
o
)
Outline not received
Ocular surface reconstruction and
articial cornea
Per Fagerholm, Sweden
08
History
Corneal grafting has been performed for more than 100 years, but it was not until the
1950ties that keratoplasty procedures became common in Europe. With development
of corneal banking during the 1980ties it became possible to have corneal tissue
waiting for the patient, rather than visa versa.
Penetrating keratoplasty in which all corneal layers are exchanged with donor tissue
was by far the most common procedure until the start of this millennium. Until then
anterior lamellar keratoplasty was only performed occasionally in selected cases due
to the associated manual stromal dissection technique. With the introduction and
development of microkeratomes, femtosecond lasers, and deep manual dissection
techniques, anterior lamellar keratoplasty has started to gain popularity in treatment of
isolated stromal diseases.
The major advantage of deep anterior keratoplasty is that the endothelium of the
recipient is preserved whereby endothelial rejection episodes do not occur.
Corneal banking
Directive 2004/23/EC of the European Parliament and the Council of 31 March 2004
on setting standards of quality and safety for the donation, procurement, testing,
processing, preservation, storage and distribution of human tissues and cells
1
,
denes the overall frames for corneal banking in Europe. Corneal donor tissue can
be collected from the donor up to several days after death. In Europe, most corneal
donor tissue is preserved in organ culture, which enables corneal tissue to be stored
for at least 4 weeks before transplantation. During the storage period, various tests for
transmissible diseases is performed on blood sampled from the donor, tissue typing can
be performed, the donor tissue is checked for sterility, and endothelial cell density is
determined. When the donor cornea is cleared for use, it is send to corneal surgeons
for use. More than 70 banks from close to 30 European countries are members of The
European Eye Bank Association
2
.
Corneal transplantation:
penetrating and deep anterior
lamellar keratoplasty
09
Corneal transplantation: penetrating and deep anterior lamellar keratoplasty
Indications
In general, penetrating or anterior lamellar keratoplasty is indicated in corneal diseases
causing decreased visual acuity, pain, or manifest or impending corneal perforation.
Whether or not to actually perform a keratoplasty procedure depends on the visual
function of the other eye, and the prognosis for a successful result in the eye to be
grafted. Whether a penetrating or a deep keratoplasty procedure should be aimed for,
depends on the state of the corneal endothelium.
Typical indications for deep anterior lamellar keratoplasty procedure are keratoconus,
corneal dystrophies located to Bowmans layer or the corneal stroma, corneal scars after
microbial keratitis or non-penetrating corneal injuries or herpetic stromal disease, and
in chaud treatment of corneal infections or inammations with present or threatening
perforation. If it is technically impossible to perform a deep anterior lamellar procedure,
a penetrating keratoplasty procedure may be performed
3,4
.
Penetrating keratoplasty is typically indicated in longstanding endothelial disease with
severe secondary changes in the corneal stroma, such as end-stage Fuchs endothelial
dystrophy and secondary bullous keratopathy.
Techniques
Penetrating or deep anterior lamellar keratoplasty is performed in either local (sub-
tenonal, peribular, or retrobulbar inltration) or general anaesthesia.
In penetrating keratoplasty, typically a 7.5 to 8.00 mechanical trephine is used together
with a diamond knife, and corneal scissors to excise the centre of the recipient cornea.
The centre of the donor cornea is punched out with a similar or slightly larger trephine
diameter. The corneal donor button is sutured in place with Nylon 10-0. The suture
technique is single sutures, single running, or double running. 16 (double running) or
24 (single or single running) stiches are typically placed.
In deep anterior lamellar keratoplasty, the stroma in the recipient is excised either by
manual deep dissection (Melles technique
5
) or by air-based loosening of Descemets
membrane from the stroma (Anwars technique
6
). Trephinations of the recipient and
donor is typically performed as in penetrating procedures, and care is taken not to
rupture Descemets membrane of the recipient. Descemets membrane of the donor
button is removed before suturing (single, single running, or double running).
09
Postoperative treatment and follow-up
Topical antibiotics and steroids are used for many months after penetrating and
deep anterior lamellar keratoplasty procedures. Systemic immunosuppression may be
used in patients with a high risk of immunological reaction towards the donor tissue
(vascularized corneal bed, re-grafting in patients with previous immunological rejection
episodes). Alternatively, tissue type matching of donor and recipient is performed in
these high-risk cases.
Sutures are typically removed 12-15 months after keratoplasty, somewhat earlier in
deep anterior keratoplasty procedures.
Complications
Common complications after keratoplasty are suture loosening, suture breaks, wound
rupture, keratitis, and graft rejection. There is a persistent increased risk for globe
rupture after minor trauma. Vision compromising optical complications in otherwise
clear grafts include irregular astigmatism, astigmatism, and spherical ametropia.
Iatrogenic complications include steroid induced glaucoma and cataract.
Results
The most important predictor for graft survival and visual rehabilitation is the original
diagnosis and presence of co-existing ocular morbidity.
The best outcomes in penetrating and deep lamellar keratoplasty are achieved in
patients with keratoconus followed by non-vascularised corneal scars and non-
recurrent stromal dystrophies (for example macular dystrophy). A 5-year graft survival
of above 95% can be anticipated, and the majority of the grafts in such patients will
also function 25 years after keratoplasty.
Much poorer outcomes can be expected in patients with vascularized herpetic corneal
disease, patients with end-stage pseudophakic bullous keratopathy, and patients with
concomitant dry eye disease. Grafts in patients with severe surface disease (alkali burns,
Stevens-Johnsons Syndrome, cicatricial pemphigoid, neuroparaesthetic corneal disease)
will all fail within months to few years after keratoplasty.
Future
Femtosecond laser trephination of recipient and donor graft has become possible within
recent years. So far, the only advantage seems to be a somewhat faster possibility for
safe suture removal and thereby faster visual recovery. Final astigmatism and visual
acuity is similar to mechanical trephination. Non-touch excimer laser based trephination
may result in less astigmatism, but the procedure is time-consuming.
Supercial cornel scars can be treated by non-suture anterior lamellar keratoplasty. In
these cases the femtosecond laser is used to produce a 0.2 mm deep anterior lamellar
cylinder shaped cut in recipient and donor. The lamellar donor cylinder is placed in the
excised bed in the recipient, and a bandage contact lens is used until epithelialisation.
Fast visual recovery is possible with this technique.
Literature
1
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:102:0048:0058:en:PDF
2
http://www.eeba.eu
3
2012-2013 Basic and Clinical Science Course, Section 8: External Disease and Cornea.
American Academy of Ophthalmology. ISBN: 978-1-61525-297-8
4
Cornea. 3rd ed. I. Krachmer, Jay H. II. Mannis, Mark J. III. Holland, Edward J. Mosby
Elsevier 2011.
5
A new surgical technique for deep stromal, anterior lamellar keratoplasty. Melles
GR, Lander F, Rietveld FJ, Remeijer L, Beekhuis WH, Binder PS. Br J Ophthalmol. 1999
Mar;83(3):327-33.
6
Big-bubble technique to bare Descemets membrane in anterior lamellar keratoplasty.
Anwar M, Teichmann KD. J Cataract Refract Surg. 2002 Mar;28(3):398-403.
Jesper Hjortdal, Clinical professor, MD, PhD.
Department of Ophthalmology, Aarhus University Hospital NBG, Denmark.
E-mail: jesper.hjortdal@dadlnet.dk.
Corneal transplantation: post lamellar
Friedrich Kruse, Germany 10
Orthotopic corneal transplantation is the oldest and most commonly performed solid
tissue transplantation in the world. Graft rejection is still the leading cause for graft
failure following full thickness keratoplasty. This is frequently caused by the induction
of an alloimmune response directed against corneal endothelial cells. Epithelial,
subepithelial or stromal rejection occurs but usually does not result in graft failure.
Corneal graft rejection is driven by a T cell mediated delayed type VI immune response
initiated by the uptake of donor antigens by dendritic cells which then migrate to
secondary lymphoid tissue. They trafc from peripheral tissue under inammatory
conditions including organ transplantation at enhanced levels to secondary lymphoid
tissue. Here they present peripherally acquired antigens to naive T cells in T cell areas
of the draining lymph nodes. Chemokines act as key regulators of leukocyte trafcking
in different organs. Uppon activation of dendritic cells the cemokine receptor CCR7
becomes upregulated on the cellular surface. It is known to regulate dendritic cell
movement from the periphery to the draining lymph nodes. Once dendritic cells reach
the T cell areas of the draining lymph nodes naive T cells become stimulated to form
effector T cells. These allogen specic human T cells reach the graft via blood vessels
which serve as the efferent arm of the immune reex arc. Findings indicate a diverse
role of CCR7 in modulating the immune response after corneal transplantation. In
addition to the initiation of allogen specic immune responses CCR7 is also involved in
the initiation of tolerogenic mechanisms by the generation of regulatory T cells which
are necessary for the long term survival of corneal grafts.
The allograft reaction can be described by the so called immune reex arc where
lymphatic vessels serve as the afferent arc for dendritic cells and blood vessels serve as
the efferent arc for effector T cells. The main risk factor for graft rejection following
corneal transplantation is corneal neovascularisation which describes the ingrowth of
both clinically vissible blood vessels (the efferent arm) and clinically invisible lymphatic
vessels (the afferent arm) into the cornea. The existence of preoperative corneal
neovascularisation has long been identied as a risk factor for immune rejection
after keratoplasty. However, additional corneal neovascularisation is also frequently
observed after low-risk as well as after high-risk corneal transplantation. In addition
to preexisting corneal neovascularisation the ingrowth of blood and lymphatic vessels
after keratoplasty has also been found to be a risk factor for graft rejection. The etiology
of postkeratoplasty neovascularisation is diverse. Hem- and lymphangiogenesis after
Corneal transplantation:
immunology and angiogenesis
Bjrn Bachmann, Germany
11
Corneal transplantation: immunology and angiogenesis
corneal transplantation is often suture related. The ingrowths of blood vessels directing
towards the sutures anchoring the graft to the host cornea is common. Even though
most sutures after low-risk corneal transplantation remain non reactive for an almost
unlimited period they can also cause a subtle chronic inammatory stimulus thus
promoting corneal hem- and lymphangiogenesis.
Current therapeutic strategies for preventing graft rejection after keratoplasty primarily
aim on the suppression of the recipients immune system. There are three groups
of immunosuppressant frequently used in this context: Corticosteroids, calcineurin
inhibitors (substantially ciclosporin) and inhibitors of the inosine monophosphate
dehydrogenase (mycophenolate mofetil). Innovative therapeutic approaches try to
modulate the immune system by reducing the preoperative as well as the postoperative
amount of corneal blood and lymphatic vessels. These antiangiogenic strategies
comprise the removal of angiogenic stimuli e.g. sutures attracting blood vessels as
well as strategies to actively reduce corneal neovascularisation using antiangiogenic
drugs. New pharmaceutical treatments aiming on decreasing a VEGF mediated
angiogenic stimulus are most effective in preventing or reducing the formation of
freshly grown blood and lymphatic vessels. Old corneal blood vessels have established
vessel walls coated by pericytes and show much less response to a gap in VEGF supply.
Thus, a pure pharmaceutical treatment can be performed in active and progressive
vascularisation rather than in established blood vessels. Established supercial corneal
neovascularisation can be treated by mechanical removal of the vascularised tissue
(pannectomy or lamellar keratectomy). Established stromal vascularisation is amenable
to coagulation of the vessels which can be performed with a focal destruction of tissue
(e.g. by ne needle diathermy). Both, the surgical approach and the pharmaceutical
treatment can be combined to maximize the antiangiogenic effect.

Corneal transplantation: immunology and angiogenesis
11
Bachmann, B. O., F. Bock, et al. (2008). Promotion of graft survival by vascular
endothelial growth factor a neutralization after high-risk corneal transplantation.
Arch Ophthalmol 126(1): 71-77.
Bachmann, B. O., E. Luetjen-Drecoll, et al. (2009). Transient postoperative vascular
endothelial growth factor (VEGF)-neutralisation improves graft survival in corneas with
partly regressed inammatory neovascularisation. Br J Ophthalmol 93(8): 1075-1080.
Cursiefen, C., J. Cao, et al. (2004). Inhibition of hemangiogenesis and lymphang-
iogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes
graft survival. Invest Ophthalmol Vis Sci 45(8): 2666-2673.
Cursiefen, C., H. Wenkel, et al. (2001). Impact of short-term versus long-term
topical steroids on corneal neovascularization after non-high-risk keratoplasty.
Graefes Arch Clin Exp Ophthalmol 239(7): 514-521.
Forster, R., A. Schubel, et al. (1999). CCR7 coordinates the primary immune
response by establishing functional microenvironments in secondary lymphoid
organs. Cell 99(1): 23-33.
LEsperance, F. A., Jr. (1985). Clinical photocoagulation with the organic dye laser.
A preliminary communication. Arch Ophthalmol 103(9): 1312-1316.
Niederkorn, J. Y. and H. J. Kaplan (2007). Immune Response and the Eye, Karger.
Ohl, L., M. Mohaupt, et al. (2004). CCR7 governs skin dendritic cell migration
under inammatory and steady-state conditions. Immunity 21(2): 279-288.
Pillai, C. T., H. S. Dua, et al. (2000). Fine needle diathermy occlusion of corneal
vessels. Invest Ophthalmol Vis Sci 41(8): 2148-2153.
Yamagami, S. and M. R. Dana (2001). The critical role of lymph nodes in corneal
alloimmunization and graft rejection. Invest Ophthalmol Vis Sci 42(6): 1293-1298.
Yamagami, S., M. R. Dana, et al. (2002). Draining lymph nodes play an essential
role in alloimmunity generated in response to high-risk corneal transplantation.
Cornea 21(4): 405-409.
Bjrn Bachmann, MD
Department of Ophthalmology, Universityhospital Erlangen
Schwabachanlage 6
91054 Erlangen, Germany
fon: 09131 / 8533001
fax: 09131 / 8536401
email: bjoern.bachmann@uk-erlangen.de
An allograft of the cornea, either lamellar or full thickness in substance, is usually
performed to restore vision when the host corneal transparency is lost in a disease
process. Corneal grafting is proven to be one of the highly successful organ
transplantation procedures.
It is a well recognised as a successful procedure for a number of conditions such as
keratoconus, corneal opacities and bullous keratopathy. Corneal graft survival as
reported by the Australian graft registry and NHS Blood and Transplant in the rst year
is 87% and 93% respectively.
(AGR, UKT)
Since then, In subsequent reports, the success
rates steadily fell over time up to 46% at 15 years .1
(AGR)
However, the viability of these transplants in recurrent and chronic inammatory
conditions like; sicca disease states, herpetic infections and vascularised corneal bed is
low. The Keratolimbal allografts performed for such conditions associated with severe
limbal stem cell deciency are also constrained by limited success and frequently require
immunosuppression for sustenance. In majority of these situations a keratoprosthesis
remains as the only viable option to bypass the ocular surface in order to restore vision.
Globally, availability of corneal donor material is limited, especially so in the developing
countries where resources and provisions are a shortage. In addition, facilities for
processing, preservation, storage and supply of the transplantable tissues is a challenge for
many nations. Besides, biological tissue transplants carry a risk of transmissible diseases
such as blood-borne infections, CJD, Tuberculosis, Hepatitis C and venereal infections.
A number of problems associated with ocular tissue transplantation such as rejection,
failure, complications related to immunosuppression and transmissible diseases can
be eliminated by the use of keratoprostheses whenever applicable. Non-biological
kertaoprostheses can ameliorate the shortage of donor tissue materials and the device
can be re-implanted when required.
History and development
The idea of replacement of a diseased cornea with an articial material was earlier than
the idea of a donor cornel graft. Pellier de Quengsy, (1789) was the rst to record his
ideas of a keratoprosthesis that consisted of a convex glass plate surrounded by a silver
rim. His method of using a porous skirt for bio-integration is still valid today. (Pellier
Bypassing the ocular surface
Restoring sight with Keratoprosthesis
Christopher Liu, United Kingdom
12
Bypassing the ocular surface - Restoring sight with Keratoprosthesis
de Quengsy) Nussbaum, (1853), described a collar-stud glass device with two plates
that sandwich the corneal tissue, which are also connected in the centre by an optical
cylinder. He performed animal experiments with his keratoprosthesis and also implanted
in humans. Interestingly, this device seems conceptually similar to the Boston KPro
of Dohlman. (Nussbaum) Heuser (1860), perhaps, was the rst to perform a human
implant of the KPro. He used quartz material for his device. (Heuser) Abbate (1862)
applied a skirt made of milk protein and rubber to the glass and implanted in animals.
Although it was extruded shortly afterwards, his efforts emphasized the importance
of a skirt material for tissue incorporation of KPro. (Forster) Salzer implanted a quartz
crystal enclosed in a platinum ring with prongs, he also recognised the importance of a
skirt material. (Salzer) Celluloid was used in a hat shaped KPro by Dimmer (1889) as a
rst polymeric biofunctional implant.
Interest in synthetic corneal devices was declined in the last century, largely due to
the raise of the cadaveric corneal transplants. In addition, the existing KPro models
were plagued by infections and extrusions. With the breakthrough discovery of
PMMA material as a potentially implantable material in the eye the interest in
keratoprosthesis was rekindled. (Wunsche, Stone) PMMA has fullled the need for
a stable and biocompatible optic. Gradually a two part core -skirt skeleton for the
KPro was recognised. Cardona used a pigmented PMMA cylinder with a fenestrated
Teon skirt. The skirt was reinforced with corneal and scleral grafts, autologous tissues
such as periosteum and conjunctiva and synthetic materials like Dacron. Another
essential contribution by Cardona was to project the optic through the lid to enhance
its retention in extremely dry ocular surfaces. Porous skirts made of proplast (Barber )
teon ( Legais) hydrogels (Craford ), polyHEMA (Mester) collagen (DeVore ) and silcone-
carbon were developed with the intention of promoting better tissue integration.
Apart from PMMA, other ploymers were also tried as optical components of the KPro.
Chirila identied in a review that SIlicone ( Ruedmann et al.), polysiloxane (Liebe et
al.) and silicone rubber (Dohlman etal.), polyvinyl alcohol hydrogels (Ikada et al.), and
polycarbonate (Worst-Singh-Andel) were used as core portions.
A two-piece KPro was developed by Choyce and stone separately. Cardona developed
a two-part nut and bolt keratoprosthesis. (Cardona)A seoul type (S KPro) device has
a double-xed design, having polypropylene haptics that are anchored to the scelra
through ab-interno xation and a skirt made of polyurethane or polypropylene.
(Kim) Legeais developed a device similar to AlphaCor in appearance, which is made
of silicone optic surrounded by an opaque and porous uorocarbon PTFE, which is
bonded chemically. (Hollick) Pintucci developed a KPro made of PMMA optic and a
dacron skirt. Implantation of the device is similar to OOKP surgery performed in 2
12
stages. Labial mucous membrane covers the ocular surface. The KPro is buried in the
submuscular pouch for 2-3months before implantation into the eye. (Pintucci)
Although many KPro models were proposed using different materials and designs,
essentially they can be described into three basic types based on their xation method
onto the eye. 1).A collar-stud device sandwiches cornea between the two skirt plates,
2). an intra-corneal device secures the skirt inside the corneal stromal layers, while 3).
an epi-corneal device is held on the top of the cornea and sclera. To implant these
devices a central corneal aperture is made to enable the optical portion to passthrough.
A number of KPro materials, models and techniques were described but only two
prostheses, Boston KPro-1 and osteo-odonto-keratoprosthesis(OOKP) have with stood
the tests of time. We discuss some of the prominent KPros in this article.
General considerations for KPro Surgery
A keratoprosthesis is generally indicated when a corneal graft is deemed not suitable
to restore vision and is highly likely to fail. Patients being considered for these
procedures should be thoroughly and carefully evaluated for their suitability. Often
these patients had multiple corneal grafts, ocular surface and lid reconstruction
procedures performed before being referred to a KPro surgeon. and A knowledge of
the underlying diagnosis, present condition of the eye, previous treatments including
the number and types of ocular surgeries and use of steroids or immunosuppression
is required. Often these patients have lid malpositions. Tear secretion should be
assessed and the amount of scarring, forniceal shortening and surface keratinisation
should be noted. Ability to apply and retain of soft contact lens should be assessed
if a Boston type-1 keratoprosthesis is considered. Glaucoma is a frequent association
due to the primary disease process involving the trabeculum, steroid treatments,
disturbed angular anatomy and surface scarring of the conjunctiva that limits episcleral
venous drainage. Fundal examination in these patients is usually not adequate due
to corneal and lenticular opacities. Visual potential needs to be carefully estimated
before offering surgery, especially the presence of a retinal pathology and glaucoma
should be considered. Ultrasound examination with B-Scan of the retina and if possible
anterior segment OCT or ultrasound biomicroscopy to determine the anterior segment
structures and status of the irido-corneal angle is very useful before planning surgery.
By and large KPro patients cannot perform satisfactory visual eld tests. Absence
of light perception indicates poor prognosis. An inaccurate light projection may be
acceptable since it could due to associated media opacities rather than actual retinal or
optic nerve disease process. Electrophysiological tests like ERG, EOG and VEP could be
of help. History of visual regain with previous surgical procedures is a good indication.
Presence or absence of IOL and axial length are essential to know to determine the
choice KPro to be implanted and the sequence of surgical steps to undertake. In
general keratoprosthesis is offered to patients with an end stage ocular surface disease
and bilateral poor vision up to hand moments at least.
Implanting the keratoprosthesis is usually the rst step to the patients journey,
frequently these patients will have subsequent procedures to be performed to preserve
the KPro on the eye and to address arising complications. Patient counseling for KPro
surgery should be aimed at determining the visual needs and general health status
of the patient and to establish patient suitability and willingness to undertake the
surgery and to choose the correct type of keratoprosthesis when indicated. Often
these patients have psychological morbidity with associated alcohol and smoking
addictions to deal with. In addition, many of these patients have medical conditions
and associated mucosal diseases in the urethra, pharynx and oesophagus predisposing
them to the risks of anaesthesia. A mutli-disciplinary team consisting of anaesthtists,
physicians, oro-dental, oculoplastics, vitreo-retinal and glaucoma surgeons is essential.
A conscientious approach to patient expectations with the offer of psychological and
social support, while ensuring provisions for patient access to the hospital facilities in
emergency and planned follow-up care is crucial for success. Patient support groups,
leaets and written information, clear instructions and education of the patients and
carers should form part of the care pathway. Because the follow up and postoperative
care is a life long process these procedures should be offered at the specialist institutions
with sufcient work force, experience and resources in place.
AlphaCor keratoprosthesis
Lions Eye Institute in Australia developed a bio-integrable kertoprosthetic device
made of polyHEMA(poly 2-hydroxyethyl methacrylate), otherwise known as Chirila
Keratoprosthesis. It was rst implanted in humans in 1998 and was subsequently
approved by the FDA in 2003. (Hicks 2006). In gross structure it resembles the natural
cornea--containing a central zone and a peripheral skirt. The central clear part is
manufactured with a reduced water content in the polymer, while the peripheral skirt
is made with the same polymer but with a high composition of water. The two differing
polymeric zones of the of the same compound are joined by an interpenetrating
network of polymers. (chirila 1994). The main principle behind this device is that the
outer skirt is integrable with the corneal substance by the invasion of keratocytes, while
the central zone remains optically clear.
AlphaCor is indicated when a corneal graft is perceived as a high risk for failure as
in cases with a history of prior graft failures and the vision is reduced to 6/60 or light
12
perception, but with good retinal and optic nerve functions. Advanced glaucoma
is a relative contraindication. (Gomma) AlphaCor is generally suitable for eyes with
adequate tear secretion and without an active inammation or a history of herpes
infection (Jiraskova). A healthy conjunctival tissue is an important requirement when
a Gunderson ap is considered. This device is supplied for aphakic, pseudophakic and
phakic eyes separately.
AlphaCor device is implanted intrastromally into the cornea usually in 2 stages. In
the rst stage, host corneal is dissected through the superior limbus up to 1800 to
create anterior and posterior lamellae of approximately 50% thickness of each layer.
The posterior layer is trephined with a 3.5mm diameter trephine in the centre to enter
the anterior chamber. Then the prosthesis in inserted in between the lamellae and the
superior layer is closed with interrupted sutures. At this stage a conjunctival ap can
be overlaid if the corneal surface is uneven. After 2 or 3 months, the second stage
procedure is performed with the anticipation that the host stromal broblasts would
have grown into the matrix of the prosthesis. A 3.5mm dermatological trephine is used
to create an aperture through the anterior lamina.
Hicks et al., have reported a retention rate of 80% and 62% after 1 and 2 years follow
up respectively using AlphaCor. (Hicks 2006) They recommend an indenite use of
topical Medroxyprogesterone(MPG) to enhance device retention. Despite of its usage
stromal melts have occurred in 26.4% of all the implants and out of which 64.5%
have resulted in device removal. Jiraskova has reported a survival rate of 87%, 58%
and 42% respectively at 1,2 and 3 years of follow up. (Jiraskova) A 60% of their cases
had stromal melts and in 33% of the cases the device was explanted. However, their
study included a limited number of cases. Although the device is retained well in the
rst few years the visual potential is affected due to the development of deposits on the
optic portion and surface spoliation in up to 8.4% to 20% of cases. (Hicks,Jiraskova).
Since majority of these complications happen after the stage 2 procedure, Ngakeng
have chosen to avoid the second stage and left the surface layer of the cornea intact.
They reported a case series without corneal melts and device extrusions after a follow
up of 14-38months. Albeit the visual regain is compromised with this approach
the postoperative comfort and complications are improved. Owing to the risks of
complications and raise of the Boston keratoprosthesis this implant is a less favoured
option now-a-days.
Boston keratprosthesis (BKPro)
A renewed interest was brewing on PMMA material following the accidental discovery
of its tolerability in pilots eyes during the second world war. Thereafter, many KPros
were developed using PMMA material as the core optical piece and other materials as
skirts. (Chirila- Articial cornea) Since 1960, research was underway in developing a
keratoprosthesis, which has eventually resulted in the current model of Boston KPro.
FDA approved this device in 1992. Also known as Dohlman-Doane Keratoprostheis,
Boston-KPro, is made of rigid PMMA material in a collar-stud design. There are two
types: 1 and 2 with different indications.
Type-1 KPro is generally used as a corneal replacement for high risk cases for corneal
grafting like corneal opacities with severe vascularisation and repeat allograft failures.
Typical examples for such conditions include, aniridia, certain corneal dystophies
and degenerations, herpetic keratitis and corneal infections. (Khan-Advances in
Boston KPro) An adequate tear secretion and ability to wear a soft contact lens are
minimum requirements before considering type-1 KPro. In addition, similar to any KPro
procedure, the patients should be able to attend for regular follow ups and comply
with the postoperative treatment regimens. Type-2 KPro is reserved for extremely dry
and cicatrising ocular surface diseases like, Stevens-Johnson syndrome (SJS), mucous
membrane pemphigoid (MMP) and chemical burns.
BKPro Type-1
It is the most commonly used device, which contains an optical stem with convex
surface on the front that replaces the host cornea. The back plate is a disc shaped
piece of 8.5 mm diameter with a central aperture and 8 to 16 peripheral holes.
Previous thread design of the stem is modied into a snug t type in 2003. A titanium
locking ring completes the device and locks the backplate on to the stem. A donor
corneal button with a cetral trephination is sandwiched between the front piece and
backplate, which acts as a carrier of the device. The fenestrations in the backplate allow
aqueous to nourish the donor cornea. (Traish - expanding applications). It is available
in stadardised pseudophakic and customised aphakic models and can be supplied with
a small back plate (7 mm diametre) for paediatric use. A soft or contour contact lens is
applied to the eye and patient is required to wear daily. The contact lens protects the
ocualr surface from dryness and desiccation and protects against the corneal melting
and enhances retention. Daily administration of Vancomycin eye drops with or without
broad spectrum antibiotics like Fuorquinolones prevents infections and protects against
endophthalmitis. (Colby).
12
In a multicentre study, Zerbe et al., reported a postopertative increment in number
of patients from 3.6% to 57% with a visual acuity (VA) levels up to 20/200 (Snellen
equivalent-6/60).(Zerbe) This was retained up to 1year. In their longterm study, Greiner
et al., reports similar results; a 59% of patients patients have retained 20/200 VA over
an year of follow up. (Greiner) In a comparative series, Aldave reports a preoperative
VA level of 20/200 in 2% of the patients in the international group against 6% of the
patients in USA group. Postoperatively at 6months 70% of the international patients
and 69% of the USA patients regained this level of VA and their percentage has declined
gradually over two years to 59% and 60% respectively. Interestingly, the percentage
of patients with pre and post-operative VA of less than or equal to light perception
has not changes signicantly in both groups--international group: 50% preoperative
vs 60% postoperative; USA group: 9% preoperative vs 10% postoperative. (Aldave)
Anatomical retention of the device is good in the short term, Zerbe reports a 95%
retention rate in an average of 8.5months follow up. (Zerbe) Chew reports a 100%
retention at 16months, Aldave reports 84% retention at 17months of average
follow up. (Chew, Aldave-Improving outcomes) In their comparative series, Aldave
identies a device retention rate of 80.5% at a mean follow up period of 14.2months
in the international group against a similar retention rate of 80% at an average of
24.2months. (Aldave - International results) Bradley reports an anatomical retention of
81.3% with a mean follow up of 19 months. An 80% retention rate at a mean follow
up of 33.6months was reported by Greiner. (Greiner)
In eyes with successful implants, vision is affected by a number of factors in the
postoperative period;e.g., retroprosthetic membrane (RPM), glaucoma and retinal
complications. Stacy et al., reviewed the occurrence of RPM and noted an incidence
of 25-65% out of which, a 45% of these cases require treatments with Yag laser
membranectomy or surgical removal. They also performed a histological study and
hypothesise that RPM is derived from corneal stromal down growth from the host side
due to the gaping of the Descemets membrane beyond the back plate. In addition,
metaplastic lens epithelium and native iris stroma contributes to the development.
Magalhes, in their review, identied a number of causes for the development of RPM
that include anterior segment inammation, previous keratitis, and performance of
multiple intraocular surgeries at the time of KPro implantation. (Magalhes)
A keratoprosthetic implant can induce glaucoma iand a pre-existing condition is
generally worsened. Distortion of the angle structures, RPM and peripheral anterior
synechiae have all been implicated as the causes for glaucoma. Banitt reviewed and
found that glaucoma is prevalent in up to 36-76% of BKPro patients. De-novo glaucoma
occurrence was reported in 2-28% of the KPro patients. (Banitt) Glaucoma poses a
signicant challenge for KPro surgeons since its detection, monitoring and treatments.
Tonopen measurements taken at the limbus and compared with the fellow eye have
been attempted. However, digital palpation is the only useful method of estimating IOP
although the accuracy is not reliable. Again monitoring of glaucoma is difcult since
visual elds are less useful due to the small size of the available optical aperture. Disc
changes could take long times to develop and signicant damage could occur before
its detection. Imaging studies with OCT and HRT could be useful. Topical glaucoma
medication can be partially effective in reducing the IOP. Majority of the patients require
surgical treatments with drainage devices (valved or nonvalved) either at the time or
after the KPro implantation. One study reported a 58.8% of conjunctival erosions
following glaucoma drainage device in BKPro patients. (Li) Cylcophotocoagulation
could be useful in some cases and in those who dont respond to drainage tubes.
(Rivier) Presence of glaucoma is associated with poor visual prognosis and development
of erosions adversely affects visual potential of the eye. (Kamyar)
Robert MC analysed the publications of endophthalmitis following BKPro and found
that it ranges from 0-25%. Using a pooled data they estimated the prevalence
of endophthalmitis as 5.4% in the last 10 years for BKPro-1 implant. Risk of
endophthalmitis is generally considered high with inammatory conditions like,
SJS, MMP and burns. (Nouri) Although daily administration of topical vancomycin
has reduced the incidence of gram positive endophthalmitis, which was a frequent
cause, an increased incidence of gram negative bacterial and fungal endophthalmitis
is observed by some investigators. (Durand, Bradley). In case of an endophthalmitis,
device explantation with vitrectomy and injection of intravitreal antibiotics is advised in
view of high incidence of posterior segment complications (Robert MC)
Posterior segment complications like retinal detachments have been reported in the
range of 3.5-12%. (Zerbe, Ray). Altered anatomy and presence of a limited eld of
vision through the optic makes vitreo-retinal surgery a challenging task.
In spite of several problems there has been a steady increase in the number of BKpro-1
implant procedures in the USA and rest of the world. This may be largely due to the
increase in device retention rates and awareness of the procedure. (News letter)
BKPro Type-2
The less popular type-2 device is similar to type-1 but contains an enhanced optical
stem that projects through the lid. It is intended for permanent use in severe dry eyes.
The ocular surface is bared out by removing the forniceal and tarsal conjunctiva and
12
a notch is created in the upper lid for the optical portion to project through, and a
complete permanent tarsorrhaphy is performed to secure the device. Patients with
both the types of BKPros should receive prophylaxis with daily topical antibiotic drops
like vancomycin and uoroquinolones.
In a long term study of 29 eyes by Pujari et al., at 1year 57% of the followed patients
have retained a Va of 20/200. In this series, RPM was developed in approximately 50%,
retinal detachment was noted in 27.6% and endophthalmitis occurred in 1 case. A
41.4% of the patients experienced device extrusions and 70% of the patients had
pre-existing glaucoma.
Advancements in BKPro
A thick RPM development following BKPro is attributed to decreased nourishment of
cornea by impeding the aqueous ow, thereby increasing the risk of corneal melts
and subsequent KPro extrusion. (Colby Ever) Titanium backplates are associated with
reduced incidence of RPM formation than PMMA backplates. (Todani) Large titanium
backplates of 9.5mm diametre clamps the graft-host junction more effectively and
reduces RPM formation. (Colby -Acta)
Anterior segement OCT imaging is a useful adjunct in KPro service. Pre and post op
imaging can identify patients at risk of developing synaechial angle closure. It has also
been suggested that the pattern of synechiae location may be related to the graft shape
and positioning. Knowledge of this conguration could contribute to renements in
KProd design. (Xian CX ARVO paper)
Collagen cross linked corneas of rabbits with UVA/riboavin method are shown to
be resistant to enzymatic degradation. It has been suggested that cross-linking of
donor carrier corneal material could decrease the occurrence of keratolysis and device
extrusion. (Arafat ARVO paper) Glycerin preserved corneas as carrier material for BKPro
has been suggested.(Traish)
Frequent change of the contact lens and periodic administration of anti fungal drops
and perhaps betadine instillation could minimise the risk of fungal and gram negative
bacterial infections. (Colby Ever)
A ring shaped wireless intaocular pressure transducer (WIT) containing a chip and
microcoil antenna encapsualted in a silicone rubber was found to be well tolerated
after implantation into the rabbit eyes after extracapsular extraction. The measurements
were found to be reproducible and in concordance with manometry. This device may
have application in the management of glaucoma associated with KPros.
Osteo-Odonto keratoprosthesis (OOKP)
Scores of KPro skirt materials were proposed that were non-biological and often
porous; such as Dacron (Pintucci), hydroxy-apatite ( Leon-Barraquer), expanded PTFE
(Legeais), hydrogel (AlphaCor) and PMMA (Choyce, Boston KPro), nevertheless the
integration of these materials into the ocular tissues and longevity of the KPro implant
is still a concern. Biological skirt materials like tooth root and alveolar bone (Strampelli-
OOKP), cartilage (Casey) and tibial bone (Temprano) have been in practice for a number
of years.(Casey, Temprano) Hitherto, OOKP is the time tested KPro device that has
proven to last for a longer term. (Lam FC) OOKP surgery was invented by Strampelli and
subsequently improved by Falcinelli. (Strampelli, Falcinelli).
OOKP involves a complex multi-stage procedure performed by experienced oral and
ophthalmic surgeons. Details of the modied OOKP surgical technique was described
in Rome-Vienna Protocol. (Hille) Antiseptic and antifungal mouth washes are normally
prescribed before the surgery and the eye lashes are trimmed. In the rst stage,
which can be performed in 1or 2 stages, cheek mucosal membrane is excised and
covered on to the prepared ocular surface. The membrane is anchored to the four
recti muscles. Later a tooth with the surrounding piece of jaw bone is extracted. In
the same sitting the tooth is trimmed and a PMMA optical cylinder is inserted through
the central aperture. The power and size of the cylinder is determined by the axial
length of the eye and bulk of the tooth. The prepared osteo-odonto-acrylic lamina is
implanted into the subcutaneous pouch of the lower lid. The second stage is usually
performed after 3-4 months to enable naturalisation of the oral mucosa on to the
ocular surface and vascular ingrowth into the osteo-odonto-acrylic lamina. In the same
stage, the lamina is explanted from the lower lid and examined for erosions, bulk and
stability. If it is suitable for implantation further surgery is continued with. The mucosa
membrane is dissected from the sclera on the superior portion and reected into the
lower fonix to expose the cornea. The corneal epithelium is removed and a central hole
of 3mm diamtre is trephined. Crystalline lens is removed by cryo extraction, any IOL
present is removed with the bag, iris removed from its root and anterior vitrectomy is
performed. The optical cylinder is inserted through the central corneal hole and the
osteo-odonto lamina skirt is placed onto the sclera. Correct position of the lamina is
assessed with indirect ophthalmoscopic examination of the fovea and disc and adjusted
accordingly. The whole lamina is sutured tightly by passing vicryl (6.0) sutures through
the soft tissue over the lamina and to the sclera. The mucous membrane is closed
with interrupted absorbable sutures. Aseptic precautions are taken in handling the
tissues and the mucous membranes are always kept moist. The osteo-odonto lamina is
stored in heparisnised blood during the transit. prophylactic broad spectrum antibioitcs,
12
systemic acetazolamide and steroids are given during the operative and postoperative
period. Allograft patients are normally given oral cyclosporin in the postopertive period,
however, the duration of such treatment is unknown.
In our set up (Sussex Eye Hospital, Brighton,UK), patients referred for OOKP surgery are
assessed by the ophthalmologists, oral surgeons, anesthetist and a clinical psychologists.
The aim of the assessment is to establish the suitability of the patients for OOKP surgery,
to identify the factors that could inuence the surgical procedure and outcome and to
provide information to the patient and family about pre and postoperative care. Patients
are rst seen by the ophthalmologists, in the rst consultation underlying diagnosis
is ascertained, and examined for condition of the eyes--including the presence of
glaucoma, corneal thickness, lens status, previous eye surgeries, adnexal malpositions,
fundus evaluation with ophthalmoscope and B-Scan ultrasound and measurement of
the axial length. Visual potential of the eyes is estimated and the eye for proposed
surgery is chosen. In the same visit, a short examination of the oral cavity and dentition
is performed, general health is evaluated and patients are subsequently referred to the
oral surgeon and clinical psychologist. Surgery is offered to patients with bilateral poor
vision and to the eye with a good visual potential. Generally one eye is performed per
patient and the second eye serves as a spare.
Oral surgeon assesses health of the dentition and gums, and selects teeth based on clinical
and radiological examination. An orthopantomogram is usually performed. Patients are
advised to stop smoking and improve oral hygeine as appropriate. Many patients usually
have poor dental hygeine and oral mucosal disease affecting the teeth and gums. In
adentulous patients related or unrelated donors are generally considered at this stage.
Clinical psychologists assessment is pivotal in our set up--patients are thoroughly
investigated for their psychological and general health, habits, addictions, employment,
social and family structure and support mechanisms. Patients attitudes, expectations
and their ability to cope with the consequences of the surgery is assessed. Patients are
educated about the OOKP surgery and provided with written information.
A second visit is usually planned to help the patients to make a decision and family
members or patient attendants and tooth donors (if any) are also consulted. Once
a decision is made for the surgery they are referred to the anesthetist. Full details of
OOKP surgery and care can be accessed from the article, OOKP. Semin Ophthalmol
2005;20:113-28.
The principles of OOKP involve bypassing the ocular surface with a robust cheek
mucous membrane and the anterior segment with an osteo-odonto-acrylic lamina.
The mucous membrane can withstand dry conditions of the environment and sustain
inammation to some extent. The tooth-bone complex integrates well with the ocular
tissues and typically lasts longer in successful cases, therefore it is indicated for eyes with
defective lids and blinking mechanism, surface keratinisation, and severe inammatory
conditions of the ocular surface such as SJS, MMP, chemical and thermal burns, Lyell
syndrome, trachoma, Graft vs host disease, Sjgrens syndrome. (Falcinelli) OOKP is not
suitable for children due to the high bone turnover. It is contra indicate in pthisis bulbi
and eyes without light perception.
Longterm anatomical retention of the prosthesis is excellent across all the published
studies. Marchi reported a 98% retention at 20 years follow up. Falcinelli calculated
the cumulative probability of anatomical retention of osteodental lamina and reported
as more than 80% at 18 years. Hille, Tan and Marchi reported a 100% retention at
5 years follow up. Iyer published the anatomical success of OOKP lamina with mean
follow up of 15.38 months as 96%. Liu reported the probability of retention of an
autograft OOKP lamina as 81% at 5years. None of the allografts survived for more than
5years, their median survival was 30 months. Michael presented a 10 year anatomical
survival of 66% for OOKP cases and 47% for tibial KPro(OKP) cases. In a systematic
review Tan concludes that 52% of patients achieve VA better than 6/18. (Tan) Liu gave
an account of visual results from UK that 78% have achieved VA of 6/60 or better and
53% achieved 6/12 or better VA.
A signicant cause for anatomical failure of the OOKP eye is laminar resorption. In UK
study by Liu the laminar resorption was noted in 19% of cases, in Indian study by Iyer
it was 22%. De La Paz reported a 43% incidence of laminar resorption.(Liu, Iyer, De
La Paz) Resorption results in decreased thickness and defects in laminar consistency.
Owing to resorption the optic cylinder can be loosened and becomes mobile, which can
eventually lead to-aqueous leak, altered refraction, tilting of the lamina with alteration
in visual axis, and nally endophthalmitis leading to catastrophic visual loss. The clinical
detection of laminar resorption is difcult until late sequelae such as its tilt and aqueous
leak have developed. Serial imaging of the lamina and comparison of its dimensions
with a computerized tomography (CT) or Electron Beam Tomography (EBT) can detect
resorption early. Stoiber et al proposed that evaluation of laminar linear dimensions on
serial CT reconstruct images and volumetric analysis could identify resorption., however
in their study there is an element of operator induced subjectivity and data may not be
reproducible.(Stoiber) In a retrospective study, Sipkova applied an automated algorithm
called Advanced Lung Analysis Software on UK national cohort of OOKP patients
and analysed laminar volumes objectively from the serial multidimensional CT images.
This method is reproducible and identied resorption earlier than clinical examination
12
in 60% of patients. (Sipkova) Early detection of resorption could help the clinician
to monitor the rate of lamina resorption and enables to intervene in the correct
opportunity. Risk factors for laminar resorption include allografts, young age, tibial
lamina, persistent inammation and perhaps smoking and use of steroids. Patients with
these risk factors should be watched more closely.
In the early postoperative period the main causes for slow regain of visual acuity is the
presence of air bubble and vitreous hemorrhage. Hille and Tan reported intraoperative
vitreous hemorrhage in nearly 50% of their cases. In our experience some patients
could take a longer time to develop cortical adaptation to vision, perhaps 3 to 6
months. Elderly and patients with a longstanding blindness before the OOKP operation
should be prepared for this eventuality.
In anatomically successful OOKP eyes the main cause of visual loss is glaucoma. Hille in
16%, De La Paz in 17%, Iyer in 20% Marchi in 33% and Tan in 34% of their patients
had observed glaucoma. (Ref & Tan) In Rome series de novo glaucoma incidence
is 7% and recurrence is 21%, where as, in the UK series by Liu 24% had de novo
glaucoma and recurrence in 23% of the cases. Topical treatment with eye drops has
no role in OOKP eyes. In our practice, oral acetazolamide, sublingual administration
of timolol eye drops and oral betablckers have some benecial effect on lowering the
IOP. Surgical treatment is usually with drainage tubes or ciliary body ablation using
either transscleral and endoscopic lasers. Insertion of tubes is generally not performed
at the time of surgery to avoid hypotony. Baerveldt implants can be considered with
temporary occlusion of the lumen with sutures. (Liu OOKP) However, insertion of any
drainage device is fraught with difculties due to lack of clear anatomical landmarks.
In addition the effect of the device is compromised by the thick mucous membrane
that impeded episcleral drainage. Moreover, detection and monitoring of glaucoma
is difcult in OOKP similar to any other KPro device in situ. Since Until now, objective
measurement of IOP with an instrument is not possible, therefore serial disc assessment
by clinicians and disc imaging with photography, OCT or HRT and visual eld testing
remains the may stay of assessment. (Liu OOKP). In a study by Falcinelli, the pattern
electroretinogram (PERG) amplitudes and contrast sensitivities are reduced in OOKP
patients but are not specic for glaucoma subjects. However visual evoked potentials
are signicantly reduced in glaucoma patients with OOKP compared to normal OOKP
subjects. (FalcinellI) In our experience, some patients report eye pain and frontal
headache associated with raised IOP that is relieved after increasing the uptake of oral
acetazolamide. Complaints of reduced vision and eye pain should raise the suspicion of
increased IOP in OOKP patients, particularly in de novo glaucoma cases.
Retroprosthetic membrane developed in 1-7% in studies with large number of
patients (Flacinelli, De La Paz) compared to 17-20% in smaller studies (Liu, Tan). RPM
generally required yag laser treatment similar to capuslotomy. In reseistant case surgical
membranectomy may be required. In severe cases an exchange of lamina would be
required. (Liu UK report)
Hughes reported a 22.8% incidence of vitreo-retinal complications from the UK cohort
of patients that included vitreous haemorrhage, retinal detachments and sequelae
of endophthalmitis. Pars plana vitrectomy was performed through a a temporary
keratoprosthesis using binocular indirect viewing system or under enodscopic guidance.
(Hughes) Tans systematic review documented a variable incidence of 3-26% among
large case series (Falcinelli, De La Paz, Marchi) and 0-12% among small series (Liu,
Iyer, Tan, Hille). Managing vitreo-retinal complications can be challenging and requires
experienced surgeons.
Oculopastic complications account for the majority of the surgical procedures
performed on OOKP eyes. Among the reported studies, mucosal ulceration was lowest
at 8% in Falcinellis study and highest in Hilles study at 48% (Faclcinelli, Hille). Liu and
Tan reported mucosal ulceration in 28% and 25% of their cohort of cases. (Liu, Tan)
Ulceration of the mucous membrane is generally due to failure of the vascularisation
of the graft on the ocular surface. These problems are usually treated with a bucket-
handle ap, tarsal pedicle ap or a new mucosal patch graft. Mucosal membrane
overgrowth was reported by Iyer in 2%, by Liu in 33% and by Tan in 22% of the cases.
Mucosal overgrowth usually requires surgical excision. Intraoperative oral complications
were reported in nearly 1-3% of cases in Rome series. (Rome-Vienna Protocol)
Incidence of endophthalmitis is low 0-8% compared to the BKPro. (Tan) Endophthalmitis
generally occurs in the postoperative period following a surgical procedure. Unlike
BKPro the risk of endophthalmitis is not perennial since there is no use of contact lens
or corneal melt. However, laminar resorption with loosening of the optic, indwelling
glaucoma tubes and noncompliance with antibiotic ointment can predispose the eye to
the risk of endophthalmitis. Ordinarily endophthalmitis requires laminar explantation,
vitrectomy and injection of intravitreal antibiotics. The prognosis is generally poor.
12
Conclusion
Boston type-1 and OOKP are the two KPro devices with a proven record of success
among innumerable KPros that have been proposed. Globally BKPro-1 is rapidly gaining
the momentum and is being used for a number of conditions, where a conventional
corneal graft is deemed less successful. BKPro-1 is widely considered the procedure of
choice to restore vision in a wet-blinking eye. OOKP is the procedure of choice for dry
non-blinking eyes and those with lid abnormalities.
PMMA has largely solved the need for a stable and biocompatible optical component of
a KPro, nonetheless, the anchoring skirt material is still an area that requires research.
BKPro has the advantage of easy repeatability in cases of device extrusion since it is
synthetic and only requires a cadaveric corneal material as a carrier. Availability of
suitable tooth can be a major limitation for a number patients for the OOKP surgery,
for the reason that a majority of them have concomitant oral mucosal disease and poor
dental hygiene. Ophthalmologists involved in the management of patients who are
potential candidates for future OOKP surgery should pay particular attention to the oral
and dental care of the patients.
Patient selection is crucial for a successful outcome after KPro surgery. Patients should
be able accept the complications, further operations, frequent hospital visits and
should recognise and present urgently when there is an emergency. Psychological and
social support are essential elements of the patient care. Level of social care available,
capacity for self care must be clearly evaluated before offering a KPro procedure. After
a prosthesis implantation, patient follow up is life long. Selection of the correct device
for the correct patient is of paramount importance since each procedure is fraught with
multiple complications and further revision and surgeries. Switching patients from once
device to other after an implantation may not be possible.
A successful KPro typically requires frequent surgical procedures to retain the prosthesis.
Even then, glaucoma can adversely affect the longterm visual outcome. Therefore, in
majority of the situations this procedure should be taken as a temporary salvage of vision.
Venkata Avadhanam and Christopher Liu
The National OOKP Centre, Sussex Eye Hospital, Brighton, England
profchrisliu@gmail.com
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Results from the multicenter Boston Type 1 Keratoprosthesis Study. Ophthalmology
2006; 113:1779 84.
Greiner MA, Li JY, Mannis MJ. Longer-term vision outcomes and complications
with the Boston Type 1 keratoprosthesis at the University of California, Davis
experience. Ophthalmology. 2011;118(8):1543-50.
Aldave AJ, Sangwan VS, Basu S et al.International results with the Boston type I
keratoprosthesis. Ophthalmology. 2012;119(8):1530-8.
Chew HF, Ayres BD, Hammersmith KM, et al. Boston keratoprosthesis outcomes
and complications. Cornea 2009;28:98996.
Aldave AJ, Kamal KM, Vo RC, Yu F. The Boston type I keratoprosthesis: improving
outcomes and expanding indications. Ophthalmology 2009;116:640 51.
Bradley JC, Hernandez EG, Schawb IR, Mannis MJ. Boston type I keratoprosthesis:
the University of California Davis experience. Cornea. 2009;28(3):321-7.
Stacy RC, Jakobiec FA, Michaud NA, Dohlman CH, Colby KA. Characterization of
retrokeratoprosthetic membranes in the Boston type 1 keratoprosthesis.
Arch Ophthalmol. 2011;129(3):310-6.
Magalhes FP, Sousa LB, Oliveira LA. Boston type I keratoprosthesis: Review.
Arq Bras Oftalmol. 2012;75(3):218-22.
Banitt M. Evaluation and management of glaucoma after keratoprosthesis.
Curr Opin Ophthalmol. 2011;22:133136.
Li JY, Greiner MA, Brandt MC, Lim MC, Mannis MJ. Long-term complications
associated with glaucoma drainage devices and Boston keratoprosthesis.
Am J Ophthalmol 2011;152(2):209 218.
Rivier D, Paula JS, Kim E, et al. Glaucoma and keratoprosthesis surgery: role of
adjunctive cyclophotocoagulation. J Glaucoma 2009; 18:321324.
Kamyar R, Weizer JS, de Paula FH et al. Glaucoma associated with Boston type I
keratoprosthesis. Cornea. 2012;31(2):134-9.
Robert MC, Moussally K, Harissi-Dagher M. Review of endophthalmitis following
Boston keratoprosthesis type 1. Br J Ophthalmol. 2012; 96(6):776-80.
Nouri M, Terada H, Alfonso EC, et al. Endophthalmitis after keratoprosthesis:
12
incidence, bacterial causes, and risk factors. Arch Ophthalmol 2001;119:484 9.
Durand ML, Dohlman CH. Successful prevention of bacterial endophthalmitis in
eyes with the Boston keratoprosthesis. Cornea 2009;28:896e901.
Bradley JC, Hernandez EG, Schwab IR, et al. Boston type 1 keratoprosthesis:
the University of California Davis experience. Cornea 2009;28:321e7.
Ray S, Khan BF, Dohlman CH, DAmico DJ. Management of vitreoretinal complica-
tions in eyes with permanent keratoprosthesis. Arch Ophthalmol 2002;120:55966.
Boston Kpro News, Fall 2011, no. 8; available at www.masseyeandear.org;
accessed January 23, 2013.
Pujari S, Siddique SS, Dohlman CH et al. The Boston keratoprosthesis type II:
the Massachusetts Eye and Ear Inrmary experience.Cornea. 2011; 30(12):1298-303.
Casey TA. Osteo-odonto-keratoprosthesis. Proc R Soc Med 1966; 59: 5301.
Temprano J. Keratoprosthesis with tibial autograft. Refract Corneal Surg 1993; 9:
1923.
Lam FC, Liu C. The future of keratoprostheses. Br J Ophthalmol. 2011;95(3):304-5.
Strampelli B. Keratoprosthesis with osteodontal tissue. Am J Ophthalmology 1963;
89:102939.
Falcinelli GC, Missiroli A, Petitti V, et al. Osteo-odonto-keratoprosthesis up-to-date.
Acta XXV Concil Ophthalmol Milan. 1987;2:27722776.
Falcinelli GC, Barogi G, Taloni M, et al. Osteoodontokeratoprosthesis:Present
experience and future prospects. Refract Corneal Surg. 1993;9:193.
Hille K, Grabner G, Liu C et al. Standards for modied osteo-odonto-keratoprosthesis
(OOKP) surgery according to Strampelli and Falcinelli: the Rome-Vienna Protocol.
Cornea 2005; 24: 895908.
Liu C, Paul B, Tandon R et al. The osteo-odontokeratoprosthesis (OOKP). Semin
Ophthalmol 2005; 20:11328.
Falcinelli G. Modied osteo-odonto-keratoprosthesis for treatment of corneal
blindness: long-term anatomical and functional outcomes in 181 cases. Arch
Ophthalmol 2005; 123: 131929.
Marchi V, Ricci R, Pecorella I, et al. Osteo-odonto-keratoprosthesis. Description of
surgical technique with results in 85 patients. Cornea1994;13:125-30.
Hille K, Hille A, Ruprecht KW. Medium term results in keratoprostheses with
biocompatible and biological haptic. Graefes Arch Clin Exp Ophthalmol.
2006;244:696-704.
Michael R, Charoenrook V, de la Paz MF, et al. Long-term functional and anatom-
ical results of osteo- and osteoodonto-keratoprosthesis. Graefes Arch Clin Exp
Ophthalmol. 2008;246:1133-7.
Iyer G, Pillai VS, Srinivasan B, et al. Modied osteo-odonto keratoprosthesis-the
Indian experience-results of the rst 50 cases. Cornea. 2010;29:771-6.
Falcinelli G, Falsini B, Taloni M, et al. Modied osteo-odontokeratoprosthesis for
treatment of corneal blindness: long-termanatomical and functional outcomes in
181 cases. Arch Ophthalmol 2005;123:1319-29.
Tan A, Tan DT, Tan XW, Mehta JS.Osteo-odonto keratoprosthesis: systematic
review of surgical outcomes and complication rates. Ocul Surf. 2012;10(1):15-25.
Stoiber J, Forstner R, Csaky D, et al. Evaluation of bone reduction in osteoodon-
tokeratoprosthesis (OOKP) by three-dimensional computed tomography. Cornea.
2003;22(2):126-130.
Sipkova Z, Lam FC, Francis I, Herold J, Liu C. Serial 3-Dimensional Computed
Tomography and a Novel Method of Volumetric Analysis for the Evaluation of the
Osteo-Odonto-Keratoprosthesis. Cornea.2012 Jul 31.[Epub ahead of print]
Falcinelli GC, Falsini B, Taloni M, Piccardi, et al. Detection of glaucomatous damage in
patients with osteo-odontokeratoprosthesis. Br J Ophthalmol 1995;79(2):129 134.
Hughes EH, Mokete B, Ainsworth G, et al. Vitreoretinal complications of
osteoodonto keratoprosthesis surgery. Retina 2008;28:1138-45.
Colby K. Boston KPro in 2012:Preventing Complications and Optimizing
Outcomes. Ever 2012; 2012 Oct 10-13; Nice: France.
COLBY, K. (2012), Boston Keratoprosthesis in 2012: preventing complications
and optimizing outcomes. Acta Ophthalmologica, 90: 0. doi: 10.1111/j.1755-
3768.2012.4632.x
Todani A, Ciolino JB, Ament JD, et al.Titanium back plate for a PMMA keratopros-
thesis: clinical outcomes. Garefes Arch Clin Exp Ophthalmol. 2011;249(10):1515-8.
Xian CX, Hassanaly S, Harissi-Dagher M.Long-term Follow-up of Implanted Boston
Type I keratoprosthesis and angle structural changes using anterior segment optical
coherence tomography. ARVO 2012. 2012; May 10; Fort Lauderdale, Florida, USA.
Arafat SN, Shukla AN, Dohlman CH, et al.Cross-linking Donor Corneas for the
Boston Keratoprosthesis: A Method of Increasing Resistance to Collagenolytic
Degradation. ARVO 2012. 2012; May 10; Fort Lauderdale, Florida, USA.
12
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15/03/2013
1

ASSESSMENT AND STEP-BY-STEP
MANAGEMENT OF ALLERGIC EYE
DISEASE

Frank Larkin

Cornea & External Diseases Service
Moorfields Eye Hospital

Assessment and step-by-step
management of allergic eye disease
Frank Larkin, United Kingdom
13
Assessment and step-by-step management of allergic eye disease
15/03/2013
2
Allergic conjunctivitis classification
Disorders Features

Seasonal allergic conjunctivitis
Perennial allergic conjunctivitis

Giant papillary conjunctivitis Loss of CL tolerance
_________________________

Vernal conjunctivitis keratitis Limbal / Palpebral
85% male, onset <10y in 85%

Atopic keratoconjunctivitis HSV, keratoconus,
corneal vascularisation,
cataract

Allergic conjunctivitis
Investigation

Serum [IgE]
Conjunctival cytology
Tarsal conjunctival biopsy (off steroid 2 wks)
Eosinophil + mast cell infilt
n

epithelial hyperplasia, goblet cells

13
15/03/2013
3
Allergic conjunctivitis
Investigation

Serum [IgE]
Conjunctival cytology
Tarsal conjunctival biopsy (off steroid 2 wks)
Eosinophil + mast cell infilt
n

epithelial hyperplasia, goblet cells

Skin test results dont correlate with specific IgE in
tears, unhelpful in guiding management
Atopic allergic conjunctivitis
Pathogenesis
High levels of allergen-specific IgE in tears
Mast cell release of histamine
15/03/2013
4
Pathogenesis
PE isotype control CD58 *
CD11c CD11b *
CD23 FcRI
PE isotype control Normal MoDC VKC MoDC
Higher antigen-
presenting cell
expression of CD11b
and FcR1 IgE receptor
in VKC patients
Pathogenesis research
Higher antigen-presenting cell
expression of HLA class II and
co-stimulatory molecules in
VKC patients
Normal MoDC VKC
MoDC
FITC isotype
control
MHC class II *
CD86
*
CD83
*
FITC isotype
control
13
15/03/2013
5
Pathogenesis research
MLR assays
0
20000
40000
60000
80000
100000
1:10 1:20 1:40 1:80 1:160
Ratio of MoDC:T cell
T
h
y
m
i
d
i
n
e

i
n
c
o
r
p
o
r
a
t
i
o
n

(
c
p
m
)
Normal, n = 8
VKC, n = 7
Lower T-lymphocyte proliferation induced by antigen-presenting
cells from VKC patients than normal subjects
increased viral, fungal infection frequency
Manzouri et al. Br J Ophthalmol 2010;94:1662

Conjunctival signs in allergic disease
Papillae

15/03/2013
6

Papillae

Papillae

Cause no discomfort or keratopathy when
disease inactive

Association with mucus discharge indicates
activity

13
15/03/2013
7

Papillae
Reticulate scarring

Atopic keratoconjunctivitis
Vernal keratoconjunctivitis

Papillae
Reticulate scarring
Fornix shortening

Atopic keratoconjunctivitis
15/03/2013
8
Limbal signs in allergic disease
Swelling
Trantas dots
Pseudogerontoxon

Corneal signs in allergic disease
Acute punctate epitheliopathy
Macroerosion

13
15/03/2013
9
Macroerosion
Plaque

Macroerosion
Plaque

Stromal vascularisation

Surface scarring

15/03/2013
10
Keratopathy in allergic conjunctivitis: pathogenesis
ACUTE PUNCTATE EPITHELIOPATHY EROSION PLAQUE
Inflammation (mast cell + eosinophil degranulation)

epitheliotoxic cationic proteins

erosion plaque

Significant T-lymphocyte component in AKC

Allergic conjunctivitis: maintenance treatment

1. G. sodium cromoglycate (or whatever mast cell stabiliser works best)
OR
antihistamine drop if itch is the predominant symptom

2. G. olopatadine

(Adequate in seasonal + perennial conjunctivitis)

13
15/03/2013
11
Anti-allergy drops available in UK 2013

Action Constituent Commercial name
antihistamine + vasoconstrictor antazoline + xylometazoline Otrivine-Antistin
antihistamine azelastine HCl Optilast
emadastine Emadine
levocabastine Livostin
mast cell stabiliser Na cromoglycate Opticrom, etc.
ketotifen Zaditen
lodoxamide Alomide
mast cell stabiliser
+ antihistamine
olopatadine Opatanol
prostaglandin inhibitor ketorolac Acular
flurbiprofen Ocufen
diclofenac Voltarol Ophtha
steroid loteprednol Lotemax

1. Antihistamine

G. sodium cromoglycate (or whatever mast cell stabiliser works best)

2. G. olopatadine

3. G.fluorometholone available to parents for use in exacerbation

4. G.fluorometholone 1-3 times/day

5. G.dexamethasone 1/day in exacerbations

15/03/2013
12

1. Antihistamine


2. G. olopatadine




6. If dexa required more than 2-3 months / yr

Trial G.cyclosporin 0.2%, or 0.05% (Restasis)
or Optimmune 0.2% ointment

Introduce when inactive inflammation

Consider tacrolimus 0.03% ointment to lids


1. Antihistamine


2. G. olopatadine




6. If dexa required more than 2-3 months / yr

Trial G.cyclosporin 0.2%, or 0.05% (Restasis)
or Optimmune 0.2% ointment

Introduce when inactive inflammation

Consider tacrolimus 0.03% ointment to lids

7. Maintenance oral anti T-cell agent in severe AKC cases
Minimum dose for symptom control

13
15/03/2013
13
Keratopathy in allergic conjunctivitis: treatment
ACUTE PUNCTATE EPITHELIOPATHY EROSION
Plaque can appear quickly dexamethasone q1h
chloramphenicol prophylaxis
acetylcysteine can be helpful


If acute episode uncontrolled by high frequency drops

short course pred 20mg/d x 7-14 days
or
sub-conj triamcinolone upper fornix

15/03/2013
14

PLAQUE

If plaque does not spontaneously dehisce or respond to
G.acetylcysteine PF 5% or 10%

Remove plaque at slit-lamp or superficial keratectomy
to avoid vascularisation, infection
Keratectomy after first control inflammation

Atopic allergic eye disease
Sight threatening complications
HSV, fungal keratitis

13
15/03/2013
15

HSV, fungal, Gram-positive bacterial keratitis

HSV, fungal keratitis
Glaucoma induced by steroid optic neuropathy
scarring post-trab
y

15/03/2013
16

Secondary glaucoma in atopic allergic eye disease
Features

Steroid-dependent allergy symptoms (periocular skin steroid !)
Fast progressing glaucoma
Glaucoma drops tolerated *

Management problems

Topical / laser glaucoma management only for short term
Assessing IOP, fields in young children
Conj scarring post-trab
y

Recommend

Once IOP Baseline glaucoma assessment
Reassess steroid Rx
Early surgery

Glaucoma induced by steroid scarring post-trabeculectomy
optic neuropathy
Cataract

13
15/03/2013
17

Glaucoma induced by steroid scarring post-trabeculectomy
optic neuropathy
Cataract
Keratoconus, corneal transplantation oral steroid pre-/post-graft

ALLERGIC EYE DISEASE Practice points

Realistic management goals

Step-by-step maintenance treatment

Encourage patients/parents to initiate steroid, keep diary

In severe exacerbations: rapid patient access
intensive steroids
Treat plaque aggressively

Watch for HSV and steroid-induced glaucoma

Keratoconus is a bilateral, non-inammatory corneal ectasia with an incidence of
approximately one per 2,000 in the general population. The disease is characterized by
a progressive increase in corneal curvature, with apical thinning and irregular corneal
astigmatism. Eventually, an obvious cone-shaped protrusion of the corneal surface may
develop. Keratoconus often becomes apparent during the teenage years and classically
progresses until the third and fourth decades of life, when it stabilizes. The pellucid
marginal degeneration is a progressive non-inammatory ectatic disorder characterized
by an inferior peripheral corneal thinning.
Diagnosis
In advanced cases, keratoconus is readily diagnosed by characteristic slit-lamp ndings
(a Fleischer ring, Vogts striae, conical protrusion, stromal thinning, epithelial or
subepithelial scarring) or external inspection signs (Munsons sign, Rizuttis sign).
The diagnosis of keratoconus fruste, a subclinical keratoconus with a clear cornea, is
exclusively based on paraclinical investigations. Its detection remains a major challenge
because refractive surgery remains contraindicated in patients with keratoconus due to
a possible risk of accelerating the ectasia.
Corneal topography techniques using curvature-based analysis and newer forms of
elevation-based topography appear to be the most sensitive methods for detecting early
keratoconus and for monitoring the evolution of keratoconus. All these techniques have
now been integrated into sophisticated, computerized systems capable of generating
color-coded curvature and elevation maps. In anterior videotopography, the typical
topography pattern of keratoconus is an asymmetric bow tie with a skewed radial
axis. The pellucid marginal degeneration topography pattern is a central attening
accompanied by a crab-claw appearance. Most corneal topographers include multiple
computed indices, many of them created to facilitate suspicion and clinical diagnosis
of keratoconus. Thanks to newer forms of elevation-based topography (Orbscan slit
scanning topography, Penatcam Scheimpug imaging devices) anterior and posterior
corneal surface elevation data measurement and pachymetry map detection have
become possible. They are helpful to diagnose a keratoconus fruste because the
posterior surface of the cornea usually reveals the rst detectable thinning, and
Keratoconus and pellucid marginal
degeneration: diagnosis and treatment
Franois Malecaze, France
14
Keratoconus and pellucid marginal degeneration: diagnosis and treatment
presents as protrusion of its surface. When sagittal or tangential map, pachymetry map,
and posterior elevation map all show the same decentered hot spot, the diagnosis of
keratoconus fruste is more than likely.
Wavefront technology is an excellent adjunct to corneal topography in the diagnosis
of keratoconus showing signicant coma and spherical aberrations in keratoconus but
some clinical studies are needed to evaluate this method.
The Ocular Response Analyser (ORA) provides information on the biomechanical
properties of the cornea in keratoconus. But, for now, the two parameters analyzed
(corneal hysteresis and corneal resistance factor from the aplanation pressures) are not
discriminating enough.
Treatment
The spectacles are the rst option of correction in the early stages of keratoconus.
However, spectacles do not correct irregular astigmatism, and rigid gas permeable
contact lenses provide better correction in such cases. When patient is intolerant to
contact lenses or when optical correction is not satisfactory, a surgical treatment may
be necessary. The implantation of intracorneal reversible ring segments may allow a
reduction of the spherocylindrical ametropia by attening the top of the cone. The use
of toric and phakic intraocular lenses and topography guided Excimer laser provide
a therapeutic alternative, but must remain very cautious. In the presence of central
or paracentral corneal opacities, corneal transplantation is indicated (deep anterior
lamellar keratoplasty must be preferred to penetrating keratoplasty).
A cross-linking of corneal collagen is indicated in case of rapid keratometric progression
to stabilize the disease. This procedure may be associated with any treatments that
correct the irregular astigmatism (contact lens ).
These recent ndings have profoundly changed our therapeutic approach to
keratoconus, and it is now well codied and summarized in this algorithm.
Keratoconus and pellucid marginal degeneration: diagnosis and treatment
14
F.MALECAZE, A.CAUSSE ,M.CASSAGNE
Centre de Rfrence National du Kratocne,
Toulouse, France
The Chameleon of Herpetic Keratitis
Berthold Seitz
University of Saarland Medical Center UKS
Department of Ophthalmology, Homburg/Saar, Germany
Chairman: Prof. Dr. Berthold Seitz, ML, FEBO
University of Saarland Medical Center University of Saarland Medical Center UKS UKS
Department of Ophthalmology, Homburg/Saar, Germany Department of Ophthalmology, Homburg/Saar, Germany
Chairman: Prof. Dr. Berthold Seitz, ML, FEBO Chairman: Prof. Dr. Berthold Seitz, ML, FEBO
EUPO 2013
Herpes simplex Virus
3. Trigeminusast
2. Trigeminusast
1. Trigeminusast
Ganglion Gasseri
Viruspersistenz
Common Diagnoses in Patients Charts
Dendritica
Disciform keratitis
Herpetic Ulcer
Metaherpetic keratitis
Diagnostic Criteria
Very frequent !!
Unilateral
History of eye inflammation (i.e. recurrence)
Reduction of corneal sensitivity (before IOP measurement )
Discrepancy between severity of objective findings and
subjective pain
No major conjunctival involvement (esp. no follicules !)
Vital stainings (e.g. Rose Bengal)
Classification
Infectious epithelial keratitis
(dendritic/geographic keratitis)
(so-called metaherpetic keratitis)
Stromal keratitis
necrotising (herpetic ulcer)
non-necrotising (interstitial keratitis)
Endotheliitis
(disciform keratitis, keratouveitis)
(Vascularised) corneal scars
Holland EJ & Schwartz GS:
Classification of herpes simplex virus keratitis.
Cornea 1999; 18:144-154
Seitz B & Heiligenhaus A:
Herpeskeratitis Unterschiedliche
Ausprgungsformen erfordern unterschiedliche
Therapieanstze.
Ophthalmologe 2011; 108:385-398
Infectious Epithelial Keratitis
Dendritic keratitis
branching linear lesions
typically break through basal membrane
terminal enlargements
swollen epithelial margins with living virus
Geographic keratitis
DD: Acanthamoeba keratitis
DD: Epithelial closure lines
Herpetic Keratitis
Berthold Seitz, Germany 15
Herpetic Keratitis
Classical dendritic keratitis
(fluorescein / blue light)
Classical geographic keratitis
(Rose Bengal)
DD: Acanthamoeba Keratitis
Severe pain
Contact lens wear (CAVE: tub water)
Keratoneuritis
Ring infiltrate
Diffuse scleritis
Confocal microscopy
Histopathology
PCR
Feb 2009 May 2009
Dec 2010
VA sc 20/25
Feb 2010
St.p. elliptical
Excimer laser PKP
7.5x8.5 / 7.6x8.6 mm
June 2009
VA FC
DD: Acanthamoeba Keratitis
UKS
Topical: TFT or acyclovir
. or gancyclovir
NO STEROIDS !
Systemically: primarily not
Surgically: maybe epithelial abrasion
Infectious Epithelial Keratitis - Therapy
Herpetic Keratitis
15
Classification
Stromal keratitis
Endotheliitis
Cornea 1999; 18:144-154
Neurotrophic Keratopathy
Typically late stage (burned out)
No immune reaction !
No infection !
Reduced corneal innervation
Reduced tear secretion
Ulcerative neurotrophic keratopathy
Topically: Non-preserved artificial tears
Geles
Autologous serum
Systemically: none
Surgically: Amniotic membrane transplantation (AMT)
Botulinum toxin temporary iatrogenic ptosis
(temporary) tarsorrhaphy
Neurotrophic Keratopathy - Therapy
Seitz B, Grtereich M, Cursiefen C, Kruse FE:
[Conservative and surgical therapy of neurotrophic keratopathy.]
Ophthalmologe 2005; 102:15-26
Amniotic Membrane Transplantation
Patch = Overlay
Seitz B, Resch M, Schltzer-Schrehardt U, Hofmann-Rummelt C, Sauer R,
Kruse FE: Histopathology and ultrastructure of human corneas after
amniotic membrane transplantation. Arch Ophthalmol 2006; 124:1487-1490
Amniotic membrane Shallow stromal defect
Epithelium
Suture
Limbus
Botulium toxin temporary iatrogenic ptosis
Herpetic Keratitis
Classification
Stromal keratitis
Endotheliitis
Cornea 1999; 18:144-154
Necrotising Stromal Keratitis
a lot of active HSV in the stroma
typical ulcer (initially without hypopyon !!)
not rarely superinfected by bacteria
Cave: Perforation (Avoid: NSAID + fluoroquinolones !!)
Necrotising stromal keratitis
Descemetocele
Topically: Acyclovir
Antibiotics
Cycloplegics
initially NO STEROIDS !
Systemically: Acyclovir 5x400/800 mg orally
Antibiotics ?
Surgically: Amniotic membrane transplantation (AMT)
NO PTK !!
Emergency keratoplasty ( chaud) ??
Necrotising Stromal Keratitis - Therapy
Eccentric Mini-Keratoplasty
Riedel T, Seitz B, et al: [Morphological results after eccentric
penetrating keratoplasty.] Ophthalmologe 2001; 98:639-646
Ulcerative necrotising
stromal keratitis
with descemetocele
Ulcerative necrotising
stromal keratitis
with descemetocele
Herpetic Keratitis
15
3 days after excimer laser PKP (7.5/7.6 mm)
Descemetocele
Granulomatous reaction along
Descemets membrane
Problems in Emergency Keratoplasty ( chaud)
No / inadequate Donor tissue
Persistence of the infectious process
Recurrence of the infectious process
Persisting epithelial defects
Suture loosenings
Neo-Vascularisation
Immune reactions
Secundary glaucomas
!
Descemetocele after ipsilateral autologous
rotational keratoplasty for herpetic scars,
Cataracta nuclearis brunescens
Simultaneous Amnion Patch
Eccentric elliptical triple procedure
chaud using the excimer laser +
simultaneous Amnion Patch
Seitz B, Das S, Sauer R, et al:
Simultaneous amniotic membrane patch in high-risk keratoplasty.
Cornea 2011; 30:269-272
Therapeutic Step Approach with Corneal Ulcer
Antibiotics (topically and systemically?)
Emergency keratoplasty
Conjunctival flap (only in extremely severe cases)
.... MODERN ....
Amniotic membrane transplantation
Elective keratoplasty in the quiet interval
(only in case of perforation)
Suture
Amniotic membranes Deep stromal defect
Epithelium
Limbus
Focal ring-shaped
deepithelialization
Sandwich = Inlay (Graft) + Overlay (Patch)
Seitz B, et al.: Patch, Graft or Sandwich for persistent corneal ulcers
Differentiated techniques of amniotic membrane transplantation.
Clinical &Experimental Ophthalmology 2002; 30:122
Triple Graft Sandwich
Reduced signs of
Inflammation
Acceleration of
epithelial healing
Avoid emergency keratoplasty
in the severely inflamed eye
Improvement of
Graft prognosis
Triple Graft Sandwich
AMT Before Keratoplasty
Herpetic Keratitis
Quintuple-Graft AMT for deep recurrent herpetic ulcer on the corneal graft
Descemtocele 5 days (3-3-3-4-5 mm)
4 weeks
3 months - before Re-PKP
Normal thickness of cornea
Resch MD, Schltzer-Schrehardt U, Hofmann-Rummelt C, Sauer R, Kruse FE,
Beckmann MW, Seitz B: Integration patterns of cryopreserved amniotic
membranes into the human cornea. Ophthalmology 2006; 113:1927-1935
Keratoplasty in the quiet interval !!
1
2
3
4
5
Original descemetocele
Stromal Integration
Seitz B, Resch M, Schltzer-Schrehardt U, et al: Histopathology
and ultrastructure of human corneas after amniotic membrane
transplantation. Arch Ophthalmol 2006; 124:1487-1490
Classification
Stromal keratitis
Endotheliitis
Cornea 1999; 18:144-154
Non-Necrotising Stromal Keratitis
so-called interstitial keratitis (w/o neovascularisation)
so-called sclerosing keratitis
antigen-antibody-complement cascade due to
persisting HSV antigen
... should NOT be referred to as disciform keratitis
Herpetic Keratitis
15
STEROIDS !
Systemically: Acyclovir 5x400 mg orally
Steroids !
Surgically: None
Non-Necrotising Stromal Keratitis - Therapy
Classification
Stromal keratitis
Endotheliitis
Cornea 1999; 18:144-154
Endotheliitis w/o Trabeculitis
Focale / diffuse stromal edema
Clear demarcation line
Retrocorneal precipitates
Often secundary ocular hypertension
Immunologic cause +
HSV-Ag persisting in the endothelium
Classical disciform keratitis
Diffuse Endotheliitis
DD: Intracameral flotating foreign body
STEROIDS !
Antiglaucomatosa (no prostaglandin analoga !!)
Systemically: Acyclovir 5x400 mg orally
STEROIDS !
maybe antiglaucomatosa (e.g. Diamox)
Surgically: None
maybe antiglaucomatous surgery in the quiet
interval
Endotheliitis - Therapy
Herpetic Keratitis
Classification
Stromal keratitis
Endotheliitis
Cornea 1999; 18:144-154
Old scar
typically with stromal thinning
(Vascularised) Scars
Stromal edema active process !!
(Vascularised) Scars - Therapy (Vascularised) Scars - Therapy
Excimer laser PTK only very rarely
always under acyclovir protection
Preferably no lamellar keratoplasty due to
HSV persistence in the endothelium
Preferably no ipsilateral autologous rotational
keratoplasty
Prefer penetrating excimer laser keratoplasty
Examples of excimer laser
PKPs after 6 weeks
No steroids without acyclovir protection !!
Consider a long-term treatment with
acyclovir ointment 1x before sleep.
Immunologic graft reactions (DD: HSV recurrence)
will be treated with steroids AND acyclovir.
Follow-up after Keratoplasty
Postoperative acyclovir systemically for
at least 1 year (e.g. 2x400 mg)
Herpetic Keratitis
15
Geographic herpetic keratitis - Recurrence
Summary
HSV is a very frequent cause of keratitis
The herpetic keratitis can be treated quite well, given that the
various forms of appearance are known and the therapeutic
regimens are adequately chosen.
An accompanying ocular hypertension should be treated
primarily non-surgically (NO prostaglandine analoga !!).
Systemic acyclovir after keratoplasty for at least 1 year !!
Conclusions
The herpetic keratitis is a chameleon.
However, given adequate management,
it has lost ist horror today.
berthold.seitz@uks.eu berthold.seitz@uks.eu
www.unilasik-homburg.de www.unilasik-homburg.de
Thank you very much for your attention !
Herpetic Keratitis
Redaktion
F. Grehn, Wrzburg
Unter stndiger Mitarbeit von:
A. Kampik, Mnchen
B. Seitz, Homburg/Saar
Ophthalmologe 2011 108:385398
DOI 10.1007/s00347-011-2346-5
Online publiziert:31. Mrz 2011
Springer-Verlag 2011
B. Seitz
1
A. Heiligenhaus
2
1
Klinik fr Augenheilkunde und Hochschulambulanz,
Universittsklinikum des Saarlandes UKS, Homburg/Saar
2
Augenabteilung am Franziskus-Hospital, Mnster
Herpeskeratitis
Unterschiedliche Ausprgungsformen
erfordern unterschiedliche Therapieanstze
Zusammenfassung
Herpes-simplex-Virus (HSV) ist eine sehr hufige Ursache der Keratitis. Die Herpeskeratitis
ist ein Chamleon, jedoch heute gut behandelbar, wenn man die verschiedenen Ausprgungsfor-
men dieser Krankheit 1. epitheliale Keratitis (dendritica/geographica), 2. stromale Keratitis (ne-
krotisierend vs. nicht nekrotisierend = interstitiell), 3. Endotheliitis (= disziforme Keratitis), 4.
neurotrophe Keratopathie (= sog. metaherpetische Keratitis), 5. (vaskularisierte) Hornhautnar-
ben kennt und das Therapieschema bewusst darauf abstimmt. Eine begleitende okulre Hyper-
tension sollte vornehmlich medikaments (keine Prostaglandinanaloga!) behandelt werden. Im
reizfreien Intervall empfehlen sich bei geringer Schubhufigkeit Trnenersatzmittel ggf. mit Aciclo-
vir AS zum Schlafengehen, um die Rezidivneigung zu limitieren. Nach Keratoplastik und bei hu-
figen schweren Keratitisschben ist die systemische Aciclovir-Applikation (2-mal 400 mg/Tag) fr
mindestens 1 Jahr obligat! Damit hat das HSV heute auch nach Keratoplastik bei adquatem Ma-
nagement seinen Schrecken verloren.
Schlsselwrter
Herpetische Keratitis Keratitis dendritica Disziforme Keratitis Interstitielle Keratitis
Ulzerierende nekrotisierende stromale Keratitis
Herpetic keratitis Various expressions require
different therapeutic approaches
Abstract
Herpes simplex virus (HSV) is a common cause of keratitis. Herpetic keratitis is a chameleon,
which is well treatable today if the various types of clinical expression of this disease are known to
the ophthalmologist and treatment is adjusted accordingly. Types of expression include 1. epithelial
keratitis (dendritica/geographica), 2. stromal keratitis (necrotizing vs. non-necrotizing = intersti-
tial keratitis), 3. endotheliitis (=disciform keratitis), 4. neurotrophic keratopathy (=so-called me-
taherpetic keratitis) and 5. (vascularized) corneal scars. A concomitant ocular hypertension should
be treated predominantly non-surgically (no prostaglandin analogues). Topical artificial tears (if
necessary with acyclovir ointment at night) in the quiet interval are recommended to limit the ten-
dency towards recurrences. After keratoplasty and in cases of severe recurrences of herpetic kerati-
tis, systemic acyclovir application (2400 mg/day) for at least 1 year is indispensable! Overall, HSV
has lost its terror today, even after keratoplasty, given adequate management.
Keywords
Herpetic keratitis Dendritic keratitis Disciform keratitis Interstitial keratitis Ulcerating
necrotizing stromal keratitis
CME Weiterbildung Zertifizierte Fortbildung
385 Der Ophthalmologe 4 2011
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Herpetic Keratitis
15
Nach Lektre dieses Beitrags wird der Leser eine Klassifikation der verschiedenen durch
HSV verursachten Hornhautentzndungen kennen, die sich fr den praktischen Umgang
bewhrt hat. Zustzlich werden medikamentse und chirurgische Therapieanstze emp-
fohlen, die auf die verschiedenen Ausprgungsformen abgestimmt sind.
Vor mehr als 2 Jahrzehnten waren zum Teil in einem Jahr bis zu 3 Rekeratoplastiken bei Herpes-
keratitis ntig. Oft stellte eine nicht beherrschbare Keratitis geographica auf dem Transplantat
(. Abb. 1) den Anfang vom Ende (Fadenlockerung, Infiltrat, Einschmelzung, Immunreaktion,
bakterielle Superinfektion ) dar. Heute hat das Herpes-simplex-Virus (HSV) als hufiger Erreger
einer Keratitis weitgehend seinen Schrecken verloren. Hierzu ist es allerdings ntig, auch im klini-
schen Alltag nicht undifferenziert von einer Herpeskeratitis zu sprechen.
Primrinfektion: Virmie und Bildung humoraler Antikrper
Das HSV Typ l wird bei ber 95% der Flle von Herpesbefall der oberen Krperhlfte isoliert, wh-
rend im Genitalbereich Typ 2 vorherrscht. Im Laufe ihres Lebens erleiden 5090% aller Menschen
eine HSV-Infektion. Die primre Infektion mit HSV Typ 1 findet meist in der frhen Kindheit statt,
whrend Typ 2 entweder bei der Geburt oder hufiger zwischen 16 und 30 Jahren durch sexuellen
Kontakt mit einer infizierten Person erworben wird. Die primre Infektion verursacht oft eine Vi-
rmie. Diese bewirkt dann die Bildung humoraler Antikrper, die zeitlebens nachweisbar bleiben,
und zellvermittelter Immunreaktionen. Oft verluft eine solche Infektion subklinisch. Bei spteren
HSV-Erkrankungen von Personen, die eine primre Infektion bereits durchgemacht haben, handelt
es sich fast immer um Rezidive, obwohl eine Aufpfropfinfektion, d. h. der Befall durch einen ande-
ren HSV-Stamm, mglich ist.
Latenz: fortwhrende, langsame Replikation eines Teiles des Virusgenoms
Nach der primren okulren oder wesentlich hufiger oralen oder fazialen HSV-Infektion eta-
bliert das Virus eine latente Infektion (Latenz) in den Neuronen des Trigeminus, v. a. des Ganglion
Gasseri [4, 8]. Nach den aktuellen Daten ist es wahrscheinlich, dass HSV auch in der Hornhaut latent
verbleiben kann. [4, 13, 23]. Die Viren befinden sich in einem dynamischen Zustand der fortwhren-
den, langsamen Replikation eines Teiles ihres Genoms (latenzassoziierte Transkription, LAT). Wh-
rend der Latenz wird die Expression lytischer Gene weitgehend unterdrckt. LAT inhibiert die Apo-
ptose und die produktive Infektion, womit ein berleben der infizierten Neurone ermglicht und
der Zyklus aus Latenz und Reaktivierung des HSV im sensorischen Ganglion gefrdert werden [24].
Rezidiv: Strung des Gleichgewichts zwischen Wirt und Virus
Das Immunsystem des Wirtes ist dafr verantwortlich, eine disseminierte Infektion zu verhindern
und die HSV-Latenz zu kontrollieren [30]. Aufgrund der relativen Abwesenheit der viralen Gen-ex-
pression und der auf die Zelle beschrnkten HSV-Latenz kann das Virus der Beseitigung durch das
Immunsystem entkommen. Bei einer Strung des Gleichgewichts zwischen Wirt und Virus kommt es
Im Laufe ihres Lebens erleiden
5090% aller Menschen eine
HSV-Infektion
Die primre Infektion verursacht oft
eine Virmie
LAT inhibiert die Apoptose und die
produktive Infektion
Bei einer Strung des Gleichgewichts
zwischen Wirt und Virus kommt es zu
einem lokalen Rezidiv
Abb. 1 9 Keratitis herpetica geo-
graphica Rezidiv auf dem Trans-
plantat (Vitalfrbung mit Fluorescein
und Blaulicht)
386
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Der Ophthalmologe 4 2011
Herpetic Keratitis
CME
zu einem lokalen Rezidiv. Man kennt zahlreiche Fakto-
ren, die Rezidive auslsen knnen z. B. Traumen wie
Excimerlaser-Keratektomie, Sonnenlicht (besonders
UV-Anteil), Menstruation, Fieber, krperliche und see-
lische Belastung, Kortikoide, Immunsuppression, Ad-
renalin [37]. Worin die Strung des Gleichgewichts im
Einzelnen besteht, ist ungewiss.
Whrend der Reaktivierung tritt das latente Virus
wieder in die lytische Replikationsphase, nach der das
Virus durch den retrograden axonalen Transport wie-
der zur Stelle der Primrinfektion gelangt. Gelegent-
lich infiziert das Virus Neurone benachbarter Regio-
nen desselben Ganglions oder sogar anderer Ganglien,
um neue Stellen des Krpers zu infizieren. Die Hufig-
keit der HSV-Reaktivierung korreliert mit der Schwe-
re der Primrinfektion und dem Immunstatus der infi-
zierten Person. Die Rezidivrate steigt mit der Zahl frherer Rezidive. Die Hufigkeit der Rezidive be-
trgt ca. 10% nach einem Jahr, 50% nach 10 Jahren und ber 60% nach 20 Jahren. Zu einem Rezidiv
nach primrer okulrer Herpesinfektion kommt es in mindestens einem Drittel der Flle, wovon wie-
derum 50% mehr als 1-mal erkranken [35, 36]. Besonders hufig sind Rezidive bei HIV-Infizierten.
Bei frherer Beteiligung des Hornhautstromas steigt die Wahrscheinlichkeit fr sptere stromale
Entzndungen. Die Inzidenz der stromalen Keratitis betrgt 25% bei Erstmanifestation und steigt
auf 2040% bei weiteren Rezidiven [16, 38].
Diagnose der herpetischen Hornhautentzndung
Das HSV ist eine sehr hufige Ursache einer Keratitis. Man sollte immer daran denken! Typischer-
weise verluft die Krankheit einseitig (Ausnahmen fter im Kindesalter). Anamnestisch kann oft eine
zurckliegende Augenentzndung (z. B. Rezidiv) erfragt werden. Eine Reduktion der Hornhautsen-
sibilitt (vor der Augeninnendruckmessung bestimmt) ist richtungsweisend. Analog besteht hu-
fig eine Diskrepanz zwischen der Schwere des objektiven Befundes und den subjektiven Schmerzen.
Es besteht keine ausgeprgte Bindehautbeteiligung (keine Follikel!). Vitalfrbungen (z. B. Bengal-
rosa oder Fluorescein/Blaulicht) sind fr die biomikroskopische Diagnosefindung an der Spaltlam-
pe sehr hilfreich. Nur bei atypischer Klinik ist eine Labordiagnostik sinnvoll. Whrend serologische
Tests ohne Relevanz sind, ist die Real-time-PCR aus Hornhautgewebe oder Trnenfilm in der Lage,
den Verdacht zu besttigen und die Menge des Virusgenoms im Gewebe zu bestimmen. Eine groe
Zahl von HSV-Genkopien ist bei Patienten mit Steroidtherapie, hufigen Schben, schwerer Erkran-
kung, Hornhautneovaskularisation und Transplantatversagen nachweisbar [22].
Einteilung der Keratitis herpetica
Die wichtigste ophthalmologische Manifestation der HSV-Erkrankung ist die herpetische Keratitis
[41, 42]. Hierbei handelt es sich immer um ein Rezidiv, wenn man von der seltenen primren Horn-
hautinfektion absieht.
Oft liest man in den Krankenakten etwas undifferenziert Begriffe wie Dendritika, herpetisches
Ulkus oder den von vielen Augenrzten missverstandenen sehr nebulsen Begriff der metaherpe-
tischen Keratitis.
Cave: Die HSV-Keratitis ist ein Chamleon.
Die HSV-Keratitis kann vorliegen als (. Tab. 1):
. infektise epitheliale Keratitis (Keratitis dendritica/geographica),
. stromale immunologische Keratitis [entweder nekrotisierend (Ulkus) oder nicht nekrotisie-
rend (Interstitielle Keratitis)],
. Endotheliitis (disziforme Keratitis),
. neurotrophe Keratopathie (sog. metaherpetische Keratitis).
. Nicht selten endet sie als mehr oder weniger dichte Hornhautnarben mit Stromaverdnnung,
die mehr oder weniger vaskularisiert sein knnen.
Die Hufigkeit der HSV-Reaktivierung
korreliert mit der Schwere der Primr-
infektion und dem Immunstatus der
infizierten Person
Das HSV ist eine sehr hufige Ursache
einer Keratitis
Vitalfrbungen sind fr die biomik-
roskopische Diagnosefindung an der
Spaltlampe sehr hilfreich
Die HSV-Keratitis ist ein Chamleon
Tab. 1 Klassifikation der Herpeskera-
titis. (Mod. nach [15])
Infektise epitheliale Keratitis
(Keratitis dendritica/geographica)
Stromale immunvermittelte Keratitis
Nekrotisierend (herpetisches Ulkus);
infektis und immunologisch
Nicht nekrotisierend (interstitielle Kera-
titis); immunologisch
Endotheliitis
(disziforme Keratitis); immunologisch
Neurotrophe Keratopathie
(sog. metaherpetische Keratitis)
(Vaskularisierte) Hornhautnarben
Keratouveitis
|

Herpetic Keratitis
15
Die genannten Krankheitsbilder knnen aber auch auseinander hervorgehen und nebeneinander be-
stehen. Eine Uveitis mit/ohne akute okulre Hypertension kann gleichzeitig vorhanden sein.
Diese Einteilung ist modifiziert nach Holland und Schwartz [15], die fr den praktischen Ge-
brauch bersichtlicher erscheint als die von Liesegang [17].
Pathogenese der HSV-Keratitis
Bei der infektisen epithelialen Keratitis dominiert die 7 lytische Virusreplikation. Bei den stro-
malen Formen der Herpeskeratitis steht die 7 Immunreaktion im Vordergrund. Whrend sich bei
der nekrotisierenden ulzerativen Verlaufsform in der betroffenen Hornhaut viele replizierende (ak-
tive) Viren befinden, ist dies bei der nicht nekrotisierenden interstitiellen Keratitis nicht der Fall.
Bestandteile der angeborenen Immunreaktion (z. B. Toll-like-Rezeptoren) stellen wichtige Effek-
tormechanismen dar, mit denen das Virus aus der Hornhaut beseitigt werden kann. Aktivierte Zel-
len der Hornhaut selbst und antigenprsentierende Zellen sezernieren proinflammtorische Zytoki-
ne und Chemokine, die zu einem Einwandern von neutrophilen Granulozyten, Makrophagen, den-
dritischen Zellen und T-Lymphozyten in die Hornhaut fhren. Der chronische Prozess der stroma-
len Entzndung wird vorrangig durch CD4
+
-T-Lymphozyten vermittelt, die Interleukin-2, Tumor-
nekrosefaktor , Interferon oder Interleukin-17 sezernieren. Schlielich kann sich eine insbeson-
dere durch Vascular Endothelial Growth Faktor (VEGF) induzierte Angiogenese oder eine durch
lytische Enzyme (z. B. Matrixmetalloproteinase) induzierte Ulzeration entwickeln [41].
Epitheliale HSV-Keratitis
Erscheinungsbild
Typisch ist die Keratitis dendritica (. Abb. 2). Im Frhstadium kann man punkt- oder sternfrmi-
ge, opake Plaques aus geschwollenen Epithelzellen beobachten. Daraus entwickelt sich die Keratitis
dendritica oder bei Konfluenz dieser Lsionen eine Keratitis geographica (besonders nach Kortikoid-
therapie). Typisch fr die dendritischen Lsionen sind die epithelialen Infiltrate mit kolbenfrmigen
Auslufern, die replizierendes Virus beinhalten. Innerhalb einiger Tage entsteht ein leichtes subepi-
theliales Infiltrat, das oft nach Wischabrasion zurckbleibt.
Therapie
Die Lokaltherapie (. Tab. 2) besteht aus Trifluorthymidin (TFT) AT 5-mal, Aciclovir AS 5-mal,
Gancyclovir AG 5-mal oder Bromovinyldeoxyuriden (BVDU) AS 5-mal ausschleichend ber weni-
ge (meist 23) Wochen. Obschon diese Medikamente eine hnliche Wirksamkeit aufweisen, sind die
moderneren Wirkstoffe besser vertrglich [3, 12, 20].
Bei Langzeittherapie treten nicht selten toxische oder allergische Reaktionen auf. Resistenzen
gegen Virustatika sind bei Patienten mit intaktem Immunsystem selten [1].
Vidarabin und Foscarnet sind im Fall von Aciclovir-Resistenz vorgeschlagen worden [6]. Cido-
fovir hat sich wegen starker lokaler Toxizitt in wirksamer Dosierung nicht durchgesetzt. Eine sys-
Eine Uveitis mit/ohne akute okulre
Hypertension kann gleichzeitig vor-
handen sein
7 Lytische Virusreplikation
7 Immunreaktion
Typisch fr die dendritischen Lsio-
nen sind die epithelialen Infiltrate mit
kolbenfrmigen Auslufern, die repli-
zierendes Virus beinhalten
Bei Langzeittherapie treten nicht
selten toxische oder allergische Reak-
tionen auf
Abb. 2 8 Klassische Keratitis dendritica (Vitalfrbung mit Fluorescein und
Blaulicht)
Abb. 3 8 Ulzerierende nekrotisierende stromale Keratitis (herpetisches
Ulkus) mit Descemetozele (Pfeil; Vitalfrbung mit Bengalrosa)
388
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Herpetic Keratitis
CME
temische Aciclovir-Therapie ist primr nicht ntig. Die 2. Herpetic Eye Disease Study (HEDS) zeig-
te allerdings, dass Aciclovir 400 mg 2-mal tglich p.o. fr 1 Jahr die Rezidivrate und das Fortschrei-
ten zur stromalen Keratitis erheblich reduzierte [36]. Diese Behandlungsstrategie ist nur bei Patien-
ten mit hoher Rezidivrate, schwerer epithelialer Verlaufsform (z. B. geografische oder multiple Lsio-
nen), bergang in die stromale Form und nach Keratoplastik angezeigt. Die kurzfristige orale Acic-
lovir-Behandlung (fr 3 Wochen) reduzierte (im Gegensatz zur langfristigen Gabe) bei einer Beob-
achtungsdauer von einem Jahr die Wahrscheinlichkeit des bergangs in eine stromale Herpeskera-
titis nicht [35].
Cave: Lokale Kortikosteroide sind bei epithelialer HSV-Keratitis kontraindiziert!
Da es nach 23 Wochen in der Regel zur Spontanheilung kommt und die Rezidivrate sowie die
Hufigkeit der sekundren Stromabeteiligung mit und ohne Therapie hnlich sind, besteht der Wert
der Therapie in der Verkrzung der Erkrankungsdauer. Diese betrgt mit Virostatika durchschnitt-
lich etwa 1 Woche [33]. Durch eine schonende partielle Wischabrasio des Hornhautepithels mit dem
Wattetrger lassen sich nahezu 100% der Viren zusammen mit dem Epithel entfernen. Heutzutage
erscheint die Abrasio wegen der Verfgbarkeit gut wirksamer Virustatika nur noch bei Patienten mit
groflchigen Lsionen, verzgerter Abheilung oder etwaiger Resistenzentwicklung empfehlenswert.
Stromale immunvermittelte HSV-Keratitis
Hier mssen wir unterscheiden zwischen
F der ulzerierenden nekrotisierenden stromalen Keratitis (herpetisches Ulkus) und
F der interstitiellen Keratitis.
Ulzerierende nekrotisierende stromale Keratitis
Erscheinungsbild. Beim Ulkus findet sich reichlich aktives (replizierendes) Virus im Stroma
(. Abb. 3). Ulkusgrund und -rnder weisen ein dichtes, weiliches, entzndliches Infiltrat und
dem auf. Bei verzgerter Abheilung und Rezidiven entstehen dichte Narben, Gewebeverlust und
Neovaskularisation. Unbehandelt ist das Perforationsrisiko sehr gro. Typischerweise verluft die
Krankheit initial ohne Hypopyon, nicht selten ist das Ulkus jedoch bakteriell superinfiziert. Typi-
scherweise tritt der Befund einseitig auf, und die Hornhautsensibilitt ist mehr oder weniger deut-
lich herabgesetzt. Es lassen sich Virusgenom und -antigen im befallenen Hornhautgewebe nachwei-
sen [14].
Therapie. Lokal: Aciclovir AS 5-mal, Antibiotika (z. B. Moxifloxacin AT 5-mal), Zykloplegika (z. B.
Atropin EDO AT 2-mal). Initial sollten keine Steroide verabreicht werden! Da aber klinisch und ex-
perimentell die Begleitentzndung eine groe Rolle spielt [23], sollten wenige Tage nach suffizienter
antiviraler und antibiotischer Behandlung lokale Steroide vorsichtig addiert werden [41]. Da Cyclo-
sporin A eine wirksame T-Lymphozyten-Blockade und Entzndungshemmung erzielt, das Ulzera-
tions- und Perforationsrisiko aber nicht steigert, stellt es gerade in der akuten ulzerativen Phase ein
hilfreiches zustzliches Medikament dar [7, 9].
Systemisch: Aciclovir 5-mal 400/800 mg oral fr etwa 4 Wochen, dann auf 2-mal 400 mg reduzie-
ren. In den Augen mit nekrotisierender HSV-Keratitis verbessert die Zusatzbehandlung mit systemi-
schem Virustatikum das endgltige Resultat.
Lokale Kortikosteroide sind bei epi-
thelialer HSV-Keratitis kontraindiziert
Der Wert der Therapie besteht in der
Verkrzung der Erkrankungsdauer
Unbehandelt ist das Perforationsrisi-
ko sehr gro
Initial sollten keine Steroide verab-
reicht werden
Tab. 2 bersicht ber die medikamentse Therapie der herpetischen Keratitis
Erkrankungstyp Virustatika Kortiko-
steroide
Anti-
biotika
Zyklo-
plegika
Pflege
Topisch Systemisch
Epitheliale Keratitis + (+) KI (+) (+)
Stromale Keratitis
Infektis + + (+) + (+)
Interstitiell + (+) + (+)
Disziforme Keratitis + (+) + (+)
Sogenannte metaherpetische Keratitis (+) (+) (+) ++
+ empfohlen, (+) unter besonderen Umstnden empfohlen, KI kontraindiziert.
|

Herpetic Keratitis
15
Die Keratoplastik chaud sollte im Zeitalter der Amnionmembrantransplantation (AMT) auf die
Perforation beschrnkt bleiben. Ansonsten erlaubt die AMT (typischerweise als Multigraft-Sand-
wich) im Akutstadium, die Keratoplastik in das reizfreie und damit prognostisch wesentlich gnsti-
gere Intervall zu postponieren [10, 11, 28]. Eine phototherapeutische Keratektomie (PTK) mit dem
Excimerlaser ist kontraindiziert.
Cave: NSAID sind im Hinblick auf die mgliche Hornhautperforation kontraindiziert!
Interstitielle Keratitis: Immunreaktion ohne replizierendes Virus
Bei der interstitiellen Keratitis dominiert die 7 Entzndungsreaktion im Stroma. Man geht von
einer Kombination aus einer T-Zell-vermittelten und Antigen-Antikrper-Komplement-Kaskade
aufgrund von im Stroma verbliebenem Virusantigen aus [23, 34, 41]. Bislang empfiehlt die Mehrzahl
der Autoren die kombinierte Therapie mit topischen Kortikoiden und Virustatika [33, 34]. Wir wen-
den primr die topische Therapie mit Aciclovir AS (5-mal) und Prednisolonacetat 5-mal an. Beide
Medikamente schleichen wir unter Reduktion der Applikation alle 2 Wochen langsam aus. Eine Do-
sisreduktion sollte nur dann erfolgen, wenn klinisch eine Reizfreiheit (keine entzndliche Infiltration
und dem im Stroma, keine aktiven Keratoprzipitate) zu sehen ist. Bei unzureichendem Effekt und
bei ausgeprgter Keratouveitis oder Sekundrglaukom geben wir systemisch Aciclovir 5-mal 400 mg
fr 4 Wochen mit anschlieender Reduktion auf 2-mal 400 mg ber mehrere Monate (alternativ Va-
laciclovir 3-mal tglich 1 g, spter 2-mal 500 mg). Die langfristige Prophylaxe mit 400 mg Aciclovir
2-mal tglich reduzierte die stromale Rezidivrate von 28 auf 14% [36].
Bei Therapieresistenz knnen auch systemische Steroide kurzfristig erwogen werden. Eine chir-
urgische Therapie ist nicht indiziert. Bei chronischem Verlauf ist topisches Cyclosporin A AT 3-mal
zur Steroideinsparung zu erwgen [9, 21].
Keratitis disciformis
Erscheinungsbild
Etwa jeder 6. Patient mit epithelialem Herpes entwickelt spter eine Keratitis disciformis. Klinisch
findet sich ein fokales, manchmal auch diffuses (!) Stromadem (ohne Infiltrat!) mit meist klarer
Demarkationslinie, mikrozystischem Epitheldem, Descemet-Falten und mehr oder weniger fei-
nen (dendritischen) und speckigen retrokornealen Przipitaten (. Abb. 4). Als Differenzialdiag-
nose muss der retinierte, intrakamerale, flottierende Fremdkrper nach einer Verletzung stets aus-
geschlossen werden. Manchmal erinnern sich Patienten erst nach forcierter Anamnese an einen
derartigen Vorfall.
Bei Begleituveitis zeigen sich bei der Untersuchung mit der Spaltlampe auch Zellen in der Vor-
derkammer und ein positiver Tyndall-Effekt. Eine sekundre okulre Hypertension ist nicht selten.
Typisch fr die herpetische Keratouveitis (. Abb. 5) sind:
F fokale Irispigmentblattdefekte (Differenzialdiagnose: Zustand nach akutem Winkelblockglau-
kom),
F sekundre okulre Hypertension bei Trabekulitis,
F schnelle Synechienbildung,
F spontane Vorderkammerblutungen mglich (durch Bildung von Brckengefen bzw. Vaskuli-
tis/Nekrose in Iris und Kammerwinkel),
F auch als isolierte anteriore Uveitis ohne Keratitis mglich [, ].
Pathogenese der HSV-Uveitis
Die Uveitis wird durch eine zytolytische Virusreplikation im uvealen Gewebe und Trabekelmaschen-
werk ausgelst. Dieser folgt eine antivirale Immunreaktion. Das HSV und sein Genom knnen im
Kammerwasser nachgewiesen werden [5, 26, 31]. Histologisch lassen sich ein zellulres Infiltrat im
Irisstroma und eine Perineuritis und Perivaskulitis nachweisen. Den sektoriellen Irisatrophien und
Blutungen liegt eine entzndlich bedingte okklusive Vaskulitis zugrunde. Die zytolytische Virusrep-
likation im Trabekelendothel fhrt zur okulren Hypertonie. Bei ischmiebedingter Nekrose des Zi-
liarkrpers kann eine persistierende okulre Hypotonie resultieren [18, 19].
Cave: Prostaglandinanaloga sind zur Drucksenkung kontraindiziert, weil sie den Entzndungs-
zustand unterhalten bzw. verstrken knnen.
Die AMT erlaubt im Akutstadium, die
Keratoplastik in das reizfreie und
damit prognostisch wesentlich gns-
tigere Intervall zu postponieren
7 Entzndungsreaktion im Stroma
Die Mehrzahl der Autoren empfiehlt
die kombinierte Therapie mit
topischen Kortikoiden und Virustatika
Bei chronischem Verlauf ist topisches
Cyclosporin A AT 3-mal zur Steroid-
einsparung zu erwgen
Als Differenzialdiagnose muss der
retinierte, intrakamerale, flottierende
Fremdkrper nach einer Verletzung
ausgeschlossen werden
Eine sekundre okulre Hypertension
ist nicht selten
Prostaglandinanaloga sind zur Druck-
senkung kontraindiziert, weil sie den
Entzndungszustand unterhalten
bzw. verstrken knnen
390
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Herpetic Keratitis
CME
tiologie
Neben dem direkten Virusbefall des Endothels (HSV-Ag persistiert im Endothel; [13]) stehen ver-
mutlich immunologische Vorgnge (T-Zell-vermittelte Immunreaktion) im Vordergrund [15, 23].
Therapie
Topische Kortikoide sind wegen der immunologischen Vorgnge therapeutisch unabdingbar [33, 34].
Um ein epitheliales Rezidiv (Reaktivierung der zytolytischen Virusreplikation) zu verhindern, wer-
den gleichzeitig 7 Virustatika (topisch und/oder systemisch) erforderlich.
Der konkrete Therapievorschlag lautet in Abhngigkeit von der Ausprgung einer Keratouvei-
tis oder herpetischen Trabekulitis: Prednisolonacetat (oder Rimexolon) 5-mal, Aciclovir AS 5-mal:
beides alle 2 Wochen, aber nur bei Reizfreiheit, um 1 Applikation pro Tag reduzieren, bei 1-mal Ste-
roid frh und 1-mal Aciclovir-Salbe zur Nacht fr einige Monate belassen. Bei ausbleibender Bes-
serung, Reaktivierung unter Dosisreduktion und anteriorer Uveitis systemische Gabe von Aciclovir,
5-mal 400 mg 4 Wochen, dann Reduktion auf 2-mal 200 mg ber 36 Monate. Alternativ Valaciclo-
vir 3-mal tglich 1 g fr 4 Wochen, dann 2-mal 500 mg ber 36 Monate. Systemische Kortikoste-
roide (z. B. 100 mg Urbason rasch ausschleichend) werden bei therapierefraktrem Krankheitsbild,
schwerer anteriorer Uveitis und/oder Trabekulitis verabreicht.
Tipp: Nichtsteroidale Antiphlogistika spielen bei der Therapie der disziformen Keratitis keine
Rolle.
Metaherpetische Keratitis
Erscheinungsbild
Bei der sog. metaherpetischen Keratitis handelt es sich typischerweise um ein Sptstadium (ausge-
brannter Herpes) mit beeintrchtigter kornealer Innervation und persistierendem Verlust der Horn-
hautsensibilitt und reduzierter Trnensekretion im Sinne einer 7 neurotrophen Keratopathie. Ur-
schlich ist neben der Infektion selbst oft ein Medikamentenschaden (berbehandlungsulkus). Ty-
pischerweise bestehen keine Immunreaktion und keine Virusreplikation!
Es dominieren in erster Linie Oberflchenstrungen analog denen einer neurotrophen Kerato-
pathie anderer Genese. Analog der blichen Klassifikation knnen die Strungen von der Kerato-
pathia superficialis puctata ber die Erosio corneae bis zum metaherpetischen Ulkus reichen
(. Abb. 6).
Therapie
Alle toxischen Augentropfen (Virustatika, Kortikoide und alle Augentropfen mit Konservierungs-
mitteln) werden abgesetzt und stattdessen konservierungsmittelfreie Trnenersatzmittel (am bes-
ten mit Hyaluronsure), pflegende Gele sowie Vitamin-A- oder Dexpanthenol-haltige Augensalben
appliziert. Ein Druckverband zur Nacht kann gnstig sein. Sehr hilfreich ist heute die Option der
7 autologen Serumaugentropfen, die wir 100%ig 5- bis 10-mal pro Tag applizieren. Bei Therapie-
resistenz knnen 7 therapeutische Kontaktlinsen, bei ulzersen Prozessen evtl. Kollagenasehem-
mer sinnvoll sein [27].
7 Virustatika
Nichtsteroidale Antiphlogistika spie-
len bei der Therapie der disziformen
Keratitis keine Rolle
7 Neurotrophe Keratopathie
Die Strungen von der Keratopathia
superficialis puctata knnen ber die
Erosio corneae bis zum metaherpeti-
schen Ulkus reichen
7 Autologe Serumaugentropfen
7 Therapeutische Kontaktlinsen
Abb. 4 8 Klassische disziforme Keratitis (fokale herpetische Endotheliitis) Abb. 5 8 Irispigmentepitheldefekte (im regredienten Licht) als Zeichen
einer herpetischen Keratouveitis
|

Herpetic Keratitis
15
In hartnckigen Fllen fhren wir eine 7 Amnionmembrantransplantation (AMT meist als
Patch), eine Botulinumtoxin-Injektion zur Induktion einer temporren iatrogenen Ptosis oder eine
(temporre) laterale Tarsorrhaphie durch. Heute muss die Bindehautdeckung als Ultima Ratio er-
achtet werden [27].
(Vaskularisierte) stromale Hornhautnarben
Eine mehr oder weniger vaskularisierte stromale Hornhautnarbe mit Stromaverdnnung (. Abb. 7, 8)
stellt das typische 7 Sptstadium nach hufig rezidivierender (ulzerierender) herpetischer Kerati-
tis dar.
Aufgrund der Tiefe der Narbe und der Stromaverdnnung ist eine Excimerlaser-PTK nur selten
sinnvoll wenn berhaupt, dann nur unter systemischem Aciclovir-Schutz. Von einer lamellren Ke-
ratoplastik sehen wir wegen der von Holbach, Asano und Naumann [13] nachgewiesenen Virusper-
sistenz im Endothel eher ab. Aus dem gleichen Grund empfiehlt sich prinzipiell auch die ipsilatera-
le Autorotationskeratoplastik nicht. Mit einer perforierenden Keratoplastik sollte grundstzlich ge-
wartet werden, bis das Auge mglichst ein halbes Jahr lang entzndungsfrei gewesen ist (. Abb. 9).
Erste Erfahrungen zeigen, dass mit der Anwendung von anti-VEGF-Augentropfen eine Reduk-
tion der Neovaskularisation erzielt werden kann [25]. Dies scheint insbesondere bei visusmindern-
der zentraler Neovaskularisation mit Lipidkeratopathie oder zur Vorbereitung auf eine elektive Kera-
toplastik sinnvoll zu sein. Bei rezidivierender Entzndung hat diese Therapie allerdings keinen ber-
zeugenden Langzeiteffekt.
Cave: Ein persistierendes Hornhautdem ist als Hinweis fr einen noch aktiven Prozess zu ver-
stehen, und daher sollte mit einem operativen Eingriff zugewartet werden.
Cave: Nach Keratoplastik sollten keine Steroide ohne Aciclovir-Schutz appliziert werden!
Postoperativ hilft Aciclovir in einer Dosierung von 2-mal 400 mg tglich p.o. fr 1 Jahr ggf. zusam-
men mit einer Langzeittherapie mit topischer Aciclovir-Applikation als Salbe direkt vor dem Schla-
fengehen, ein Wiederaufflammen der Virusinfektion im Transplantat mit/ohne nachfolgende/r Ab-
stoungsreaktion zu vermeiden [40].
7 Amnionmembrantransplanta-
tion
7 Sptstadium
Mit einer perforierenden Keratoplas-
tik sollte gewartet werden, bis das
Auge mglichst ein halbes Jahr lang
entzndungsfrei gewesen ist
Nach Keratoplastik sollten keine Ste-
roide ohne Aciclovir-Schutz appliziert
werden
Abb. 7 8 Alte avaskulre herpetische Narbe meist durchgreifend und mit Stromaverdnnung a im bersichts-
bild, b im Spaltlicht
Abb. 6 9 Ulzerierende neurotro-
phe Keratopathie im Sinne einer
therapieresistenten sog. metaher-
petischen Keratitis
392
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Herpetic Keratitis
CME
Tipp: Grundstzlich sollten Transplantatreaktionen stets kombiniert mit Aciclovir und Steroiden
behandelt werden, weil ein Herpesrezidiv in praxi nie lehrbuchgem (Immunreaktion: Przipitate
auf das Transplantat beschrnkt!) ausgeschlossen werden kann.
Durch organkultiviertes Spendergewebe kann das HSV sehr selten im Rahmen einer 7 Kornea-
transplantation auf den Patienten bertragen werden. Bei jeder primren Transplantatinsuffizienz
sollte an die Mglichkeit einer herpetischen Endotheliitis des Transplantates gedacht werden und der
Patient entsprechend (s. oben) behandelt werden [2, 29].
Prophylaxe von Herpesrezidiven nicht sicher mglich
Eine sichere Prophylaxe von Herpesrezidiven ohne Nebenwirkungen, wie sie oft von besorgten Pa-
tienten gefordert wird, ist nicht mglich. Allerdings haben sich in der Praxis folgende Anstze be-
whrt:
F Aciclovir AS -mal direkt vor dem Schlafengehen,
F knstliche Trnen konsequent,
F -mal mg Aciclovir oral ber Monate,
F (je nach Ausprgung) -mal Prednisolonacetat AT -mal frh
Eine multizentrische Studie besttigte die prophylaktische Ntzlichkeit von niedrig dosiertem 7 Acic-
lovir (400 mg 2-mal tglich oral; [36]), besonders fr die stromale Keratitis. Bei epithelialen HSV-Re-
zidiven unter langfristiger Aciclovir-Gabe sollte bedacht werden, dass eine Virustatikaresistenz vor-
liegen knnte.
Tipp: Die Aciclovir AS zur Nacht wird direkt vor dem Schluss der Lider zum Schlaf appliziert.
Fazit fr die Praxis
F Die HSV-Keratitis ist ein Chamleon. Sie kann vorliegen als infektise epitheliale Keratitis, stro-
male immunologische Keratitis, Endotheliitis, neurotrophe Keratopathie. Nicht selten entstehen
mehr oder weniger dichte Hornhautnarben mit Stromaverdnnung, die mehr oder weniger vas-
kularisiert sein knnen.
F Die genannten Krankheitsbilder knnen aber auch auseinander hervorgehen und nebeneinan-
der bestehen. Eine Uveitis mit/ohne akute okulre Hypertension kann gleichzeitig vorhanden
sein.
F Unterschiedliche Ausprgungsformen der Krankheit erfordern unterschiedliche Therapieanst-
ze. Lokale Kortikosteroide sind bei epithelialer HSV-Keratitis kontraindiziert!
7 Korneatransplantation
7 Aciclovir
Abb. 8 8 Gering vaskularisierte stromale Hornhautnarbe herpetischer
Genese. Hierbei handelt es sich nicht um eine Hochrisikokeratoplastik Abb. 9 8 Perforierende Excimerlaser-Keratoplastik mit 8 Orientierungs-
zhnchen (Pfeile) bei avaskulrer stromaler Hornhautnarbe nach rezidivie-
render ulzerierender stromaler Keratitis herpetischer Genese mit doppelt
fortlaufender Kreuzstichnaht
|

Herpetic Keratitis
15
F Bei der ulzerierenden nekrotisierenden stromalen Keratitis erlaubt die AMT (typischerweise als
Multigraft-Sandwich) im Akutstadium, die Keratoplastik in das reizfreie und damit prognos-
tisch wesentlich gnstigere Intervall zu postponieren.
F Bei der interstitiellen Keratitis dominiert die Entzndungsreaktion im Stroma. Bei der endothe-
lialen Keratitis disciformis sind wie bei der interstitiellen Keratitis topische Kortikoide wegen der
immunologischen Vorgnge therapeutisch unabdingbar.
F Prostaglandinanaloga sind bei okulrer Hypertension im Rahmen einer Keratouveitis herpetica
zur Drucksenkung kontraindiziert, weil sie den Entzndungszustand unterhalten bzw. verstr-
ken knnen.
F Bei der sog. metaherpetischen Keratitis handelt es sich typischerweise um eine Sptstadium
(ausgebrannter Herpes) mit beeintrchtigter kornealer Innervation und persistierendem Ver-
lust der Hornhautsensibilitt und reduzierter Trnensekretion im Sinne einer neurotrophen Ke-
ratopathie.
F Nach einer Keratoplastik hilft Aciclovir in einer Dosierung von 2-mal 400 mg tglich p.o. fr
1 Jahr, ein Wiederaufflammen der Virusinfektion im Transplantat mit/ohne nachfolgende/r Ab-
stoungsreaktion zu vermeiden. Grundstzlich sollten Transplantatreaktionen stets kombiniert
mit Aciclovir und Steroiden behandelt werden, weil ein Herpesrezidiv in praxi nie lehrbuchge-
m ausgeschlossen werden kann.
Korrespondenzadresse
Prof. Dr. B. Seitz
Klinik fr Augenheilkunde und Hochschulambulanz, Universittsklinikum des Saarlandes UKS
Kirrbergerstr. 1, 66424 Homburg/Saar
berthold.seitz@uks.eu
Interessenkonflikt. Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.
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118:16171625
Group (2001) Predictors of recurrent
herpes simplex virus keratitis. Cornea
20:123128
39. Van der Lelij A, Ooijman FM, Kijlstra
A, Rothova A (2000) Anterior uveitis
with sectoral iris atrophy in the ab-
sence of keratitis: a distinct clinical
entity among herpetic eye diseases.
Ophthalmology 107:11641170
40. Rooij J van, Rijneveld WJ, Remeijer L
et al (2003) Effect of oral acyclovir af-
ter penetrating keratoplasty for her-
petic keratitis. A placebo-control-
led multicenter trial. Ophthalmology
110:19161919
41. Verjans GMG, Heiligenhaus A (2011)
Herpes simplex virus-induced ocu-
lar diseases: detrimental interaction
between virus and host. Current Im-
munol Rev (im Druck)
42. Zierhut M, Ziemssen F, Bodaghi B
(2007) Augenbeteiligungen bei HSV-
Infektion. In: Zierhut M, Hansen L,
Jahn G (Hrsg) Viruserkrankungen des
Auges. Kaden, Heidelberg, S 5065
|

Herpetic Keratitis
15
D
Mitmachen, weiterbilden und CME-Punkte sichern durch die Beantwortung der Fragen im Internet unter CME.springer.de
Was ist keine Erscheinungs-
form der rezidivierenden
herpetischen Keratitis?
o
Epitheliale Keratitis (dendritica,
geographica).
o
Stromale Keratitis (nekrotisie-
rend, interstitiell).
o
Endotheliale disziforme Kerati-
tis.
o
Neurotrophe Keratopathie.
o
Serpiginse Keratitis.
Welche Aussage zur epithelia-
len Keratitis trifft nicht zu?
o
Typisch ist die Keratitis dendri-
tica.
o
Im Frhstadium kann man
punkt- oder sternfrmige,
opake Plaques aus geschwol-
lenen Epithelzellen beobach-
ten.
o
Die Lokaltherapie besteht aus
Trifluorthymidin AT, Aciclovir
AS oder Gancyclovir AG.
o
Lokale Kortikosteroide verkr-
zen den Verlauf einer epithe-
lialen HSV-Keratitis.
o
Cidofovir hat sich wegen star-
ker lokaler Toxizitt in wirksa-
mer Dosierung nicht durchge-
setzt.
Welche Aussage zur ulzerieren-
den nekrotisierenden stroma-
len Keratitis trifft nicht zu?
o
Beim herpetischen Ulkus fin-
det sich reichlich aktives Virus
im Stroma.
o
Typischerweise verluft die
Krankheit initial ohne Hypo-
pyon.
o
Typischerweise tritt der Be-
fund einseitig auf, und die
Hornhautsensibilitt ist mehr
oder weniger deutlich herab-
gesetzt.
o
Die phototherapeutische Ke-
ratektomie (PTK) mit dem Ex-
cimerlaser ist der chirurgische
Therapieansatz der ersten
Wahl.
o
Unter lokaler Aciclovir- und
Antibiotikatherapie erlaubt
die Amnionmembrantrans-
plantation (AMT; typischerwei-
se als Multigraft-Sandwich)
im Akutstadium, eine ntige
Keratoplastik in das reizfreie
Intervall zu postponieren.
Welche Aussage zur intersti-
tiellen Keratitis herpetischer
Genese trifft zu?
o
Bei der interstitiellen Kerati-
tis finden sich eine T-Zell- und
Immunkomplex-vermittelte
Immunreaktion im Stroma.
o
Antigen-Antikrper-Komple-
ment-Kaskaden aufgrund von
im Stroma verbliebenem Vi-
rusantigen spielen pathophy-
siologisch keine Rolle.
o
B-Zellen sind essenziell fr die
Entwicklung einer interstitiel-
len HSV-Keratitis.
o
Topische Kortikosteroide sind
kontraindiziert.
o
Die Keratoplastik chaud ist
die chirurgische Therapie der
ersten Wahl.
Welche Aussage zur
HSV-Endotheliitis trifft zu?
o
Sie tritt nie nach einer Keratitis
dendritica auf.
o
Als Keratitis disciformis fin-
det sich typischerweise ein
Stromadem mit feinen und
speckigen retrokornealen Pr-
zipitaten.
o
Differenzialdiagnostisch ist der
retinierte, intrakamerale, flot-
tierende Fremdkrper vllig
abwegig.
o
Eine sekundre okulre Hyper-
tension ist eine Raritt.
o
Ein Prostaglandinanalogon ist
zur Drucksenkung bei HSV-
Endotheliitis Medikament der
ersten Wahl, weil es gleichzei-
tig viruzid wirkt.
Welche Aussage zur HSV-
Endotheliitis trifft nicht zu?
o
Neben dem direkten Virusbe-
fall des Endothels stehen ver-
mutlich immunologische Vor-
gnge im Vordergrund.
o
Topische Kortikosteroide oder
Cyclosporin A sind wegen der
immunologischen Vorgnge
therapeutisch unabdingbar.
o
Um ein epitheliales Rezidiv zu
verhindern, werden gleichzei-
tig Virustatika (topisch und/
oder systemisch) erforderlich.
o
Alternativ zum Aciclovir kann
auch Valaciclovir oral appli-
ziert werden.
o
Nichtsteroidale Antiphlogisti-
ka sind den Kortikosteroiden
bei der Therapie der diszifor-
men Keratitis berlegen.
Welche Aussage zur herpeti-
schen Keratouveitis trifft zu?
o
Typisch sind fokale Irispig-
mentblattdefekte.
o
Eine sekundre okulre Hyper-
tension bei Trabekulitis
kommt so gut wie nie vor.
o
Typischerweise kommt es
nicht zu einer Synechienbil-
dung.
o
Spontane Vorderkammerblu-
tungen sind mit diesem Krank-
heitsbild nicht assoziiert.
o
Topische -Blocker drfen zur
Drucksenkung keinesfalls ein-
gesetzt werden.
Welche Aussage zur sog.
metaherpetischen Keratitis
trifft nicht zu?
o
Typischerweise ist die kornea-
le Innervation beeintrchtigt,
und es dominieren ein per-
sistierender Verlust der Horn-
hautsensibilitt und eine redu-
zierte Trnensekretion im Sin-
ne einer neurotrophen Kerato-
pathie.
o
Typischerweise keine Immun-
reaktion!
o
Typischerweise keine Virusrep-
likation!
o
Analog der blichen Klassifi-
kation knnen die Strungen
von der Keratopathia superfi-
cialis puctata ber die Erosio
corneae bis zum sog. meta-
herpetischen Ulkus reichen.
o
Autologe Serumaugentropfen
sind kontraindiziert, weil sie
zu einem HSV-Rezidiv fhren
knnen.
396
|

Herpetic Keratitis
CME
Welche Aussage zur sog.
metaherpetischen Keratitis
trifft zu?
o
Alle toxischen Augentropfen
(Virustatika, Kortikoide und al-
le Augentropfen mit Konser-
vierungsmitteln) werden ab-
gesetzt und stattdessen kon-
servierungsmittelfreie Trnen-
ersatzmittel, pflegende Gele
sowie Vitamin-A- oder Dex-
panthenol-haltige Augensal-
ben appliziert.
o
Therapeutische Kontaktlinsen
sind kontraindiziert.
o
Lokale Virustatika und Kortiko-
steroide sind fr den Therapie-
erfolg unabdingbar.
o
Die Amnionmembrantrans-
plantation (AMT) ist kontrain-
diziert.
o
Eine Botulinumtoxin-Injektion
zur Induktion einer tempo-
rren iatrogenen Ptosis oder
eine (temporre) laterale Tar-
sorrhaphie ist kontraindiziert.
Welche Aussage zur Kornea-
transplantation bei herpeti-
scher Keratitis trifft nicht zu?
o
Eine mehr oder weniger vas-
kularisierte stromale Horn-
hautnarbe mit Stromaverdn-
nung stellt das typische Spt-
stadium nach hufig rezidivie-
render (ulzerierender) herpeti-
scher Keratitis dar.
o
Mit einer perforierenden Kera-
toplastik sollte grundstzlich
gewartet werden, bis das Au-
ge mglichst ein halbes Jahr
lang entzndungsfrei gewe-
sen ist.
o
Nach Keratoplastik sollten kei-
ne Kortikosteroide ohne Acic-
lovir-Schutz appliziert werden!
o
Postoperativ kann Aciclovir
in einer Dosierung von 2-mal
400 mg tglich p.o. fr min-
destens 1 Jahr das Risiko eines
HSV-Rezidivs reduzieren.
o
Die primre Transplantatinsuf-
fizienz kann nicht Folge einer
HSV-Infektion sein.
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12 Monate auf
CME.springer.de verfgbar.
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erfahren Sie unter
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The incidence of microbial keratits varies in different parts of the world. In USA the
incidence is 11 to 30 cases in 100000 people [1-2]. The most frequent causative organisms
in bacterial keratitis in developed countries are Staphylococcus spp. ~ 30%-60%,
Pseudomonas spp. ~15%-30% and Streptococcus. spp. ~15%.
Bacterial Keratitis rarely occurs in normal eyes because of the human corneas natural
resistance to infection. Intact epithelium is the most important barrier to microbial
invasion, while epithelial defect is a major risk factor for infection. While in the developed
countries contact lens wear and ocular surface diseases are the most commom reasons
for infections [~25-50% each], trauma is the most common reason in the developing
countries [3]. Systemic disorders such as immunosuppression [HIV, etc] DM,
ch. alcoholism or long hospitalization are also risk factors for microbial keratitis.
The major factors inuencing the nal outcome of the infection are
1. virulence of the bacteria: its ability to invade or resist host defense and to produce
tissue damage and
2. the tissue response including non-cellular [cytokines, antibody, enzymes] or cellular
[T-cell lymphocytes polymorphonuclear neutrophils, macrophages] responses.
The infection may rapidly progress such as in pseudomonas or gonococcal infections
and cause corneal perforation and endophthalmitis within 24 hours. It can also take an
indolent course as in mycobacterial infections. It may end with minimal or signicant
corneal scarring and signicant loss of vision when the visual axis is involved.
Clinical assessment at the rst examination has to be properly done. Detailed corneal
evaluation and clinical drawing are important and should include the size of epithelial
defect, the size and depth of the inltrate, the stromal edema intensity and size and
the stromal loss. AC inammation has to be recorded as well as secondary glaucoma
if it exists.
The non-severe ulcers are small, located in the supercial cornea, they progress slowly
and the risk of perforation is minimal. The severe ulcers are large [>6 mm] involving the
inner third of the cornea, they may progress very rapidly and cause corneal perforation.
The differential diagnoses of bacterial keratitis includes: HSK, neurotrophic keratitis,
marginal ulcerative/inltrative keratitis, mycotic keratitis and others.
Bacterial keratitis
Joseph Frucht-Pery, Israel 16
Bacterial keratitis
It is a good practice to take smears and cultures in order to identify the pathogen.
However only in two-thirds of cases the culture yield positive. It is extremely important
to take cultures when the infection is severe or non-responding to treatment or when
non-bacterial infections are considered. The majority of community-acquired infections
are successfully treated empirically without smears [4].
Once the clinical diagnosis is made, the immediate goal is to treat aggressively with
frequent topical antibiotics in order to eliminate the pathogen(s) and to prevent host
tissue destruction, scarring and neovascularization and to preserve corneal transparency
and function. It is suggested to hospitalize the patients with severe and moderate
corneal ulcers and to treat aggressively with intensive broad spectrum antibiotics. For
mild infections outpatient care with close monitoring is the preferred practice.
In hospitalized cases the initial treatment is impiric, before the type of bacteria is
identied. Broad-spectrum fortied antibiotics such as fortied Cefazolin 50mg/
ml and Tobramicin 14mg/ml [or Gentamicin] are used to cover gram positive and
negative bacteria. Other combinations may also include Vancomycin, Ceftazidine or
Fluoroquinolone. Initial loading of topical fortied antibiotics is done by 5 applications
of 1 drop of each drug every 2 min. During the rst 24-48 hours the drugs are applied
hourly, day and night. After 2 days the dose of medications may be decreased slowly,
depending upon initial clinical ndings and clinical judgment. Recently some studies
reported that 4th generation of Fluoroquinolones may be as effective as combined
broad spectrum therapy for corneal ulcers [5]. In mild corneal ulcers commercial
Fluoroquinolones such as drops of gatioxacin 0.3% and moxioxacin 0.5% can
be applied X 2h, and the patients examined in the clinic every other day. Within the
rst 48-76 hours of treatment the pain decreases, the inltrate consolidates, and the
epithelialization begins. One can stop antibiotics after complete epithelialization has
occurred and the inltrate signicantly decreased. However, in some bacteria such as
P. aeruginosa, longer treatment may be required.
In cases of clinical improvement with initial antibiotics there is no need for alternative
drugs regardless if bacteria were isolated or not. Modication of therapy is considered
when after a few days of initial treatment there is a progression of stromal
inltration or progression of intraocular inammation. One should consider drug
resistance, multibacterial infection and rare pathogens such as mycobacteria, fungi
or acanthamoeba. In these cases one should reevaluate the case including cessation
of therapy, reculturing and treating according to cultures outcome. Recently, some
reports suggested the adjunctive use of crosslinking in some cases.
Adjunctive therapy with corticosteroids is still controversial. When the clinical
Bacterial keratitis
16
improvement is obvious there is no need to add steroids. However, when the inltrate
is central or inammation is signicant, some will add steroids. Steroids are safer to
apply in gram+ vs gram- infections. It is important always to use steroids under the
cover of antibiotics.
References
[1] Pepose JS. et al. Divergent approaches to the management of corneal ulcers.
Am. J Ophthalmol. 1992; 630-2.
[2] McRae S. et al. Corneal ulcers and adverse reaction rates in pre-marked contact
lens stadies. Am. J Ophthalmol. 1991; 457-65.
[3] Predisposing Factors for Microbial Keratitis in Paris. Bourcier T. et al. Bacterial
keratitis: predisposing factors, clinical and microbiological review of 300 cases.
Br. J Ophthalmol. 2003; 834-8
[4] McLeod SD. et al. The role of smears, cultures, and antibiotic sensitivity testing in
the management of suspected infectious keratits. Ophthalmology 1996;23-8
[5] Costantinou M. et al. Clinical efcacy of moxioxacin in the treatment of bacterial
keratitis. Ophthalmology 2007;1623-30
Prof. Joseph Frucht-Pery
Hadassah University Hospital
Jerusalem, Israel
Fungal keratitis
Introduction
Fungal keratitis is caused by yeast (e.g. Candida) or molds (lamentary fungi). Yeasts
grow as creamy, opaque pasty colonies on culture media. Molds exhibit feathery or
powdery growth on the surface of culture media (Aspergillus, Fusarium).
Epidemiology
Fungal keratitis was rst described by Leber in 1879, a case of Aspergillus. In the
industrialized world fungal keratitis is rather uncommon, but is one of the major
causes of keratitis in tropical areas of the world. The incidence varies according to the
geographical location: in temperate regions yeasts will prevail, whereas in the tropics
Aspergillus and Fusarium are more common. The incidence of fungal keratitis is on the
rise over the past 30 years for several reasons: widespread use of antibiotics; increased
prevalence of immune suppressed patients; better isolation techniques; and use of
multipurpose no-rub contact lens solutions. A recent outbreak of Fusarium keratitis
was reported in the USA, in Singapore, and in Europe (U.K., Belgium, and France),
probably related to the use of no-rub multipurpose products (BL ReNu Moisture Lock).
Pathophysiology
Fungi gain access into the corneal stroma through a defect in the epithelium. The
organisms can penetrate intact descemet membrane, proliferate in the anterior
chamber and spread to the posterior segment causing fungal endophthalmitis.
Risk factors
corneal trauma with vegetable material (plant or soil matter)
corneal trauma related to contact lens wear
therapeutic lenses (candida)
refractive lens wear (fusarium)
topical steroids (but also systemic steroids)
corneal surgery (PKP, RK)
chronic keratitis (HSV, HZV, VKC)
immunosuppressive disease
Fungal and chlamydial infections
Philippe Kestelyn, Belgium
17
Clinical presentation
A fungal keratitis shows fewer inammatory signs and symptoms during the initial period
than a bacterial keratitis. As the keratitis progresses, intense suppuration may develop and
the lesions may resemble bacterial keratitis. At this point rapidly progressive hypopion and
anterior chamber inammatory membranes will appear. If untreated extension in to the
anterior chamber will occur and the fungus may invade the iris or the posterior chamber!
The clinical picture is different according to the causative organism. Filamentous
fungal keratitis often follows corneal trauma. The lesion presents as a gray-white, dry-
appearing inltrate that may appear elevated. It has irregular feathery of lamentous
margins with occasionally multifocal or satellite inltrates. The initial break in the
epithelium may have healed so that a deep stromal inltrate is observed in the presence
of an intact epithelium. Endothelial plaque and/or hypopion formation may also occur
if the inltrates are sufciently deep or large.
The picture is somewhat different in yeast fungal keratitis. Here the normal microora
invades a preexisting epithelial defect. Most cases tend to remain supercial and
present as supercial white raised colonies in a structurally altered eye. Occasionally
deep invasion may occur with suppuration resembling bacterial keratitis.
In summary the most important clues to the diagnosis of fungal keratitis are the
protracted time course, the discrepancy between the inltrate and the level of
inammation, the presence of a plaque against the endothelium, the shape of the
hypopion, and the association of intact epithelium over a deep inltrate. When in doubt,
confocal microscopy may be a useful technique. Confocal microscopy is a non-invasive,
high resolution technique which allows rapid detection of fungal hyphae in the cornea
long before laboratory cultures give conclusive results. If performed by an experienced
observer a sensitivity of 50% and a somewhat higher specicity are obtained.
Laboratory examinations
Smears, culture, histopathology and PCR are all potential techniques to consolidate the
clinical suspicion. Smears with conventional staining have a sensitivity of about 50% to 80%.
Drawbacks of conventional stains include the frequent presence of background artifacts
with potassium hydroxide (KOH), the weak staining (yeast) and interference with
background staining for the Gram stain, and the need for an expensive uorescence
microscope for calcouor white staining. Therefor there is a need for a new staining
technique that is rapid, easy to perform, highly sensitive and specic, and that can be
done with a routine microscope. [chlorazol black E mounts? very rapid (30 secs), not as
sensitive as gram or lactophenol staining, more specic].
17
Culture is performed on Sabouraud and blood agar at 25C. Most fungi can be isolated
within 48-96h of incubation, but at least 25% require an incubation period of up to
three weeks.
Histopathology a corneal biopsy can be considered when corneal smears and cultures
are negative at 48-72 hours, in a patient who is strongly suspected of having a fungal
infection or who is not improving on the initial, broad-spectrum antibacterial therapy.
PAS and Grocott are classic stains for histopathology specimens. Fungal specic
antibodies may be used as well.
PCR detects microbial DNA in the majority of fungal corneal ulcers and identies
potentially pathogenic organisms in a high proportion of culture-negative cases. The yield
and concordance with culture are higher for fungal than bacterial ulcers. Unfortunately,
there is a very high rate of false positives for apparently nonpathogenic organisms.
Treatment
The most important antifungal agents are the polyene and the azole components:
polyenes
amphotericine B 0,15% (Candida)
natamycine 5% (only commercially available drop)
azoles
econazole 2%
voriconazole 1% (Fusarium)
Different routes of administration have been tried:
topical
hourly
with frequent (every other day) debridement of the epithelial layer
intracamerular
subconjunctival
intrastromal injection
Surgical therapy is an option when medical treatment fails. If the infection extends
into the anterior chamber under therapy, debulk with early PKP (use of UBM/visante
OCT), remove and culture or perform pathology of all infected tissue. Rinse the
anterior chamber and clean the instruments. Interrupted sutures are recommended.
The postoperative management should include topical and systemic antifungals,
cyclosporin A and no steroids in the immediate postoperative period, until adequate
control of infection is assured.
Adult inclusion conjunctivitis
Introduction
The chlamydiae are nonmotile, gram-negative bacteria that are metabolically decient
in their ability to synthesize ATP. Their dependency on an exogenous source of
energy explains their obligate intracellular life cycle. Chlamydiae undergo a biphasic
development cycle, forming distinctive intracellular inclusions that permit identication
by light or uorescence microscopy.
The genus Chlamydia is composed of four species: Chlamydia trachomatis, Chlamydia
pneumoniae, Chlamydia psittaci, and Chlamydia pecorum. The different serovariants
or serovars of Chlamydia trachomatis are responsible for the following diseases:
serovars A, B, Ba, and C cause trachoma, a chronic and potentially blinding
keratoconjunctivitis endemic in many developing countries where poverty goes along
with decient sanitation and poor hygiene; serovars D to K are the cause of one of the
most common sexually transmitted diseases worldwide and both adult and neonatal
inclusion conjunctivitis arise from transfer of bacteria from the genitalia to the eye;
serovars L1, L2, and L3 are the etiological agent in venereal lymphogranulomatosis. The
observation under the microscope of inclusion bodies in conjunctival cells infected with
Chlamydiae explains the term inclusion conjunctivitis (18, 19).
Epidemiology
Adult inclusion conjunctivitis is due to Chlamydia trachomatis serovars D, E, F, G,
H, I, J, and K. The bacterial reservoir is the genital tract of the sexually active adult.
Urogenital chlamydiosis is the most common STD in the developed world and accounts
for approximately 3 million new cases each year in the United States (4). The highest
prevalence is found in young, sexually active adults. The disease accounts for 40%
to 50% of all cases of non-gonococcal urethritis in men (10).According to the WHO
chlamydial prevalence rates in pregnant women range from 2.7% to 8% in Europe (24).
Fifty to 70% of genital infections are asymptomatic and less than 10% of prevalent cases
are diagnosed (20,21). The genital infection causes urethritis, cervicitis, endometritis,
salpingitis, and perihepatitis in women and is a major cause of sterility. In men it causes
balanitis, urethritis, prostatitis, and epididymitis (3). The rising prevalence of chlamydial
infection and its association with an increased risk of cervical cancer, sterility and
acquisition of HIV brings up the question whether a comprehensive European-wide
screening policy is needed (16).
Transmission to the eye occurs in the vast majority by autoinoculation with infected
17
genital secretions from either the patient or his partner. Direct infection from the eye
of one patient to the eye of another is possible but uncommon and could account for
the small number of affected patients without concomitant genital disease. Indirect
infection from inadequately disinfected swimming pools and from contact with
contaminated inert surfaces has been described but is rare (23, 11, 13).
Clinical picture
The incubation period of adult inclusion conjunctivitis varies from 2 days to 3 weeks. It
starts as a unilateral, papillary conjunctivitis with mucopurulent secretions and a swelling
of the ipsilateral premandibular lymph glands. Later on typical follicules will develop on
the upper and the lower tarsal plate. Swelling and inltration of the subconjunctival
tissue may obscure the vertical vessels of the upper tarsal plate mimicking the classic
picture of inammatory trachoma at this stage (1, 6). Pseudomembrane formation seen
in neonatal inclusion conjunctivitis is not seen in the adult form. Involvement of the
second eye may ensue, but is not always present.
Corneal involvement includes discrete pannus formation, supercial punctate
keratopathy, and more seldom marginal inltrates (7). Frank corneal neo-vascularisation
and conjunctival scarring typical of trachomatous keratoconjunctivitis are not observed
in adult inclusion conjunctivitis.
The initial phase of acute infection is often missed and most patients will present with
a chronic red eye. They will complain of mucopurulent secretions and sticky eyes in the
morning, a foreign body sensation and photophobia. Inspection at this stage will show
a papillary and follicular conjunctival reaction, eventually discrete corneal changes, but
the inammatory swelling of the subconjunctival tissue will no longer be present (8).
The differential diagnosis of adult inclusion conjunctivitis is in the rst place the
differential diagnosis of chronic follicular conjunctivitis and should include the following
entities: classic trachoma, adenoviral epidemic keratoconjunctivitis, herpes, Newcastle
disease virus conjunctivitis, chronic allergic conjunctivitis, acnea rosacea and chronic
blepharitis, and even oppy eyelid syndrome (15).
Laboratory diagnosis
The clinical diagnosis of adult inclusion conjunctivitis may be difcult and therefore
identifying chlamydiae in conjunctival scrapings or direct diagnosis may be very useful.
Because chlamydiae are obligate intracellular pathogen, the scraping should include
infected cells. Therefore, specimens that contain only exudate or secretions but no
cells are unsatisfactory. For conjunctival specimens any purulent exudate should be
removed before collecting epithelial cells by vigorously rubbing a dry swab over the
everted palpebral conjunctiva. The specimen is then transferred to a transport medium
that makes it possible to perform both culture and DNA amplication techniques from
a single swab. The lilelyhood of isolation is optimized if specimens are refrigerated
immediately after collection at 2 to 8 Celsius and kept at this temperature during
transport. The delay between collection and laboratory processing should be less than
48 hours. Specimens that cannot be processed within 48 hours may be frozen at 70
Celsius, but this is likely to result in a 20% loss of viability. Freezing at 20 Celsius
should be avoided altogether (2).
The following laboratory methods are available to identify chlamydial infection:
1. Culture methods
2. Nonculture methods
a/ Direct cytologic examinaton to identify inclusion bodies by staining methods
b/ Identication of chlamydial antigen
c/ nucleic acid amplication techniques (NAATs)
3. Serologic tests
Culture methods
Culture methods on viable cells used to be the gold standard for the diagnosis of
chlamydial infection. They have lost this status with the advent of nuclear acid
amplication techniques or NAATs during the last decade because of their
relative insensitivity: culture methods have a specicity that approaches 100% ,
but their sensitivity is only 70 to 85% in comparison with NAATs (cfr. infra). Other
disadvantages of culture techniques include the requirement for a stringent cold chain
for transportation of specimens, high cost, high level of technical expertise and a time
delay to obtain results from 3 to 7 days.
Nonculture methods
a. Staining of conjunctival scrapings with Giemsa to demonstrate typical
chlamydial inclusion bodies is not recommended for the diagnosis of adult
inclusion conjunctivitis due to its lack of sensitivity (17). Moreover, recognition
of chlamydial inclusions requires considerable expertise.
b. Antigen detection methods include the DFA test based on direct visualization
of the chlamydial organism by staining with uorescein-labeled specic
antibody, the EIA test based on immunochemical detection of antigen, and
the DNA hybridization probe to detect chlamydial rRNA. All these tests are
17
commercially available and commonly used (Microtrak DFA, Behring Diagnostics;
Chlamydiazyme, Abbott Diagnostics; Microtrak EIA, Behring; PACE 2, Gen-
Probe).
c. The development of NAATs has been the major advance in the eld of
chlamydial diagnosis in the last decade. A number of commercial tests are
available: polymerase chain reaction or PCR tests (Amplicor, Roche Diagnosts),
strand displacement amplication (SDA, Becton Dickinson), and ligase chain
reaction (LCR, Abbott Laboratories). They all combine exquisite sensitivity with
very high specicity and are considered the new gold standard in the diagnosis
of chlamydial disease (12).
Serologic tests
Serologic tests are general not useful in the diagnosis of genital tract infection caused
by Chlamydia trachomatis. Antibodies elicited by infection are long lived and a positive
titer will not distinguish a previous from a current infection. The presence of IgM is
an unreliable marker of acute infection since it is often not present. The presence of
antichlamydial IgG in tears might be helpful for diagnosis in patients with suspected
chlamydial conjunctivitis, since IgG seems to be absent in tears from patients with only
urethritis (9).
Treatment
Since adult inclusion conjunctivitis results from autoinfection in patients with genital
disease in the vast majority of cases, systemic treatment is mandatory to prevent
extraocular morbidity and ocular reinfection. The classic treatment includes oral
doxycycline, 100 mg twice a day for one week; or in pregnant women erythromycin,
500 mg four times a day for one week. Azythromycin, 1 g as a single dose is equally
effective, more patient friendly, but more expensive (14). Oral uoroquinolones are also
effective agents against C. trachomatis. Screening and treatment of infected sexual
partners of the patients as well as counseling about safe sex should be part of the
comprehensive care (5).
The CDC does not recommend routine test-of-cure visits during the post treatment
period. If for some reason a test-of-cure seems indicated, only culture methods should
be used. NAATs are less useful for this indication as they may pick up residual DNA in
the early post treatment period in patients whose infection has been cured (2).
Summary for the clinician
urogenital chlamydiosis due to C. trachomatis serovars D-K is the most
frequent STD in the industrialized world
although often asymptomatic, it is responsible for signicant morbidity
adult inclusion conjunctivitis arises from transfer of bacteria from the genitalia
to the eye (autoinoculation)
the prevailing clinical presentation is that of a chronic red eye with a moderate
amount of mucopurulent secretions
the differential diagnosis includes the different causes of follicular and chronic
conjunctivitis, uni- or bilateral
the clinical suspicion is conrmed by laboratory methods
nucleic acid amplication tests have the highest sensitivity and specicity and
have supplanted culture methods as the gold standard
systemic administration of doxycycline, erythromycin, azythromycin or
uoroquinolones is the treatment of choice
sexual partners of the patient should be screened as well
counseling about safe sex should be provided to the patient and his partners
Trachoma
Trachoma is the second or the third most important cause of blindness in the world
(either before or after glaucoma). According to WHO estimates 150 million people are
infected and 5.5 million people are blinded by this disease. Blinding trachoma is the
end result of repetitive infections that cause scarring of the tarsal plate and trichiasis
which predisposes the corneal surface to micro-erosions and subsequent bacterial
superinfections.
Risk factors for the disease:
- lack of personal hygiene
- absence of pit latrines
- keeping cattle in the immediate vicinity of the house
- crowding
- presence of waste and feces in the open air
All these factors will attract ies that feed on the nasal secretions and the tears of
children and carry the infection from one person to the other. Children will get the
infection at an early age and will reinfect the adults taking care of them, mainly
women (mother, grandmother, elder sister). Reinfection of the adults creates a cycle
of repetitive infections leading to chronic inammation of the tarsal plate. This chronic
inammation will cause scarring and contraction of the inner lamellae of the tarsal plate.
17
Inward bowing of the upper eyelid causes trichiasis: the cilia of the upper eyelid will rub
against the corneal surface. Chronic rubbing of the cilia will cause micro-erosions and
subsequent bacterial superinfections. The cornea will gradually become opaque and
vascularized as a result of the repetitive infections.
Simplied WHO classication of trachoma
The WHO has proposed a simplied classication of trachoma that is useful
for the diagnosis and the staging of the individual patient. Moreover it is a
useful tool to assess the importance and the dynamics of the disease in the
community.
TF Trachomatous Inammation Follicular (TF)
Tat least 5 follicles on the at surface of the upper tarsal plate
TI Trachomatous Inammation Intense (TI)
Inammatory thickening of the tarsal conjunctiva that obscures
at least half of the normal deep tarsal vessels
TS Trachomatous Scarring Scarring
Citracial trachoma, presence of ne white lines in the tarsal
conjunctiva
TT Trachomatous Trichiasis
At least one eyelash rubs on the eyeball
CO Corneal Opacity
Opacity of the cornea extending over part of the pupil
Screening of a population for trachoma with the aid of this grading system allows the
following conclusions:
- the number of individuals with TF is a measure for the incidence (early infection
= new cases)
- the number of individuals with TI is a measure for the prevalence of active
disease; both TF and TI individuals need antibiotic treatment
- the number of individuals with TT is a measure for the magnitude of the
population at risk of becoming blind; trichiasis surgery should be made available
to this group
- the number of individuals with CO is a measure for the importance of trachoma
as a blinding disease in that particular community
Differential diagnosis:
- with vernal keratoconjunctivitis
- with ocular pemphigoid
Medical treatment (TF and TI)
- Tetracycline ointment BID for 6 weeks
- Azythromycine eyedrops BID for 3 days
- Doxycycline 100 mg per day for 3 weeks
- Tetracycline 250 mg QID for 3 weeks
- Azythromycine 1G as a single dose treatment
Surgical treatment
- Epilation
- Electrolysis
- Cryoablation
- Trichiasis surgery (bilamelllar tarsal rotation procedure)

References
1. Bialasiewicz AA (1994) Ocular features of oculogenital Chlamydial infections.
Bialasiewicz AA, Schaal KP. Infectious diseases of the eye. Aeolus PRESS. 561-575
2. Blythe M, Katz BP, Batteiger BE, Ganser JA, Jones RB (1992) Recurrent genitourinary
chlamydial infections in sexually active female adolescents. J Pediatr 121:487-493
3. Cates W Jr, Wasserheit JN (1991) Genital chlamydial infections: epidemiology and
reproductive sequelae. Am J Obstct Gynccol 164:1771-1781
4. Centers for Disease Control and Prevention: MMWR Morb Mortal Wkly Rep (2005)
Reporting of chlamydial infection-Massachusetts, January-June 2003, 54(22):558-560
5. Centers for Disease Control and Prevention: MMWR Recommendations and
Reports (2006) Sexually transmitted Diseases Treatment Guidelines 2006
55(RR11):1-94, p. 54.
6. Creuzot-Garcher C, Guerzider V (2001) Chlamydial conjunctivitis. In: Hoang-Xuan
T, Baudouin C, Creuzot-Garcher C, Inammatory diseases of the Conjunctiva,
Georg Thieme Verlag Stuttgart-New York, p 121-132
17
7. Darougar S, Viswalingam M (1988) Marginal corneal abscess associated with
adult Clamydial ophthalmia. Br J Ophthalmol 72:774-777
8. Dawson C (1998) Chlamydial diseases. Kaufman HE, Barron BA, McDonald MB.
The cornea. Butterworth-Heinemann, p 315-329
9. Haller EM, Auer-Grumbach P, Stuenzer D, Kessler HH, Pierer K, Muellner K, Zenz H
(1996) Detection of antichlamydial antibodies in tears. Ophthalmology 104:125-130
10. Holmes KK, Handseld HH, Wang SP, Wentworth BB, Turck M, Anderson JB, Alexander
ER (1975) Etiology of nongonococcal urethritis. N Engl J Med 292:1199-1205
11. Jones BR (1964) Ocular syndromes of TRIC virus infection and their possible genital
signicance. Br J Vener Dis 10:3-18
12. Martin DH, Nsuami M, Schachter J, Hook EW 3
rd
, Ferrero D, Quinn TC, Gaydos
C (2004) Use of multiple nucleic acid amplication tests to dene the infected-
patient gold standard in clinical trials of new diagnostic tests for Chlamydia
trachomatis infections. J Clin Microbiol 42(10):4749-4758
13. Novak KD, Kowalski RP, Karenchak LM, Gordon YI (1995) Chlamydia trachomatis
can be transmitted by a non porous plastic surface in vitro. Cornea 14:523-526
14. Rahangdale L, Guerry S, Bauer HM (2006) An observational cohort study of
Chlamydia trachomatis treatment in pregnancy. Sex Transmit Dis 33:106-110
15. Rapoza PA, Quinn TC, Tery AC, Gottsch JD, Kiessling LA, Taylor HR (1990) A
systematic appraoach to the diagnosis and treatment of chronic conjunctivitis .
AM J Ophthalmol 109:138-142
16. Roberts TE, Robinson S, Barton P, Bryan S, Low N, Chlamydia Screening Studies
(ClaSS) Group (2006) Screening for Chlamydia trachomatis: a systematic review
of the economic evaluations and modeling. Sex Transm Infect 82(3):193-200,
discussion 201
17. Schachter J (1980) Chlamydiae In: N.R. Rose and H. Friedman (ed.), Manual of
clinical microbiology , 2
nd
ed. American Society for Microbiology, Washington,
D.C., p 701-706
18. Schachter J, CR Dawson (1978) Human chlamydial infections, PGG Publishing Co.,
Littleton, Mass, p. 187
19. Schachter J, Stamm WE (1995) Chlamydia, In: Murray PR, Pfaller MA, Tenover
FC, Yolken RH (ed), Manual of clinical microbiology, 6
th
ed. American Society for
Microbiology, Washington DC, p 669-677
20. Schachter J, Stoner E, Moncada J (1983) Screening for chlamydial infections in
women attending family planning clinics. West J Med 138:375-379
21. Stamm WE, Cole B (1986) Asymptomatic Chlamydia trachomatis urethritis in men.
Sex Trans Dis 13:163-165
22. Stamm WE, Koutsky A, Benedetti JK, Jourden JL, Brunham RC, Holmes KK (1984)
Chlamydia trachomatis urethral infections in men. Prevalence, risk factors, and
clinical manifestations. Ann Intern Med 100:47-51
23. Weinstock H, Dean D, Bolan G (1994) Chlamydia trachomatis infections. Sexually
transmitted diseases in the AIDS era, part II. Infect Dis Clin North Am 8:797-819
24. www.who.int/docstore/hiv/GRSTI/003.htm
Prof. Philippe KESTELYN
University Hospital Gent
Gent, Belgium
18/03/2013
1
Acanthamoeba keratitis
John Dart
NIHR-BMRC for Ophthalmology
Moorelds Eye Hospital
The InsFtute of Ophthalmology, UCL

Current strategies for inflammatory and infectious
diseases of the cornea EUPO Course 2013
Disclosure Statement of Financial
Interest
John Dart DOES NOT have a
financial interest/arrangement or
affiliation with one or more
organisations which could be
perceived as a real or apparent
conflict of interest in the context of
the subject of this presentation.
John Dart, United Kingdom 18
18/03/2013
2
90% of CL related Acanthamoeba
keratitis is avoidable
CL use factors related to AK
Disinfection system failures
Swimming or Showering in CL
Poor Disinfection Practice:
Solution reuse, use of non sterile water
Infrequent lens case replacement
Environmental factors related to AK
Trauma in an agricultural setting
Exposure to lake, sea or well water

Dont forget AK in non CL users
AK pathogenesis
Importance of cysts vs trophozoites 1970s
Extra-corneal invasion rare (4 cases) 90s
Inflammatory complications of AK in the
absence of viable organisms 1993 2008
Importance of innate immune response & role
of macrophages (animals)1992-8

18
18/03/2013
3
The clinical features of Acanthamoeba keratitis
1 Epithelial disease
2 Perineural infiltrates
3 Stromal disease
4 Ulceration
5 Ring abscess
6 Secondary infection
7 Scleritis
Diagnosing Acanthamoeba keratitis
1 Characteristic clinical features
Perineurals
2 Microscopy
Wet preps
Stained smears
3 Confocal microscopy
Immediate, sensitivity
and specificity 70-90%
Viability undetermined
4 Culture
5 Histology
Viability cannot
be assessed
6 PCR
Use whats available lab. diagnosis for unresponsive cases
18/03/2013
4
How can we treat Acanthamoeba
keratitis?
Which drugs
How to use the drugs
Should we control corneal inflammation
Treating limbitis & scleritis
Managing pain
Treating glaucoma and hypotension
Treating persistently culture positive
keratitis
Which drugs for Acanthamoeba keratitis?
Must be cysticidal Choice based on in vitro
cysticidal data & experience
2 3
PHMB
CHX
No role for topical
amino-glycosides or
azoles (except
possibly voriconazole)
18
18/03/2013
5
Which drugs for Acanthamoeba keratitis?
Diamidines (0.1%) drops
Propamidine (Brolene)
Hexamidine (Desomedine)
Biguanides (0.02% drops)
Polyhexanide (PHMB)
Chlorhexidine
Therapy is effective IF definitive treatment is
started within 3-4 weeks from the onset
Potential new therapies
Cationic amidoamines
Voriconazole
X-linking
How to use the drugs
Drug administration
Hourly day and night for 2 days
Hourly day only for 3 days
Then reduce to 6x daily taper to 4x
Drug toxicity common
Controlling corneal inflammation
Defer topical steroids for 2 weeks or more
For deteriorating inflammation & pain
Continue anti-amoebics for 4 weeks after
steroids discontinued
18/03/2013
6
Treating limbitis & scleritis
NSAIDs (Flurbiprofen)
Frequent steroid drops
Oral Prednisolone 80mg/day
Oral Ciclosporin 5-7.5mg/kg
Oral Vori or Itraconazole
Managing pain
Control inflammation
NSAIDs (Flurbiprofen)
Analgesia (Codeine)
Retrobulbar alcohol
Enucleation
Treating persistently
culture positive keratitis
Occurred in 6% of 180 Cult + cases
Switch diamidines and biguanides
Increase PHMB from 0.02 to 0.06%
Use chlorhexidine 0.2%
Add oral Voriconazole
Cryotherapy
Superficial keratectomy
The role of CXL uncertain
Keratoplasty
Recurrence common in 10-21 days
Inflammation may be exacerbated
Persisting inflammation does not always equate to viable
organisms (3/16 biopsies containing cysts cult positive)
Late diagnosed
patients
18
John Dart
NIHR-BMRC for Ophthalmology
Moorelds Eye Hospital
The Institute of Ophthalmology, UCL
18/03/2013
7
Acanthamoeba keratitis challenges
Considering the diagnosis early (within 3 wks)
Increasing the availability of confocal and
PCR for diagnosis
Preventing new cases by educating patients
and physicians
Better cysticidal therapy
Understanding reasons for in vivo failures
Understanding host organism interactions
Treating the host inflammatory response
FURTHER READING: Dart J et al. Acanthamoeba keratitis:
diagnosis and treatment update 2009. A perspective. Am J
Ophthalmol 2009 148(4):487-499
Ocular rosacea is frequent and its morbidity is far from negligible. Effective treatments are
available, but inappropriate treatment can lead to sight-threatening ocular and iatrogenic
complications. It can remain isolated, with no cutaneous involvement (acne rosacea),
or can precede the cutaneous signs sometimes by several years. Ophthalmologists
often fail to identify the cutaneous signs of rosacea, because rosacea is dened by
highly pleomorphic criteria. They consist of a combination of signs visible on the face:
telangectasia, ushing, and papules or pustules. The rhinophyma is highly evocative, but
it is rare and occurs only in certain advanced forms. Rosacea generally affects middle-
aged adults of all races, between 40 and 60 years, but can also occur during childhood.
Meibomian dysfunction is one of the key mechanism of ocular rosacea. It is responsible for
tear lm instability, excessive tear evaporation, and a dry-eye syndrome. The lipases produced
by the bacteria of the commensal ora appear to be indirectly responsible for meibomitis,
by favoring lipolysis of the cholesterol esters present in meibum and the release of toxic
free fatty acids. Direct lipase toxicity and an immune reaction to an exotoxin produced by
commensal bacteria may also play a role in the inammation associated with ocular rosacea.
The symptoms of ocular rosacea are usually mild, consisting of blepharitis and chronic
conjunctivitis, which are linked together. The eyelid margins are hyperemic, irregular
and thickened. The orices of the meibomian glands can be occluded by yellowish,
solidied meibum plugs. Digital pressure to the lid margin expresses a more or less
viscous and cloudy, sometimes granular or doughy material from the meibomian
orices. There is often a history of chalazia. Ocular manifestations are nonspecic, and
may include a burning sensation, a foreign body sensation, irritation, and sometimes
itching and visual uctuations. Many patients themselves complain of a sensation of
dryness. The conjunctiva may be white or, on the contrary, diffusely hyperemic.
The best-known ocular complication, albeit rare, is phlyctenular keratoconjunctivitis,
with peripheral keratitis and corneal neovascularization. Other complications include
conjunctival brosis which can lead to fornix foreshortening, symblepharon formation,
and trichiasis, epithelial punctate keratitis, catarrhal inltrates, peripheral ulcerative
keratitis, scleritis and episcleritis. The clinical presentation of ocular rosacea in children
is usually phlyctenular keratoconjunctivitis and skin lesions of rosacea are exceptional.
The principal differential diagnoses are dryness, allergy, and toxic conjunctivitis. These
diagnoses are particularly difcult to rule out because they can be associated with
ocular rosacea.
Meibomian gland dysfunction,
ocular rosacea
Thanh Hoang-Xuan, France
19
Meibomian gland dysfunction, ocular rosacea
The patient must be informed from the outset that ocular rosacea is a chronic condition,
that treatment will no doubt be lengthy. Daily lid hygiene is the cornerstone in the treatment
of ocular rosacea. The eyelids must be warmed by applying for several minutes a facecloth
or packs soaked in warm water. The patient must be shown how to perform a rm and
effective nger massage of the four eyelids. Diverse devices are also marketed to facilitate
this eyelid warming and massage. Finally, the eyes are rinsed with preservative-free
saline. Oral tetracycline, its derivatives (oxytetracycline and doxycycline), and minocycline
have proven their efcacy in ocular rosacea. The mode of action of the cyclines is not
clear. They appear to act by reducing lipase production by staphylococci present in the
commensal ora, thereby reducing the release of toxic free fatty acids through meibomian
lipid hydrolysis. They also have anticollagenase activity, suppress neovascularization, and
have an antichemotactic effect. Tetracycline and its derivatives must be reserved for
severe forms of ocular rosacea and thier contraindications must be respected. Topical
corticosteroid eyedrops are only indicated to control an acute inammatory exacerbation,
and only for a brief period. Topical 2% cyclosporine is very effective in childhood ocular
rosacea. Oral cyclines are contraindicated and can be replaced by erythromycine. Recently
topical azythromycine has been proven to be effective in children and represents therefore
an excellent alternative to steroids and cyclosporine. In very few patients, temporary
meibomian duct orices have been opened with special ultrathin probes.
References
Long-term visual outcome of childhood blepharokeratoconjunctivitis.
Doan S, Gabison EE, Nghiem-Buffet S, Abitbol O, Gatinel D, Hoang-Xuan T.
Am J Ophthalmol. 2007 Mar;143(3):528-9.
Topical cyclosporine A in severe steroid-dependent childhood phlyctenular
keratoconjunctivitis.
Doan S, Gabison E, Gatinel D, Duong MH, Abitbol O, Hoang-Xuan T.
Am J Ophthalmol. 2006 Jan;141(1):62-66.
Inammatory Diseases of the Conjunctiva.
T Hoang-Xuan, C Baudouin, C Creuzot-Garcher (Eds). Georg Thieme Verlag
(Publ), Stuttgart, New-York, 2001.
Professor Thanh HOANG-XUAN
Head of Ophthalmology Unit at American Hospital Paris
e-mail address: thx0106@gmail.com
Dry eye and clinical disease of tear
lm, diagnosis and management
Jesus Merayo, Spain
20
1. Introduction
Photorefractive keratectomy (PRK) is the oldest photoablation process for reshaping
the supercial stroma. The procedure varies according the types of corneal epithelial
removal. The most frequent technique, mechanical debridment, removes the corneal
epithelium with a blade or spatula. Alternatively, in transepithelial ablation the epithelium
is removed by the excimer laser itself. Other techniques for en bloc epithelial removal
include the application of diluted alcohol suspension on the corneal surface to harden
and then loosen the epithelium, knowing as Laser-Assisted SubEpithelial Keratomileusis
(LASEK). Techniques utilizing a mechanical microkeratome for epithelial ap formation
have also been introduced. This procedure is called Epi-LASIK.
Phototherapeutic keratectomy (PTK) is widely used of removal of corneal precipitates or
scars or for smoothening of the stromal surface or treatment of basement membrane
dystrophy related problems (recurrent erosions or irregular epithelial astigmatism).
It can also be combined with manual or lamellar surgery.
2. Refractive results
Published data about postoperative outcomes of PRK with at least one-year follow-up
1--15

show a relatively good efcacy, safety and stability. More recently, studies with at least
5 years follow-up
16-21
have demonstrated that these results persist in time.
Most studies with short follow-up reported a postoperative UCVA 20/50 in more that
80% of eyes. These values in long-term follow-up studies continue, yet attempted
corrections (over 6 D) tend to decline the efcacy.
19, 20
. Predictability of MRSE within
1.00 D after 1 to 3 years postoperatively have been reported in around 70% of eyes.
In long-term follow-up studies predictability of MRSE within 1.00 D varies between
34% to 91%. These differences can be explained by the inclusion criteria, sunlight
exposure or ethnical background of patients in these studies, the postoperative goal,
and again the amount of attempted correction. This is the case of Rajan et al
21
that
reported variation of MRSE within 1.00 D in 75% and 22% of eyes which underwent
an attempted correction of -2 D and -7 D, respectively. Yet, long-term follow-up studies
that included correction less that -7.5 D
17, 20
reported MRSE within 1.00 D in more
than 75% of the eyes at last follow-up. The postoperative loss of 2 or more lines of
Surface photoablation
Timo Tervo, Finland 21
BCVA in average seems to be less than 4% in review studies 15. This has been reported
to increase in corrections over 6 D.
19
Corneal postoperative haze, that could explain
the loss of lines of BCVA, have been reported to be cleared within 12 months in low
correction and within 24 months in moderate high corrections.
22,23
. PRK studies have
previously shown that the stability tends to be reached during the rst 6 months 24 up
to a year.
25
. An association has been found between regression and high attempted
myopic correction
13, 15, 21
, and age.
21
The highest myopic regression reported in
PRK studies was 1.60 D.
2
In long-term studies no signicant difference were found
in change of MRSE at 1, 6 and 12 years follow-up.
21
. Yet, a slightly but continuous
myopic progression have been reported in all the others long-term follow-up studies
16, 17, 19, 20
.
PRK vs. LASIK.
Several studies compared PRK and LASIK outcomes at least one year after surgery.
26-28
In low-to-moderate attempted correction (<6. 00 D) efcacy and safety were similar,
yet stability was reported to be better after LASIK than after PRK. In correction over
6.00 D efcacy, safety and stability were superior in LASIK. Yet, in a recent editorial
Waring GO
29
compared the long-term results of PRK and LASIK
29
closer to the todays
criteria (less than 6.00 and 10.00 D for PRK and LASIK, respectively) and concluded that
PRK showed more regression, and loss of BCVA than LASIK eyes.
Our results
30, 31
revealed that in long-term the number of eyes that achieved uncorrected
visual acuity (UCVA) 0.0 and 0.5 (logMAR) was higher after PRK than after LASIK,
yet postoperative stability was slightly better after PRK than after LASIK. No differences
were found in percentages of eyes with best corrected visual acuity (BCVA) between
PRK and LASIK in the long-term. The postoperative long-term outcomes of PRK with
two different delivery systems broad beam and scanning laser were compared and
revealed no differences. We demonstrated that the long-term outcomes after PRK and
LASIK were safe and efcient, with similar stability for both procedures. Postoperative
outcomes of moderate-to-high astigmatism yielded better results in terms of UCVA and
less compromise of BCVA after LASIK that after PRK. Vector analysis showed that LASIK
outcomes tended to be more accurate than PRK outcomes, yet no statistically differences
were found. We demonstrated that LASIK was better than PRK to correct moderate-
to-high astigmatism, yet both procedures showed a tendency of undercorrection.
Wide and/or customized ablation proles might be more problematic with PRK than LASIK.
21
3. Haze
Incidence of haze is higher after surface ablations, specially after correction of
moderate to high myopia.
32
Haze reaches its maximum between the second and third
months,
33
but resolves spontaneously by 6 months to 1 year. In surface ablations,
the absence of epithelial basement membrane and/or Bowmans layer are thought
to allow the entry of epithelium derived cytokines into the stroma necessary and lead
to myobroblast alteration and formation of scar-type ECM. Postoperative haze may
continue to disappear, even after the rst postoperative year. Twelve years follow-up
after PRK reported no haze in 94% of the eyes. Transepithelial PRK photoablation has
been reported to induce less stromal cell apoptosis than PRK performed after surgical
scraping of the epithelium.
34

4. Regression
Myopia regression after PRK is thought to result from resynthesis of ECM by activated
broblasts and altered keratocytes. A relation between regression and age has been
described,
21
yet none relation with epithelial thickness has been reported as in LASIK.
In some cases, regression of myopia may continue even up to 5 years after PRK.
35
.
We found an amount of regression after PRK similar to that reported in other long-term
studies.
30
Yet, when delivery systems were compared, we found that myopic regression
favored the initial overcorrection achieved by the Scanning slit laser type laser. LASIK
refractive outcomes are relatively good in the short terms, but tend to decline over
time. The incidence of myopic regression was more pronounced when the intended
correction was >6.0 D and in patients aged <30 years.
31
5. Corneal nerves
Nerve damage in the anterior corneal stroma appears to be less severe in PRK than
in LASIK.
36
Histological sections have revealed presumably regenerating nerve bres
already on day one post-PRK.
37
Neural orientation and regrowth may be affected
by the absence of Bowmans layer in corneas after PRK. PRK ablates the supercial
subbasal nerves resulting in less stromal nerve destruction. Thus, the neural recovery
after PRK is usually faster. Nerve density after PRK improves signicantly still after
1 year, and reaches near normal mean values at 2 years. Hyperopic PRK may induce
even more profound sensory denervation, since it damages the thick peripheral nerve
bundles. It also needs a longer period to stabilize and is less predictability and is usable
to only up to + 4D provided that the cornea is not very deep preoperatively.
Hyperesthesia to chemical sensitivity is attributable to sensitization. At 10 years after
PRK, mechanical and chemical sensitivity recovered normal values, suggesting that new
regenerating nociceptive corneal nerves slowly invade the denervated area. (Neira W,
ARVO 2013)
6. Postoperative pain
Pain is often felt after surface ablations although it shows a large inter-individual
variation. Patients who receive PRK typically have moderate to severe pain for 14 days
after the procedure, and usually recovery of visual performance takes less than two
weeks.
38
Different techniques have been tried in order to decrease postoperative pain
but have shown only limited success. Less pain- and probably haze has been reported
after epiLASIK and LASEK vs. PRK but contradictory reports have also been published.
39

7. Phototherapeutic keratectomy (PTK)
The therapeutic treatment of corneal opacities and irregularities by excimer laser
is called phototherapeutic keratectomy (PTK). It refers to a regular and sequential
ablation of the anterior layers of the cornea. In general, PTK has been used to remove
supercial opacities, treat surface irregularities, and to correct complications after
photorefractive keratectomy (PRK) or Laser in-situ keratomileusis (LASIK) or even post
LASIK inammations. PTK may induce postoperative hyperopia. Patients with anterior
opacities or anterior elevated stromal changes are suitable, whereas deep stromal
changes or stromal depressions are often difcult to treat.
Anterior basement membrane dystrophy, such as RCES (MDF), resulting from
from abnormal adhesion between the epithelium and the basement membrane-
Bowmans layer complex. This, in addition to variable epithelial thickness may contribute
or generate a morphologically irregular anterior corneal surface. Eyes with history of
MDF / RCES that did not show changes at the slit lamp biomicroscopy examination,
but showed CCTs compatibles with irregular astigmatism that affects the VA can be
corrected with simple PTK. Consequently, wave front analysis is unreliable in these
cases, and simple epithelial abrasion and PTK should be performed rst and the patient
re-examined after PTK prior to any stromal re-sculpture
21
7. Comparation/ Indications
PRK LASIK
Small corrections Corrections -5 to -10D
Custom ablations? Higher astigmatism
Thin corneas Poor corneal sensitivity (Post corneal
graft, tight cerclage
Recurrent erosion, supercial
irregularities (MDF)
Shorter postoperative therapy,
compliance
Predisposition to trauma athletics Bilateral operation
Small deep eyes UV exposure
Post RK

8. Conclusion:
Surface ablations still have pros and cons, indications and contraindications. Surface
ablation is often the method of choice in small deep eyes, thin corneas, corneas with
penetrating wounds such as RK. Short topical postoperative mitomycin-C treatments with
a low concentration may in selected cases also improve the results of surface ablations.
9. References
1. Snibson GR, Carson CA, Aldred GF, et al. One-year evaluation of excimer laser
photorefractive keratectomy for myopia and myopic astigmatism. Melbourne
Excimer Laser Group. Arch Ophthalmol 1995;113:994-1000.
2. Amano S, Shimizu K. Excimer laser photorefractive keratectomy for myopia: two-
year follow up. J Refract Surg 1995;11:S253-60.
3. Chan WK, Heng WJ, Tseng P, et al. Photorefractive keratectomy for myopia of 6 to 12
diopters. J Refract Surg 1995;11:S286-92.
4. Goes FJ. Photorefractive keratectomy for myopia of -8.00 to -24.00 diopters.
J Refract Surg 1996;12:91-97.
5. Tuunanen TH, Tervo TT. Results of photorefractive keratectomy for low,
moderate, and high myopia. J Refract Surg 1998;14:437-446.
6. Waring GO,3rd, OConnell MA, Maloney RK, et al. Photorefractive keratectomy
for myopia using a 4.5-millimeter ablation zone. J Refract Surg 1995;11:170-180.
7. McCarty CA, Aldred GF, Taylor HR. Comparison of results of excimer laser
correction of all degrees of myopia at 12 months postoperatively. The Melbourne
Excimer Laser Group. Am J Ophthalmol 1996;121:372-383.
8. Spadea L, Colucci S, Bianco G, et al. Long-term results of excimer laser
photorefractive keratectomy in high myopia: a preliminary report. Ophthalmic
Surg Lasers 1998;29:490-496.
9. Haw WW, Manche EE. One-year evaluation of myopic laser photoastigmatic
refractive keratectomy using the summit apex plus: phase III of a Food and Drug
Administration clinical trial. Ophthalmology 2000;107:1572-1577.
10. Keskinbora HK. Long-term results of multizone photorefractive keratectomy for
myopia of -6.0 to -10.0 diopters. J Cataract Refract Surg 2000;26:1484-1491.
11. Nagy ZZ, Krueger RR, Suveges I. Photorefractive keratectomy for astigmatism
with the Meditec MEL 60 laser. J Refract Surg 2001;17:441-453.
12. Stevens J, Giubilei M, Ficker L, et al. Prospective study of photorefractive
keratectomy for myopia using the VISX StarS2 excimer laser system. J Refract
Surg 2002;18:502-508.
13. Seiler T, McDonnell PJ. Excimer laser photorefractive keratectomy. Surv
Ophthalmol 1995;40:89-118.
14. Ang EK, Couper T, Dirani M, et al. Outcomes of laser refractive surgery for
myopia. J Cataract Refract Surg 2009;35:921-933.
15. Steinert RF, Bafna S. Surgical correction of moderate myopia: which method
should you choose? II. PRK and LASIK are the treatments of choice. Surv
Ophthalmol 1998;43:157-179.
16. Bricola G, Scotto R, Mete M, et al. A 14-year follow-up of photorefractive
keratectomy. J Refract Surg 2009;25:545-552.
17. Pietila J, Makinen P, Pajari T, et al. Eight-year follow-up of photorefractive
keratectomy for myopia. J Refract Surg 2004;20:110-115.
18. Koshimizu J, Dhanuka R, Yamaguchi T. Ten-year follow-up of photorefractive
keratectomy for myopia. Graefes Arch Clin Exp Ophthalmol 2010.
19. Alio JL, Muftuoglu O, Ortiz D, et al. Ten-Year Follow-up of Photorefractive Keratectomy
for Myopia of More Than -6 Diopters. Am J Ophthalmol 2008;145:37-45.
20. Alio JL, Muftuoglu O, Ortiz D, et al. Ten-year Follow-up of Photorefractive
Keratectomy for Myopia of Less Than -6 Diopters. Am J Ophthalmol 2008;145:29-36.
21
21. Rajan MS, Jaycock P, OBrart D, et al. A long-term study of photorefractive
keratectomy; 12-year follow-up. Ophthalmology 2004;111:1813-1824.
22. Fagerholm P. Wound healing after photorefractive keratectomy. J Cataract
Refract Surg 2000;26:432-447.
23. Moilanen JA, Vesaluoma MH, Muller LJ, et al. Long-term corneal morphology
after PRK by in vivo confocal microscopy. Invest Ophthalmol Vis Sci
2003;44:1064-1069.
24. Klyce SD, Smolek MK. Corneal topography of excimer laser photorefractive
keratectomy. J Cataract Refract Surg 1993;19 Suppl:122-130.
25. Pallikaris IG, Siganos DS. Excimer laser in situ keratomileusis and photorefractive
keratectomy for correction of high myopia. J Refract Corneal Surg 1994;10:498-510.
26. Helmy SA, Salah A, Badawy TT, et al. Photorefractive keratectomy and laser in
situ keratomileusis for myopia between 6.00 and 10.00 diopters. J Refract Surg
1996;12:417-421.
27. Wang Z, Chen J, Yang B. Comparison of laser in situ keratomileusis and
photorefractive keratectomy to correct myopia from -1.25 to -6.00 diopters. J
Refract Surg 1997;13:528-534.
28. el Danasoury MA, el Maghraby A, Klyce SD, et al. Comparison of photorefractive
keratectomy with excimer laser in situ keratomileusis in correcting low
myopia (from -2.00 to -5.50 diopters). A randomized study. Ophthalmology
1999;106:411-20; discussion 420-1.
29. Waring GO. Have you seen the 10-Year long-term safety data on laser in situ
keratomileusis? Am J Ophthalmol 2008;145:1-2.
30. Zalentein WN, Tervo TM, Holopainen JM. Long-term follow-up of photorefractive
keratectomy for myopia: Comparative study of excimer lasers. J Cataract Refract
Surg 2011;37:138-143.
31. Zalentein WN, Tervo TM, Holopainen JM. Seven-year follow-up of LASIK for
myopia. J Refract Surg 2009;25:312-318.
32. Frueh BE, Cadez R, Bohnke M. In vivo confocal microscopy after photorefractive
keratectomy in humans. A prospective, long-term study. Arch Ophthalmol
1998;116:1425-1431.
33. Corbett MC, Prydal JI, Verma S, et al. An in vivo investigation of the structures
responsible for corneal haze after photorefractive keratectomy and their effect
on visual function. Ophthalmology 1996;103:1366-1380.
34. Lee HK, Lee KS, Kim JK, et al. Epithelial healing and clinical outcomes in excimer
laser photorefractive surgery following three epithelial removal techniques:
mechanical, alcohol, and excimer laser. Am J Ophthalmol 2005;139:56-63.
35. Kim JH, Kim MS, Hahn TW, et al. Five years results of photorefractive
keratectomy for myopia. J Cataract Refract Surg 1997;23:731-735.
36. Gallar J, Acosta MC, Moilanen JA, et al. Recovery of corneal sensitivity to
mechanical and chemical stimulation after laser in situ keratomileusis. J Refract
Surg 2004;20:229-235.
37. Tervo K, Latvala TM, Tervo TM. Recovery of corneal innervation following
photorefractive keratoablation. Arch Ophthalmol 1994;112:1466-1470.
38. Jackson WB, Casson E, Hodge WG, et al. Laser vision correction for low
hyperopia. An 18-month assessment of safety and efcacy. Ophthalmology
1998;105:1727-38; discussion 1737-8.
39. Gamaly TO, El Danasoury A, El Maghraby A. A prospective, randomized,
contralateral eye comparison of epithelial laser in situ keratomileusis
and photorefractive keratectomy in eyes prone to haze. J Refract Surg
2007;23:S1015-20.
Timo M.T. Tervo, M.D., Ph.D. and Waldir Neira, M.D. Ph.D.
Department of Ophthalmology, University of Helsinki, Finland
Since itss introduction in 1990 by Pallikaris (Pallikaris et al, 1990), laser in situ
keratomileusis (LASIK) has become the surgical treatment of choice for correction of
ametropia. Since then, LASIK has developed from an innovative new procedure to a
standard of care. (Kiraly et al, 2012) The procedure is safe, effective, predictable and,
also regarding long term evaluatons, stable. (Skimoto et al 2006, Rosman 2010, Kiraly
et al, 2012)
The creation of the anterior corneal lamella (ap) prior to stromal ablation with an
excimer laser, is a crutial step for a succesful LASIK procedure. While Pallikaris initially
introduced mechanical knives (microceratomes) , today more and more surgeons prefer
femtosecond lasers (fs-LASIK) for this purpose. (Kohnen et al 2008) These have proven
to create precicer aps and and less complications. (von Jagow and Kohnen 2009)
LASIK however has, as any surgical intervention, specic complications. If those have
a negatve effect on postoperative quality of vision and / or quality of life, patients
will recognize them as particularily hard, as their vision was usually very good with
glasses or contact lenses prior to surgery. Besides early and relatively easy treatable
ones like endothelial ingrowths in the interface, dry eye or diffuse lamellar keratitis
(DLK), especially iatrogenic ectasia is a severe problem. (Randleman and Shah 2012,
Dawson et al, 2009) Analysing the impact of these complications, model evaluations
show a similar long term impact on visual acuity as soft contact lenses. (McGee and
Mathers 2009)
The talk will briey show basic methods of preoperative diagnostics and patient
selection. Surgical procedures (LASIK and fs-LASIK) will be explained. Visual long term
results and intraoperative as well as long term complications will be discussed.
Laser in situ keratomileusis:
Microkeratome or femtosecond laser
Thomas Kohnen, Germany
22
Laser in situ keratomileusis: Microkeratome or femtosecond laser
Refrences
Pallikaris IG, Papatzanaki ME, Stathi EZ, Frenschock O, Georgiadis A. Laser in situ
keratomileusis. Lasers Surg Med. 1990;10(5):463-8.
Kiraly L, Skarupinski P, Duncker G. [LASIK - a new treatment or the standard]. Klin
Monbl Augenheilkd. 2011 Nov;228(11):995-8.
Rosman M, Alio JL, Ortiz D, Perez-Santonja JJ. Refractive Stability of LASIK with the
VISX 20/20 Excimer Laser vs ZB5M Phakic IOL Implantation in Patients with High
Myopia (>-10.00 D): A 10-Year Retrospective Study. J Refract Surg. 2010 Jul 23:1-8.
Kohnen T, Strenger A, Klaproth OK. Basic knowledge of refractive surgery:
correction of refractive errors using modern surgical procedures. Dtsch Arztebl Int.
2008 Feb;105(9):163-70; quiz 70-2.
von Jagow B, Kohnen T. Corneal architecture of femtosecond laser and
microkeratome aps imaged by anterior segment optical coherence tomography.
J cataract Refract Surg. 2009 Aug;35:35-41.
Dawson DG, Randleman JB, Grossniklaus HE, OBrien TP, Dubovy SR, Schmack I,
et al. Corneal ectasia after excimer laser keratorefractive surgery: histopathology,
ultrastructure, and pathophysiology. Ophthalmology. 2008 Dec;115(12):2181-91 e1.
Randleman JB, Shah RD. LASIK interface complications: etiology, management,
and outcomes. J Refract Surg. 2012 Aug;28(8):575-86.
McGee HT, Mathers WD. Laser in situ keratomileusis versus long-term contact lens
wear: decision analysis. J Cataract Refract Surg. 2009 Nov;35(11):1860-7.
History
Femtosecond lasers used in corneal surgery are based on solid state Nd-Glass lasers.
The laser emits ultrashort pulses with time duration in the order of some femtoseconds
(1015 second). The laser light is focused to a very small spot using advanced optics.
When laser energy is sufciently high, plasma formation takes place and disrupts the
tissue in an area of micrometers. The focus for the laser is changed and by repeating
the laser shots in a controlled pattern, the femtosecond laser can behave as a non-
invasive knife
1
.
Corneal femtosecond lasers were originally developed for intrastromal treatments; it
was assumed that plasma bubble formation within the stroma could result in controlled
and non-invasive correction of at least small refractive errors. It became clear, that this
was not possible. Instead the femtosecond laser was developed into a surgical knife,
being able create the ap used in LASIK surgery and excisional cuts used in keratoplasty
procedures. Recent developments in femtosecond laser technology have resulted in
development of techniques for femtosecond lenticule extraction and small-incision
lenticule extraction.
Techniques
All devices for femtosecond laser cutting of the cornea need to secure a stable
attachment between the applicator and the cornea. This is done by suction at the
peripheral cornea or limbus and by at or curved applanation of the corneal surface.
The rst application of corneal femtosecond lasers was for creation of the corneal,
hinged ap in LASIK surgeries.
In LASIK, the diameter, thickness, edge width, and shape of the ap edge can be
programmed. After loosening of the ap, conventional excimer laser ablation of the
stroma is performed and the ap is repositioned as after microkeratome based LASIK.
With newer, faster femtosecond lasers, the procedure takes 10-15 seconds.
Channel cutting for intra corneal ring segments can be performed with most
femtosecond lasers. The diameter, channel width and depth, and the location of the
incision are programmed into the laser. After channel cutting, the ring segments are
Femtosecond laser corneal surgery
Jesper Hjortdal, Denmark 23
implanted as in conventional manual channel formation. The actually cutting of the
channel takes 10-15 seconds.
Refractive lenticule extraction was introduced only 5 years ago
2
. By this technique,
the femtosecond laser is used to actually cut the refractive surfaces and edges of an
intrastromal lenticule that afterwards is removed manually. The technique has been
developed as a LASIK-like procedure with cutting of the lenticule and a ap, which is
lifted completely. A more advanced variation is named small-incision lenticule extraction.
In this procedure the lenticule is removed through a 2 to 3 mm wide peripheral corneal
incision. Thus, most of the corneal surface is left as an intact cap. Lenticule diameters,
incision length, cap diameter and thickness, and of course the desired refractive
correction is programmed before surgery. With the most recent software, cutting of a
refractive lenticule takes 20-30 seconds.
Application of a femtosecond laser pulse pattern in the stroma without actual removal
of corneal tissue has been used to generate biological diffractive gratings in the stroma
as a treatment for presbyopia.
Advantages of femtosecond laser use for corneal procedures
Compared with manual microkeratomes femtosecond laser based LASIK surgery results
in creation of corneal aps with more reproducible thickness and less tendency for
epithelial ingrowth. An additional advantage is the simplicity of using the femtosecond
laser compared with a microkeratomes making LASIK surgery technically easier.
Femtosecond laser based intra corneal ring segment implantation is also technically
easier than manual dissection possibly resulting in fewer surgery related complications.
All-in-one femtosecond laser based corneal refractive surgery makes the excimer laser
unnecessary. In SMILE, only a small peripheral corneal incision is made, which in theory
would result in better preservation of corneal biomechanics and corneal sensitivity.
Recent studies suggest that the procedure has predictability, efcacy, and safety similar
to LASIK
3
.
Specic femtosecond laser related complications
Correct dosage of the femtosecond laser energy and spot size is crucial. Too low energy
will result in insufcient cutting of corneal brils. Too high energy will results in formation
of conuent larger air bubbles (opaque bubble formation) with resulting incomplete
or irregular cutting. In FS-LASIK such problems rarely result in visual problems for the
patient. But in refractive lenticule extraction, incomplete cutting of the lenticule may
result in cutting of an irregular lenticule that is difcult to remove.
23
Literature
1
Kymionis GD, Kankariya VP, Plaka AD, Reinstein DZ. Femtosecond laser technology in
corneal refractive surgery: a review. J Refract Surg. 2012 Dec;28(12):912-20.
2
Sekundo W, Kunert K, Russmann C, Gille A, Bissmann W, Stobrawa G, Sticker M,
Bischoff M, Blum M. First efcacy and safety study of femtosecond lenticule extraction
for the correction of myopia: six-month results. J Cataract Refract Surg. 2008
Sep;34(9):1513-20.
3
Hjortdal J, Vestergaard AH, Ivarsen A, Ragunathan S, Asp S. Predictors for the
outcome of small-incision lenticule extraction for Myopia. J Refract Surg. 2012
Dec;28(12):865-71.
Jesper Hjortdal, Clinical professor, MD, PhD.
Department of Ophthalmology, Aarhus University Hospital NBG, Denmark
E-mail: jesper.hjortdal@dadlnet.dk.
1
Quality of Vision after Refractive Quality of Vision after Refractive
Surgery Surgery
Dimitri Dimitri T. Azar, T. Azar, MD, MBA MD, MBA
Dean, College of Medicine
B.A. Field Chair of Ophthalmologic Research
Professor of Ophthalmology, Pharmacology,
and Bioengineering and Bioengineering
University of Illinois at Chicago
Non-Custom LASIK
1. Measurement of spherocylindrical error
2. Flap dissection with microkeratome &
3. photoablation with excimer laser p
Number of LASIK Procedures in US
1998 430,000
1999 800,000
2000-2007 (projected) 1.5-2 mil./yr
Complication rate 0 5% - 2% Complication rate 0.5% 2%
Mechanical complications relate to the flap
Optical complications relate to decentration, optical
zone size, positive asphericity, and uncorrected
HOA
Quality of vision after refractive surgery
Dimitri Azar, United States
24
2
VISX Laser Technology
Advancements
Iris Registration
Multifocal Ablations
B&L Laser Technology
Advancements
Multifocal Ablations
24
3
Allegretto Laser Technology
Advancements
Mixed Astigmatism Approval
Instantaneous Pachymetric y
monitoring
Femtosecond Optical Delivery System
Glass Lens applanates
cornea to flatten eye &
maintain precise
distance from laser
head to focal point
Tear Film
Epithelium
Bowmans
Descemets
Stroma
Endothelium
4
Mechanical complications may be reduced
with newer technologies
Laser is set to desired
depth
Defined distance from bottom
of glass applanation surface
Pulses delivered in a
prescribed pattern creating a
horizontal or vertical cleavage
plane in the cornea plane in the cornea
Optical complications may be reduced with custom
LASIK and newer technologies of laser delivery
LASIK Limitations LASIK Limitations
Potential Flap Potential Flap--related Complications related Complications
Custom corneal limitations Custom corneal limitations
E t i E t i Ectasia Ectasia
24
5
Epithelial Cysts
Striae
6
Corneal Ectasia in Myopia Corneal Ectasia in Myopia
Preexisting KC Preexisting KC
Deep flap Deep flap
High myopia High myopia
Deep laser ablation Deep laser ablation
(Ectasia is more likely to occur after LASIK) (Ectasia is more likely to occur after LASIK) ( y ) ( y )
Potential Complications in Patients with Coexistent
Keratoconus and Fuchs Dystrophy
Case 1. Top, Orbscan
t h h d topography showed
advanced inferior
steepening consistent
with keratoconus
changes on the right eye
(OD), despite a diffusely
thick cornea. Slit-lamp
photography showed
corneal guttae. Specular
microscopy was unable
to provide an image of
the eye due to corneal
edema. Bottom, Orbscan
topography showed
inferior steepening
i i h consistent with
keratoconus. Specular
microscopy of the left
eye (OS) captured
multiple guttae, with
inability to perform cell
counts. N = nasal; T =
temporal.
Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187 Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187--97. 97.
24
7
Potential Complications in Patients with Coexistent
Keratoconus and Fuchs Endothelial Dystrophy
Case 2. Top, Orbscan
t h h d topography showed
inferior steepening of the
right eye (OD) consistent
with keratoconus. Slit-
lamp photography
showed multiple guttae.
Specular microscopy was
unable to provide an
image. Bottom, Orbscan
topography showed
inferior steepening of the
left eye (OS). Corneal
guttae were noted on slit-
lamp photography. p p g p y
Specular microscopy was
unable to provide an
image of the eye. N =
nasal; T = temporal.
Jurkunas U, Azar DT. Ophthalmology. 2006 Dec;113(12):2187-97.
Ectatic Disorders Associated with a Claw-Shaped
Pattern on Corneal Topography
Lee BW, Jurkunas UV, Harissi Lee BW, Jurkunas UV, Harissi--Dagher M, Poothullil AM, Tobaigy FM, Azar DT. Am J Ophthalmol. 2007 Jul;144(1):154 Dagher M, Poothullil AM, Tobaigy FM, Azar DT. Am J Ophthalmol. 2007 Jul;144(1):154- -156. 156.
8
Surface Ablation? Surface Ablation?
Potential Flap Potential Flap--related Complications related Complications
Custom corneal limitations Custom corneal limitations
E t i E t i Ectasia Ectasia
Surface Ablation, Combined with MMC, May Surface Ablation, Combined with MMC, May
Overcome Several Limitations of Phakic IOLs Overcome Several Limitations of Phakic IOLs
Shallow AC Shallow AC
Low initial endothelial cell counts Low initial endothelial cell counts
Progressive endothelial cell loss Progressive endothelial cell loss
Cataract formation Cataract formation
Serious Intraoperative/Postoperative Serious Intraoperative/Postoperative
Complications Complications
24
9
Retrospective, nonrandomized, control Retrospective, nonrandomized, control- -matched study matched study
The charts of 2257 eyes that underwent LASEK or LASIK The charts of 2257 eyes that underwent LASEK or LASIK
Control Control- -Matched Comparison of Matched Comparison of
LASEK and LASIK LASEK and LASIK
yy
treatment were reviewed. treatment were reviewed.
Inclusion criteria: patients who were 21 years of age or Inclusion criteria: patients who were 21 years of age or
older having between 0.75 and 6.00 diopters (D) of older having between 0.75 and 6.00 diopters (D) of
myopia with up to 2.25 D of astigmatism. myopia with up to 2.25 D of astigmatism.
One hundred twenty One hundred twenty- -two LASEK two LASEK- -treated eyes were treated eyes were
matched with 122 LASIK matched with 122 LASIK--treated eyes having preoperative treated eyes having preoperative
spheres cylinders and SE within spheres cylinders and SE within 0 50 D 0 50 D spheres, cylinders, and SE within spheres, cylinders, and SE within 0.50 D. 0.50 D.
Both groups had similar preoperative best spectacle Both groups had similar preoperative best spectacle- -
corrected visual acuity (BSCVA), laser platform, and follow corrected visual acuity (BSCVA), laser platform, and follow- -
up durations. up durations.
Tobaigy FM, Ghanem RC, Sayegh RR, Hallak JA, Azar DT. Am J Ophthalmol. 2006; 142(6): 901 Tobaigy FM, Ghanem RC, Sayegh RR, Hallak JA, Azar DT. Am J Ophthalmol. 2006; 142(6): 901--88
Control-Matched Comparison of
LASEK and LASIK
Line Loss/Gain of 122 LASEK Eyes
Matched with 122 LASIK Eyes
Postoperative results:
M SE 0 15 0 40 D
Matched with 122 LASIK Eyes
25.4
67.2
28.7
62.3
30
40
50
60
70
80
%

o
f

E
y
e
s
Mean SE was 0.15 0.40 D
for LASEK and 0.37
0.45 D for LASIK
Mean logMAR of BSCVA was
0.03 0.06 (20/19) for
LASEK and 0.02 0.05
(20/19) for LASIK.
No eye lost 2 or more lines
f BSCVA i b th
0.0 0.8 0.0 0.8
5.7
9.0
0.0 0.0
0
10
20
-2 Lines -1 Line No Loss +1 Line +2 Lines + 3 Lines
LASEK LASIK
of BSCVA in both groups.
Tobaigy FM, Ghanem RC, Sayegh RR, Hallak
JA,Azar DT. Am J Ophthalmol. 2006;
142(6): 901-8
10
Conclusions: Conclusions:
Control Control- -Matched Comparison of LASEK Matched Comparison of LASEK
and LASIK for Low to Moderate Myopia and LASIK for Low to Moderate Myopia
Although there were some differences in the Although there were some differences in the
visual and refractive results favoring LASEK, visual and refractive results favoring LASEK,
they were not clinically significant. they were not clinically significant.
Both procedures seemed safe, effective, and Both procedures seemed safe, effective, and
predictable for the treatment of low and predictable for the treatment of low and pp
moderate myopia. moderate myopia.
Nomogram adjustment may be necessary for Nomogram adjustment may be necessary for
LASIK surgeons adopting surface ablation. LASIK surgeons adopting surface ablation.
Attempted versus Achieved Spherical Equivalent
Correction at the Final Visit
Epi-LASIK Attempted versus achieved spherical equivalent correction
3
4
5
6
7
8
A
t
t
e
m
p
t
e
d

(
D
)
0
1
2
0 1 2 3 4 5 6 7 8
Achieved (D)
24
11
Surface Ablation Surface Ablation
ADVANTAGES: ADVANTAGES:
Surface ablation is a viable alternative to LASIK alternative to LASIK
especially in young patients with thin especially in young patients with thin
pachymetry, steep K, and/or corneal
irregularities.
Microkeratome and flap- related complications
are avoided.
Surface ablation is a reasonable alternative to alternative to
phakic IOLs phakic IOLs in patients with low endothelial cell
counts, shallow AC, early lens opacities, and/or
hi h i i high astigmatism.
LIMITATIONS: LIMITATIONS:
The long long- -term risks of prophylactic MMC term risks of prophylactic MMC are
unknown.
D it t d t d fi l BSCVA D it t d t d fi l BSCVA
LASIK in the Presbyopic Age Group: LASIK in the Presbyopic Age Group: Safety, Efficacy Safety, Efficacy
and Predictability in 40 and Predictability in 40- -69 Year Old Patients 69 Year Old Patients
Despite a trend towards worse final BSCVA Despite a trend towards worse final BSCVA
and higher retreatment rates in older patients, and higher retreatment rates in older patients,
a greater risk of visual loss after LASIK was a greater risk of visual loss after LASIK was
not observed with increasing age. not observed with increasing age.
LASIK for myopia and hyperopia has LASIK for myopia and hyperopia has
reasonable safety efficacy and predictability reasonable safety efficacy and predictability reasonable safety, efficacy and predictability reasonable safety, efficacy and predictability
profiles in the presbyopic age group. profiles in the presbyopic age group.
Ghanem RC, de la Cruz J, Tobaigy FM, Ang LP, Azar DT. Ophthalmology. 2007 Jul;114(7):1303 Ghanem RC, de la Cruz J, Tobaigy FM, Ang LP, Azar DT. Ophthalmology. 2007 Jul;114(7):1303- -10 10
12
AFFERENT ARM EFFERENT ARM
++
Corneal Topography/
Wavefront Analyzer
Custom Ablation Custom Ablation Custom Ablation Custom Ablation
Scanning Laser
++
==
What are the Optical Limits to
Corneal Refractive Surgery?
24
13
Comparison of Outcomes of
Custom and Non-custom LASIK
FDA trials of LVC
Subgroups: 0 to -2D, -2 to -4D, -4 to -7D,
0 to +2D, +2 to +4, & +4 to +6D
Pooled data of approved lasers (3 custom and
5 non-custom) rather than head-to-head
comparisons of individual lasers
Literature Search (past 10 years); data pooled
Outcomes: % > 20/20; % > 20/40; % + 0.50D;
%+ 1D; % loss of > 2 Snellen lines
Sakimoto T, Rosenblatt MI, Azar DT - - Lancet 4/2006
14
24
15
Limitations in Wavefront Analysis:
Measurement Steps
W f t t t d/ l d Wavefronts reconstructed/analyzed
higher order Zernike polynomial or
Fourier representation of wavefront
generated.
Effective clinical prescription generated p p g
and compared to phoropter.
Repeat measurements compared for
consistency.
A id f E d ift
Scanning and Tracking Laser
Technology Limitations
Avoidance of Eye drift
during surgery
Tracking of cornea in
3 dimentions: x, y, and
rotational
Differentiation of
rotational vs.
translational
movement (eye mvt vs
head mvt)
16
Additional Limitations of Wavefront-
guided Excimer Laser Ablations
The refractive outcomes may be altered by
surgically-induced HOA:
Wound healing ou d ea g
Biomechanical changes after surgery
(collagen relaxation, ectasia)
24
17
Corneal Asphericity
Spherical surface (Shape factor: Q = 0);
or Oblate surface (Shape factor: Q > 0) :
Peripheral rays are bent more than the para-axial rays
Q Q > > 00
18
Myopic LASIK: Myopic LASIK: Myopic LASIK: Myopic LASIK:
Central area flatter than
Peripheral untreated zone
Is the treatment zone oblate?
y
Preoperative Corneal Asphericity
Original curvature: Prolate;
low spherical aberrations
0
R
1
R
2
X
1
(y) X
1
(y)
t(y)
X
2
(y)
R
1
S/2
x
Spherically-based treatment
X
1
(y)
X
2
(y)=X
1
(y)+t(y)
Gatinel and Azar Invest. Ophthalmol Vis Sci
24
19
C(y)
S/2
y
0
R1
R
2
X1(y) X2(y)
t(y)
x
X1(y)
X2(y)
C(y) : conic section with apical radius R
2
and shape factor p
c
20
Outcome of Asphericity R1=7.8
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Magnitude of treatment (D)
Prolate and Oblate Outcomes
1
1,5
2
2,5

P
p1=1.4
p1=1.3
p1=1
sphere
prolate
-1
-0,5
0
0,5
p1=0.75
p1=0.4
oblate
24
21
1 1
8 Q DR dQ ~
|
|
.
|
\
|
+
|
|
.
|
\
|
|
|
.
|
\
|
+
|
|
.
|
\
|
|
|
.
|
\
|
+ ~
3
1
4 2
2
1
2
1
2 2 2
128 3 16
3
3 3
3
3 R
dQS D S
R
S Q D S S D S
dZ
22
Gatinel, Malet, H-Xuan, Azar, Invest. Ophthalmol Vis Sci, April 2004
24
23
CONCLUSIONS CONCLUSIONS
Recent improvements in LVC include improved
technology, patient selection, surface ablation
(Epi-LASIK), monovision, and customized
wavefront-guided LASIK.
Despite improved outcomes of custom LVC,
biomechanical changes and WH interfere with
the ability to eliminate optical aberrations
Other limitations include inability to measure
and render all HOA at all wavelengths, inability
to predict the surgically-induced aberrations,
and inability to perfectly position Rx on the
corneal plane.
Thank you for your attention
Dimitri T. AZAR, Dimitri T. AZAR, MD, MBA MD, MBA
Dimitri T. Azar, MD, MBA
Dean, College of Medicine
B.A. Field Chair of Ophthalmologic Research
Professor of Ophthalmology, Pharmacology, and Bioengineering
University of Illinois at Chicago
EVER the European Association for Vision and Eye Research, is the leading
ophthalmological research association in Europe which covers all areas of
ophthalmology and the visual sciences. Membership is open to individuals of
any nationality engaging in or with an interest in ophthalmic and vision research.
EVER 2013 will be held in France at the Nice Acropolis Convention Center
from September 18-21, 2013.
Visit www.ever.be for daily updates
EVER
f
Visit www.ever-f.eu for more information about the EVER foundation.
EVER 2014 Oct 1-4, Nice - joint meeting with EUPO
EVER 2015 Oct 7-10, Nice
E
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p
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a
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a
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E
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www.ever.be
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2
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21 CME CREDITS
Keynote Lectures
Keynote Lectures - Bal CHAUHAN, Canada
- Alfredo SADUN, USA
- Nicholas BAZAN, USA
EVER Lecture - Leopold SCHMETTERER, Austria
EVER - Acta Lecture - Tero KIVEL, Finland
Ophthalmic Research Lecture - Neville Osborne, UK
European Ophthalmic Heritage Lecture - Andrzej GRZYBOWSKI, Poland
Joint meetings with Acta Ophthalmologica, ARVO, EBO, EEBA, FAN, FRO, ISCEV,
KPro, OOG, SOIE
EUPO
EUPO 2014
Sept 30 - Oct 1
NICE
France
In conjunction with
EVER 2014
EUPO Ofce Kapucijnenvoer 33 3000 Leuven Belgium www.eupo.eu ofce@eupo.eu
PROGRAMME EUPO 2013
Friday, June 7
08.30 - 10.00 Morphology, anomalies and dystrophies
10.15 - 11.45 Tumours, examination and inammation
13.00 - 14.30 Non-inammatory pathology and keratoplasty
14.45 - 16.15 Keratoplasty and keratoprosthesis
16.30 - 18.00 Allergy, keratoconus and herpetic disease
18.30 EUPO Party
Saturday, June 8
08.15 - 09.45 Bacterial, fungal and acanthamoeba keratitis
10:15 - 11:45 Opening Ceremony
13:30 - 14:15 Key Note Lecture: Reza Dana, United States
14.30 - 16.00 Dry eye, eyelids and refractive surgery
16.30 - 18.00 Refractive surgery
EUPO Course 2013
June 7-8, 2013 - Copenhagen, Denmark

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